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AU2002218365B2 - Heterocyclylalkyl piperidine derivatives and their use as antimicrobial agents - Google Patents

Heterocyclylalkyl piperidine derivatives and their use as antimicrobial agents Download PDF

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AU2002218365B2
AU2002218365B2 AU2002218365A AU2002218365A AU2002218365B2 AU 2002218365 B2 AU2002218365 B2 AU 2002218365B2 AU 2002218365 A AU2002218365 A AU 2002218365A AU 2002218365 A AU2002218365 A AU 2002218365A AU 2002218365 B2 AU2002218365 B2 AU 2002218365B2
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Prior art keywords
propyl
methoxyquinolin
chloro
acid
piperidine
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AU2002218365A1 (en
Inventor
Eric Bacque
Jean-Christophe Carry
Youssef El Ahmad
Michel Evers
Philippe Hubert
Jean-Luc Malleron
Serge Mignani
Guy Pantel
Michel Tabart
Fabrice Viviani
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Novexel SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Description

IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/FR01/03559 I, John Neil Albert SWEENEY BSc, PhD, Dip. Trans. IoL, translator to RWS Group plc, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, do solemnly and sincerely declare that I am conversant with the English and French languages and am a competent translator thereof, and that to the best of my knowledge and belief the following is a true and correct translation of the PCT Application filed under No. PCT/FR01/03559.
Date: 22 April 2003 F N. A. SWEENEY For and on behalf of RWS Group pic (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International publication date 23 May 2002 (23.05.2002) (10) International publication number WO 02/40474 A2
PCT
7 (51) International patent classification: C07D 409/14,401/06, 401/14, 417/14, A6 IK 31/47, A6 IP 31/04 Robinson, F-92290 CHATENAY-MALABRY (FR).
PANTEL, Guy; 12 rue Jean-Baptiste Clement, F-945 LA QUEUE EN BRIE TABART, Michel; 3 rue Paul Langevin, F-9 1290 LA NOR VILLE (FR).
VIVIANI, Fabrice; 46 rue Jules Fossier, F-95380 LOUVRES (FR).
(74) Representative: LOBJOIS, Franqoise; AVENTIS PHARMA Direction Brevets, 20 avenue Raymond Aron, F-92 165 ANTONY CEDEX (FR).
(21) International application number: PCT/FROI/03559 (22) International filing date: 14 November 2001 (14.11.2001) Language of filing: French (26) Language of publication: French Data relating to the priority: 00/14,738 15 November 2000 (15.11.2000) FR (71) Applicant: AVIENTIS PHARMA S.A. [FRIFRI; 20 avenue Raymond Aron, F-92 160 ANTONY (FR).
(72) Inventors: BACQUE, Eric; 123 all~e de la Clairi~re, F-91 190 GIF SUR YVETTE CARRY, Jean-Christophe; 41 rue du Dauphin6, F-94100 SAINT MAUR DES FOSSES (FR).
EL-AHMAD, Youssef;, 11 avenue de Verdun, F-94000 CRETEIL EVERS, Michel; 8 rue Robert Schumann.
F-94510 LA QUEUE.EN BRIE HUBERT, Philippe; 22 rue Georges Gaume, F-94700 MAISONS-ALFORT (FR).
MALLERON, Jean-Luc; 2 all6e Renoir, F-9 1460 MARCOUSSIS MIGNANI, Serge; 14 avenue de (81) Designated states (national): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR. BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, H-R, RU. ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, Zw.
(84) Designated states (regional): ARIPO Patent (GH, GM, KE, LS, MW, MZ, SD' SL, SZ, TZ, UG, ZW), Eurasian Patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European Patent (AT, BE, CR, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OAPI Patent (BF, BJ, CF, CG, CL, CM, GA, GN, GQ, OW, ML, MR, NE, SN, TD, TG).
[continued on next page] As printed (54) Itle: HETEROCYCLYLALKYL PIPERIDINE DERIATIVES THEIR CONTAINING SAWE PREPARATION AND COMPOSITIONS (54) litre: DERIES HEMEOCYCLYLALCOYL PIPERIDINE, LEUR PREPARATION Fr' LBS COMPOSITIONS QLJI LES CON'I1ENNENT (57) Abstract: The invention concerns heterocyclylalkyl piperidine y N-N derivatives of general formula wherein X 1
X
2
X
3
X
4 and X 5 we sC-R', to >C-R' 5 or one at moat represents N; R2 is COOH, alkyloxycartionyl, X' Ncycloalkyloxyc rbonyl, C M. CONRaR t or R 2 is CH 2 H, alkyl substituted -CH=CH-Rc; R 3 is phenyl, heterocyclyl. alk-R* 3 Y represents >CH-Re or a X21 X X4difluoromethylene, carbonyl, hydroxyiminomiethylene, alkyloxyiminomethy.
lana, cycloaikyloxyiminornethylcne radical, or a cycloalkylene-1.I radical; and n 0 to 4 provided that the radicals or phenyl or heterocyclyl portions mentioned above can optionally be substituted, in the enantiomeric or diastereoisomeric formns or mixtures thereof, and/or as the case may be in their syn or anti form or mixture thereof and their salts.
S(n7 Abrigi Ddrivds hdt~rocyclylalcoyI pipdridine de formule gdndmle pour lesquels: X 1 X2, X 3 X4 et X 5 sont >C-R 1
A
on bien l'un an plus repr~sente N, R 2 est COOH, alcoyloxycarbanyle, cycloalcoyloxycarbonyle, CN, -CONRaRb on Ra eat CH2OH, alcoyle substitud on R 2 eat -CF 2 -Rc, -C(CH3)-Rc, -CO-Rc, -CHOH-Rc. -C(cycloalcoyle)-Rc ou -CH=CH-Rc, R3 eat Sphenyle, hdttmucycyle, alk-R* 3 Y reprfscnte >C1-Re on un radical drfluoromfthylbne, carbonyle, hydroxyiminomithylbne, alcoy.
O oxyizinomiftykaa, cycloalcoyloxyiminomdthylbia, ou un radical cycloalcoyltn-1, 1, at n 0 A 4 dtant entandu que las radicaux on portions phenyle on hiftfrcyciyle mentionnds ci-dessns peuvesit etre dventuellement substituds, sous laurs formes dnantiom~res Son diasthrdoisomhres on las mdlanges do ors formes, at/au la cas dchdant sous leur forme syn on anti on lIcr m~lange sinai que lawrs sels.
WO 02/40474 A2 Published: Without the International Search Report and to be republished once the report has been received.
For an explanation of the two-letter codes and the other abbreviations, reference is made to the explanations ("Guidance Notes on Codes and Abbreviations") at the beginning of each regular edition of the PCT Gazette.
WO 02/40474 PCT/FR01/03559 HETEROCYCLYLALKYLPIPERIDINE DERIVATIVES, THEIR PREPARATION AND COMPOSITIONS CONTAINING SAME The present invention relates to heterocyclylalkylpiperidine derivatives of general formula: (CH,)n N I P y rN 1 1 x2 X4 X3 N which are active as antimicrobial agents. The invention also relates to their preparation and to compositions containing them.
Patent applications WO 99/37635 and WO 00/43383 disclose antimicrobial quinolylpropylpiperidine derivatives of general formula:
A-B-(CH
2 )n N-R, A-B-(CH)n N-R 4 12R3 or 7[ R or Z R 3 N Z 4 in which the radical R 1 is especially (Cl-6) alkoxy, R 2 is hydrogen, R 3 is in position -2 or -3 and represents (Cl-6) alkyl which may optionally be substituted with 1 to 3 substituents chosen from thiol, halogen, alkylthio, trifluoromethyl, carboxyl, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxyl optionally substituted with alkyl, etc., R 4 is a group -CH 2
-R
5 for which Rs is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted heteroarylalkyl, optionally substituted heteroaryl, etc., n is 0 to 2, m is 1 or 2 and A and B are especially oxygen, sulfur, sulfinyl, sulfonyl, NR 11
CR
6
R
7 for which
R
6 and R 7 represent H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxyl, amino, and ZI to Z 5 are N or CRia, etc. These products show antimicrobial activity. However, no derivative disubstituted in position -4 of the piperidine had been synthesized hitherto and consequently no biological activity had been discovered for such products either.
Since slight modifications to the structures already known can result in large variations in activity, it was not obvious that derivatives disubstituted in position -4 of the piperidine would also have antibacterial activity.
European patent application EP 30044 discloses quinoline derivatives which are useful as cardiovascular agents, corresponding to the general formula:
A-B-
in which RI is especially alkyloxy, A-B is -CH 2
-CH
2
-CHOH-CH
2
-CH
2 -CHOH-, -CH 2 -CO- or -CO-CH 2 RI is H, OH or alkyloxy, R 2 is ethyl or vinyl, R 3 is especially alkyl, hydroxyalkyl, cycloalkyl, hydroxyl, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl, optionally substituted diphenylalkyl, optionally substituted phenylalkenyl, optionally substituted benzoyl or benzoylalkyl, optionally substituted heteroaryl or heteroarylalkyl, and Z is H or alkyl or forms with R 3 a cycloalkyl radical.
It has now been found, and this forms the subject of the present invention, that the products of general formula for which:
X
1
X
2
X
3
X
4 and X 5 represent, respectively, >C-R'i to >C-R' 5 or alternatively not more than one of them represents a nitrogen atom,
R
1
R'
1
R'
2
R'
3 R'4 and R'5 are identical or different and represent a hydrogen or halogen atom or an alkyl, cycloalkyl, phenyl, phenylthio, mono- or bicyclic aromatic heterocyclyl or heterocyclylthio, hydroxyl, alkyloxy, trifluoromethoxy, alkylthio, trifluoromethylthio, cycloalkyloxy, cycloalkylthio, cyano, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, -NRaRb or -CONRaRb radical (for which Ra and Rb can represent hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain another heteroatom chosen from O, S and N and, where appropriate, bearing an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent on the nitrogen atom or, where appropriate, the sulfur atom of which is oxidized in the form of sulfinyl or sulfonyl), or represent a methylene radical substituted with fluoro, hydroxyl, alkyloxy, alkylthio, cycloalkyloxy, cycloalkylthio, phenyl, mono- or bicyclic aromatic heterocyclyl, carboxyl, alkyloxycarbonyl, .cycloalkyloxycarbonyl, -NRaRb or -CONRaRb for which Ra and Rb are defined as above, or represent phenoxy, heterocyclyloxy, benzyloxy, heterocyclylmethyloxy, or alternatively Ri can also represent difluoromethoxy, or a radical of structure -CmF2m+l -SCmF2m+i or -OCmF2m+1 for which m is an integer from 1 to 6, or alternatively R' 5 can also represent trifluoroacetyl,
R
2 represents carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, cyano, -CONRaRb (for which Ra and Rb represent, respectively, hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, or Ra or Rb represents hydroxyl, alkyloxy, cycloalkyloxy, or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain another heteroatom chosen from O, S and N and, where appropriate, bearing an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent on the nitrogen atom or, where appropriate, the sulfur atom of which is oxidized in the form of sulfinyl or sulfonyl), or R 2 represents hydroxymethyl, alkyl containing 1 or 2 carbon atoms substituted with carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, cyano or -CONRaRb for which Ra and Rb are defined as above, or R 2 represents a radical of structure -CF 2 -Rc, -C(CH 3 2 -Rc, -CO-Rc, -CHOH-Rc, -C(cycloalkyl)-Rc, or -CH=CH-Rc for which Rc is carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, or -CONRaRb for which Ra and Rb are defined as above,
R
3 represents a phenyl, mono- or bicyclic aromatic heterocyclyl or alk-R 0 3 radical for which alk is an alkyl radical and R 0 3 represents hydrogen, halogen, hydroxyl, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylamino, Ncycloalkyl-N-alkylamino, -N-(cycloalkyl) 2 acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylamino, N-alkyl-Nphenylamino, N-cycloalkyl-N-phenylamino, -N-(phenyl) 2 phenylalkyloxy, phenylalkylthio, phenylalkylsulfinyl, phenylalkylsulfonyl, phenylalkylamino, N-alkyl-Nphenylaminoalkyl, N-cycloalkyl-N-phenylalkylanino, benzoyl, mono- or bicyclic aromatic heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, heterocyclylamino, N-alkyl-N-heterocyclylamino, Ncycloalkyl-N-heterocyclylamino, heterocyclylcarbonyl, heterocyclylalkyloxy, heterocyclylalkylthio, heterocyclylalkylsulfinyl, heterocyclylalkylsulfonyl, heterocyclylalkylamino, N-alkyl-N-heterocyclylaminoalkyl, N-cycloalkyl-N-heterocyclylaminoalkyl, (the heterocyclyl portions mentioned above being mono- or bicyclic aromatic), carboxyl, alkyloxycarbonyl, -NRaRb or -CO-NRaRb for which Ra and Rb are defined as above in the definition of R 2 or alternatively R 0 3 represents -CR'b=CR'c-R'a for which R'a represents phenyl, phenylalkyl, heterocyclyl or heterocyclylalkyl in which the heterocyclyl portion is mono- or bicyclic aromatic, phenoxyalkyl, phenylthioalkyl, phenylsulfinylalkyl, phenylsulfonylalkyl, phenylaininoalkyl, N-alkyl-Nphenylaminoalkyl, heterocyclyloxyalkyl, heterocyclylthioalkyl, heterocyclylsulfinylalkyl, heterocyclylsulfonylalkyl, heterocyclylaminoalkyl, Nalkyl-N-heterocyclylaminoalkyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, (the heterocyclyl portions mentioned above being mono- or bicyclic aromatic), phenylthio, phenylsulfinyl, phenylsulfonyl, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or alternatively R 0 3 represents a radical -C=C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, mono- or bicyclic aromatic heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, heterocyclylthioalkyl, heterocyclylaminoalkyl, N-alkyl-N-heterocyclylaminoalkyl, (the heterocyclyl portions mentioned above being mono- or bicyclic aromatic), or alternatively R 0 3 represents a -CF 2 -phenyl or mono- or bicyclic aromatic -CF 2 -heterocyclyl radical, Y represents a radical >CH-Re for which Re is hydrogen, fluoro, hydroxyl, alkyloxy, cycloalkyloxy, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, -NRaRb or -CO-NRaRb for which Ra and Rb are defined as above for
R
2 or one represents a hydrogen atom and the other represents an alkyloxycarbonyl, acyl, cycloalkylcarbonyl, benzoyl or heterocyclylcarbonyl radical in which the heterocyclyl portion is mono- or bicyclic aromatic, or alternatively Y represents a difluoromethylene, carbonyl, hydroxyiminomethylene, alkyloxyiminomethylene or cycloalkyloxyiminomethylene radical or a 1,1-cycloalkylene radical containing 3 to 6 carbon atoms, and n is an integer from 0 to 4 it being understood that the phenyl, benzyl, benzoyl or heterocyclyl radicals or portions mentioned above may optionally be substituted on the ring with 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, alkyloxyalkyl, haloalkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, carboxyl, alkyloxycarbonyl, cyano, alkylamino, -NRaRb for which Ra and Rb are defined as above, phenyl, hydroxyalkyl, alkylthioalkyl, alkylsulfinylalkyl and alkylsulfonylalkyl, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and/or, where appropriate, in their syn or anti form or a mixture thereof, as well as the salts thereof, are powerful antibacterial agents.
It is understood that the alkyl or acyl radicals and portions contain (except where especially mentioned) 1 to 10 carbon atoms in a straight or branched chain and that the cycloalkyl radicals contain 3 to 6 carbon atoms.
It is also understood that the radicals which represent or bear a halogen atom represent a halogen chosen from fluorine, chlorine, bromine and iodine, preferably fluorine.
In the above general formula, when the radicals represent or bear a mono- or bicyclic aromatic heterocyclyl substituent, this substituent contains 5 to chain members and may be chosen (in a nonlimiting manner) from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, benzothienyl, benzofuryl indazolyl, benzothiazolyl, naphthyridinyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalyl, benzoxazolyl and benzimidazolyl which may optionally be substituted with the substituents listed above.
According to the invention, the products of general formula may be obtained by coupling the chain
R
3 with the heterocyclylalkylpiperidine derivative of general formula: (CH )n NH Y/ R NH X R2 I I 2 X N in which X1, X 2
X
3
X
4
X
5
R
2 Y and n are defined as above, and R 2 is protected when it bears a carboxyl or amino radical, optionally followed by removal of the acid-protecting or amine-protecting radical, optional separation of the enantiomeric or diastereoisomeric forms and/or, where appropriate, of the syn or anti forms and optional conversion of the product obtained into a salt.
The coupling of the chain R 3 with the piperidine is advantageously carried out by the action of a derivative of general formula:
R
3 -X (IIa) in which R 3 is defined as above and X represents a halogen atom, a methylsulfonyl radical, a trifluoromethylsulfonyl radical or a p-toluenesulfonyl radical, working in anhydrous medium, which is preferably inert (for example nitrogen or argon) in an organic solvent such as an amide (for example dimethylformamide), a ketone (for example acetone) or a nitrile (for example acetonitrile) in the presence of a base such as an organonitrogen base (for example triethylamine) or a mineral base (alkaline carbonate, for example potassium carbonate) at a temperature of between 20 0 C and the reflux temperature of the solvent. It is understood that the nitrogen atom of the piperidine in the derivative of general formula (II) is optionally protected according to the usual methods which do not affect the rest of the molecule or the reaction; for example, the protection is carried out by a protecting radical chosen from t-butoxycarbonyl and benzyloxycarbonyl.
Preferably, a derivative of general formula (IIa) for which X is a bromine or iodine atom is reacted.
When R 3 is a phenyl radical, it is also possible to act on the iodo or bromo derivative R 3 -X in the presence of a palladium catalyst according to the method described in J. Org. Chem., 6066 (1997) or Tet.
Lett., 6359 (1997). The palladium catalyst may be chosen from tris(dibenzylideneacetone)dipalladium, and palladium diacetate with a ligand such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or 2-(di-t-butylphosphino)biphenyl, for example, a base such as sodium tertbutoxide or cesium carbonate in a solvent such as tetrahydrofuran, tetraglyme or toluene, optionally in the presence of a crown ether such as 18-C-6 (1,4,7,10,13,16hexaoxacyclooctadecane). The reaction is carried out at a temperature of between 20 0 C and 110 0
C.
When R 3 represents a radical -alk-R 3 for which alk is an alkyl radical and R 0 3 represents -C=C-Rd in which Rd is phenyl, phenylalkyl, heterocyclyl or mono- or bicyclic aromatic heterocyclylalkyl, it is often preferable to couple an alkynyl halide: HC=C-alk-X for which alk is defined as above and X is a halogen atom, and then to substitute the chain with a phenyl, phenylalkyl, heterocyclyl or heterocyclylalkyl radical.
In this alternative, the addition of the alkynyl chain is carried out using an alkynyl halide HC=C-alk-X for which X is preferably a bromine atom, under the conditions listed above for the coupling of the -chain R 3 in the presence or absence of an alkali metal iodide such as, for example, potassium iodide or sodium iodide.
The substitution with a phenyl or heterocyclyl radical is carried out by the action of a halide derived from the cyclic radical to be substituted, in the presence of triethylamine, in anhydrous medium in a solvent such as an amide (for example dimethylformamide) or a nitrile (for example acetonitrile) and in the presence of a palladium salt such as, for example, tetrakis(triphenylphosphine)palladium and cuprous iodide, at a temperature of between 200C and the reflux temperature of the solvent.
The substitution with a phenylalkyl or heterocyclylalkyl radical is carried out by the action of the corresponding halide, in basic medium, for example in the presence of potassium hydride or sodium hydride or nbutyllithium, in a solvent such as an ether (tetrahydrofuran) or an amide (dimethylformamide) at a temperature of between -600C and the boiling point of the reaction medium.
It is understood that, if the alkyl radicals represented by R 3 bear carboxyl or amino substituents, these substituents are protected beforehand then freed after .the reaction. The process is performed according to the usual methods which do not affect the rest of the molecule, in particular according to the methods described by T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis 2 nd edition), A. Wiley Interscience Publication (1991), or by McOmie, Protective Groups in Organic Chemistry, Plenum Press (1973).
The protected carboxyl radical borne by R 2 may be chosen from readily hydrolyzable esters. Examples which may be mentioned are the methyl, benzyl and tertbutyl esters, or the phenyl propyl or allyl esters. The protection of the carboxyl radical is optionally carried out at the same time as the reaction.
Where appropriate, the amino radical is protected using the usual protecting radicals mentioned in the above references.
These protecting radicals are installed and removed according to the usual methods, mentioned above for R 3 When R 3 represents a radical-alk-R 3 for which alk is an alkyl radical and R 0 3 represents a phenoxy, phenylthio, phenylamino, heterocyclyloxy, heterocyclylthio or heterocyclylamino radical in which the heterocyclyl portion is aromatic, it may be preferable to construct the chain step by step by first condensing a chain HO-alk-X, for which X is a halogen atom and preferably iodine, under the conditions described above for the reaction of the product of general formula (IIa), and then by converting the hydroxyalkyl chain into a haloalkyl, methanesulfonylalkyl or p-toluenesulfonylalkyl chain, and finally by reacting, in basic medium, an aromatic derivative of structure Ar-ZH for which AR is an aromatic phenyl or heterocyclyl radical and Z is a sulfur, oxygen or nitrogen atom.
The conversion of the hydroxylated chain into a haloalkyl or p-toluenesulfonyl chain is carried out according to the usual methods of halogenation or sulfonylation, especially by reacting a halogenating agent, for instance, thionyl chloride, halophosphorus derivatives: for example phosphorus trichloride or tribromide or a sulfonylating agent such as, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonic anhydride. The reaction is carried out in an organic solvent, for instance a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of between 0°C and 60 0 C. In certain cases, it may be advantageous to work in the presence of a base, for instance pyridine or triethylamine.
The reaction of the aromatic derivative Ar-ZH is advantageously carried out as described above for the action of the derivative of general formula (IIa), in the presence of a base, .for example such as a nitrogenous base, in an organic solvent such as an amide (for example dimethylformamide), a ketone (for example acetone) or a nitrile (for example acetonitrile), in the presence of a base such as a nitrogenous organic base (for example triethylamine) or a mineral base (alkali metal carbonate: for example potassium carbonate) at a temperature of between 20 0 C and the reflux temperature of the reaction mixture. It may be advantageous to work in the presence of potassium iodide.
According to the invention, the heterocyclylalkylpiperidine derivatives of general formula (II) may be prepared according to the coupling method described below, and then where appropriate converted according to one of the methods 0 to below, via a subsequent operation starting with one of the derivatives of general formula (II) already obtained, to prepare the derivatives corresponding to the various alternatives of Y and/or of R 1
R'
1
R'
2
R'
3
R'
4 or R' 5 It is understood that when carboxylic acid radicals are present on the molecule, these radicals are protected beforehand and then freed after the reaction according to the usual methods which do not affect the rest of the molecule, especially according to the methods mentioned in the references cited above. It is also understood that, prior to the reactions which may interfere with the amine of the piperidine in the derivative of general formula this amine is protected, and then freed after the reaction. The protection is carried out according to the usual methods, as specified above, especially via a t-butoxycarbonyl or benzyloxycarbonyl radical.
According to the invention, the preparation of the products of general formula (II) for which Re in Y is a hydrogen atom is carried out by coupling a heterocyclic derivative of general formula: Hal "7 ~hl1(III) in which RI, X 1
X
2
X
3
X
4 and Xs are defined as above and Hal represents a halogen atom, with a piperidine derivative of general formula:
S(IV)
(CH,)n (CHR N-Rz in which Rz is a protecting radical and R" 2 is defined as above or represents a protected radical if R 2 represents or bears a carboxylic acid function, followed by removal of the protecting radicals and/or followed by conversion, via a subsequent operation, of the substituents of the bicycle of the heterocyclylalkylpiperidine derivative of general formula (II) thus obtained, to give the expected derivative bearing the radical R 1
R'
1
R'
2
R'
3
R'
4 or
R'
5 and, where appropriate, removal of the protecting radical(s) still present on the molecule.
The radical Rz may be any protecting group for the nitrogen atom which is compatible with the reaction (for example t-butyloxycarbonyl or benzyloxycarbonyl).
The protecting groups for the acid functions are chosen from the usual groups whose installation and removal do not affect the rest of the molecule, especially those mentioned in the references cited above.
The reaction is carried out by the successive action of an organoborane (for example 9-borabicyclo- [3.3.1]nonane) in a solvent such as an ether (for example tetrahydrofuran or dioxane) at a temperature of between -200C and 20 0 C, and then of the bicyclic derivative of general formula (III) for which Hal preferably represents a bromine or iodine atom or a chlorine atom, by analogy with the methods described by Suzuki et al. Pure and Appl. Chem., 57, 1749 (1985). The reaction is generally carried out in the presence of a palladium salt (for example diphenylphosphinoferrocenepalladium chloride) and of a base such as potassium phosphate, at a temperature of between 20 0 C and the reflux temperature of the solvent.
The heterocyclylalkylpiperidines of general formula (II) for which Re in Y represents a hydroxyl radical may be prepared by oxidation in basic medium of the corresponding heterocyclylalkylpiperidine derivative of general formula (II) for which Re in Y is a hydrogen atom. The oxidation is carried out by the action of oxygen, preferably in an inert solvent such as dimethyl sulfoxide in the presence of tert-butanol and of a base such as potassium tert-butoxide or sodium tert-butoxide at a temperature of between 0°C and 100 0
C.
The heterocyclylalkylpiperidine derivative for which Re in Y is a fluorine atom is prepared by fluorination starting with a derivative for which Re is hydroxyl. The reaction is carried out in the presence of a sulfur fluoride [for example in the presence of an aminosulfur trifluoride (diethylaminosulfur trifluoride (Tetrahedron, 44, 2875 (1988), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®), or morpholinosulfur trifluoride, for example) or alternatively in the presence of sulfur tetrafluoride Org. Chem., 40, 3808 (1975)]; alternatively, the fluorination reaction can also be carried out using a fluorinating agent such as hexafluoropropyldiethylamine (JP 2 039 546) or N-(2chloro-1,1,2-trifluoroethyl)diethylamine.
The process is performed in an organic solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform) or in an ether (for example tetrahydrofuran or dioxane) at a temperature of between -780C and 400C (preferably between 0°C and 300C). It is advantageous to work in inert medium (especially argon or nitrogen).
The heterocyclylalkylpiperidine derivative of general formula (II) for which Re in Y is an alkyloxy or cycloalkyloxy radical is prepared by the action of an alkyl or cycloalkyl halide on the corresponding derivative of general formula (II) for which Re is hydroxyl. The reaction is generally carried out using the bromide or chloride, in an inert solvent such as N,Ndimethylformamide or dimethyl sulfoxide, in the presence of an acid acceptor such as a trialkylamine (for example triethylamine) or an alkali metal hydride (for example sodium hydride), at a temperature of between 200C and 1000C.
The heterocyclylalkylpiperidine derivative of general formula (II) for which Y is a carbonyl radical may be prepared by oxidation of the corresponding derivative of general formula (II) for which Re in Y is a hydroxyl radical. This oxidation is carried out, for example, using potassium permanganate optionally in a solution of sodium hydroxide (for example 3N sodium hydroxide), at a temperature of between -200C and 200C, or alternatively by the action of oxalyl chloride in the presence of dimethyl sulfoxide, followed by the addition of an amine such as triethylamine, in an inert solvent such as dichloromethane or dimethyl sulfoxide, .at a temperature of between -600C and 20 0 C, by analogy with the method described by D. Swern et al., J. Org. Chem., 44, 4148 (1979).
The heterocyclylalkylpiperidine derivative of general formula (II) for which Y is a difluoromethylene radical may be prepared by dihalogenation of the product of general formula (II) for which Y is carbonyl, under conditions analogous to those of the fluorination described above.
The heterocyclylalkylpiperidine derivative of general formula (II) for which Y is a hydroxyiminomethylene radical may be prepared by the action of hydroxylamine on a derivative of general formula (II) for which Y is a carbonyl radical. The reaction is generally carried out in an inert solvent such as an alcohol (methanol or ethanol) and optionally in the presence of sodium hydroxide (for example lN sodium hydroxide), at a temperature of between 0°C and the boiling point of the reaction mixture.
The heterocyclylalkylpiperidine derivative of general formula (II) for which Y is an alkyloxyiminomethylene or cycloalkyloxyiminomethylene radical may be prepared by the action of an alkyl or cycloalkyl halide on the corresponding derivative of general formula (II) for which Y is hydroxyiminomethylene. The reaction is generally carried out in an inert solvent such as N,N-dimethylformamide or dimethyl sulfoxide, in the presence of an acid acceptor such as a trialkylamine (for example triethylamine) or an alkali metal hydride (for example sodium hydride), at a temperature of between 20 0
C
and 100 0 C. A bromide is preferably used.
The heterocyclylalkylpiperidine derivative of general formula (II) for which Re in Y is a radical -NRaRb may be prepared from the corresponding tosyloxy derivative by the action of an amine HNRaRb (or, where appropriate, of ammonia when Re is -NH 2 in an inert solvent such as N,N-dimethylformamide or dimethyl sulfoxide, at a temperature of between 200C and the boiling point of the reaction mixture. When ammonia is reacted, the process is preferably performed under pressure (2 to 20 atmospheres) at a temperature of between 200C and 100 0 C. When the process is performed using an amine HNRaRb, the reaction is optionally carried out in the presence of a base such as a trialkylamine (for example triethylamine), pyridine or an alkali metal hydride (for example sodium hydride).
The derivative for which Re in Y is tosyloxy is obtained from the product of general formula (II) for which Re in Y is hydroxyl, by the action of tosyl chloride in pyridine, at a temperature of between -100C and 200C.
The heterocyclylalkylpiperidine derivative of general formula (II) for which Re in Y is a carboxyl radical may be prepared by the action of an alkaline cyanide on the corresponding tosyloxy derivative, in an organic solvent such as dimethylformamide or dimethyl sulfoxide or in aqueous-organic medium, for example a water-alcohol mixture, at a temperature of between 0 0
C
and the boiling point of the reaction mixture, followed by hydrolysis of the nitrile obtained by the action of a strong acid such as hydrochloric acid, and optionally of a lower aliphatic alcohol, at a temperature of between 0°C and the boiling point of the reaction mixture. Sodium cyanide or potassium cyanide is preferably used.
The heterocyclylalkylpiperidine derivative of general formula (II) for which Re in Y is an alkyloxycarbonyl or cycloalkyloxycarbonyl or -CO-NRaRb radical may be prepared by the action, respectively, of the alcohol or of the corresponding amine on the derivative of general formula (II) for which Re in Y is a carboxyl radical. The reaction is carried out in the presence of a coupling agent such as a carbodiimide (for example N,N'-dicyclohexylcarbodiimide) or N,N'carbonyldiimidazole, in an inert solvent such as an ether (for example tetrahydrofuran or dioxane), an amide (N,Ndimethylformamide), a chlorinated solvent (for example methylene chloride, 1,2-dichloroethane or chloroform) or dimethyl sulfoxide, at a temperature of between 0°C and the reflux temperature of the reaction mixture.
The heterocyclylalkylpiperidine derivative of general formula (II) for which Y is a 1,1-cycloalkylene radical may be prepared by the action, in basic medium, of a product of structure Hal-Alk-Hal for which Alk is an alkylene radical corresponding to the expected cycloalkylene, on a heterocyclylalkylpiperidine derivative for which Re in Y is a hydrogen atom. The reaction is generally carried out in an inert solvent such as N,N-dimethylformamide or dimethyl sulfoxide, in the presence of an acid acceptor such as an alkali metal hydride (for example sodium hydride), at a temperature of between 20 0 C and 100 0
C.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which one from among RI, R'1,
R'
2
R'
3
R'
4 and R' 5 represents an alkyl, cycloalkyl, phenyl, heterocyclyl, benzyl or heterocyclylmethyl radical may be prepared by the action of a boron derivative of structure R'iB(OH) 2 (R'i meaning one of the substituents R 1 R'i, R' 2
R'
3 R'4 or R's) or of 9alkyl- (or 9-cycloalkyl)-9-borabicyclo[3.3.1]nonane structure on a derivative of general formula (II) for which the substituent R'i is a bromine, iodine or chlorine atom, by analogy with the methods described by F. Diederich and P. J. Stang, Metal Catalysed Crosscoupling Reactions, Wiley-VCH, (1997) in the presence of a palladium salt (for example tetrakis(triphenylphosphine) [lacuna] or diphenylphosphinoferrocenepalladium chloride) and of a base such as potassium phosphate, in an inert solvent such as an amide (for example N,N-dimethylformamide), an ether (for example tetrahydrofuran) or a nitrile (for example acetonitrile), at a temperature of between 200C and the reflux temperature of the reaction mixture.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which one from among RI, R' 1
R'
2
R'
3 R'4 and R' 5 represents a radical -NRaRb may be prepared by the action of an amine HNRaRb on a derivative of general formula (II) for which the substituent R'i (R'i meaning one of the substituents RI, R' 1
R'
2
R'
3 R'4 or R' 5 is a bromine, iodine or chlorine atom, by analogy with the methods described in J. Org. Chem., 6066 (1997) and Tetrahedron Lett., 6359 (1997) in the presence of a palladium catalyst, under conditions similar to those described for 'the reaction of the halo derivative of formula (III) with the derivative of general formula
(II).
When Ra and Rb represent hydrogen atoms, the amino derivative obtained may be converted into a fluoro derivative by the action of an alkaline nitrite (for example sodium nitrite) in acidic medium (tetrafluoroboric acid or hexafluorophosphoric acid) in water at a temperature of between -100C and 20 0 C, to prepare a diazonium tetrafluoroborate or hexafluorophosphate, followed by pyrolysis of the product obtained according to the Baz-Schieman reaction, Org.
Synth., Coll 5, 133 (1973).
The heterocyclylalkylpiperidine derivatives of general 'formula (II) for which R, R'i, R' 2
R'
3
R'
4 or R's represents an alkyloxy, alkylthio, cycloalkyloxy, cycloalkylthio, benzyloxy or heterocyclylmethyloxy radical, may be prepared by the action of the alcohol or of the corresponding thiol on the heterocyclylalkylpiperidine derivative for which one of the radicals R'i is a bromine, iodine or chlorine atom. The reaction is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran or dioxane), an amide (for example N,N-dimethylformamide) or dimethyl sulfoxide, in the presence of an acid acceptor such as a trialkylamine (for example triethylamine), an alkali metal hydride (for example sodium hydride), methyllithium or n-butyllithium, at a temperature of between 0°C and the reflux temperature of the reaction mixture.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which R 1 R'i, R' 2
R'
3
R'
4 or
R'
5 represents a hydroxyl radical may be.prepared from the corresponding derivative for which one of the radicals R'i is methoxy by the action of a strong acid such as hydrobromic acid, at a temperature of between 20 0 C and the reflux temperature of the reaction mixture.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which RI, R' 1
R'
2
R'
3
R'
4 or
R'
5 represents a trifluoromethoxy radical may be obtained by analogy with the method described by Sun W.Y.
Synlett., 11, 1279 (1997) to prepare a derivative for which R'i is an -O-CS-SCH 3 radical, starting with the corresponding hydroxyl derivative; this radical is converted into a trifluoromethyl radical by applying the methods described by Kuroboshi M. et al., Tetrahedron Lett., 33(29), 4173 (1992) in the presence of 1,3in an HF-pyridine complex at a temperature of between 0°C and 20 0
C.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which RI, R' 1
R'
2
R'
3
R'
4 or
R'
5 represents an alkyloxy, cycloalkyloxy, phenoxy, benzyloxy, heterocyclyloxy or heterocyclylmethyloxy radical may be obtained by the action of the corresponding halo derivative on the derivative of general formula (II) for which the R'i to be modified is hydroxyl. The process is preferably performed using the bromo derivative, in an inert solvent such as an ether (for example tetrahydrofuran or dioxane), an amide (for example N,N-dimethylformamide) or dimethyl sulfoxide, in the presence of an acid acceptor such as a trialkylamine (for example triethylamine), an alkali metal hydride (for example sodium hydride), methyllithium or N-butyllithium, optionally in the presence of a palladium salt [by analogy with the methods described in J. Am. Chem. Soc., 4369 (1999); Tetrahedron Lett., 8005 (1997); Angew. Chem.
Int. Ed. Engl., 2047 (1998)], at a temperature of between 0°C and the reflux temperature of the reaction mixture.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which RI represents a trifluoromethyl radical may be prepared by the action of a trifluoromethylating agent (especially a bromo derivative Br-CF 3 or an iodo derivative I-CF 3 on the heterocyclylalkylpiperidine derivative for which one of the radicals RI is a bromine, iodine or chlorine atom, in the presence of copper or a copper(I) salt such as CuI, in a solvent such as dimethylformamide, between 20 0 C and 150 0 C, by analogy with J.C.S. Chem. Commun., 1, 53 (1992) or Chem. Commun., 18, 1389 (1993).
O The heterocyclylalkylpiperidine derivatives of general formula (II) for which RI, R'i, R' 2
R'
3
R'
4 or
R'
5 represents an alkylthio, cycloalkylthio, trifluoromethylthio, phenylthio or heterocyclylthio radical may be obtained by the action of the corresponding halo derivative on the heterocyclylalkylpiperidine derivative bearing a mercapto substituent. The process is preferably performed using the bromo derivative, under the conditions described above for the action of a halo derivative on an alcohol, at a temperature of between 20 0 C and the reflux temperature of the reaction mixture. In the case of the trifluoromethylthio radical, the process is performed by analogy with the method described in Tet. Lett., 33(44), 6677 (1992).
The mercapto derivative of the heterocyclylalkylpiperidine of general formula (II) may be obtained from the heterocyclylalkylpiperidine derivative for which one of the radicals R'i is a bromine, iodine or chlorine atom (preferably a bromine atom) by analogy with the methods described by Q.L. Zhou et al., Tetrahedron, 15, 4467 (1994); C. Bieniauz et al., Tetrahedron Letters, 34, 6, 939 (1993) and E.D. Amstuts, J. Am. Chem. Soc., 68, 498 (1946). The reaction is carried out, for example, in the presence of Na 3
PO
3 S or Na 2 S in an inert solvent such as an alcohol (for example methanol or ethanol), optionally in the presence of water, at a temperature of between 20 0 C and the reflux temperature of the reaction mixture.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which RI, R' 1
R'
2
R'
3
R'
4 or
R'
5 represents a cyano radical may be obtained from the corresponding derivative for which one of the radicals R'i is a halogen atom, preferably a bromine or iodine atom, by applying the methods described by Halley F. et al., Synth. Comm., 27, 7, 1199 (1997) and Tschaen D. M.
et al., J. Org. Chem., 60, 14, 4324 (1995), in the presence of CuCN, or KCN and optionally in the presence of a catalyst.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which R 1
R'
1
R'
2
R'
3
R'
4 or
R'
5 represents a carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl or -CO-NRaRb radical may be prepared from the cyano derivative, according to the usual methods for conversion into an acid, an ester and an amide, which do not affect the rest of the molecule, and some of the implementation conditions of which have been recalled above. In particular, in the presence of a carbodiimide (N,N'-dicyclohexylcarbodiimide) or N,N'carbonyldiimidazole, in an ether (tetrahydrofuran or dioxane), an amide (N,N-dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2dichloroethane or chloroform), at a temperature of between 0°C and the reflux temperature of the reaction mixture.
S The heterocyclylalkylpiperidine derivatives of general formula (II) for which RI, R'i, R' 2
R'
3
R'
4 or
R'
5 represents a hydroxymethyl radical may be obtained by reducing a heterocyclylalkylpiperidine derivative of general formula (II) :for which one of the radicals R'i represents a carboxyl .radical, using a:reducing agent such as, for example, lithium aluminum.hydride or a borohydride, in an inert solvent such as an ether (for -example tetrahydrofuran or dioxane) or a chlorinated solvent (for example methylene chloride, 1,2dichloroethane or chloroform), at a temperature of between 0°C and the reflux temperature of the reaction mixture.
The heterocyclylalkylpiperidine derivatives of general formula for which R 1 R'I, R' 2
R'
3 R'4 or
R'
5 represents an alkyloxymethyl or cycloalkyloxymethyl radical may be obtained-by the action of the corresponding halo derivative (preferably the bromo derivative) on the corresponding heterocyclylalkylpiperidine derivative for which the radical R'i represents a hydroxymethyl radical. The reaction is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran or dioxane), an amide (for example N,N-dimethylformamide) or dimethyl sulfoxide, in the presence of an acid acceptor such as a trialkylamine (for example triethylamine) or an alkali metal hydride (for example sodium hydride), at a temperature of between 200C and 1000C.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which RI, R' 1
R'
2
R'
3
R'
4 or
R'
5 represents a fluoromethyl radical may be obtained by the action of a fluorinating agent on the heterocyclylalkylpiperidine derivative for which the corresponding radical R'i represents a hydroxymethyl radical. The reaction may be carried out under the fluorinating conditions described above for the installation of a radical Re meaning fluorine.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which RI, R' 1
R'
2
R'
3
R'
4 or
R'
5 represents an alkylthiomethyl or cycloalkylthiomethyl radical may be obtained by the action of the corresponding thiol on a heterocyclylalkylpiperidine derivative for which the radical R'i to be modified is .halomethyl (halogen preferably being a bromine or chlorine atom). The reaction is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran or dioxane), an amide (for example N,Ndimethylformamide) or dimethyl sulfoxide, in the presence of an acid acceptor such as a trialkylamine (for example triethylamine) or an alkali metal hydride (for example sodium hydride), at a temperature of between 200C and the reflux temperature of the reaction mixture.
The heterocyclylalkylpiperidine derivatives bearing a halomethyl radical R'i are prepared from the corresponding derivative for which R'i is a hydroxymethyl radical by the action of a halogenating agent (halophosphorus derivative or thionyl chloride). The reaction is optionally carried out in an inert solvent such as dichloromethane, at a temperature of between 0°C and 60 0 C, optionally in the presence of a base such as pyridine.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which R 1 R'i, R' 2
R'
3
R'
4 or
R'
5 represents a radical -CH 2 -NRaRb may be obtained by the action of an amine HNRaRb on a heterocyclylalkylpiperidine derivative for which the radical R'i to be modified is halomethyl (the halogen preferably being a bromine or chlorine atom). The reaction is carried out in an inert solvent such as an ether (for example tetrahydrofuran or dioxane), an amide (for example N,Ndimethylformamide) or dimethyl sulfoxide, in the presence of an acid acceptor such as a trialkylamine (for example triethylamine) or an alkali metal hydride (for example sodium hydride), at a temperature of between 200C and the reflux temperature of the reaction mixture. The halomethyl derivative is prepared as described above.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which RI, R'i, R' 2
R'
3
R'
4 or
R'
5 represents a carboxymethyl radical may be obtained by the action of an alkaline cyanide on a heterocyclylalkylpiperidine derivative for which the radical R'i to be modified is halomethyl (the halogen preferably being a bromine or chlorine atom), followed by hydrolysis of the nitrile. The reaction is carried out using sodium cyanide or potassium cyanide in an organic solvent such as dimethyl sulfoxide or dimethylformamide, or in a wateralcohol mixture, at a temperature of between 0°C and the boiling point of the reaction mixture, followed by the action of a strong acid such as hydrochloric acid, optionally in the presence of a lower aliphatic alcohol, at a temperature of between 0°C and the boiling point of the reaction mixture.
The heterocyclylalkylpiperidine derivatives of general formula (II) for which R 1 R'i, R' 2
R'
3 R'4, or
R'
5 represents an alkyloxycarbonylmethyl, cycloalkyloxycarbonylmethyl or -CH 2 -CO-NRaRb radical may be obtained from the corresponding acid according to the usual methods for converting an acid to an ester or amide which do not affect the rest of the molecule, especially in the presence of a coupling agent such as a carbodiimide as described above.
The heterocyclic derivatives of general formula (III) for which Hal is a bromine atom, RI is defined as above, X 1 to X 4 represent, respectively, >C-R'i to >C-R' 4 and X 5 represents >CH, may be prepared by brominating the corresponding 4-hydroxyquinolines using a brominating agent such as phosphorus oxitribromide or thionyl bromide without a solvent, at a temperature of between 20 0 C and 1150C.
The 4-hydroxyquinolines may be prepared by decarboxylating the corresponding 3-carboxy-4-hydroxyquinolines, working in a solvent such as diphenyl ether at a temperature of between 100 0 C and 260 0
C.
The 3-carboxy-4-hydroxyquinolines may be prepared by analogy with the method described in European patent application EP-A-0 379 412, starting with the desired aniline derivative.
The heterocyclic derivatives of general formula (III) for which Hal is a bromine atom, RI is defined as above, X 1 to X 4 represent, respectively, >C-R'i to >C-R' 4 and Xs represents >C-C1, may be prepared by brominating the corresponding 3-chloro-4-hydroxyquinoline. The bromination is generally carried out with triphenylphosphine dibromide in acetonitrile at a temperature of between 20 0 C and 85 0
C.
The 3-chloro-4-hydroxyquinolines may be prepared by chlorinating a 4-hydroxyquinoline. The chlorination is carried out, for example, using N-chlorosuccinimide in a solvent such as acetic acid, at a temperature of between 20 0 C and 100 0
C.
The heterocyclic derivatives of general formula (III) for which Hal is a bromine atom, RI is defined as above, X 1 to X 4 represent, respectively, >C-R' 1 to >C-R'4 and X 5 represents >C-COCF 3 may be prepared by analogy with the preparation of the derivatives for which X represents >CH, by brominating the corresponding 4hydroxy-3-fluoroacetylquinoline derivative. The reaction is carried out without a solvent, using a brominating agent such as phosphorus oxytribromide, at -a temperature of between 20 0 C and 115 0 C. The 4-hydroxy-3-trifluoroacetylquinoline may be prepared by analogy with the method described for the preparation of 3-carboxy-4- :hydroxyquinoline.
The heterocyclic derivatives of general formula (III) for which Hal is an iodine atom, RI is a methoxy radical, X 1 to X 4 represent, respectively, >C-R' 1 to
>C-R'
4 and X 5 represents may be prepared by analogy with the studies of E. Arzel et al., Tetrahedron, 12149-12156 (1999) starting with 3-fluoro-6-methoxyquinoline, by the successive action of a base and then iodine. For example, lithium diisopropylamide in a solvent such as an ether (tetrahydrofuran) at-a temperature of between -80 0 C and 200C is used.
The 3-fluoro-6-methoxyquinoline may be obtained by pyrolysis of 6-methoxyquinoline diazonium 3-tetrafluoroborate or 3-hexafluorophosphate according to the Balz-Schieman reaction, Org. Synth., Coll 5, 133 (1973), at a temperature of between 1000C and 240 0 C. 6-Methoxyquinoline diazonium 3-tetrafluoroborate or 6-methoxyquinoline diazonium 3-hexafluorophosphate may be obtained from 3-amino-6-methoxyquinoline by the action of an alkaline nitrite (for example sodium nitrite) in acidic medium (tetrafluoroboric acid or hexafluorophosphoric acid) in a solvent such as water at a temperature of between -10 0 C and +20 0 C, by analogy with the studies of A. Roe et al., J. Am. Chem. Soc., 71, 1785-86 (1949) or by the action of an alkyl nitrite (such as, for example, isoamyl nitrite) and of the trifluoroborate/diethyl ether complex in a solvent such as an.ether (for example tetrahydrofuran) at a temperature of between -10 0 C and 0
C.
3-Amino-6-methoxyquinoline is prepared as described by N. Heindel, J. Med. Chem. (1970) 13, 760.
The heterocyclic derivatives of general formula (III) for which Hal is a bromine atom, RI is defined as above, X 2 to X 4 represent, respectively, >C-R' 2 to >C-R' 4 and Xi represents a nitrogen atom or alternatively X 1
X
3 and X 4 represent, respectively, >C-R' 3 and >C-R'4 and X 2 represents a nitrogen atom, and X 5 represents >CH or >C-C1, may be prepared by analogy with the methods described above when Xi to X 4 represent, respectively, >C-R'I to >C-R' 4 or according to the syntheses described by Adams J.T. et al., J. Am. Chem. Soc., 68, 1317 (1946) for the 1,5-naphthyridines and S. Radl et al., Collect.
Czech. Chem. Commun., 56, 2420 (1991) for the 1,7naphthyridines, starting with 3-aminopyridines.
The hydroxynaphthyridine required to carry out the reaction is also prepared by analogy with the methods described above for the hydroxyquinolines, but starting with 3-aminopyridine or its substituted derivatives. The 3-aminopyridine derivatives may be obtained by adaptation of the methods described in "The Chemistry of Heterocyclic Compounds", Vol. 14, Pyridines and its derivatives, Supplement Part III, page 41. Ed. R.A.
Abramovitch, InterScience Publication.
The heterocyclic derivatives of general formula (III) for which Hal is a bromine atom, R 1 is defined as above, Xi, X 2 and X 4 represent, respectively, >C-R' 1
>C-R'
2 and >C-R' 4
X
3 represents a nitrogen atom and X represents >CH or >C-C1, may be prepared by analogy with the methods described above when Xi to X 4 represent respectively, >C-R' 1 to >C-R' 4 or according to the syntheses described by D. Heber et al., Arzneim-Forsch, 44, 809 (1994) starting with 2-aminopyridines or substituted derivatives thereof.
The 2-aminopyridines may be obtained by applying or adapting the methods described in "The Chemistry of Heterocyclic Compounds", Vol. 14, Pyridines and its derivatives, Supplement Part III, page 41. Ed. R. A.
Abramovitch, Interscience Publication.
The derivatives of general formula (III) for which Hal is a bromine atom, RI is defined as above and Xs represents a nitrogen atom may be obtained from 2-aminobenzenamides as described in J. Am. Chem. Soc., 69, 184 (1947). 2-Amino-benzenamide is cyclized in the presence of an alkyl orthoformate such as ethyl orthoformate in a solvent such as diethylene glycol at a temperature of between 1050C and 1200C to give 4-hydroxyquinazoline, which is brominated as described above. The 2-aminobenzenamide is obtained from the corresponding aniline by applying or adapting the methods described by V. Snieckus, Chem. Rev., 90, 879 (1990) and Pure Appl.
Chem., 62, 2047 (1990).
The heterocyclic derivatives of general formula (III) for which Hal is a bromine atom, RI is defined as above and X 4 is a nitrogen atom may be obtained from 2acetylaniline as described in Synth. Commun., 19, 3087 (1989). The 4-hydroxycinnoline obtained is brominated under the conditions described above. The 2-acetylanilines are obtained from the corresponding aniline by applying the methods cited above for 2-aminobenzenamide.
The piperidine derivatives of general formula (IV) for which n 0 and R" 2 represents carboxyl may be prepared from the corresponding piperidine derivative of general formula: R"2 N-Rz (V) in which R" 2 defined as above is protected beforehand and Rz is defined as above, by analogy with the studies of Koppel, J. Chem. Soc. Chem. Commun., 473 (1975) by reaction between the piperidine derivative and vinyl phenyl sulfoxide in the presence of a base (for example sodium hydride, lithium diisopropylamide or lithium hexamethyldisyliylamide) in a solvent such as an ether (for example tetrahydrofuran) at a temperature of between 0°C and 100 0 C. The intermediate adduct obtained is then thermolyzed at between 60 0 C and 150 0 C in an inert solvent (for example chloroform, tetrahydrofuran, toluene or xylene). Rz is advantageously a protecting group for the nitrogen atom such as, for example, t-butyloxycarbonyl.
The piperidine derivatives of general formula (IV) for which n 1 or 2 and R" 2 represents carboxyl may be prepared from the corresponding piperidine derivative of general formula for which R" 2 is protected beforehand, according to or by analogy with the methods described below in the examples. In particular, the process is performed by the successive action of a base such as, for example, lithium diisopropylamide or n-butyllithium, in a solvent such as an ether (for example tetrahydrofuran) at a temperature of between 0 C and 0°C, and then of an alkenyl halide (allyl halide or l-halo-3-butene).
The piperidine derivatives of general formula (IV) for which n is defined as above and R" 2 is alkyloxycarbonyl, cycloalkyloxycarbonyl, -CO-NRaRb, alkyloxycarbonylmethyl, alkyloxycarbonylethyl, cycloalkyloxycarbonylmethyl, cycloalkyloxycarbonylethyl,
-CH
2 -CONRaRb, or -(CH 2 2 -CONRaRb or for which Rc in R 2 represents alkyloxycarbonyl, cycloalkyloxycarbonyl or -CO-NRaRb may be prepared from the corresponding carboxylic acid derivative, according to .the usual methods for converting into ester or amide which do not affect the rest of :the molecule. The esters are prepared in the presence of a coupling agent such as a carbodiimide (for example (N,N'-dicyclo[lacuna]carbodiimide) or N,N'-carbonyldiimidazole in-an ether (for example tetrahydrofuran or dioxane), an amide (for example dimethylformamide) or a chlorinated solvent (for example dichloromethane, 1,2-dichloroethane or chloroform), -at a temperature of between 0°C and the reflux temperature of the reaction mixture. The amides are prepared by the action of the corresponding amine under conditions identical to those described above. In particular also, when it involves the preparation of a derivative for which Rc in R" 2 is an ester, by analogy with the methods described by Saha et al., J. Chem. Soc.
Perkin I, 505 (1985), by the action of a diazoalkane (for example diazomethane) in an ether (for example diethyl ether) at a temperature of between -10 0 C and The piperidine derivatives of general formula (IV) for which n is defined as above and R" 2 represents cyano, -CH 2 -CN or -(CH 2 2 -CN may be prepared from the corresponding amides by the action of a dehydrating agent, by adapting the method described by Bieron et al., Zabicky "The chemistry of amides" Wiley, pp. 274-283 (1970). The reaction is carried out in the presence of phosphorus pentoxide or phosphorus oxychloride with or without solvent, at a temperature of between 20 0 C and the reflux temperature of the reaction mixture.
The piperidine derivatives of general formula (IV) for which n is defined' as above and R" 2 represents hydroxymethyl, cyanomethyl or carboxymethyl may be prepared from the piperidine derivative of general formula:
(CH
2 )n RyO N-Rz (VI)
O
0 in which Rz and n are defined as above, and Ry represents a readily hydrolyzable protecting radical, in particular by the action of a hydride (for example lithium aluminum hydride or diisobutylaluminum hydride) in a solvent such as an ether (for example tetrahydrofuran) at a temperature of between 20 0 C and 60 0 C to prepare the piperidine derivative for which R" 2 is hydroxymethyl, followed by converting the hydroxymethyl radical into a cyanomethyl radical and then a carboxymethyl radical according to the usual methods which do not affect the rest of the molecule.
When Ry represents a readily hydrolysable radical, it may be chosen especially from alkyl (1 to 4 carbon atoms in a straight or branched chain), benzyl, cycloalkyl, phenylpropyl and allyl.
The conversion into acid may be carried out in particular from the latter compound, by the action of a halogenating agent such as, for example, thionylchloride or phosphorus trichloride or tribromide or by the action of an alkanesulfonyl chloride (for example methanesulfonyl chloride or p-toluenesulfonyl chloride) in an inert solvent (for example dichloromethane), followed by the action of an alkaline cyanide (for example potassium cyanide or sodium cyanide) and hydrolysis. The halogenation reaction is carried out in a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of between O°C and the reflux temperature of the reaction mixture. The reaction of the alkaline cyanide may be carried out in dimethyl sulfoxide, an amide (for example dimethylformamide), a ketone (for example acetone), an ether (for example tetrahydrofuran) or an alcohol (for example methanol or ethanol), at a temperature of between 20 0 C and the reflux temperature of the reaction mixture. The nitrile is hydrolyzed according to the conventional methods which do not affect the rest of the molecule, especially by the action of hydrochloric acid in methanolic medium, at a temperature of between 20 0 C and 70 0 C, followed by saponification of the ester obtained (for example with sodium hydroxide in a mixture of dioxane and water), or directly by the action of aqueous sulfuric acid at a temperature of between 50 0 C and 80 0
C.
The piperidine derivatives of general formula (IV) for which n and Rz are defined as above and R" 2 represents a 2-carboxyethyl radical may be prepared from the derivative of general formula (IV) for which R" 2 represents a hydroxymethyl radical via the halo derivative (prepared as described above) and then coupling with the sodium salt of diethyl malonate followed by acidic hydrolysis in aqueous medium of the product obtained.
The piperidine derivatives of general formula (IV) for which n and Rz are defined as above and R" 2 represents carboxyhydroxymethyl or carboxycarbonyl may be prepared by homologation of the piperidine derivative of general formula: (CH,)n HOKCN-Rz
(VII)
O
0 in which Rz and n are defined as above, by applying or adapting the methods described by M. Mizuno et al., Tetrahedron Lett. 39, 9209 (1998). The reaction is carried out by the action of a dialkyl phosphorocyanidate (for example diethyl phosphorocyanidate) in the presence of an organic base (for example triethylamine) in an ether (for example tetrahydrofuran) at a temperature of between -50 0 C and 10 0 C. The intermediate dicyanophosphate obtained is then hydrolyzed in acidic medium (for example concentrated hydrochloric acid) in a polar solvent (for example water) at the reflux temperature of the reaction mixture. The derivatives for which R" 2 is carboxycarbonyl are obtained by oxidation of the corresponding ester, by adapting the methods described by Burhardt et al., Tetrahedron Lett., 29, 3433 (1988) followed by hydrolysis of the product obtained. In particular by the action of an oxidizing agent such as triacetoxy-l,1-dihydro-l,2benziodoxol-3(lH)one in a solvent such as a nitrile or a chlorinated derivative (for example acetonitrile or dichloromethane) at a temperature of between 0°C and 0 C, followed by hydrolysis by the action of a base (for example sodium hydroxide) in an aqueous-alcoholic solvent (for example water-methanol) at a temperature of between 0 C and the reflux temperature of the reaction mixture.
The piperidine derivatives of general formula (IV) for which n and Rz are defined as above and R" 2 represents -CF 2 -Rc may be prepared by the action of a fluorinating agent on a piperidine derivative of general formula (IV) for which R" 2 is a radical -CO-Rc, Rc being an ester, by analogy with the methods described by M.
Parisi et al., J. Org. Chem, 60, 5174 (1995), optionally followed by hydrolysis of the ester if it is desired to obtain a piperidine derivative for which Rc is carboxyl.
The fluorinating conditions are similar to those described above for the preparation of derivatives for which Re in Y is a fluorine atom. The hydrolysis is carried out by the action of a base in an -aqueousalcoholic solvent under the conditions described above.
The piperidine derivatives of general formula (IV) for which n and Rz are defined as above and R" 2 represents a radical -CH=CH-Rc may be prepared by oxidation to aldehyde of the derivative of general formula (IV) for which R" 2 represents a hydroxymethyl radical by adapting the methods described in Org. Synth.
Coll., Vol. II, p. 541, Coll. Vol. 5 p. 242 followed by conversion to a derivative for which R" 2 is -CH=CH-Rc in which Rc is an ester, by applying the Wittig method optionally followed by hydrolysis of the ester obtained to an acid. The oxidation is carried out by the action of an oxidizing agent (for example potassium dichromate) in acidic medium (for example sulfuric acid) in a polar .solvent (for example water) or chromium oxide in the presence of a base (for example pyridine) in a chlorinated solvent (for example dichloromethane) at a temperature of between 0 C and 20 0 C. The conversion to an unsaturated derivative is carried out by adapting the methods described by Johnson in "Ylid Chemistry" Academic Press (1966) by the action of a phosphorus ylid (for example carbethoxymethylenetriphenylphosphorane) in a hydrocarbon (for example toluene) at a temperature of between 60 0 C and the reflux temperature of the reaction mixture. The hydrolysis is carried out according to the methods described above.
The piperidine derivatives of general formula (IV) for which n and Rz are defined as above and R" 2 represents a radical C(CH 3 2 Rc or -C(cycloalk)Rc may be prepared from a derivative of general formula (IV) for which R" 2 is an ester of the acid for which R" 2 is -CH 2
COOH
by adapting the methods described by Ashutosh et al., Tetrahedron Lett., 40, 4733 (1999) and Sauers, J. Org.
Chem., 57, 671 (1992) optionally followed by hydrolysis of the ester obtained. The reaction is carried out in particular by the successive action of an amide (for example lithium diisopropylamide) followed by a methyl halide (for example methyl iodide) or a derivative of formula Hal-Alk-Hal (Hal preferably being a bromine atom) in a polar solvent (for example hexamethylphosphorotriamide) at a temperature of between 0°C and 60 0
C.
It is understood that the processes listed above for the preparation of the piperidine derivatives of general formula (IV) may also be applied to the derivatives of general formula (II) if it is preferred firstly to couple the piperidine with the heterocyclic derivative of general formula (III) and then to convert the radical R 2 under the conditions described above.
It is also understood that the methods described below in the examples also form part of the present invention.
It is understood that the derivatives of general formulae and (II) may exist in enantiomeric or diastereoisomeric forms or in syn or anti form. The enantiomeric or diastereoisomeric and syn or anti forms and the mixtures thereof also fall within the context of the present invention. These forms may be separated according to the usual methods, especially by chromatography on silica or by high performance liquid chromatography (HPLC).
The heterocyclylalkylpiperidine derivatives of general formula may be purified, where appropriate, by physical methods such as crystallization or chromatography.
The heterocyclylalkylpiperidine derivatives of general formula may, where appropriate, be converted into addition salts with acids, by the known methods. It is understood that these salts also fall within the context of the present invention.
As examples of addition salts with pharmaceutically acceptable acids, mention may be made of the salts formed with mineral acids (hydrochlorides, hydrobromides, sulfates, nitrates and phosphates) or with organic acids (succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, phenylsulfonates, ptoluenesulfonates, isethionates, naphthylsulfonates or camphorsulfonates, or with substitution derivatives of these compounds).
Some of the heterocyclylalkylpiperidine derivatives of general formula bearing a carboxyl radical may be converted into metal salts or into addition salts with nitrogen bases according to the methods that are known per se. These salts also fall within the context of the present invention. The salts may be obtained by the action of a metallic base (for example an alkali metal or alkaline-earth metal), ammonia or an amine, on a product according to the invention, in a suitable solvent such as an alcohol, an ether or water, or by exchange reaction with a salt of an organic acid.
The salt formed precipitates after optional concentration of the solution, and is separated out by filtration, settling or freeze-drying. Examples of pharmaceutically acceptable salts which may be mentioned are the salts with alkali metals (sodium, potassium or lithium) or with alkaline-earth metals (magnesium or calcium), the ammonium salts or the salts of nitrogen bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N-N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-P-phenethylamine, N,N'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine or dibenzylamine).
The heterocyclylalkylpiperidine derivatives according to the invention are particularly advantageous antibacterial agents.
In vitro, the heterocyclylalkylpiperidine derivatives according to the invention have been found to be active on gram-positive microorganisms at concentrations of between 0.03 pg/ml and 4 pg/ml on meticillin-resistant Staphylococcus aureus AS5155, and also, for most of them, at concentrations of between 0.03 pg/ml and 8 pg/ml on Streptococcus pneumoniae 6254- 01; they have also been found to be active on gramnegative microorganisms such as, for example, and in a nonlimiting manner, on Moraxella catarrhalis IPA 152, at concentrations of between 0.12 pg/ml and 64 jg/ml. In vivo, they have been found to be active on experimental infections of mice with Staphylococcus aureus IP8203, either subcutaneously at doses of between 18 mg/kg and 150 mg/kg (DC 50 or orally at doses of between 20 mg/kg and 150 mg/kg.
Finally, the products according to the invention are particularly advantageous on account of their low toxicity. None of the products has shown any toxicity subcutaneously at the dose of 100 mg/kg in mice (2 administrations).
In the general formula the products for which Xi, X 2
X
3
X
4 and Xs represent, respectively, >C-R'i to >C-R' 5 or alternatively -not more than one of them represents a nitrogen atom, RI, R' 1
R'
2
R'
3
-R'
4 and R' 5 are identical or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a methylene radical substituted with alkyloxy.
'R
2 represents carboxyl, alkyloxycarbonyl or -CONRaRb (for which Ra represents a hydrogen atom and Rb represents a hydrogen atom or a hydroxyl radical) or
R
2 represents hydroxymethyl, alkyl containing 1 or 2 carbon atoms substituted with carboxyl or alkyloxycarbonyl,
R
3 represents a radical alk-R°3 for which alk is an alkyl radical and R 0 3 represents hydrogen, cycloalkyl, cycloalkylthio, phenyl, phenoxy, phenylthio, phenylamino, heterocyclyloxy or heterocyclylthio or alternatively R°3 represents -CR'b=CR'c-R'a for which R'a represents phenyl, and for which R'b and R'c represent hydrogen, Y represents a radical >CH-Re for which Re is hydrogen, fluoro or hydroxyl, n is an integer from 2 to 3, it being understood that the phenyl or heterocyclyl radicals or portions mentioned above may be optionally substituted on the ring with 1 to 4 halogens, are particularly advantageous.
Especially the heterocyclylalkyl piperidine derivatives of general formula mentioned below: 9 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2- (thien-2-yl) thioethyllpiperidine-4-carboxylic acid .0 4- [3-(3-Chloro-6-methoxyquinolin-4-yl)propyl)-1- [2- 5-difluorophenoxy) ethyllpiperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl-l-(2- 1 thiazol-2-thioethyl)piperidine-4-carboxylic acid *1-(2-Cyclopentylthioethyl)-4-[3-(3-fluoro-6methoxyquinolin-4-yl) propyllpiperidine-4-carboxylic acid 0 4 -[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-(3phenylallyl) piperidine-4-carboxylic acid and also the salts thereof.
Among the products according to the invention that may be more particularly mentioned are the heterocyclylalkylpiperidine derivatives of general formula the names of which follow: 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] -1-heptylpiperidine-4-carboxylic acid 4- [3-(3-Chloro-6-methoxyquinolin-4-yl)propyl [4-phenylbutyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2fluorophenyl) propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3fluorophenyl) propyl] piperidine-4-carboxylic acid 4-13- (3-Chloro-6-methoxyquinolii-4-yl)propyl] (4fluorophenyl )propyl Ipiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4fluorophenyl )butyl ]piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinoliri-4-yl)propyl]-1-[3-(2,3difluorophenyl) propyl IIpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3difluorophenyl) propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,6difluorophenyl) propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,6difluorophenyl) propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl difluorophenyl) propyl] piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-rnethoxyquinolin--4-yl)propyl]-1-[3-(2,3,5trifluorophenyl )propyl ]piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyli-1-[3-(2,4,6trifluorophenyl )propyl ]piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenyl )propyl Ipiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-y1)propyl [3-phenylthio'propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2fluorophenylthio) propyl] piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3fluorophenylthio) propyl] piperidine-4-carboxylic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl] 2- (4fluorophenylthio) ethyl 1piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4fluorophenylthio )propyl IIpiperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,3difluorophenylthio) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3difluorophenyithia) propyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2,6difluorophenylthio) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenyithia) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (2,4,6trifluorophenyithia) ethyl] -piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,4,5trifluorophenyithia) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenoxy) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenoxy) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenoxy) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl difluorophenylamino) ethyl] -piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,3,5trifluorophenylatino) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenylamino) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (3,4,5trifluorophenylanino) ethyl] -piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,6difluorophenylthio) propyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2chlorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2chlorophenylthio )propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-niethoxyquinolin-4-yl)propyl] (3chlorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (3chlorophenylthio) propyl] piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-l-[2-(4chlorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4chlorophenylthio) propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2inethylphenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (2methylphenylthio) propyl] -piperidine-4-carboxylic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl] (3methyiphenyithia) ethyl] piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-l-[3-(3methylphenylthio)propyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4rnethylphenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4methyiphenyithia) propyl] -piperidine-4-carboxylic acid 4-l3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2trifluoroniethylphenylthio) ethyl] -piperidine-4-carboxylic -acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2trifluoromethyiphenyithia) propyl] -piperidine-4-carboxyWlic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3trifluoromethylphenylthio) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3trifluoroinethylphenylthio) propyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquiriolin-4-yl)propyl (4trifluoromethylphenylthio) ethyl] -piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(4trifluoromethylphenylthio) propyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquiriolin-4-yl)propyl (2methoxyphenylthio) ethyl] -piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2methoxyphenylthio) propyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3methoxyphenylthio) ethyl] -piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3rnethoxyphenylthio) propyl] -piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(4rnethoxyphenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4methoxyphenyithio) propyl I-piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] -1- [cyclopentylmethyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyguinolin-4-yl)propyl] (cyclopentyl) ethyl] piperidine-4-carboxylic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl [2- (cyclopentyithio) ethyl] piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3- (cyclopentylthio) propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6--methoxyguinolin-4-yl)propyl] (cyclohexyithio) propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (thien-2yl )butyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (thien-2yl) thiopropyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (thien-3yl )propyl ]piperidine-4-carboxylic acid 4 -[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[4-(thien-3yl )butyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (thien-3yl) thioethyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (thien-3yl) thiopropyllpiperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-y1)propyl]-1-[3-(1,3thiazol-2-yl )propyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (1,3thiazol-2-yl) butyl ]piperidine-4-carboxyiic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (1,3thiazol-2-yl) thioethyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) propyl ]piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) butyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-y1)propyl] (pyrid-2yl) thiopropyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-3yl) propyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-3yl )butyl Ipiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-3yl) thioethyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-3y1) thiopropyllpiperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinoin-4-y)propy]-l[3(pyrid4 yl) propyl] piperidine-4-carboxylic acid 4-13- (3-Chloro-6-methoxyquinolin-4-yl)propyl] -1-14- (pyrid-4yl) butyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-4yl) thicethyl] piperidirae-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-4yl) thiopropyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyj (pyrazia- 2-yl) propyl ]piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrazin- 2-l) butyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrazin- 2-yl) thioethyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrazin- 2-yl) thiopropyl] piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-1-[3-(4fluorophenyl )prop-2-ynyl ]piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3,4difluorophenyl) prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyciyinolin-4-yl)propyl (2,4difluorophenyl) prop-2-ynyl] piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,3,5trifluorophenyl )prop-2-ynyl ]piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenyl) prop-2-ynyl Ipiperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(3,4,5trifluorophenyl) prop-2-ynyl ]piperidine-4-carboxylic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl] 3- (4chloro-3-fluorophenyl )prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (3chloro-4-fluorophenyl.) prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2chloro-4-fluorophenyl )prop-2-ynyl] piperidine-4-carboxylic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3- )prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4chloro-2-fluorophenyl )prop-2-ynyl] piperidine-4-carboxylic -acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl fluoro-4-methylphenyl )prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] bis (trifluoromethyl) phenyl) prop-2-ynyl] piperidirie-4carboxylic acid 4- [3-(3-Chloro-6-methoxyquinolin-4-yl)propyl (thien-2yl )prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (thien-3yl)prop-2-ynyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (1,3thiazol-2-yl) prop-2-ynyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (1,3thiazol-4-yl)prop-2-ynyllpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (1,3prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-ntethoxyquinolin-4-yl)propyl (pyrid-2yl) prop-2-ynyl IIpiperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-3yl )prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyll (pyrid-4yl) prop-2-ynyl~piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyl] piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [3- (phenyl) propyl] piperidine-4-carboxylic acid 4-[3-(3-Methyl--6-methoxyquinolin-4-yl)propyl]-l-[3-(2,3,5trifluorophenyl )propyl] piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] difluorophenylanino) ethyl] -piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenylamino) ethyl] -piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl difluorophenoxy) ethyl] -piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenoxy) ethyl] -piperidine-4-carboxylic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-l-[2- (cyclopentylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] 2- (pyrid-2yl) thioethyllpiperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (thien-2yl) thioethyl] piperidine-4-carboxylic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5trifluorophenyl) prop-2-ynyl Ipiperidine-4-carboxylic acid 4- (3-methyl-6-methoxyquinolin-4-yl)propyl]-l- (thien-2yl) prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinollin-4-yl)propyl (2,3,5trifluorophenyl) propyl ]piperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl~propyl difluorophenylamino) ethyl Ipiperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluorophenoxy) ethyllpiperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenoxy) ethyllpiperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (2,3,5trifluorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (pyrid-2yl) thioethyllpiperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (2,3,5trifluorophenyl )prop-2-ynyl Ipiperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2yl) prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyl] piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [3- (phenyl )propyl] piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [3- 3, 5-trifluorophenyl )propyl] piperidine-4-carboxylic acid 4- (3-Dimethylamnino-6-iethoxyquinolin-4-yl)propyl [2- 5-difluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 3, 5-trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Direthylamino-6-methoxyquinolin-4-yl)propyl [2- (2 5-trifluorophenoxy) ethyllpiperidine-4-carboxylic acid 4- (3-Direthylamino-6-rethoxyqinolin-4-yl)propyl [2- (2 5-trifluorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Dimethylaxnino-6-methoxyqiiinolin-4-yl)propyl [2- (cyclopentylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- (pyrid-2-yl) thioethyl] piperidine-4-carboxylic acid (3-Dimethylaxino-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyllpiperidine-4-carboxylic acid 4- (3-Dimethylarino-6-methoxyquinolin-4-yl)propyl [3- 3, 5-trifluorophenyl )prop-2-ynyl ]piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [3- (thien-2 -yl )prop-2 -ynyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [3- (phenyl)propyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] 3, 5-trifluorophenyl )propyl] piperidine-4-carboxylic acid 4- (3-Hydroxynethyl-6-methoxyquinolin-4-yl)propyl] 5-difluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] 3, 5-trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-rnethoxyqiuinolin-4-yl)propyl [2- 5-difluorophenoxy) ethyl]piperidirae-4-carboxylic acid 4- (3-IHydroxymethyl-6-rethoxyquinolin-4-yl)propyl] 2, 3,5-trifluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-niethoxyquinolin-4-yl)propyl [2- 3, 5-trifluorophenyithia) ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxyrnethyl-6-rethoxyquinolin-4-yl)propyl [2- (cyclopentylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-rnethoxyquinolin-4-yl)propyl [2- (pyrid-2-yl) thioethyl] piperidine-4-carboxylic acid 4- (3-Hydroxyrnethyl-6-rethoxyquinolin-4-yl)propyl [2- (thien-2-yl) thicethyl] piperidine-4-carboxylic acid 4- (3-Hydrox-yrethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl )prop-2-ynyl ]piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [3- (thien-2-yl)prop-2-ynyllpiperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- (phenyl) propyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)propyllpiperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- (3-Fluoroiethyl-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 3, 5-trifluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)pjropyl [2- 5-trifluorophenylthio) ethyllpiperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclopentyithio) ethyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- (pyrid-2-yl) thioethyllpiperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyl] piperidine-4-carboxylic acid 4- (3-Fluoroiethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-carboxylic acid 4- (3-Fluoroiethyl-6-methoxyquinolin-4-yl)propyl] (thien-2-yl) prop-2-ynyl Ipiperidine-4-carboxylic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyl] piperidirie-4-carboxylic acid 4-[3-(3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-l-[3- (phenyl )propyl] piperidine-4-carboxylic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)propyllpiperidine-4-carboxylic acid 4- (3-Aminomethyl-6-rnethoxyquinolin-4-yl)propyl [2- 5-difluorophenylatino) ethyl] piperidine-4-carboxylic acid 4- (3-Aiinomethyl-6-methoxyquinolin-4-yl)propyl 3, 5-trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- (3-Aminoiethyl-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) ethyllpiperidine-4-carboxylic acid 4- (3-Axinomethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- 3, 5-trifluorophenyithio) ethyl] piperidine-4-carboxylic acid 4- (3-Aiinorethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclopentylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Axinomethyl-6-methoxyquinolin-4-yl)propyl [2- (pyrid-2-yl) thioethyl] piperidine-4-carboxylic acid 4- (3-Axinomethyl-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyl ]piperidine-4-carboxylic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-carboxylic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- (thien-2-yl) prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Morpholiriomethyl-6-methoxyquinolii-4-yl)propyl] -1- (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- (3-morpholinornethyl-6-methoxyquinolin-4-yl )propyl 1-1- (phenyl) propyl] piperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl -1- 5-trifluorophenyl)propyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl -1- 5-difluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenylanino) ethyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl -1- 5-difluorophenoxy) ethyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 3, 5-trifluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-rnethoxyquinolin-4-yl) propyl] 5-trifluorophenylthio) ethyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- (cyclopentyithio) ethyl] piperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl 1-1- (pyrid-2-yl) thioethyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-rnethoxyquinolin-4-yl) propyll-1- (thien-2-yl) thioethyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl)prop-2-ynyl]piperidine-4carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl 1-1- (thien-2-yl)prop-2-ynyllpiperidine-4-carboxylic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,4,6trifluorophenyl )propyl] piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (3,4,5tri fluorophenyl )propyl] piperidine-4-carboxylic acid 4- (3-Methyl-6-rnethoxyquinolin-4-yl)propyl] (2,4,6trifluorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] (2,4,6trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,4,5trifluorophenylamino) ethyllpiperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] (2,4,6trifluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Methyl-6-rnethoxyquinolin-4-yl)propyl]-l- (3,4,5trifluorophenoxy) ethyl] piperidine-4-carboxylic acid 4-[3-(3-methyl-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,4,6trifluorophenyl) prop-2-ynyl ]piperidine-4-carboxylic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenyl) prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Fluoro-6-rnethoxyquinolin-4-yl)propyl] (2,4,6trifluorophenyl) propyl] piperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,4,5trifluorophenyl) propyl] piperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,4,6trifluorophenylthio) ethyl] -piperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5trifluorophenylthio) ethyl] -piperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenylaxnino)ethyl] -piperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenylanino) ethyl] -piperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenoxy) ethyl] -piperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxypuinolin-4-yl)propy1 (3,4,5trifluorophenoxy) ethyl] -piperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-y1)propyl]-l-[3-(2,4,6trifluorophenyl )prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenyl )prop-2-ynyl ]piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl) -propyl] piperidine-4-carboxylic acid 4- (3-Dimethylaxnino-6-methoxyquinolin-4-yl)propyl [3- 4, 5-trifluorophenyl) -propyl] piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-Inethoxyquinolin-4-yl)propyl [2- 4, 6-trifluorophenylthio) -ethyl] piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylthio) -ethyl] piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenylamino) -ethyl] -piperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenylamino) -ethyl] piperidine-4-carboxylic acid 4- (3-Dimethylanino-6-methoxyquinolin-4-yl)propyl] 2- 6-trifluorophenoxy) -ethyllpiperidine-4-carboxylic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) -ethyllpiperidine-4-carboxylic acid 4- (3-Dimethylaxnino-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenyl )prop-2-ynyl ]piperidine-4-carboxylic acid (3-Dimethylaxnino-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Hydroxyrnethyl-6-methoxyquinolin-4-yl)propyl [3- 4, 5-trifluorophenyl) propyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-methoxyquiraolin-4-yl)propyl] 6-trifluorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxyiethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-rnethoxyquinolin-4-yl)propyl [2- 6-trifluorophenylamino) ethyl]piperidine-4-carboxylic acid 4- (3-Hydroxyiethyl-6-methoxyquinolin-4-yl)propyll 5-trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxyiethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenoxy) -ethyl] piperidine-4-carboxylic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenoxy) -ethyllpiperidine-4-carboxylic acid 4- [3-(3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenyl) prop-2-ynyl ]piperidine-4-carboxylic acid 4-[3-(3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl]-1-[3- 5-trifluorophenyl) prop-2-ynyl ]piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] -1-13- 6-trifluorophenyl)propyllpiperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 4, 5-trifluorophenyl) propyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 4, 6-trifluorophenylthio) ethyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 4, 5-trifluorophenylthio) ethyl] -piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-mnethoxyquinolin-4-yl)propyl] 6-trifluorophenylamino) -ethyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylamino) -ethyl] piperidine-4-carboxylic acid 4- (3-Fluorornethyl-6-rethoxyquinolin-4-yl)propyl [2- 6-trifluorophenoxy) -ethyllpiperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 4, 5-trifluorophenoxy) -ethyl] piperidine-4-carboxylic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 4, 6-trifluorophenyl )prop-2-ynyl Ipiperidine-4-carboxylic acid 4- (3-Fluororethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop--2-ynyllpiperidine-4-carboxylic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl)propyllpi'peridine-4-carboxylic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)propyllpiperidine-4-carboxylic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenylthio) ethyllpiperidine-4-carboxylic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenyithia) ethyllpiperidine-4-carboxylic acid 4- (3-Aiinomethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- (3-Axinomethyl-6-methoxyquinolin-4-yl)propyll-l- [2- 5-trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- (3-Arinomethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Aiinomethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Aminorethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenyl )prop-2-ynyl] piperidine-4-carboxylic acid 4- (3-Aminornethyl-6-rethoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenyl) -propyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl) -propyl] piperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl -1- 6-trifluorophenylthio) -ethyl] piperidine-4-carboxylic acid 4- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl -1- 5-trifluorophenylthio) -ethyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenylanino) ethyllpiperidine-4-carboxylic acid (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl] -1- 5-trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-inethoxyquinolin-4-yl) propyl] -1- 6-trifluorophenoxy) -ethyllpiperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl] -1- 5-trifluorophenoxy) ethyl] piperidine-4-carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenyl) -prop-2-ynyllpiperidine-4carboxylic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl) -prop-2-ynyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] -1-heptylpiperidine-4-carboxylic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl [4-phenylbutyllpiperidine-4-carboxylic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-carboxylic acid 4- -Hyciroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (2-f luorophenyl )propyl] piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (3-f luorophenyl)propyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyl)butyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenyl)propyllpiperidine-4carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl] 3-difluorophenyl)propyllpiperidine-4carboxylic acid S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 6-difluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenyl)propyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl)-l- 5-difluorophenyl)propyllpiperidine-4- *carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-nethoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] -1-[3-phenylthio-propyl ]piperidine-4-carboxylic acid 4- S) -Hyd-roxy-3-(3-chloro-6-methoxyquinolin-4yl) propyl1-1- (2-f luorophenylthio)propyl] piperidine-4carboxylic acid 4- S) -Hyciroxy-3- (3-chloro-6-rnethoxyquinolin-4yl )propyl] (3-f luorophenylthio)propyl] piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenylthio)ethyllpiperidine-4carboxylic acid 4- (R,S)-Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll (4-f luorophenylthio)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenyithia) ethyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenylthio)propyllpiperidine-4carboxylic acid, 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenylthio)ethylllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 5-trifluoropheaylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 6-trifluoropheayithic) ethylipiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-' yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propylll--[2- 6-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-inethoxyquinolin-4yl)propyl] 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l- (2,3,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- (R,S)-Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l- (2,4,6trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propylll--[2- (3,4,5trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Hyciroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenylthio)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-chlorophenylthio) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-chlorophenylthio)propyllpiperidine-4carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl] (3-chlorophenylthio) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6--methoxyquinolin-4yl)propyl (3-chlorophenylthio)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl] (4-chlorophenylthio)ethyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-inethoxyquinolin-4yl)propyll (4-chlorophenylthio)propyljpiperidine-4carboxylic acid 4- (R,S)-Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] 2- (2-methylphenylthio) ethyl Ipiperidine-4carboxylic acid 4-13- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (2-methylphenylthio)propyl Ipiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyll-1- (3-methylphenylthio) ethyl] piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (3-methylphenylthio)propyllpiperidiie-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-methylphenylthio) ethyllpiperidine-4carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4l) propyl] (4-methylphenylthio) propyl] piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (2trifluoromethylphenylthio) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(2trifluoromethylphenylthio) propyl] piperidine-4-carboxylic acid S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (3trifluoromethylphenylthio) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (3trifluorornethylphenylthio) propyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (4trifluoromethylphenylthio) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4trifluoromethyiphenyithia) propyl] piperidirie-4-carboxylic acid 4- S) -H-ydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-methoxyphenylthio) ethyllpiperidine-4carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl )propyl] (2-methoxyphenylthio) propyl] piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-inethoxyquinolin-4yl)propyl (3-methoxyphenyithic) ethyllpiperidine-4carboxylic acid.
4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl] (3-methoxyphenylthio)propylljpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-methoxyphenylthio) ethyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl (4-methoxyphenylthio) propyl] piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl1-1- [cyclopentylmethyl Ipiperidine-4-carboxylic acid 4- (R,S)-Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclopentyl) ethyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyl]piperidine-4-carboxylic acid 4- S) -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (cyclopentylthio) ethylllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclopentylthio)propyllpiperidine-4carboxylic acid 4-13- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (cyclohexylthio)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll (thien-2-yl)butyllpiperidine-4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1- (thien-2-yl) thiopropyllpiperidine-4carboxylic acid 4-13- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl)propyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (thien-3-yl)butyllpiperidine-4-carboxylic acid 4- S) -Iydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyljpiperidine-4carboxylic acid 4-13- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl) thioethylllpiperidine-4carboxylic acid 4-[3-(R,S)-Hyctroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl)ll--[3- (thien-3-yl) thiopropyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 3-thiazol-2-yl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[ 4 -(1,3-thiazol-2-yl)butyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolii-4yl)propyl]-1- (1,3-thiazol-2-yl)thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (pyrid-2-yl )propyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl)butyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thiopropyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)propyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-3-yl)butyllpiperidine-4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-3-yl) thioethyllpiperidine-4carboxylic acid 4-[13- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl) thiopropyllpiperidine-4carboxylic acid 4- S) -I-ydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (pyrid-4-yl)propyllpiperidine-4-carboxylic acid 4-[13- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] -1-14- (pyrid-4-yl)butyllpiperidine-4-carboxylic acid 4-113- (R,S)-Hydroxy-3- (3-chloro-6-rnethoxyquinolii-4yl)propyl -1-112- (pyrid-4-yl) thioethyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl) thiopropyllpiperidine-4carboxylic acid 4-113- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propylj (pyrazin- 2 -yl)propyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazir-2-yl)butyllpiperidine-4-carboxylic acid 4 -[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl) thioethyllpiperidine-4carboxylic acid 4 -[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl) thiopropylllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6--rethoxyquinolin-4yl) propyl] (4-f luorophenyl )prop-2-ynyl] piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 4 -difluorophenyl)prop-2-ynyl]piperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] 4-difluorophenyl )prop-2-ynyl Iipiperidine- 4-carboxylic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propylli-l-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-niethoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolii-4yl)propyl]-1-[3-(4-chloro-3-fluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (3-chloro-4-fluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (2-chloro-4-fluorophenyl) prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-chloro-5-fluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chloro-2-fluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-f luoro-4-methylpheiyl)prop-2ynyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyll-l-[3-(3,5-bis(trifluoromethyl)phenyl)prop-2yriyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-yriyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl)prop-2-ynyllpiperidine-4carboxylic acid S) -}ydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(1,3-thiazol-2-yl)prop-2-yxyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(1,3-thiazol-4-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(1,3-thiazol-5-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)prop-2-ynyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propylj-1- (pyrid-4-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl] (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4yl) propyl] (phenyl )propyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-rethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4y1)p~ropy1]-1- (2,3,5trifluorophenylamino) ethyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-rethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy)ethyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-methyl-6-nethoxyqu~inolin-4yl)propyl 5-trifluorophenylthio) ethyl]piperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-rethyl-6-methoxyquinolin-4yl)propyl] (cyclopentylthio) ethyl] piperidine-4carboxylic acid 4- (R,S)-Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-rethyl-6-iethoxyquinolin-4yl)propyll-l-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-nethyl-6-methoxyquinolin-4yl)propyl]-1- (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl) propyl] (phenyl) propyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-f 1uoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl] 5-difluorophenylan) ethyllpiperidiie-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyll-1- (2,3,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoro-6-rnethoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl] (cyclopentylthio) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-fluoro-6-rnethoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- CR, S)-Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- CR, S) -ydroxy-3- (3-dimethylamino-6-methoxyquinolii-4yl)propyl] (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl) propyl1-1- (phenyl )propyl Ipiperidirie-4-carboxylic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyll-1-[3-(2,3,5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl) propyl] 5-difluorophenylamino) ethyl Ipiperidine-4carboxylic acid 4- -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1-[2- (2,3,5trifluorophenylaiino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl] 5-difluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-dimethylarnino-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid CR, S)-Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1- 4-carboxylic acid 4-13- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyl~piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-dirnethylamno-6-rethoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-direthylaxino-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1- (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)p~ropy1 5-trifluorophenyl)propylljpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenylamino) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyguinolin-4yl)propyl]-1- 12- (2,3,5trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenoxy) ethyllpiperidiie-4carboxylic acid 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl]-l- 5-trifluorophenoxy)ethyl]piperidine-4carboxylic acid 4-113- (R,S)-Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4-113-(R, S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (cyclopentyithio) ethyllpiperidine-4carboxylic acid 4-113- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyljll--[2- (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,3,5-trifluorophenyl)prop-2yriyl] piperidine-4-carboxylic acid 4- S)-Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl )propyl] (thien-2-yl) prop-2-ynyl] piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-rnethoxyquinolin-4yl)propyl 5-trifluoropheriyl)propyl~piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquiiolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- (2,3,5trifluorophenylamino) ethyltlpiperidine-4-carboxylic acid 4- S)-Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luorornethyl-6-rethoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyithia) ethyl IIpiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- C3-fluoromethyl-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperidine-4carboxylic acid 4- SI ydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] (thien-2-yl) thioethylljpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-l- (2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid (R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl )propyl] (cyclohexyl) ethyl] piperidine-4-carboxylic acid 4- -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-carboxylic acid 4- SI-Hydroxy-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylanino) ethyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5trifluorophenylanino) ethyllpiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-axinomethyl-6-rnethoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperidiie-4carboxylic acid 4- S) -Hydroxy-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl]-l- 5-trifluorophenoxy)ethyllpipe!ridine-4carboxylic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-tritluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4-13- (R,S)-Hydroxy-3- (3-arinomethyl-6-methoxyquinolin-4yl)propyl] (cyclopentylthio) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyguinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid S) -Hydroxy-3- (3-arinomethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-aiinomethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquiaolin- 4-yl)propyl (cyclohexyl) ethyl]piperidine-4-carboxylic acid 4- S) -J-ydroxy-3- (3-mnorpholinomethyl-6-methoxyquinolin- 4-yl) propyl] (phenyl )propyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl) propyl] 5-difluorophenylanino) ethyllpiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholiriomethyl-6-methoxyquinolin- 4-yl)propyl] (2,3,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 5-difluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 5-trifluorophenoxy) ethyllipiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-rorpholinomethyl-6-methoxyquinolin- 4-yl)propyl]-1-[2-(2,3,5trifluorophenylthio) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (cyclopentylthio) ethyllpiperidine-4carboxylic acid 4- S)-Hyclroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 2- (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyguinolin- 4-yl)propyl]-1-113-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4-13- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (thien-2-yl)prop-2-ynyl~piperidine-4carboxylic acid 4- (R,S)-Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-l- 6-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-rethyl-6-rethoxyquinolin-4yl)propyl 5-trifluoropheiyl)propylllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-rethyl-6-methoxyquinolin-4yl) propyl] 6-trifluorophenylthio) ethyl] piperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-rethyl-6-methoxyquinolii-4yl)propyl]-l- 4-carboxylic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-l- (2,4,6trifluorophenylanino) ethyllpiperidine-4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-rnethyl-6-methoxyquinolin-4yl)propyl]1-1- (3,4,5trifiluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyll-1- 6-trifluorophenoxy)ethy1]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-rethyl-6-methoxyquinolin-4yl)propyl]-l-[ 2 4 ,5-trifluorophenoxy)ethyllpiperidine-4 carboxylic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluoropheiyl)prop-2ynyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-rnethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyll 6-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenylthio)ethyl]piperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl )propyl 4, 5-trifluorophenylthio) ethyl] piperidine- 4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1- (2,4,6trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4-1:3- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl]-1-[12- (3,4,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-fluoro-6-niethoxyquinclin-4yl)propylll--[2- 6-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl 13- 6-trifluorophenyl)prop-2yriyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-direthylaxino-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyl]piperidine-4carboxylic acid 4- -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4-13- S) -Hydroxy-3- (3-dimethylainino-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-dimethylarnino-6-methoxyquinolin-4yl)propyl] (2,4,6trifluorophenylanino) ethyl Ipiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-diiethylamino-6-methoxyquiinolin-4yl)propyl)l-[2-(3,4,5trifluorophenylam-ino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl]-l- 6-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- (R,S)-Hydroxy-3- (3-dimethylamno-6-methoxyquinolin-4yl)propyljll--[2- 5-trifluorophenoxy)ethyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propylll-l-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-direthylaxino-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluoropheiyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllipiperidine- 4-carboxylic acid 4- (R,S)-Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] (2,4,6trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(3,4,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3-- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl]-l-112-(2,4,6-tritluorophenoxy)ethyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-hydroxyniethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-hydroxyniethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-nethoxyquiriolin-4yl)propyll-l-[3-(2,4,6-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl] 3- 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoromethyl-6-nethoxyquinolin-4yl)propyl] 6-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 100 4- S) -Hyclroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyithia) ethyl]piperidine- 4-carboxylic acid S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-112-(2,4,6trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] (3,4,5- .trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,4,6-trifluorophenoxy)ethyl]piperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(3,4,5-trifluoropheaoxy)ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,4.,6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)prop-2ynyl Ipiperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- -Hydroxy-3- (3-aminomethyl--6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 101 4-13- S) -Hydroxy-3- (3-aminomethyl-6--methoxyquinolin-4yl) propyl] 6-trifluorophenylthio) ethyl] piperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Hydroxy-3- (3-aiinomethyl-6-methoxyquinolin-4yl)propyljll--[2- (2,4,6trifluorophenylanino) ethyllpiperidine-4-carboxylic acid 4-[3-(R,S)-Hydroxy-3-(3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1-[2- (3,4,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l- 6-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4-13- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l-!13-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl] 3- 5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid (R,S)-Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4 -yl) propyl] 6-trifluorophenyl) propyl] piperidine- 4-carboxylic acid 102 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl]-1-[2-(2,4,6trifluorophenyithia) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (3,4,5trifluorophenylthio) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (2,4,6trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (3,4,5trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 6-trifluorophenoxy) ethyllpiperidine- 4-carboxylic acid 4- S) -Hyclroxy-3- (3-rorpholinomethyl-6-methoxyquinolin- 4-yl)propyl 4-carboxylic acid 4- S) -Hydroxy-3- (3-morpholi nomethyl-6-methoxyquinolin- 4-yl)propyl 13- 6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Hydroxy-3- (3-rorpholinomethyl-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine,-4-carboxylic acid 103 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] -1-heptylpiperidine-4-carboxylic acid 4- [3-CR, S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] -1-[4-phenylbutyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-carboxylic acid 4-[13- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-f luorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-f luorophenyl)propylilpiperidine-4carboxylic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll (4-f luorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyl)butyllpiperidine-4carboxylic acid 4-13- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- 3-difluorophenyl)propyl~piperidine-4carboxylic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenyl)propyllpiperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1- 6-difluorophenyl)propyllpiperidine-4carboxylic acid 104 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 6-difluorophenyl)propyl]piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl 5-difluorophenyl)propyl]piperidine-4carboxylic acid 4-13- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyljpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl [3-phenylthio-propyl ]piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-f luorophenylthio)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (3-f luorophenylthio)propyl] piperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenylthio)ethyllpiperidine-4carboxylic acid 105 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (4-f luorophenylthio)propyllpiperidine-4carboxylic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 3-difluorophenylthio)ethyl]piperidine-4carboxylic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenylthio)propyllpiperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenyithio) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro--6-methoxyquinolin-4yl)propyl 5-trifluorophenyithio) ethylipiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll 6-trifluorophenyithio) ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 106 4- 13- S) -Fluoro-3- C3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (2,3,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyll-l- (2,4,6trifluorophenylanino) ethyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid.
4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] -1-13- 6-difluorophenylthio)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] -1-12- (2-chlorophenylthio)ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-chlorophenylthio)propyl]piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (3-chiorophenyithia) ethyl] piperidine-4carboxylic acid 107 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (3-chloropheriylthio) propyl ]piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chiorophenyithia) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (4-chlorophenylthio) propyl ]piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl (2-methyiphenyithic) ethyl] piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (2-rethylphenylthio)propyl Ipiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] 2- (3-methyiphenyithio) ethyl Ipiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl]-1- (3-methylphenylthio)propyl Iipiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (4-methyiphenyithio) ethyl] piperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl )propyl] (4-methylphenylthio)propyl ]piperidine-4carboxylic acid 108 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2trifluoromethylphenylthio) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll-1-[3-(2trifluoromethylphenylthio) propyl Ipiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3trifluoromethylphenylthio) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (3trifluoromethyiphenyithia) propyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (4trifluorornethylphenylthio) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (4trifluorornethylphenylthio) propyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (2-methoxyphenyithia) ethyl] piperidine-4carboxylic acid 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (2-methoxyphenylthio) propyl] piperidine-4carboxylic acid 109 4- S) -Fluoro-3- (3-chloro-6-methoxyquiriolin-4yl)propyl (3-methoxyphenylthio) ethyllpiperidine-4carboxylic acid 4-13- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (3-methoxyphenylthio)propylllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolii-4yl)propyl] (4-methoxyphenylthio) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl (4-methoxyphenylthio) propyl] piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] -1-[cyclopentylmethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclopentyl) ethylllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (cyclopentyithia) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- chloro-6-methoxyquinolin-4yl)propyl] (cyclopentylthio)propyllpiperidine-4carboxylic acid 110 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll (cyclohexylthio)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-2-yl)butyllpiperidine-4-carboxylic acid 4- (R,S)-Fluoro-3- (3-chloro-6-methoxyquinolia-4yl)propyl (thien-2-yl) thiopropyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl1-1- (thien-3-yl )propyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl)butyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl1]-1- (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (thien-3-yl) thioethyllpiperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl) thiopropyllpiperidine-4carboxylic acid ill 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-113-(1,3-thiazol-2-yl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyayinolin-4yl)propyll-l--14-(1,3-thiazol-2-yl)butyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-thiazol-2-yl) thioethyllpiperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl 13- (pyrid-2-yl)propyllpiperidine-4-carboxylic acid 4-13- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll (pyrid-2-yl)butyllpiperidirie-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thiopropyllpiperidine-4carboxylic acid 4-13- -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (pyrid-3-yl)propyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)butyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] -1-12- (pyrid-3-yl) thioethyllpiperidine-4carboxylic acid 112 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-3-yl) thiopropyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll (pyrid-4-yl)propyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl)butyl~piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl) thiopropyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolii-4yl)propyl (pyrazin-2-yl)propyljpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl)butyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl) thioethyllpiperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl) thiopropyllpiperidine-4carboxylic acid 113 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyl)prop-2-ynyllpiperidiie-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 4-difluorophenyl)prop-2-ynyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] 4-difluorophenyl )prop-2-ynyl ]piperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2y-nyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-inethoxyquinolin-4yl)propyl]-1-[3-(4-chloro-3-fluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (3-chloro-4-fluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1- (2-chloro-4-fluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 114 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-chloro-5-fluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chloro-2-fluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-f luoro-4-methylphenyl)prop-2ynyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl 5-bis(trifluoromethyl)phenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(1,3-thiazol-2-yl)prop-2-ynyljpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(1,3-thiazo1-4-yl)prop-2-ynyllpiperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(1,3-thiazo1-5-yl)prop-2-ynyl]piperidine-4carboxylic acid 115 4- S) -Fluoro-3- C3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)prop-2-ynyl]piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (pyrid-4-yl)prop-2-yriyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- (phenyl)propyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-methyl-G--methoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-difluoropheiylamino) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- (2,3,5trifluorophenylamino) ethyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenoxy) ethyllpiperidine-4carboxylic acid 116 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyll 2- (2,3,5-trifluorophenylthio)ethylllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperidine-4carboxylic acid 4- (R,S)-Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl] (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propylj-1- (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl) propyl1-1- (cyclohexyl) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-carboxylic acid 117 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidiae-4-.
carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidiie-4carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1- (2,3,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-fluoro-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyl] piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl] 2- 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl] 2- (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-fluoro-6-methoxyquinolin-4yl)propyl] (thien-2-yl) thioethyllpiperidine-4carboxylic acid 118 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxycjuinolin-4yl)propyl (thien-2-yl)prop-2--ynyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquiiolin-4yl)propyl (cyclohexyl) ethylllpiperidine-4-carboxylic.
acid 4- S) -Fluoro-3- (3-dimethylaniino-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-dimethylamirio-6-methoxyquiiolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S)-Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-difluorophenylamia) ethyllpiperidine-4carboxylic acid S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl (2,3,5trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyl~piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5-trifluorophenoxy)ethyllpiperidine-4 carboxylic acid 119 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1- 4-carboxylic acid 4- S) -Fluoro-3- (3-dimethylanvino-6-Iethoxyquinolin-4yl)propyll 2- (cyclop~entylthio) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-dimethylainino-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propylll--[3- (thien-2-yl)prop-2-ynyl]piperidiie-4carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyll (cyclohexyl) ethyl]piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)propyl]piperidine-4carboxylic acid 120 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenylamino)ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquiiolin-4yl)propyl]-1-[2-(2,3,5trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-difluoropheioxy) ethyllpiperidine-4carboxylic acid 4- -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-rnethoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-rnethoxyquinolin-4yl)propyl] (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyljl1-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 121 4- (R,S)-Fluoro (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl )propyl l-i- (phenyl) propyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyl IIpiperidine-4carboxylic acid 4- S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyll-1- (2,3,5trifluorophenylamino) ethyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyl IIpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 4-carboxylic acid 122 4- S) -Fluoro-3- (3-f luorornethyl-6-methoxyquinolin-4yl)propyl (cyclopentyithic) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4-.
yl)propyl 5-trifluoropheriyl)prop-2ynyl] piperidine-4-carboxylic acid 4- -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4- -Fluoro-3- (3-arinomethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-carboxylic acid 4- -Fluoro-3- (3-aninomethyl-6-methoxyquinolii-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- -Fluoro-3- (3-aiinomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylanino) ethyllpiperidine-4carboxylic acid 123 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l- (2,3,5trifluorophenylanino) ethyl Ipiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-axrinomethy-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyl iipiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl )propyl] 5-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-arinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyl] piperidine- 4-carboxylic acid, 4- 13- S) -Fluoro-3- (3-arinomethyl-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyl iipiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4y1)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-amrinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyl ]piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-aintinorethyl-6-methoxyquinolin-4y1)propyl (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 124 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyll-1- (phenyl)propyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluoropheiyl)propyl]piperidiie-4carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethylL-6-methoxyquinolin-4yl)propyl] 5-difluorophenylamino) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propylll--[2- (2,3,5trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl] (cyclopentylthio) ethyllpiperidine-4carboxylic acid 125 4-113- S) -Fluoro-3- (3-rorpholinomethyl-6-methoxyquinolin-4yl)propyl -1-112- (pyrid-2-yl) thioethyl]piperidine-4carboxylic acid 4-13- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4carboxylic acid 4-13- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyll-1-113-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4-113- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1-[13- (thien-2-yl)prop-2-ynyllpiperidine-4carboxylic acid 4-[13- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyll 6-trifluoropheriyl)propyllpiperidine-4carboxylic acid 4-[13- -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- 13- -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenylthio)ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl -1-112- 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-inethoxyquinolin-4yl)propyl] (2,4,6trifluorophenylanino) ethyl]piperidine-4-carboxylic acid 126 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- trifluorophenylanino) ethyl] piperidine-4-carboxylic acid S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,4,6-trifluorophenoxy)ethyllpiperidiie-4carboxylic acid.
4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-l-[2-(3,4,5-trifluorophenoxy)ethyl]piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-l- 5-trifluoropherayl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyl]piperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyithia) ethylipiperidine- 4-carboxylic acid 127 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl (2,4,6trifluorophenylamino) ethyl IIpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-l-[2-(3,4,5trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl] 6-trifluorophenoxy) ethyllpiperidine-4carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluoropheioxy) ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-dimethylainn-6-rethoxyquinolin-4yl)propyl] 6-trifluoropheriyl)propylllpiperidine-4carboxylic acid S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl] 5-trifluoropheriyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 128 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-dimethylamirio-6-rnethoxyquinolin-4yl)propyl]-1-[2-(2,4,6trifluorophenylanino) ethyl ]piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-dimethylarnino-6-rethoxyquinolin-4yl)propyl]-l- trifluorophenylamnino) ethyllpiperidine-4-carboxylic acid 4-13- (R,S)-Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 6-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyll-l- 5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyl ]piperidine-4-carboxylic acid S) -Fluoro-3- (3-dimethylamrino-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] [sic] acid 129 4- S) -Fluoro-3- (3-hydxoxymethyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquiriolin-4yl)propyl] 5-trifluorophenyithia) ethylipiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propylll-[2- (2,4,6trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4- .yl)propyl 6-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4-13- S) -Fluoro-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-hydroxymethyj.-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4-13- (R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenyl)propyllpiperidine-4carboxylic acid 130 4- S) -Fluoro-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyl Ipiperidine- 4-carboxylic acid 4- -Fluoro--3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- (2,4,6trifluorophenylanino) ethyllpiperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l- 6-trifluorophenoxy)ethyl]piperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(3,4,5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4-[3-(R,S)-Fluoro-3-(3-fluoromethyl-5-methoxyquinolin-4yl)propyll-l--13-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 131 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,4,6-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S)-Fluoro-3- (3-aiinomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylthio) ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- (2,4,6trifluorophenylamino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6-trifluoropheraoxy)ethyllpiperidine-4carboxylic acid S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 4- S)-Fluoro-3- (3-aninorethyl-6-rethoxyquinolin-4yl)propyl] 6-trifluorophenyl)prop-2ynyl Ipiperidine-4-carboxylic acid 132 4- CR, S)-Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyll-1-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid 4- [3-CR, S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4carboxylic acid 4- CR, S)-Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethylipiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyithic) ethyllpiperidine- 4-carboxylic acid 4- S) -Fluoro-3- (3-rorpholinomethyl-6-methoxyquinolin-4yl)propyl (2,4,6trifluorophenylanino) ethyl] piperidine-4-carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5trifluorophenylanino) ethyl] piperidirie-4-carboxylic acid 4- CR, S)-Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 6-trifluoropherioxy)ethyllpiperidine-4carboxylic acid 4- CR, S)-Fluoro-3- (3-rorpholinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperidine-4carboxylic acid 133 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2yriyl] piperidirie-4-carboxylic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-carboxylic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl] -1heptylpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinalin-4-yl)propyl [4phenylbutyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [3- (phenyl )propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2fluorophenyl )propyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[4-(3fluorophenyl )propyl Ipiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4fluorophenyl) propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4fluorophenyl)butyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2,3difluorophenyl) propyl ]piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2,3difluorophenyl) propyl ]piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,6difluorophenyl) propyl ]piperidine-4-acetic acid 134 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,6difluorophelyl) propyl ]piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquiriolin-4-yl)propyl] difluorophenyl) propyl Ipiperidine-4-acetic acid 4-13-(3-Chloro-6-rethoxyquinolin-4-yl)propyl]-1-[3--(2,3,5trifluorophenyl )propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenyl )propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenyl) propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] phenyithiopropyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2fluorophenylthio) propyll piperidine-4-acetic acid 4-13-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3fluorophenyithia) propyl Ipiperidirie-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4fluorophenyithia) ethyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4fluorophenylthio) propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3difluorophenylthio) -ethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3difluorophenylthio) -propyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,6difluorophenyithia) -ethyl] piperidine-4-acetic acid 135 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl trifluorophenyithia) -ethyllpiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,4,6trifluoropheiylthio) -ethylllpiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5trifluorophenyithic) -ethylllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl difluorophenoxy) ethyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-l-[2-(2,3,5trifluorophenoxy) -ethyllpiperidine-4-acetic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenoxy) -ethyl] piperidine-4-acetic acid 4-13- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (3,4,5trifluorophenoxy) -ethyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,5difluorophenylanino) -ethyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-l-[2-(2,3,5trifluorophenylamino) -ethyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2,4,6trifluorophenylamino) -ethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenylamino) -ethyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,6difluorophenylthio) -propyl ]piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2chlorophenylthio) ethyl] piperidine-4-acetic acid 136 4-f 3- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2chiorophenyithia) propyl] piperidirie-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3chiorophenyithio) ethylllpiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(3chiorophenyithia) propyl] piperidine-4-acetic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl (4chlorophenylthio) ethyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4chiorophenyithia) propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2methylphenylthio) ethyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2methylphenylthio) -propyl ]piperidine-4-acetic acid 4--[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3methylphenylthio) ethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (3methyiphenyithio) -propyl ]piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4methylphenylthio) ethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4methiylphenylthio) -propyl ]piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2trifluoromethylphenylthio) -ethyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2trifluoromethylphenylthio) -propyl Ipiperidine-4-acetic acid 137 4- (3-Chloro-6-methoxyguinolin-4-yl)propyl (3trifluoromethyiphenyithic) -ethyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3trifluoromethylphenylthio) -propyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyll-l-[2-(4trifluoromethylphenylthio) -ethyl] piperidine-4-acetic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (4trifluoromethylphenylthio) -propyl ]piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2methoxyphenylthio) -ethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2methoxyphenylthio) -propyl~piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (3methoxyphenylthio) -ethyllpiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(3rnethoxyphenylthio) -propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4inethoxyphenyithio) -ethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4rethoxyphenylthio) -propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] -1- [cyclopentylmethyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [2- (cyclopentyl) ethyllpiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2- (cyclohexyl) ethyllpiperidine-4-acetic acid 138 4- (3-Chloro-6-methoxyquiriolin-4-yl)propyl)-1- [2- (cyclopentylthio) ethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propylj-1- [3- (cyclopentylthio)propyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3- (cyclohexyithia) propyl]piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) thioethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] 4- (thien-2yl) butyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (thien-2yl) thiopropyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (thien-3yl )propyllIpiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-y1)propyl]-l-[4-(thien-3yl )butyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (thien-3yl) thioethyllpiperidirie-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (thien-3yl) thiopropyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (1,3thiazol-2-yl) propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (1,3thiazol-2-yl) butyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-1-[3-(1,3thiazol-2-yl) thioethyllpiperidirie-4-acetic acid 139 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] 3- (pyrid-2yl) propyl ]piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) butyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) thiopropyl ]piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-3yl )propyl piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-3yl) butyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-3yl) thioethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-3yl) thiopropyllpiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(pyrid-4yl )propyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-4yl )butyl Ipiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquiriolin-4-yl)propyl (pyrid-4yl) thioethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-4yl) thiopropyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrazin- 2-yl )propyl] piperidirie-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrazin- 2-yl )butyl] piperidine-4-acetic acid 140 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrazin- 2-yl) thioethyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrazin- 2-yl) thiopropylllpiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(4fluorophenyl )prop-2-ynyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3,4difluorophenyl) prop-2-ynyl IIpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,4- -difluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl) prop-2-ynyl ]piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,4,6trifluorophenyl) prop-2-ynyllpiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(3,4,5trifluorophenyl )prop-2-ynyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4chloro-3-fluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3chloro-4-fluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2chloro-4-fluorophenyl )prop-2-ynyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (3prop-2-ynyl Ipiperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(4chloro-2-fluorophenyl) prop-2-ynyl] piperidine-4-acetic acid 4-13- (3-Chlorc-6-methoxyquinolin-4-yl)propyl (3fluoro-4-methylphenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl bis (trifluoromethyl )phenyl) prop-2-ynyl ]piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (thien-2yl) prop-2-ynyl] piperidine-4-acetic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (thien-3- 4y) prop-2 -ynyl] piperidine-4-acetic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(1,3thiazol-2-yl )prop-2-ynyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (1,3thiazol-4-yl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (1,3thiazol-5-yl)prop-2-yniyllpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) prop-2-ynyl IIpiperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-y1)propyl (pyrid-3yl) prop-2-ynyl] piperidine-4-acetic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-4yl) prop-2-ynyllpiperidine-4-acetic acid (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyllpiperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [3- (phenyl)propyl] piperidine-4-acetic acid 4- (3-Methyl-6-rnethoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl) -propyllpiperidine-4-acetic acid 142 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] difluorophenyl-anino) ethyllpiperidine-4-acetic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyll-l-[2-(2,3,5trifluorophenyl-amino) ethyllpiperidine-4-acetic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluorophenoxy) ethyl] piperidine-4-acetic acid 4- (3-Methyl-6-methoxyguinolin-4-yl)propyl]-1- (2,3,5trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] (2,3,5trifluorophenyithic) -ethyllpiperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- (cyclopentyithia) ethyl] piperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) thioethyljlpiperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (thien-2yl) thioethyl]piperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl )prop-2-ynyl] piperidine-4-acetic acid (3-Methyl-6-methoxyquinolin-4-yl)propyl (thien-2yl )prop-2 -ynyl] piperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (cyclohexyl) ethyllpiperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- (phenyl) propyl] piperidine-4-acetic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5- 'trifluorophenyl) -propyl] piperidine-4-acetic acid 143 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] difluorophenylamino) -ethyl] piperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (2,3,5trifluorophenylamino) -ethyllpiperidine-4-acetic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluorophenoxy) ethyl] piperidirie-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl trifluorophenoxy) ethyl] -piperidine-4-acetic acid 4- (3-Fluoro-6-rnethoxyquinolin-4-yl)propyl] (2,3,5trifluorophenylthio) -ethyllpiperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [2- (cyclopentylthio) ethyllpiperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) thioethyllpiperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (thien-2yl) thioethyllpiperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl )prop-2-ynyl ]piperidine-4-acetic acid 4- (3-Fluoro-6-rnethoxyquinolin-4-yl)propyl (thien-2yl )prop-2 -ynyl] piperidine-4-acetic acid (3-Dimethylamino-6-rnethoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [3- (phenyl) propyl] piperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinclin-4-yl)propyl] 5-trifluorophenyl) -propyllpiperidine-4-acetic acid 144 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenylanino) -ethyl~piperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenyl-anino) ethyl]piperidine-4-acetic acid 4- (3-Dimethylaxnino-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyll 5-trifluorophenoxy) -ethyl] piperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylthio) -ethyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-rnethoxyquinolin-4-yl)propyl [2- (cycl'opentyithio) -ethylilpiperidine-4-acetic acid 4- (3-Dimethylamino-6-rnethoxyquinolin-4-yl)propyl [2- (pyrid-2-yl) thio-ethyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thio-ethyllpiperidine-4-acetic acid 4- (3-Dimethylarnino-6-rethoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-rnethoxyquinolin-4-yl)propyl [3- (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyllpiperidine-4-acetic acid 4- (3-Hydroxyrnethyl-6-rethoxyquinolin-4-yl)propyl] (phenyl )propyl] piperidine-4-acetic acid 4-[3-(3-Hydroxyrnethyl-6-methoxyquinolin-4-yl)propyl]-1-[3- 5-trifluorophenyl) -propyl] piperidine-4-acetic acid 145 4- (3-Hydroxymethyl-6-methoxytainolin-4-yl)propyl] 5-difluorophenyl-amino) ethyl~piperidine-4-acetic acid 4- (3-Hydroxyinethyl-6-rethoxyquinolin-4-yl)propyl] 5-trifluorophenyl-amino) ethyl]piperidine-4-acetic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) -ethyllpiperidine-4-acetic acid (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylthio) -ethyllpiperidine-4-acetic acid (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl] (cyclopentyithic) -ethyllpiperidine-4-acetic acid 4- (3-Hydroxyrnethyl-6-rethoxyquinolin-4-yl)propyl [2- (pyrid-2-yl) thioethyl] -piperidine-4-acetic acid 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl] (thien-2-yl) thioethyl] -piperidine-4-acetic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [3- (thien-2-yl)prop-2-ynyl] piperidine-4-acetic acid 4- (3-Fluoromethyl-6-methoxyguinolin-4-yl)propyl [2- (cyclohexyl) ethyllpiperidine-4-acetic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- (phenyl) propyl] piperidine-4-acetic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) -propyllpiperidine-4-acetic acid 146 4- (3-Fluororethyl-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenylamino) -ethyllpiperidine-4-acetic acid 4-13- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-1- 12- 5-trifluorophenylanino) -ethyllpiperidine-4-acetic acid 4- (3-Fluororethyl-6-methoxyquinolin-4-yl)propyl]l 2- 5-difluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Fluororethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4-13- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] -1-12- 5-trifluorophenylthio) -ethyllpiperidine-4-acetic acid 4-13- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] -1-12- (cyclopentylthio) -ethyl Ipiperidine-4-acetic acid 4-13- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] -1-12- (pyrid-2-yl) thioethyl] piperidine-4-acetic acid 4-13- (3-Fluorornethyl-6-methoxyquinolin-4-yl)propyl] -1-12- (thien-2-yl) thioethyllpiperidine-4-acetic acid 4-13- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl 13- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4-13- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- (thien-2-yl) prop-2-ynyllpiperidine-4-acetic acid 4-13- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyllpiperidine-4-acetic acid 4-13- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- (phenyl)propyl] piperidine-4-acetic acid 4-13- (3-Aiinomethyl-6-rethoxyquinolin-4-yl)propyl] 5-trifluorophenyl) -propyllpiperidine-4-acetic acid 147 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl] 5-difluorophenylamino) -ethyllpiperidine-4-acetic acid 4- [37(3-Aiinorethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenylanino) -ethylllpiperidine-4-acetic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) -ethyl~piperidine-4-acetic acid (3-Aninomethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifiluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenyithia) -ethyllpiperidine-4-acetic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-y1)propyl [2- (cyclopentylthio) -ethyllpiperidine-4-acetic acid 4- (3-Aninomethyl-6-methoxyquinolin-4-yl)propyl] -1-12- (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- (3-Arinomethyl-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- (3-Amxinomethy-6-methoxyquinolin-4-yl)propy1 [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Aiinomethyl-6-methoxyquinoliri-4-yl)propyl [3- (thien-2 -yl )prop-2 -ynyl] piperidine-4 -acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- (cyclohexyl) -ethyllpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- (phenyl)propyllpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl) -propyllpiperidine-4-acetic acid 148 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-difluorophenyl-amio) ethyl]piperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl )propyl] -1- 3, 5-trifluorophenyl-anino) ethyl] piperidine-4-acetic acid 4-13- (3-Morpholinornethyl-6-methoxyquinolin-4-yl) propyl] -1- 5-difluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Morpholiromethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl-thio) ethyljpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- (cyclopentyl-thio) ethyllpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- (pyrid-2-yl) thicethyl] -piperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl] -1- (thien-2-yl) thioethyl] -piperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl) -prop-2-ynyllpiperidine-4-acetic acid 4- [3-(3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl] -1- (thien-2-yl)prop-2-ynyllpiperidiae-4-acetic acid 4- (3-Methyl-G-methoxyquinolin-4-yl)propyl] 3- (3,4,5trifluorophenyl) -propyl] piperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenyithia) -ethyl] piperidine-4-acetic acid 149 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5trifluorophenyithia) -ethyl] piperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenylamino) -ethyl] piperidine-4-acetic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,4,5trifluorophenylaiino) -ethyllpiperidine-4-acetic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,4,6trifluorophenoxy) ethyl] -piperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenoxy) ethyl] -piperidine-4-acetic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,4,6trifluorophenyl) prop-2-ynyl] piperidine-4-acetic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] trifluorophenyl )prop-2-ynyl ]piperidine-4-acetic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,4,6trifluorophenyl)propyl] -piperidine-4-acetic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[3-(3,4,5trifluorophenyl )propyl] -piperidine-4-acetic acid 4- (3-Fluoro-6-rnethoxyquinolin-4-yl)propyl (2,4,6trifluorophenylthio) ethyl] -piperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (3,4,5trifluorophenylthio) ethyl] -piperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenylanino) -ethyllpiperidine-4-acetic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,4,5trifluorophenylamino) -ethyl] piperidine-4-acetic acid 150 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] 4,6trifluorophenoxy) ethyl] -piperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (3,4,5trifluorophenoxy) ethyl] -piperidine-4-acetic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,4,6trifluorophenyl )prop-2-ynyl] piperidine-4-acetic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl) propyl] trifluorophenyl )prop-2-ynyl] piperidine-4-acetic acid 4- (3-Dimethylarnino-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl) -propyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) -propyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenylthio) -ethyllpiperidine-4-acetic acid 4- (3-Dimethylam-ino-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenyithio) -ethyllpiperidine-4-acetic acid 4- (3-Dimethylanmino-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenyl-amino) ethyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenyl-amino) ethyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-y1)propyl [2- 6-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Dimethylainino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Dimethylamino-6-rnethoxyquinolin-4-yl)propyl] 6-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 151 4-13- (3-Dimethylaxnino-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Hydroxyrnethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenyl) -propyllpiperidine-4-acetic acid 4- (3-Hydroxyrnethyl-6-methoxyquinoliri-4-yl)propyl [2- 6-trifluorophenyithia) -ethyllpiperidine-4-acetic acid 4- (3-Hydrox-yrethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenyithia) -ethylilpiperidine-4-acetic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenylanino) -ethyllpiperidine-4-acetic acid 4- (3-Hydroxyrnethyl-6-rethoxyquinolin-4-yl)propyl [2- 5-trifluorophenylanino) -ethyllpiperidine-4-acetic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4-[3-(3-Hydroxymethyl-6-rnethoxyquinolin-4-yl)propyl]-1-[2- 5-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl)prop-2-yriyllpiperidine-4-acetic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl) -propyllpiperidine-4-acetic acid 4- (3-FluoromethylL-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) -propyllpiperidine-4-acetic acid 4- (3-FluoromethylL-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenylthio) -ethylllpiperidine-4-acetic acid 152 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenyithia) -ethyllpiperidine-4-acetic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenylamino) -ethyl]piperidine-4-acetic acid (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylanino) -ethyllpiperidine-4-acetic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenoxy) ethyl] -piperidine-4-acetic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4-[3-(3-Axninomethyl-6-methoxyquinolin-4-yl)propyl]-1-[3- 6-trifluorophenyl) -propyl] piperidine-4-acetic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-1- [3- 5-trifluorophenyl) -propyllpiperidine-4-acetic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenylthio) -ethyllpiperidine-4-acetic acid 4- (3-Aiinomethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenylthio) -ethyllpiperidine-4-acetic acid 4- (3-Aminorethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenylanino) -ethyllpiperidine-4-acetic acid 4-[3-(3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-1-[2- 5-trifluorophenylanino) -ethyl] piperidine-4-acetic acid 153 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Aminomethyl-6-rnethoxyquinolin-4-yl)propyl] 5-trifluorophenoxy) -ethyllpiperidine-4-acetic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenyl) -propyllpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl )propyl] -1- 5-trifluorophenyl) -propyllpiperidine-4-acetic acid 4-13- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenylthio) -ethyllpiperidine-4-acetic acid 4- (3-Morpholinonlethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenylthio) -ethyllpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenyl-amino)ethyllpiperidine-4-acetic acid 4- (3-morpholinomethyl-6-methoxyquinolin-4-yl )propyl] -1- 5-trifluorophenyl-amino) ethyllpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluoro-phenoxy) ethyllpiperidine-4-acetic acid 154 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluoro-phenoxy)ethyllpiperidine-4-acetic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluoro-phenyl)prop-2-ynyllpiperidine-4-acetic acid 4- (3-Morpholinomrethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluoro-phenyljprop-2-ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquiiolin-4yl)propyl] -1-heptylpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl [4-phenylbutyl] -piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll (phenyl)propyl] -piperidine-4-acetic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-f luorophenyl) -propyllpiperidine-4-acetic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll (3-f luorophenyl) -propyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-xnethoxyquinolin-4yl)propyl (4-f luorophenyl) -propylljpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (4-f luorophenyl) -butyllpiperidine-4-acetic acid 155 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluoro-phenyl)propyllpiperidine-4acetic acid 4- S) -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 3-difluoro-phenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluoro-phenyl)propyl]piperidine-4acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl 6-difluoro-phenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl 5-difluoro-phenyl)propylljpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- C3-chloro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyllpiperidine-4acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl )propyl] -1-[3-phenylthio-propyl] piperidine-4-acetic acid 156 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (2-f luorophenylthio) propyl ]piperidine-4acetic acid 4- S) -Hyciroxy-3- (3-chloro-6-methoxyquinolia-4yl)propyl] (3-f luorophenylthio)propylljpiperidine-4acetic acid 314- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyithia) ethyllpiperidine-4acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl) propyl] (4-f luorophenylthio)propyl ]piperidine-4acetic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 3-difluorophenylthio) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenylthio)propyllpiperidine-4acetic acid 4- -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl 6-difluorophenylthio) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 157 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethylipiperidine- 4-acetic acid S) -Hydroxy-3- (3-chloro-6-rnethoxyqiainolin-4yl)propyl] 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquiiolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- -Hydroxy-3- (3-chloro-6-niethoxyquinolin-4yl)propyl]-1- 6-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-inethoxyquinolin-4yl)propyllj-1-[2-(2,3,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l- trifluorophenylamino) ethyllpiperidine-4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 158 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenylthio)propylpiperidine.4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-chlorophenylthio)ethyllpiperidine-4acetic acid 4- [3-CR, S) -Hydroxy-3- (3-chloro-6-methoxyquinoljn-4yl )propyl] (2-chlorophenylthio) propyl ]piperidine-4acetic acid 4 -[3-(R,S)-Hydroy-3-(3-choro-6-methounolin-4 yl)propyl (3-chlorophenylthio) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-chlorophenylthio)propyllpiperidine-4 acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chlorophenylthio) ethyllpiperidine-4acetic acid 4- CR, S)-Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chlorophenylthio)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-rethylphenylthio) ethyllpiperidine-4acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4.
yl )propyl] (2-nethyiphenyithia) propyl ]piperidine-4acetic acid 159 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl.) propyl] (3-methyiphenyithia) ethyl] piperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl )propyl1-1- (3-methylphenylthio)propyl] piperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl (4-methylphenylthio) ethyl ]piperidine-4acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl )propyl] (4-methylphenylthio) propyl Ipiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l- (2trifluoromethylphenylthio) ethyllpiperidirie-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2trifluoromethylphenylthio) propyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll-l1-[2-(3trifluoromethyiphenyithia) ethyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (3trifluoromethylphenylthio) propyl ]piperidine-4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl] (4trifluoromethylphenylthio) ethyl] piperidine-4-acetic acid 160 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (4trifluoromethylpheiylthio) propyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-methoxyphenyithic) ethyllpiperidine-4acetic acid 4- S) -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (2-methoxyphenylthio) propyl] piperidine-4acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (3-methoxyphenylthio) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (3-methoxyphenylthio) propyl] piperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-mrethoxyquinolii-4yl) propyl] (4-methoxyphenylthio) ethyl] piperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl]-1- (4-methoxyphenyithia) propyl] piperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl [cyclopentylmethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyguinolin-4yl)propyl (cyclopentyl) ethyl]piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 2- (cyclohexyl) ethyllpiperidine-4-acetic acid 161 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4y1)propyl (cyclopentyithia) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclopentylthio)propyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (cyclohexylthio)propyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl]-1- (thien-2-yl)butyl]piperidine-4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (thien-2-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl)propyllpiperidine-4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl)butyl]piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl) thioethyllpiperidine-4-acetic acid 162 4- S) -H-ydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (thien-3-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll-1- 3-thiazol-2-yl)propyl]piperidine-4-acetic acid 4- S) -Hyciroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- 3-thiazol-2-yl)butyllpiperidine-4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1- 3-thiazol-2-yl) thioethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl)propyllpiperidine-4-acetic acid 4-[3-(R,S)-H-ydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl)butyllpiperidine-4-acetic acid 4- S) -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thiopropyllpiperidine-4-acetic acid 4-13- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)propylllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)butyl~piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl) thioethyllpiperidine-4-acetic acid 163 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinclin-4yl)propyl] (pyrid-3-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-inethoxyquinolin-4yl)propyl (pyrid-4-yl)propyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl)butylljpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (pyrid-4-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Hydxoxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl)propyllpiperidine-4-acetic acid 4- S) -H-ydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazir-2-yl)butyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin -2-yl) thioethyljpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl) thiopropyl]piperidine-4-acetic acid 4 -[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyl)prop-2-ynyl]piperidine-4acetic acid 164 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] 4-difluorophenyl )prop-2-ynyl] piperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl.) propyl1-1- 4-difluorophenyl )prop-2-ynyl] piperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chloro-3-fluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-chloro-4-fluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquiriolin-4yl)propyl (2-chloro-4-fluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (3-chloro-5-fluorophenyl)prop-2ynyllpiperidine-4-acetic acid 165 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propylll-1--3-(4-chloro-2-fluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (3-f luoro-4-methylphenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolii-4yl)propyl 5-bis (trifluoromethyl)phenyl)prop-2ynyl] piperidine-4-acetic acid 4- (R,S)-Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thierx-3-yl)prop--2-ynylpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propylj-l- 3-thiazol-2-yl)prop-2-ynyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(1,3-thiazol-4-yl)prop-2-ynyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 3-thiazol-5-yl)prop-2-ynyllpiperidine-4acetic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-y1)prop-2-ynylllpiperidine-4-acetic acid 166 4- S) -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-3-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid- 4 -yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-nethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propylj-l- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl (2,3,5trifluorophenylamino) ethyl IIpiperidine-4-acetic acid 4 -[3-(R,S)-H-ydroxy-3-(3-methyl-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyl] piperidine-4acetic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolia-4yl)propyl 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 167 4- S) -Hyclroxy-3- (3-methyl-6-methoxyqtiinolin-4yl)propyl 5-trifluorophenylthio) ethyllipiperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl (cyclopentyithia) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydxoxy-3- (3-rethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,3,5-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyl]piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl] (cyclohexyl) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4acetic acid 168 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl] 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-f luoro-6-rnethoxyquinolin-4yl)propyll 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoro-"6-methoxyquinolin-4yl)propyl]-l- 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)prop-2ynyl]*piperidine-4-acetic acid 169 4- S) -Hydroxy-3-(3-f luoro-6-methoxyguinolin-4yl)propyll-1- (thien-2-yl)prop-2-ynyl]piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-direthylaiino-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-dimethylainino-6-methoxyquiriolin-4yl)propyl] (phenyl)propyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-l- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-direthylamino-6-methoxyquinolin-4yl) propyl 5-difluorophenylamino) ethyl] piperidine-4acetic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5trifluorophenylanino) ethyl ]piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 170 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propylll--[2- (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-direthylaxino-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- (R,S)-Hydroxy-3- (3-direthylamiro-6-methoxyquinolin-4yl)propy1]-1-[3-(2,3,5-trifuoropheiy),prop-2yriyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-dimethylarnino-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyl~piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propylll--[3- (phenyl)propylllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-hydroxyrethyl-6-methoxyquinolin-4yl)propyl] -1-13- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyll 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4- S) -Hyclroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (2,3,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-hydroxyrethyl-6-methoxyquinolin-4yl)propyll 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluorophenoxy)ethyljpiperidine-4acetic acid 4- -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] (cyclopentylthio) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-hydroxyiethyl-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- S),-Hyciroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1- (thien-2-yl)thioethyllpiperidine-4-acetic acid S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 172 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-1- (cyclohexyl)ethyllpiperidine-4--acetic acid 4- -Hydroxy-3- (3-fluoromethyl-6-rnethoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-acetic acid 4- S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propyl]piperidiae-4acetic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquiriolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-l- (2,3,5trifluorophenylanino) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolii-4yl)propyl 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 2- (cyclopentyithia) ethyllpiperidine-4-acetic acid 173 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidirie-4-acetic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-inethoxyquinolin-4yl)propyl]-1- (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoromethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyl~piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyll (cyclohexyl) ethyllpiperidine-4-acetic acid 4- S) -Hyclroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl] (phenyl)propyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquiiolin-4yl)propyll-1- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4-[3-(R,S)-Hydroxy-3-(3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l- (2,3,5trifluorophenylanino) ethyl] piperidine-4-acetic acid 174 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethylllpiperidine-4acetic acid S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyithia) ethyl]piperidine- 4-acetic acid 4-[3-(R,S)-Hyclroxy-3-(3-aiinomethyl-6-methoxyquinolin-4yl)propyl (cyclopentyithia) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-arinomethyl-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl) thioethyllpiperidine-4-acetic acid S) -Hydroxy-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-rorpholinomethyl-6-methoxyquinolin- 4-yl)propyl] (cyclohexyl) ethyllpiperidine-4-acetic acid 175 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (phenyl)propyl~piperidine-4-acetic acid 4- S) -Hyciroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 5-difluorophenylamino) ethyllpiperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethy1-6-methoxyquinolin- 4-yl)propyl]-1-[2-(2,3,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenoxy) ethyllpiperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-rnethoxyquinolin- 4-yl)propyl (2,3,5trifluorophenyithia) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-morpholinornethyl-6-methoxyquinolin- 4-yi)propyl (cyclopentyithia) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- 3 -morpholinomethyl-6-mrethoxyquinolin- 4-yl)propyl (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 176 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- .4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (thien-2-yl)prop-2-ynylLjpiperidine-4acetic acid 4- (R,S)-Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4yl)propyll 6-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4yl)propylll--[3- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolira-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- -Hydroxy-3- (3-iethyl-6-rnethoxyquiriolin-4yl)propyllj-1-[2- 4-acetic acid 4- -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- trifluorophenylamino) ethyllpiperidine-4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-methyl-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 177 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquiraolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-fluoro-6-rnethoxyquinolin-4yl)propyl 5-trifluoropheriyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenylthio)ethyllpiperidine- 4-acetic acid S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyithio) ethyllpiperidine- 4-acetic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl (2,4,6trifluorophenylaino) ethyl] piperidine-4-acetic acid 178 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylamino) ethyllpiperidirae-4-acetic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenoxy)ethyl]piperidine-4acetic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yIl)propyl]-l- 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4 -[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4 yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-dixethylamino-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine-4 acetic acid 4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl] 6-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyithia) ethyllpiperidine- 4-acetic acid 179 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propylll-[2- (2,4,6trifluorophenylanino) ethyl] piperidine-4-acetic acid 4- -Hydroxy-3- (3-dimethylanlino-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5trifluorophenylanino) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl~propyl]-1- 6-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- (R,S)-Hydroxy-3- (3-dimethylarnino-6-methoxyquinolin-4yl)propyll-1- 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-dimethylarnino-6-methoxyquinolin-4yl)propyl] 6-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hyclroxy-3- (3-hycroxymethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4y1)propyll 6-trifluorophenylthio) ethyl]piperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 180 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyljll--[2- (2,4,6trifluorophenylamino) ethyllpiperidine-4-acetic acid 4- -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5trifluorophenylanino) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-rnethoxyquinolin-4yIl)propyl]-1- 12- 6-trifluoropherioxy)ethyllpiperidine-4acetic acid 4- (R,S)-Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenoxy)ethyljpiperidine-4acetic acid 4- S) -Hyclroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-fluoromethyll-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -1ydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl] 3- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 181 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl 4-acetic acid' 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6trifluorophenylamino) ethyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l- (3,4,5trifluorophenylam-ino) ethylllpiperidine-4-acetic acid 4- (R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propylll--[2- 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]l-[-3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- (R,S).-Hydroxy-3- (3-fluoromethyl-6-rnethoxyquinolin-4yl)propylj-1-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4acetic acid 182 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenylthio)ethyllpiperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-alinomethyl-6-methoxyquinolin-4yl)propyl]-1- 4-acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l- (2,4,6trifluorophenylamino) ethyl] piperidine-4-acetic acid 4- (R,S)-Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylamino) ethyllpiperidine-4-acetic acid 4- S) -Hydx-oxy-3- (3-aminomethyl-6-methoxyquinolin-4yl) propyl] 4, 6-trifluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Hydroxy-3- (3-aminorethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylb)prop-2ynylllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 6-trifluorophenyl)propyllpiperidine- 4-acetic acid 183 4- S) -Hydroxy-3- 3 -morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyll-1-[2-(2,4,6trifluorophenylthio) ethyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-rorpholinomethyl-6-methoxyquinol in- 4-yl)propyl-l- (3,4,5trifluorophenylthio) ethyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- (3-Iorpholinomethy1-6-methoxyquinolin- 4-yl)propyl]-1- (2,4,6trifluorophenylanino) ethyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (3,4,5trifluorophenylanino) ethyl] piperidine-4-acetic acid 4- S) -Hydroxy-3- 3 -morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 6-trifluorophenoxy) ethylipiperidine- 4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethy1-6-methoxyquinolin- 4-yl)propyl]-1- 4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 6-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 184 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] -1-heptylpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] -1-[4-phenylbutyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 4- (2-f luorophenyl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-fluorophenyl)propylllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyl)butyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolia-4yl)propyl] 3-difluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenyl)propyllpiperidine-4acetic acid 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 6-difluorophenyl)propyllpiperidine-4acetic acid 185 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenyl)propyllpiperidine-4 acetic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenyl)propyllpiperidine-4 acetic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoyuinolin-4 yl)propyl G-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4 acetic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] -1-[3-phenyithia-propyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (2-f luorophenylthio) propyl ]piperidine-4acetic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-f luorophenylthio)propyllpiperidine-4acetic acid 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyithio) ethylLpiperidine-4acetic acid 186 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl (4-f luorophenylthio)propyl Ipiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenylthio) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl 3-difluorophenylthio)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenylthio) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethylipiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl 5-trifJluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy) ethyllpiperidine-4acetic acid 187 4- S) -Fluoro-3- (3-chloro--6-methoxyquinolin-4yl)propyl 6-trifluorophenoxy) ethyl]piperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[2-(3,4,5-trifluorophenoxy)ethyllpiperidine-4 acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1- (2,3,5trifluorophenylanino) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (2,4,6trifluoropheiylanino) ethyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl] (3,4,5trifluorophenylamino) ethylllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenylthio)propyljpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (2-chlorophenylthio) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-ntethoxyquinolin-4yl) propyl] (2-chiorophenyithia) propyl] piperidine-4acetic acid 188 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-chlorophenylthio)ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (3-chlorophenylthio)propyl ]piperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propylj-1- (4-chlorophenylthio)ethyllpiperidine-4acetic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyll (4-chlorophenylthio)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-methylphenylthio) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (2-methylpheraylthio) propyl Ipiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquiriolin-4yl )propyl] (3-methyiphenyithia) ethyl] piperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (3-methylphenylthio) propyl] piperidine-4acetic acid 4 -13-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl (4-rethylphenylthio) ethyllpiperidine-4acetic acid 189 4-13- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll (4-methylphenylthio)propyljpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[2-(2trifluoromethylphenylthio) ethyl]piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2trifluoromethylphenylthio) propyl] piperidine-4-acetic acid 4 -[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl (3trifluoroniethylphenylthio) ethyl]piperidine-4-acetic acid 4- S) -Fluorc,-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (3trifluoromethylphenylthio) propyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (4trifluorornethylphenylthio) ethyl IIpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]l--[3-(4trifluoromethyiphenyithia) propyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-methoxyphenylthio) ethyllpiperidine-4acetic acid 4-113- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (2-methoxyphenylthio) propyl ]piperidine-4acetic acid 190 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-methoxyphexylthio) ethyl]piperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (3-methoxyphenylthio) propyl] piperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (4-methoxyphenylthio) ethyljpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl3-1- (4-methoxyphenylthio) propyl] piperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] -1-[cyclopentylmethyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclopentyl) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-acetic acid S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclopentyithia) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (cyclopentylthio) propyl ]piperidine-4-acetic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl (cyclohexylthio)propyllpiperidine-4-acetic acid 191 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-2-yl)butyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (thien-2-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (thien-3-yl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl)butyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl) thioethyllipiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolii-4yl)propyl (thien-3-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 3 -thiazol-2-yl)propyllpiperidine-4-acetic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-nethoxyquiiolin-4yl)propyl] 3-thiazol-2-yl)butyllpiperidine-4-acetic acid 192 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (1,3-thiazol-2-yl)thioethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid- 2 -yl)propyl]piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl]-l- (pyrid-2-yl)butyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquiriolin-4yl)propyl (pyrid-2-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propylll--[4- (pyrid-3-yl)butylllpiperidine-4-acetic acid 4 -[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquiriolin-4yl)propyl (pyrid-4-yl)butyllpiperidine-4-acetic acid 4 -[3-(R,S)-Fluoro-3-(3-chloro-6-nethoxyquinolin-4yl)propyl (pyrid-4-yl) thioethyllpiperidine-4-acetic acid 193 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl)butyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl) thiopropyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (4-f luorophenyl )prop-2-ynyl] piperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] 4-difluorophenyl) prop-2-ynyl] piperidine- 4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-m-ethoxyquinolin-4yl )propyl] 4-difluorophenyl )prop-2-ynyl ]piperidine- 4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 194 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)prcpyl 6-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll-1-[3-(3,4,5-trifluorophenyl)prop-2ynyll piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propylj-1- (4-chloro-3-tluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-chloro-4-fluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propylj-1- (2-chloro-4-fluorophenyl)prop-2ynyJljpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (3-chloro-5-fluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (4-chloro-2-fluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-f luoro-4-methylphenyl)prop-2ynyllpiperidine-4-acetic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-nethoxyquinolin-4yl)propyl 5-bis (trifluoromethyl)phenyl)prop-2ynyllpiperidine-4-acetic acid 195 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl)prop-2-ynyl]piperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(1,3-thiazo1-2-yl)prop-2-ynyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolii-4yl)propyl]-l-[3-(1,3-thiazo1-4-yl)prop-2-ynyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(1,3-thiazol-5-yl)prop-2-ynyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolii-4yl)propyll (pyrid-2-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl)prop-2-ynyllpiperidine-4-acetic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyqyinolin-4yl)propyl] (cyclohexyl) ethyllpiperidine-4-acetic acid 196 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl (phenyl)propyl]piperidine-4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl) propyl] (2,3 ,5-trifluorophenyl )propyl ]piperidine-4acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl (3 ,'5-difluorophenylamino) ethylllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5trifluorophenylamino) ethylllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenoxy)ethyl]piperidine-4acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl (cyclopentyithia) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethylllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4-acetic acid 197 4-[13- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl] 3- 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolii-4yl)propyl] -1-13- (thien- 2 -yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyguinolin-4yl)propyl]-l- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl )propyl] 5-difluorophenylamino) ethyl] piperidine-4acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-l- (2,3,5trifluoropheiylamino) ethyl] piperidine-4--acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl] -1-12- 5-trifluorophenoxy) ethyllpiperidine-4acetic acid 198 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl) propyl] 3, 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl (cyclopentyithia) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyll (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4-[3-(R,S)-Fluoro-3-(3-fluoro-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethylllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluoropheiyl)prop-2ynyllpiperidine-4-acetic acid S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl] (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethylllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-rnethoxyquinolin-4yl)propyl 5-trifluorophenyl)propyl]piperidine-4acetic acid 199 4- S) -Fluoro-3- (3-direthylamino-6-methoxyquinolin-4yl)propyl] 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5trifluorophenylanino) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yi)propyi 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- (R,S)-Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluorophenoxy)ethy.]piperidine-4acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl (cyclopentyithia) ethyllpiperidine-4-acetic acid S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4-acetic acid S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1- (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- -Fluoro-3- (3-dimethylamino-6-rnethoxyquinolin-4yl)propyl]-1- (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 200 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyljpiperidirae-4-acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (phenyl)propylllpiperidine-4-acetic acid 4- -Fluoro-3- (3-hydroxymethyl-6-methoxyquiiolin-4yl)propyl 5-trifluorophenyl)propylllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] (2,3,5trifluorophenylamino) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] 5-difluoropherioxy)ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- (R,S)-Fluoro-3- (3-hydroxyxnethyl-6-methoxyquinolin-4yl)propylll 5-trifluorophenylthio) ethyl IIpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (cyclopentyithio) ethyllpiperidine-4-acetic acid 201 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidirie-4-acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-l- (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- (R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyl]piperidine-4acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- trifluorophenylanino) ethyl] piperidine-4-acetic acid 202 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- 4-acetic acid 4- 13- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyljpiperidine-4-acetic acid 4- (R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4y1)propyl] (cyclohexyl) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-acetic acid 203 4-13- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyll-l--13-(2,3,5-triflucrophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-axinomethyl-6-iethoxyquinolin-4yl)propyll 5-difluorophenylanino) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-aiinomethyl-6-methoxyquinolin-4yl)propyl] (2,3,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 4-113- -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl]-1- (3,5-difluorophenoxy)ethyl]piperidine-4acetic acid 4-113-(R, S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenoxy)ethylllpiperidine-4acetic acid 4-113-(R, S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4-113-(R, S) -Fluoro-3- (3-aiinomethyl-6-methoxyquinolin-4yl)propyl] -1-12- (cyclopentyithio) ethylllpiperidine-4-acetic acid 4-13- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl -1-112- (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- (R,S)-Fluoro-3- (3-axinomethyl-6-rethoxyquinolin-4yl)propyl (thien-2-y1) thioethyllpiperidine-4-acetic acid 204 4-13- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl] 3- 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-aminornethyl-6-inethoxyquinolin-4yl)prapyl] (thien-2-yl)prop-2-ynyl]piperidine-4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolix-4yl)propyl (cyclohexyl) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-morpholinoinethyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperidine-4acetic acid 4- -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-l- (2,3,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 4- S)-Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 205 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylthio) ethyl]piperidine- 4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4acetic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 206 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6trifluorophenylamino) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-l- trifluorophenylamino) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethylljpiperidine-4acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenyl)prop-2ynyllpiperidirae-4-acetic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-fluoro-6-rnethoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4acetic acid 207 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllipiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1- 4-acetic acid 4-13- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyll-1- (2,4,6trifluorophenylanino) ethyllpiperidine-4-acetic acid 4 -[3-(R,S)-Fluoro-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylamino) ethyllpiperidine-4-acetic acid S) -Fluoro-3- (3-fluoro-6-methoxycjuinolin-4yl)propyl]-l-[ 2 -(2,4,6-trifluorophenoxy)ethyllpiperidine-4 acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2ynyljpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-fluoro-6-niethoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynylljpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-direthylamino-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyl]piperidine4 acetic acid 208 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 6-trifluorophenyithio) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenyithia) ethyllpiperidine- 4-acetic acid 4- -Fluoro-3- (3-dimethylainino-6-methoxyquinolin-4yl)propyl (2,4,6trifluorophenylamino) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl]-l- trifluorophenylaiino) ethyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-diiethylamino-6-methoxyquinolin-4yl)propyl] 6-trifluorophenoxy) ethyl]piperidine-4acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-dimethylainino-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 209 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl--6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-hydroxyrethyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethylipiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (2,4,6trifluorophenylanino) ethyl ]piperidine-4-acetic acid.
4- S) -Fluoro-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl] (3,4,5trifluorophenylamino) ethyl ]piperidine-4-acetic acid 4- S) -Fluoro-3 -(3-hydroxymethyl-6-methoxyquinolin-4yl)propylll--[2- 6-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propylll--[2- 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyllpiperidine-4-acetic acid 210 4- -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l- 6-trifluoropheriyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- (R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenylthio)ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- (2,4,6trifluorophenylatino) ethyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 6-trifluoropheioxy) ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 211 4- S) -Fluoro-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluoropheayl)prop-2y-nyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyll-l-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-arinomethyl-6-methoxyquinolin-4y1)propyl]-1- 6-trifluorophenyl)propyllpiperidine-4acetic acid 4- (R,S)-Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-ainrorethyl-6-iethoxyquinolin-4-.
yl)propyl]-1- 4-acetic acid 4- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6trifluorophenylanino) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylanino) ethyllpiperidine-4-acetic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenoxy) ethyllpiperidine-4acetic acid 212 4- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-aminomethyl-6-nethoxyquiriolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-am-inornethyl-6-rnethoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S)-Fluoro-3- (3-morpholinomethyl-6-methoxyquiiolin-4yl)propyl]-l-[3-(2,4,6-trifluorophenyl)propyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyljpiperidine-4acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolii-4yl)propyl] -1-12- 6-trifluorophenyithia) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperidine- 4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl (2,4,6trifluorophenylanino) ethyllpiperidine-4-acetic acid 4-113- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1- (3,4,5trifluorophenylamino) ethyl] piperidine-4-acetic acid 213 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1-[12- 6-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenoxy)ethyllpiperidine-4acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2ynyl] piperidine-4-acetic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl] -1heptylpiperid-4 -ylmethano.
4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[4phenylbutyl] piperid-4 -ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2fluorophenyl) propyl ]piperid-4-ylrnethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (3fluorophenyl) propyl ]piperid-4-ylmethanol 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (4fluorophenyl )propyl ]piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4fluorophenyl) butyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,3 di fluorophenyl) propyl ]piperid- 4-ylniethanol 214 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2,3difluorophenyl) propyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,6difluorophenyl) propyllpiperid-4-ylnethanol 4-[3-(3-Chloro-6-methoxyquiriolin-4-yl)propyl]-1-[4-(2,6difluorophenyl) propyl ]piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl difluorophenyl) propyllpiperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl) -propyl] piperid-4-ylmethanol (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,4,6tri fluorophenyl) -propyl] piperid-4-ylmethanol 4- (3-Chloro-6--methoxyquinolin-4-yl)propyl (3,4,5tri fluorophenyl) -propyl] piperid-4 -ylmethanol 4- (3-Chloro-6-methoxyqunolin-4-yl)propyl [3phenylthiopropyl] piperid- 4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2- .fluorophenylthio) propyl] piperid-4-yJlmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3fluorophenylthio) propyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4fluorophenylthio) ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4fluorophenyithia) propyl] piperid-4-ylnethano.
4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3difluorophenyl-thio) ethyl] piperid-4-ylmethanol 215 4-13- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3difluorophenyl-thio) propyl ]piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,6difluorophenyl-thio) ethyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-l-[2-(2,3,5trifluorophenyl-thio) ethyl] piperid-4-ylrnethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenyl-thio) ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (3,4,5trifluorophenyl-thio) ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2,3,5trifluorophenoxy) -ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2,4,6trifluorophenoxy) -ethyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-l-[2-(3,4,5trifluorophenoxy) -ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] difluorophenylamino) -ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3,5- 'trifluorophenylanino) -ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2,4,6trifluorophenylamino) -ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (3,4,5trifluorophenylamino) -ethyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-y1)propyl]-l-[3-(2,6difluorophenylthio) -propyl] piperid-4-ylmethanol 216 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2chiorophenyithia) ethyl] piperid-4-ylrnethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2chiorophenyithi propyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3chlorophenylthio) ethyl] piperid-4-ylrnethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3chlorophenylthio) propyl] piperid-4-ylmethanol 4- (3-Chloro-6-Inethoxyquinolin-4-yl)propyl (4chlorophenylthio) ethyl] piperid-4-ylinethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4chlorophenylthio) propyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2methylphenylthio) ethyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-rnethoxyquinolin-4-y1)propylj-l-[3-(2- 'nethyiphenyithia) propyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3rnethylphenylthio) ethyl] piperid-4-ylmethaiol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3methylphenylthio) propyl Ipiperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4mrethylphenylthio) ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4methyiphenyithia) propyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-1-[2-(2trifluoromethylphenylthio) -ethyl] piperid-4-ylmethanol 217 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2trifluoromethyiphenyithio) -propyl ]piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3trifluoromethylphenylthio) -ethyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-yl~propyl]-l-[3-(3tri fluoromethylphenylthio) -propyl] piperid-4-ylinethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4trifluoromethylphenylthio) -ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4trifluoromethylphenylthio) -propyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2rnethoxyphenylthio) ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2rnethoxypheriylthio) -propyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]ll[2-(3 .methoxyphenylthio) ethyl] piperid-4-ylrnethanol 4- (3-Chloro-6-nmethoxyquinolin-4-yl)propyl (3methoxyphenylthio) -propyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4niethoxyphenylthio) ethyl] piperid-4-ylinethanol 4- (3-Chloro-6-methoxyqtiinolin-4-yl)propyl (4methioxyphenylthio) -propyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] -1- [cyclopentylmethyl] piperid-4-ylmethanol 4 3 -(3-Chloro-6-inethoxyquinolin-4-yl)propyl]-1-[2- (cyclopentyl) ethyl] piperid-4-ylmethanol 218 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [2- (cyclopentyithia) ethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl]-1- [3- (cyclopentylthio) propyl] piperid-4 -ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3- (cyclohexyithic) propyl ]piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (thien-2yl) butyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (thien-2yl) thiopropyllpiperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (thien-3yl )propyl ]piperid-4-ylniethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (thien-3yl) butyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-y1)propy1]-1-[2-(thien-3yl) thioethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (thien-3yl) thiopropyl ]piperid-4-ylmethaiol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (1,3thiazol-2 -yl )propyl] piperid-4 -ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (1,3thiazol-2-yl )butyl] piperid-4-ylmethanol 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl] (1,3thiazol-2 -yl) thioethyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(pyrid-2yl) propyl] piperid-4-ylmethanol 219 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) butyl ]piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) thiopropyl ]piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl]-1- (pyrid-3yl) propyll]piperid-4-ylniethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-3yl) butyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-3- -yl) thioethyllpiperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-3yl) thiopropyl ]piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-4yl )propyl Ipiperid-4-ylmethaiol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-4yl) butyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-4yl) thioethyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquiriolin-4-yl)propyl (pyrid-4yl) thiopropyllpiperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrazin- 2-yl) propyl ]piperid-4-ylrnethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrazin- 2-yl )butyl] piperid-4-ylmethanol 4-i3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2- (pyrazin-2-yl) thioethyl] piperid-4-ylmethanol 220 (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrazin- 2 -yl) thiopropyl] piperid-4-ylmethanol (3-Chloro-6-methoxyquinolin-4-yl)propyl (4fluorophenyl) prop-2-ynyl] piperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyguinolin-4-yl)propyl]-l-[3-(3,4difluorophenyl )prop-2 -ynyl] piperid-4-ylmethanol 4- (3-Chloro-6-Inethoxyquinolin-4-yl)propyl (2,4di fluorophenyl) prop-2 -ynyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl )prop-2-ynyl Ipiperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,4,6trifluorophenyl )prop-2-ynyl] piperid-4-ylrnethanol- 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenyl) prop-2 -ynyl Ipiperid-4-ylmethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]--[3-(4chloro-3-fluorophenyl )prop-2-ynyl] piperid-4-ylrnethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (3chloro-4-fluorophenyl )prop-2-ynyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2chloro-4-fluorophenyl )prop-2-ynyl] piperid-4-ylnethaiol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3- )prop-2-ynyl] piperid-4-ylniethanol 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (4chloro-2-fluorophenyl )prop-2-ynyl] piperid-4-ylrnethanol 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(3fluoro-4-methylphenyl )prop-2 -ynyl IIpiperid-4-ylmethanol 221 4-13- (3-Chloro-6-methoxyquinolin-4-yl)propyl bis (trifluoromethyl )phenyl) prop-2-ynyl] piperid-4-ylrnethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (thieri-2yl) prop- 2-ynyl] piperid- 4-yjlmethariol 4 -[3-(3-Chloro-6-methoxyquinolin-4-y1)propyl]-l-[3-(thien3.
yl) prop-2-ynyl] piperid-4-ylmethaiol 4-13- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (1,3thiazol-2-yl )prop-2-ynyljpiperid-4-ylmethanol 4-113-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl] -1-13- (1,3thiazol-4-yl)prop-2-ynyllpiperid-4-ylmethanol 4-13- (3-Chloro-6-methoxyquinolin-4-yl)propyl -1-113- (1,3- )prop-2-ynyl Ipiperid-4-ylmethanol 4-13- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-2yl )prop-2-ynyl] piperid-4-ylmethanol 4 3 -(3-Chloro-6-methoxyquinolin-4-y1)propylJ-l-[3-(pyrid-3.
yl )prop-2-ynyl] piperid-4-ylmethanol 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (pyrid-4yl )prop-2 -ynyl] piperid-4-ylmethanol 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyl] piperid-4-ylmethanol 4-13- (3-Methyl-6-methoxyquinolin-4-yl)propyl [3- (phenyl) propyl] piperid-4-ylmethanol 4- (3-Methyl-6-niethoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl) propyllpiperid-4-ylmrethanol 4-[3-(3-Methyl-6-methoxyquinolin-4-y1)propyl]-l-[2-(3,5difluorophenylamino) ethyl] piperid-4-ylmethanol 222 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenylamiao) ethyl] piperid-4-ylrnethanol 4-13- (3-Methyl-6-methoxyquinolin-4-yl)propyl] di fluorophenoxy) ethyl] piperid-4 -ylmethanol 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,3,5trifluorophenoxy) -ethyl] piperid-4-ylmethaiol 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] (cyclopentylthio) ethyl] piperid-4-ylmethanol 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (pyrid-2yl) thioethyllpiperid-4-ylmethanol 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] (thien-2yl) thioethyl ]piperid-4-ylmethanol 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] (2,3,5- *trifluorophenyl) prop-2-ynyl ]piperid-4-ylmethanol 4-[3-(3-Methyl-6-methoyqinolin-4-yl)propyl]-l-[3-(thien2 yl )prop-2 -ynyl Ipiperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] 2- (cyclohexyl) ethyl] piperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- (phenyl) propyllpiperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl) -propyl ]piperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl difluorophenyl-amiio) ethyl] piperid-4-ylmethanol 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,3,5trifluorophenyl-amino) ethyl] piperid-4-ylmethanol 223 (3-Fluoro-6-methoxyquinolin-4-yl)propyl difluorophenoxy) ethyl] piperid-4-ylmethanol (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (2,3,5trifluorophenoxy) -ethyl] piperid-4-ylmethanol 4-i3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,3,5trifluorophenylthio) -ethyl] piperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [2- (cyclopentyithic) ethyl] piperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (pyrid-2yl) thioethyllpiperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (thien-2yl) thioethyl] piperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl )prop-2-ynyl] piperid-4-ylmethanol 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2yl )prop-2-ynyl] piperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] (cyclohex-yl) ethyl] piperid-4-ylmethanol 4- (3-Dimethylamino-6-rnethoxyquinolin-4-yl)propyl [3- (phenyl) propyl] piperid-4-ylmethanol 4- (3-Dimethylaniino-6-rethoxyquinolin-4-yl)propyl] 5-trifluorophenyl) propyl] piperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-difluoro-phenylamino) ethyl] piperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluoro-phenylanino) ethyllpiperid-4-ylmethanol 224 (3-Dimethylaxnino-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) -ethyl] piperid-4-ylmethaxol 4-113- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) -ethyllpiperid-4-ylmethanol 4-113- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 3, 5-trifluorophenylthio) -ethyl] piperid-4-ylrnethanol 4-113- (3-Dimethylaimino-6-methoxyquinolin-4-yl)propyl] (cyclopentyithic) -ethyl] piperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- .(pyrid-2-yl) thioethyl] -piperid-4-ylmethanol 4- (3-Dimethylarnino-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyl] -piperid-4-ylmethaiol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl )prop-2-ynyl ]piperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [3- (thien-2 -yl) prop-2 -ynyl] piperid-4 -yJlmethanol 4- (3-Hydroxymethyl-6-rnethoxyquinolin-4-yl)propyl] [2- (cyclohexyl) ethyl] piperid-4-ylmethanol 4- (3-Hydroxymethyl-6-inethoxyquinolin-4-yl)propyl] (phenyl )propyl] piperid-4-ylmethanol 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenyl) -propyl ]piperid-4-ylmethanol 4- (3-Hydroxyinethyl-6-methoxyquinclin-4-yl)propyl] 5-difluorophenylamino) -ethyl] piperid-4-ylmethanol 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylamino) -ethyllpiperid-4-ylmethanol 225 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) -ethyl]piperid-4-ylmethanol 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluoropheioxy) -ethyllpiperid-4-ylinethanol 4- (3-Hydroxymethyl-6-rnethoxyquinolin-4-yl)propyl] 5-trifluorophenyithia) -ethyllpiperid-4-ylrnethanol 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclopentylthio) -ethyl] piperid-4-ylrnethanol 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl [2- (pyrid-2-yl) thio-ethyl] piperid-4-ylmethanol 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] (thien-2-yl) thia-ethyl] piperid-4-ylmethanol 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) prop-2-ynyl] piperid-4-ylmethaiol 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [3- (thien-2-yl )prop-2-ynylJ -piperid-4-ylmethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyl] piperid-4-ylinethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- (phenyl )propyl] piperid-4-ylmethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl )propyl] piperid-4-ylmethanol 4- (3-Fluoromethyl-6-m-ethoxyquinolin-4-yl)propyl [2- 5-difluorophenyl-amino) ethyl] piperid-4-ylmethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenyl-amino) ethyl]piperid-4-ylmethanol 226 4- 3 -Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) -ethyl] piperid-4-ylinethanol 4- 3 -Fluoromethyl-6-methoxyquinolin-4-yl)propyl] [2- 3, 5-trifluorophenoxy) -ethyl] piperid-4-ylinethanol 4- (3-Fluoromethy1-6-methoxyquinolin-4-yl)propyl] 3, 5-trifluorophenylthio) -ethyl] piperid-4-ylrnethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- (cyclopentylthio) ethyl] -piperid-4-ylimethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] (pyrid-2-yl) thioethyl] piperid-4-ylmethanol 4- 3 -Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyl] piperid-4-ylmethanol 4- 3 -Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) prop-2-ynyl ]piperid-4-ylmethanol 4- 3 -Fluoromethyl-6-methoxyquinolin-4-yl)propyl] [3- (thien-2-yl )prop-2-ynyl] piperid-4-ylinethanol 4- 3 -Alinorethyl-6-methoxyquinolin-4-yl)propyl] -l-12- (cyclohexyl) ethyl] piperid-4-ylinethanol 4- 3 -Am-inomethyl-6-methoxyquinolin-4-yl)propyll l[3- (phenyl) propyl] piperid- 4-ylmethanol 4- 3 -Anminomethyl-6-methoxyquinolin-4-yl)propy1l.. 5-trifluorophenyl) -propyl ]piperid-4-ylmethanol 4- 3 -Aminomethyl-6-methoxyquinolin-4yl)propyl].1-[2- 5-difluorophenylanino) -ethyl] piperid-4-ylmethanol 4 3 3 -Aminomethyl-6-methoxyuinoin-4-yl)propyl>..[2- 5-trifluorophenylamino) -ethyl ]piperid-4-ylmethanol 227 4-13- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- 5-difluorophenoxy) -ethyl] piperid-4-ylmethanol 4- (3-Aminomethyl-6-methoxyquiriolin-4-yl)propyl] [2- 3, 5-trifluorophenoxy) -ethyl] piperid-4-ylmethanol 4- (3-Axinomethyl-6-methoxyquinolin-4-yl)propyl [2- 3, 5-trifluorophenyithic) -ethyl] piperid-4-ylmethanol 4-13- (3-Aminomethyl-6-rnethoxyquiriolin-4-yl)propyl [2- (cyclopentylthio) -ethyl] piperid-4-ylmethanol 4- (3-Axinomethyl-6-methoxyquinolin-4-yl)propyl [2- (pyrid-2-yl) thioethyl] piperid-4-ylmethanol 4- (3-Axinorethyl-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyl ]piperid-4-ylmethanol 4- (3-Aminorethyl-6-methoxyquinolin-4-yl)propyl [3- 3, 5-trifluorophenyl) prop-2-ynyl] piperid-4-ylmethanol 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- (thien-2-yl )prop-2-ynyl] piperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propylj -1- (cyclohexyl) -ethyl] piperid-4-ylmethaiol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl )propyl] -1- (phenyl) propyl Ipiperid-4-ylmethanol 4- (3-Morpholinoinethyl-6-methoxyquinolin-4-yl )propyl] -1- 5-trifluorophenyl) -propyllpiperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-difluorophenylanino) ethyl] piperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 3, 5-trifluorophenyl-anino) ethyl] piperid-4-ylmethanol 228 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-difluorophenoxy) -ethyllpiperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -l- 5-trifluorophenoxy) -ethyllpiperid-4-ylrnethanol 4- (3-Morpholinomrethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl-thio) ethyljpiperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- (cyclopentyithia) -ethyl] piperid-4-ylmethanol 4-13- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- (pyrid-2-yl) thioethyl] -piperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl] -1- (thien-2-yl) thioethyl] -piperid-4-ylmethanol 4- (3-Morpholinornethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluoro-phenyl)prop-2-yrnyllpiperid-4-ylmethanol 4-13- (3-Morpholinoinethyl-6-methoxyquinolin-4-yl)propyl] -1- (thien-2-yl) prop-2-ynyl] piperid-4-ylrnethanol 4-[3-(3-Methyl-6-rnethoxyquinolin-4-yl)propyllj-l-[3-(2,4,6trifluoro-phenyl )propyl] piperid-4-ylmethanol 4-13- (3-Methyl-6-methoxyquinolin-4-yl)propyl (3,4,5trifluoro-phenyl )propyl] piperid-4-ylmethanol 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenyl-thio) ethyl] piperid-4-ylmethanol 4-13- (3-Methyl-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenyithia) -ethyl] piperid-4-ylmethanol 4-[3-(3-Methyl-6-methoxycjuinolin-4-yl)propyl]-l-[2-(2,4,6trifluorophenylamino) -ethyl] piperid-4-ylmethanol 229 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenylamino) -ethyl] piperid-4-ylmethanol 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenoxy) -ethyl] piperid-4-ylmethanol 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,4,5trifluorophenoxy) -ethyl] piperid-4-ylrnethanol 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,4,6trifluorophenyl) prop-2-ynyl] piperid-4-ylmethanol 4- (3-methyl-6-methoxyquinolin-4-yl)propyl] (3,4,5trifluorophenyl )prop-2-yriyllpiperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] 6trifluorophenyl) -propyl] piperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl tri fluorophenyl) -propyl ]piperid-4 -ylmethanol 4-[3-(3-Fluoro-6-rnethoxyquinolin-4-yl)propyl]-l-[2-(2,4,6- .trifluorophenylthio) -ethyl] piperid-4-ylrnethanol 4- (3-Fluoro-6-rnethoxyquinolin-4-yl)propyl] (3,4,5trifluorophenyithia) -ethyl] piperid-4-ylrnethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,4,6trifluorophenyl-amino) ethyl] piperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (3,4,5trifluorophenyl-anino) ethyl] piperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (2,4,6tri fluorophenoxy) -ethyl] piperid-4-ylmethanol 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,4,5trifluorophenoxy) -ethyl Ipiperid-4-ylmethanol 230 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl 4,6trifluorophenyl) prop-2-ynyl] piperid-4-ylmethanol 4- (3-Fluoro-6-methoxyquinolin-4-yl~propyl] (3,4,5tri fluorophenyl )prop-2 -ynyl] piperid-4 -ylmethanol 4- (3-Dimethylainino-6-rethoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl) -propyl] piperid-4-ylmethanol 4- (3-Dimethylaxnino-6-rethoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) -propyl] piperid-4-ylmethanol 4- (3-Dimethylanino-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenyl-thio) ethyllpiperid-4-ylmethanol 4-13- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenyl-thio) ethyl] piperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenyl-amino) ethyllpiperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenyl-amino) ethyllpiperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenoxy) -ethyllpiperid-4-ylrnethanol 4- (3-Dimethylaxino-6-methoxyquinolin-4-yl)propyl [2- 5-trifluoro-phenoxy) ethyllpiperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyll 6-trifluorophenyl) prop-2-ynyl ]piperid-4-ylmethanol 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) prop-2-ynyl] piperid-4-ylmethanol 4-[3-(3-Hydroxyrnethyl-6-methoxyquinolin-4-yl)propyl]-1-[3- 5-trifluoro-phenyl) propyl ]piperid-4-ylmethano.
231 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propy1 [2- 4, 6-trifluorophenyl-thio) ethyl] piperid-4-ylmethanol 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenyl-thic) ethyllpiperid-4-ylmethaiol 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenyl-anino) ethyllpiperid-4-ylmethanol 4- (3-Hydroxyrnethyl-6-rrethoxyquinolin-4-yl)propyl] 5-trifluorophenyl-aino) ethyl] piperid-4-ylmethanol 4- (3-Hydroxyinethyl-6-Iethoxyquinolin-4-yl)propyl]-1- [2- 6-trifluorophenoxy) -ethyl] piperid-4-ylmethanol 4- (3-Hydroxynethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) -ethyllpiperid-4-ylmethanol 4- (3-Hycroxymethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenyl) prop-2-ynyl] piperid-4-ylmethanol 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenyl)prop-2-ynyllpiperid-4-ylmethanol 4- (3-Fluoromethyl-6-methoxycquinolin-4-yl)propyl [3- 6-trifluorophenyl) propyl] piperid-4-ylmethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) propyl] piperid-4-ylmethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenyl-thia) ethyl] piperid-4-ylmethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenyl-thio) ethyl] piperid-4-ylmethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenyl-anino) ethyl] piperid-4-ylmethanol 232 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenyl-amino) ethyl] piperid-4-ylmethanol 4- 3 -Fluoromethyl-6-rnethoxyquinolin-4-yl)propyl [2- 6-trifluorophenoxy) -ethyl] piperid-4-yhnethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenoxy) -ethyl] piperid-4-ylmethanol 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl) prop-2-ynyl Ipiperid-4-ylmethanol 4-13- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) prop-2-ynyl] piperid-4-ylmethanol 4- [3:-(3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl) -propyl] piperid-4-ylmethanol 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) -propyl] piperid-4-ylmethanol 4- (3-Aminolethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenyithia) -ethyl] piperid-4-ylinethanol 4- (3-kninomethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenylthio) -ethyl] piperid-4-ylmethanol 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenyl-amino) ethyl] piperid-4-ylmethanol 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylamino) -ethyl] piperid-4-ylmethanol 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-l- [2- 6-trifluorophenoxy) -ethyl] piperid-4-ylmethanol 4 -[3-(3-Axninomethyl-6-methoxyquinolin-4-yl)propyl]ll[2- 5-trifluorophenoxy) -ethyl] piperid-4-ylmethanol 233 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl) prop-2-ynyl] piperid-4-ylmethanol 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) prop-2-ynyl] piperid-4-ylmethanol 4- (3-Morpholinornethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenyl) -propyllpiperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl) -propyl] piperid-4-ylmethaiol 4- (3-Morpholinornethy1-6-methoxyquinolin-4-yl) propyl] -1- 6-trifluorophenylthio) -ethyljpiperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl )propyl] -1- 5-trifluorophenyithia) -ethyl] piperid-4-ylmethanol 4- (3-Morpholinornethyl-6-methoxyquinolin-4-yl) propyl 1-1- 6-trifluorophenyl-amino) ethyl iipiperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl -1- 5-trifluorophenyl-anino) ethyllpiperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenoxy) -ethyllpiperid-4-ylmethanol 4- (3-Morpholinomethyl-6-rnethoxyquinolin-4-yl)propyl] -1- 5-trifluorophenoxy) -ethyllpiperid-4-ylmethanol 4- (3-Morpholinomethy1-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenyl) -prop-2-ynyllpiperid-4-ylmethanol 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl )propyl] -1- 5-trifluorophenyl) -prop-2-ynyl] piperid-4-ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl )propyl] -1-heptylpiperid-4-ylmethanol 234 S) -Hydroxy-3- (3-chloro-6-mnethoxyquinolin-4yl) propyl] -1-[4-phenylbutyl ]piperid-4-ylmethanol 4- S) -H-ydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (phenyl)propyl] -piperid-4-ylmethanol -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl (2-f luorophenyl) propyl Ipiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl (3-f luorophenyl )propyl ]piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxycxyinolin-4yl )propyl (4-f luorophenyl) -propyl Ipiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolii-4yl) propyl] (4-f luorophenyl) -butyl] piperid-4-ylmethaiol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenyl) -propyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 3-difluorophenyl) -propyllpiperid-4ylmethanol S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 6-difluorophenyl)-propyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 6-difluorophenyl)-propyllpiperid-4ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenyl) -propyllpiperid-4ylrnethanol 235 4-13- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyl]piperid-4ylmethano 1 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] -1-[3-phenyithia-propyl] piperid-4-ylmethanol 4-113- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] -1-13- (2-f luorophenyl-thio)propyllpiperid-4ylmethanol 4-113-(R, S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(3-fluorophenyl-thio)propyl]piperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyl-thic) ethyllpiperid-4ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4y1)propyl (4-f luorophenyl-thio)propyl]piperid-4ylrnethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propylll--[2- 3-difluorophenyl-thio)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenyl-thio)propyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenyl-thio)ethyllpiperid-4ylmethanol 236 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5-trifluorophenylthio)ethyl]piperid-4ylmethano 1 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 6-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propylJ-1-[2-(3,4,5-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquiriolin-4yl)propyl] 5-difluoro-phenoxy) ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl~propyl]-1-[2-(2,3,5-trifluoro-phenoxy)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluoro-phenoxy) ethyllpiperid-4ylrnethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll-1-[2-(3,4,5-trifluoro-phenoxy)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 5-difluoro-phenylamino) ethyllpiperid-4ylmethanol 4-[3-(R,S)-H-ydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl] 5-trifluoro-phenylamino) ethyl]piperid- 4 -ylmethanol 237 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl 6-trifluoro-phenylanino) ethyllpiperid- 4 -ylmethanol 4- S) -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluoro-phenylam-ino) ethylipiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- 6-difluoro-phenylthio)propyllpiperid-4ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl] (2-chloro-phenylthio) ethyllpiperid-4ylmethano 1 4- S) -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-chloro-phenylthio)propyllpiperid-4ylmethanol 4-13- S) -Hydroxy-3- (3-chloro-6-mrethoxyquinolin-4yl) propyl1-1- (3-chiloro-phenylthio) ethyl] piperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-chloro-phenylthio)propyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chioro-phenyithia) ethyllpiperid-4ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl )propyl] (4-chioro-phenyithic) propyl] piperid-4ylmethanol 238 4-13- S) -Hylroxy-3- (3-chloro-6-methoxyquinolin-4yJ.)propyl (2-methylphenyl-thio) ethyllpiperid-4ylmethanol 4- S) -Hycroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (2-methylphenyl-thio) propyl] piperid-4ylmethaio 1 4- S) -Hydroxy-3- (3-chloro-6-methoxyquiaolin-4yl)propyl (3-methylphenyl-thio) ethyllpiperid-4ylmethano 1 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (3-methylphenyl-thio)propyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-chloro-6-inethoxyquinolin-4yl)propyl] (4-methylphenyl-thio) ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl1-1- (4-methylphenyl-thio) propyl] piperid-4ylmethano 1 S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll (2-trifluoromethyl-phenyithic) ethyl Ipiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-trifluoromethylphenylthio) propyl Ipiperid- 4-ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl) propyl] (3-trifluoromethyl-phenyithio) ethyl] piperid- 4 -ylmethanol 239 4- S) -Hydroxy-3- (3-chloro-6-methoxyguinolin-4yl)propyl (3-trifluoromethylphenylthio) propylllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl) propyl] (4-trifluoromethyl-phenylthio) ethyl] piperid- 4 -ylmethano 1 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (4-trifluoromethylphenylthio) propyl] piperid-4-ylinethanol 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll (2-methoxyphenyl-thio) ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (2-methoxyphenyl-thio) propyl ]piperid-4ylmethanol -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl] (3-methoxyphenyl-thio) ethyl]piperid-4ylmethano 1 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (3-methoxyphenyl-thio) propyl] piperid-4ylmethanol 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (4-methoxyphenyl-thio) ethyl] piperid-4ylinethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl )propyl] (4-methoxyphenyl-thio) propyl] piperid-4ylrnethano 1 240 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] -1-[cyclopentylmethyl] -piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclopentyl) ethyl] -piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (cyclohexyl) ethyl] -piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (cyclopentylthio) -propyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (cyclohexyithio) propyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl) thioethyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyguinolin-4yl)propyl (thien-2-yl)butyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl1-1- (thien-2-yl) thiopropyl] piperid-4-ylrnethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl (thien-3-yl) propyl ]piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (thien-3-yl)butyl]piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (thien-2-yl) thioethyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (thien-3-yl) thiopropyl ]piperid-4-ylrnethanol 241 4- S) -Hydroxy-3- (3-chloro-6-methoxyguinolin-4yl)propyl]-1-[3-(1,3-thiazol-2-yl)propyllpiperid-4ylmethano 1 4- S) -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-thiazol-2-yl)butyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-thiazol-2-yl) thioethyllpiperid-4ylinethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl)propyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4y propyl] (pyrid-2-yl )butyl] piperid-4-ylmethaiol S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl] 3- (pyrid-2-yl) thiopropyl] piperid-4-ylmethaiol 4 -[3-(R,S)-IHydroxy-3-(3-chloro-6-methoxyquinolin-4yl )propyl (pyrid-3-yl) propyl ]piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)butyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl) thioethyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (pyrid-3-yl) thiopropyl] piperid-4-ylmethaiol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-4-yl)propyllpiperid-4-ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl)butyllpiperid-4-ylmethanol 242 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl) thioethyllpiperid-4-ylmethanol 4- S) -Hyclroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl (pyrid-4-yl) thiopropyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4- 4l)propyl] (pyrazin-2-yl )propyl Ipiperid-4-ylrnethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl)butyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4yl) propyl] (pyrazin-2-yl) thioethyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl) thiopropyllpiperid-4ylmethanol S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(4-fluorophenyl)prop-2-ynyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl 4-difluoropheriyl)prop-2-ynyl]piperid-4ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl 4-difluorophenyl)prop-2-ynyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)prop-2-ynylljpiperid- 4-ylmethanol 243 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(2,4,6-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethano 1 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chloro-3-fluorophenyl)prop-2ynyl] piperid- 4-ylmethanol 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-chloro-4-fluorophenyl)prop-2ynyl] piperid-4-ylrnethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquainolin-4yl)propyl] (2-chloro-4-fluorophenyl)prop-2ynyl Ipiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyqainolin-4yl )propyl] (3-chloro-5-fluorophenyl) prop-2ynyl] piperid- 4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(4-chloro-2-fluorophenyl)prop-2ynyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl (3-f luoro-4-methylphenyl) prop-2ynyl] piperid-4-ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl 5-bis (trifluorornethyl)phenyl)prop-2yriyl] piperid-4-ylmethanol 244 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (thien-2-yl.) prop-2-ynyl Ipiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl) propyl (thien-3-yl )prop-2-ynyl ]piperid-4-ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(1,3-thiazol-2-yl)prop-2-ynyllpiperid-4ylmethaiol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyll-l-[3-(1,3-thiazol-4-yl)prop-2-ynyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolii-4yl)propyll-l-[3-(1,3-thiazol-5-yl)prop-2-ynyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolii-4yl)propyl (pyrid-2-yl)prop-2-ynyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl)prop-2-ynyllpiperid-4-ylmethano.
4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4yl )propyl1-1- (pyrid-4-yl) prop-2-ynyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-rethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperid-4-ylrnethanol 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl) propyl] (phenyl )propyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)propyllpiperid-4ylmethanol 245 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylaiino) ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylaxnino)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolia-4y1)propyl] 5-difluorophenoxy) ethyllpiperid-4ylmethano 1 4-[3-(R,S)-Hydroxy-3-(3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio)ethylljpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl )propyl] (cyclopentylthio) ethyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperid-4-ylmethaiol 4-[3-(R,S)-Hydxoxy-3-(3-methyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluoropherayl)prop-2-ynyllpiperid- 4 -ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-methyl-6-methoxyquinolin-4yl)propyl (thien-2-y1)prop-2-ynyl]piperid-4-ylmethanol 246 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl) propyl] (cyclohexyl) ethyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-f luoro-6-mrethoxyquinoliri-4yl )propyl] (phenyl )propyl] piperid-4-ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)propyl]piperid-4ylmethano 1 4- S) -Iydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl] 5-difluo'rophenylaiino) ethyllpiperid-4ylmethariol 4- S) -Hydroxy-3- (3-f luoro-6-rnethoxyquinolin-4yl)propyl]-1- 5-trifluorophenylarnino)ethyllpiperid-4ylmethaao 1 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1- 5-difluorophenoxy) ethyllpiperid-4ylmethaiol 4- S) -I-ycroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5-trifluorophenoxy)ethyllpiperid-4ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenylthio)ethyllpiperid-4ylnethanol 4- S) -Hydroxy-3- (3-fluoro-6-methoxyguinolin-4yl )propyl] (cyclopentyithia) ethyl] piperid-4-ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl )propyl] (pyrid-2-yl) thioethyl] piperid-4-ylmethanol 247 4-13- S) -Hydroxy-3- (3-flIuoro-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperid-4-ylnethanol 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4-ylmethanol 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl) propyl] (thien-2-yl )prop-2-ynyl Ipiperid-4-ylmethanol 4- S) -Hycdxoxy-3- (3-dimethylamino-6-rnethoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperid-4-ylrnethanol 4- -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl) propyl 1-1-13- (phenyl) propyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)propyllpiperid-4ylmethanol 4- -Hydroxy-3- (3-diiethylarino-6-methoxyquinolin-4yl) propyl] 5-difluorophenylamino) ethyl] piperid-4ylmethano 1 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenylamino)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1- 5-difluorophenoxy)ethyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluorophenoxy)ethyllpiperid-4ylmethanol 248 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5-trifluorophenylthio)ethyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl )propyl] (cyclopentylthio) ethyl Ipiperid-4-ylrnethanol 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl )propyl] (pyrid-2-yl) thioethyl] piperid-4-ylmethanol S) -Hydroxy-3- (3-direthylamino-6-methoxyquinolin-4yl )propyl] (thien-2-yl) thioethyl ]piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-dimethylainino-6-methoxyquinolin-4yl)propyl]-l- 5-trifluorophenyl)prop-2-ynyl]piperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-direthylamino-6-methoxyquinolin-4yl )propyl] (thien-2-yl )prop-2 -ynyl ]piperid-4-ylmethaiol 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperid-4-ylmethaiol 4- S) -Hydroxy-3- (3-hydroxymethyl-6-ntethoxyquinolin-4yl )propyl] (phenyl) propyl] piperid-4-ylmethaiol 4- S) -Hydroxy-3- (3-hydroxymethyl-6--methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)propyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenylamino) ethyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-hydroxyrethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylainino)ethyl]piperid-4ylrnethanol 249 4- S) -Hydroxy-3- (3-hydrox-yrethyl-6-methoxyquiriolin-4yl)propyl]-1- 5-difluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5-trifluorophenoxy)ethyl]piperid-4 ylmethanol 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl)-l-[2-(2,3,5-trifluorophnylthio)ethyllpiperid4 ylmethanol 4- S)-Hydroxy-3- (3-hiydroxymrethyl-6-methoxyq-uinolin-4yl )propyl] (cyclopentyithio) ethyl] piperid-4-ylmethanol S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl )propyl] (pyrid-2-yl) thioethyl Ipiperid-4-ylmethanol S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperid-4-ylmethanol S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol yl )propyl] (thien-2-yl )prop-2-ynyl Ipiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] (cyclohexyl) ethyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl )propyl1-1- (phenyl )propyl ]piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperid-4ylmethanol 250 4-13- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylanino) ethyllpiperid-4ylmethanol S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluorophenylamino)ethyl~piperid-4ylmethano 1 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenoxy)ethyllpiperid-4ylmethano 1 4- -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy)ethyllpiperid-4ylmethaio 1 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl )propyl] (cyclopentylthio) ethyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperid-4-ylmethanol 4- -Hydroxy-3- (3-fluorornethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-f luoroznethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyl]piperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-f 1uoromethyl-6-methoxyquiinolin-4yl )propyl] (thien-2-yl )prop-2-ynyl] piperid-4-ylmethanol 251 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-axinomethyl-6-methoxyquinolin-4yl) propyl] -1-13- (phenyl )propyl] piperid-4-ylmethanol 4-113- -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl] -1-13- 5-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-alinomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl] -1-12- 5-trifluorophenylamino)ethyllpiperid-4ylmethanol 4- 5) -Iydroxy-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,5-difluorophenoxy)ethyllpiperid-4ylrnethanol 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperid-4ylmethano 1 4 -[3-(R,S)-Hydroxy-3-(3-aminomethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylthio)ethyl]piperid-4ylrnethanol 4- -Hydroxy-3- (3-aminorethyl-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperid-4-ylmethanol 4-113- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperid-4-ylmethanol 252 4-113- S) -Hydroxy--3- (3-axinomethyl-6-methoxyquinolin-4yl) propyl] (thien-2-yl) thioethyl] piperid-4-ylmethanol 4-113- S) -Hydroxy-3- (3-aminorethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,3,5-trifluorophenyl)prop-2-ynyllpiperid- 4-ylmethanol 4- S) -Hydroxy-3- (3-aminorethyl-6-methoxyquinolin-4yl)propyl -1-113- (thien-2-yl)prop-2-ynyllpiperid-4-ylmethanol 4-13- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (cyclohexyl) ethyllpiperid-4-ylmethanol 4-113- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl) propyl] -1-13- (phenyl) propyl ]piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-rorpholinomethyl-6-rnethoxyquinolin- 4-yl)propyl] 5-trifluorophenyl)propyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 5-difluorophenylamino) ethyl]piperid-4ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenylamino) ethyllpiperid- 4-ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yI)propyl] 5-difluorophencxy)ethyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4 -yl)propyl]-1-[2-(2,3,5-trifluorophenoxy)ethyllpiperid-4ylrnethariol 253 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 4-ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolii- 4-yl)propyl (cyclopentylthio)ethylllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl) propyl] 2- (pyrid-2-yl) thioethyl Ipiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (thien-2-yl) thioethylllpiperid-4-ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenyl)prop-2ynyl] piperid- 4-ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl (thier-2-yl)prop-2-ynyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyl~piperid-4ylmethano 1 4-[3-(R,S)-Hydroxy-3-(3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenylthio)ethyllpiperid-4ylmethanol 254 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio)ethyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-methyl-6-mrethoxyquinolin-4y1)propyl]-1-[2-(2,4,6-trif1uorophenylamino)ethy1]piperid-4ylmethanol 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquiriolin-4yl)propyl]-l-[2-(3,4,5-trifluorophenylamino)ethyl]piperid-4ylmethanol 4- (R,S)-Hydroxy-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,4,6-trifluorophenoxy)ethyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-iethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-rethyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol S) -Hydroxy-3- (3-rethyl-6-methoxyquinoliri-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperid-4ylmethanol 4-[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)propyllpiperid-4ylmethano 1 255 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Hyclroxy-3- (3-f 1uoro-6-methoxyquinolin-4yl)propyll-l-[2-(3,4,5-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenylaxnino)ethyl]piperid-4ylmethano 1 4 -[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylamiao) ethyl]piperid-4ylmethanol 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-l-[2-(2,4,6-trifluorophenoxy)ethyllpiperid-4 ylmethanol 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl]-l-[3-(2,4,6-trifluorophenyl)prop-2-ynylpiperid.
4 -ylmethanol 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-dimethylalnino-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyljpiperid-4ylmethanol 256 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -H-ydroxy-3- (3-dimethylamino-6-methoyquinolin-4 yl)propyl]-l-[ 2 2 ,4,6-trifluorophnylthio)ethyllpiperid-4 ylmethano 1 4- S) -Hyclroxy-3- (3-dimethylamino-6-methoxyquinolin-4 yl)propyll-1- 5-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-dimethylamno-6-methoxyquinolin-4yl)propyl]-1- E-trifluorophenylamrino)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-dimethylarino-6-methoxyquinolin-4 yl)propyl 5-trifluorophenylamino)ethyl]piperid-4ylmethanol 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4 yl)propyl 6-trifluorophenoxy)ethyllpiperid-4ylmethanol.
4- S) -Hydroxy-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl]-l-[ 2 -(3,4,5-trifluorophenoy)ethyl]piperid-4 ylmethanol 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin-4 yl)propyl 6-trifluorophenyl)prop-2-ynyljpiperid- 4 -ylrnethariol 4- S) -Hydroxy-3- (3-dimethylamino-6-Inethoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 257 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluoraphenyl)propyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,4,6-trifluorophenylthio)ethyllpiperid-4ylrnethanol 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenylthio)ethyllpiperid-4ylmethano 1 4- (R,S)-Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6-trifluoropheiylamino)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluoropheriylamino)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6-trifluorophenoxy)ethyl]piperid-4ylmethanol 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-hydrox-yiethyl-6-methoxyquiriolin-4yl)propyl] 6-trifluorophenyl)prop-2-ynylllpiperid- 4 -ylmethanol 4- -Hydxoxy-3- (3-hycroxymethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 258 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,4,6-trifluorophenyl)propylpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-f luoroinethyl-6-rethoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)propyl~piperid-4 ylmethanol 4- S) -Hydroxy-3- (3-f luoromethyl-6-rnethoxyquinolin-4yl)propylj-1- 6-trifluorophenylthio)ethyljpiperid-4ylmethanol 4- -Iydroxy-3- (3-f luorornethyl-6-rnethoxyquinolin-4yl)propylj-1- 5-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenylamrino)ethyllpiperid-4ylrnethariol 4- S) -Hydroxy-3- (3-fluoromethyl-6-niethoxyquinolin-4yl)propyl 5-trifluorophenylaxnino)ethyllpiperid-4ylmethanol2 4- S) -Hydroxy-3- (3-fluororethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6-trifluorophenoxy)ethyllpiperid-4 ylmethanol 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(3,4,5-trifluorophenoxy)ethyllpiperid-4 ylrnethanol 4 -[3-(R,S)-Hydroxy-3-(3-fluoromethyl-6-methoxyuinolin-4 yl)propyl 6-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylxnethariol 259 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenyl)propyl]piperid-4ylmethanol 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)propyljpiperid-4 ylmethanol 4- (R,S)-Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyll-1- 6-trifluorophenylthio)ethyllpiperid-4ylmethaiol 4- -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyl]piperid-4ylmethanol S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenylamtino)ethyl]piperid-4ylmethano 1 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenylaxnino)ethyllpiperid-4ylmethano 1 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenoxy)ethyllpiperid-4ylrnethanol 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperid-4ylrnethanol 260 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-aiinomethyl-6-methoxyquinolin-4yl)propyl]-1-113-(3,4,5-trifluorophenyl)prop-2-ynyl]piperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl]-1-113-(2,4,6-trifluorophenyl)propyllpiperid-4ylrnethano.
4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl]-l-[3-(3,4,5-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -Hydrcoxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 6-trifluorophenylthio) ethyllpiperid- 4-ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 5-trifluorophenylthio) ethyllpiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl]-1-[2-(2,4,6-trifluorophenylaxnino)ethyllpiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 5-trifluorophenylamino) ethylipiperid- 4 -ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-rnethoxyquinolin- 4-yl)propyl]-1- 6-trifluorophenoxy)ethyllpiperid-4ylmethano 1 261 4- CR, S)-Hydroxy-3- C3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl] 5-trifluorophenoxy) ethyllpiperid-4ylmethanol 4- CR, S)-Hydroxy-3- (3-morpholinomethyl-6-rnethoxyquinolin- 4-yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperid-4-ylmethanol 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenyl)prop-2ynyl] piperid-4-ylmethanol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl) propyl] -l-heptylpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] -1-[4-phenylbutyl ]piperid-4-ylmethanol 4- CR,5) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (phenyl )propyl] piperid-4-ylmethanol 4- CR, S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (2-f luorophenyl) propyl Ipiperid-4-ylmethanol 4- CR, S)-Fluoro-3- C3-chloro-6-methoxyquinolin-4yl )propyl] luorophenyl )propyl] piperid-4-ylmethanol 4- CR,5) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] luorophenyl )propyl] piperid-4-ylmethanol 4- CR,5) -Fluoro-3- C3-chloro-6-methoxyquinolin-4yl )propyl] (4-f luorophenyl )butyl] piperid-4-ylmethanol 4- CR,5) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenyl)propyllpiperid-4ylmethano 1 262 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenyl)propyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll-l-[3-(2,6-difluorophenyl)propyllpiperid-4 ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-difluorophenyl)propylLpiperid-4ylmethanol 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- 5-difluorophenyljpropyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyllpiperid-4ylmethaiol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperid-4ylrnethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)propyllpiperid.4ylrnethanol 4- S) -Fluoro-3- (3-chloro-6-inethoxyquinolin-4yl )propyl] -1-[3-phenylthio-propyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (2-f luorophenylthio)propyllpiperid-4ylmethano 1 263 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (3-f luorophenylthio)propyl ]piperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (4-f luorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenylthio)propyllpiperid-4ylmethanol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl 3-difluorophenyithia) ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl] 3-difluorophenylthio)propylipiperid-4ylmethanol 4- -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl 6-difluorophenylthio) ethyl]piperid-4ylrnethanol S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio)ethyl]piperid-4ylmethanol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-rnethoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyl]piperid-4ylrnethariol 264 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluoropheioxy)ethyl]piperid-4ylmethaiol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 6-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[2-(3,4,5-trifluorophenoxy)ethyljpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperid-4ylmethanol S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamino) ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluoropheiylamrino)ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylamino)ethyl]piperid-4ylrnethano 1 4-[3-(R,S)-Fluoro-3-(3-chloro-6--methoxyquinolin-4yl)propyl] 6-difluorophenylthio)propyllpiperid-4ylrnethano 1 265 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-chlorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (2-chlorophenylthio)propyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-chlorophenylthio)ethyljpiperii-4ylmethano 1 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (3-chlorophenylthio)propyl] piperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chlorophenylthio)ethyllpiperid-4ylmethariol 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (4-chlorophenylthio)propyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4- 'yl)propyl] 2- (2-methylphenylthio) ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (2-methylphenylthio)propyllpiperid-4ylinethanol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl (3-methylphenylthio) ethyllpiperid-4ylmethaio 1 266 S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (3-methylphenylthio)propyl ]piperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-methylphenylthio)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (4-methyiphenyithio) propyl ]piperid-4ylmethano 1 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl )propyl] (2-trifluoromethyiphenyithic) ethyl] piperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (2-trifluoromethyiphenyithic) propyl] piperid- 4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl )propyl] (3-trifluoromethylphenylthio) ethyl] piperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (3-trifluorornethylphenylthio) propyl] piperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl )propyl] (4-trifluoromethylphenylthio) ethyl] piperid- 4 -ylrnethariol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-nethoxyquinolin-4yl )propyl] (4-trifluoromethylphenylthio) propyl] piperid- 4-ylrnethanol 267 4- S) -Fluoro-3- (3-chloro-6--methoxyquinolin-4yl)propylj -1-12- (2-methoxyphenylthio) ethyllpiperid-4ylmethano 1 4-13- S) -Fluoro-3- (3-chloro-6--methoxyquinolin-4yl)propyl] -1-13- (2-methoxyphenylthio)propyllpiperid-4ylrnethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (3-methoxyphenylthio) ethylllpiperid-4ylmethanol 4-13- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] -1-13- (3-methoxyphenylthio)propyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-methoxyphenylthio) ethyllpiperid-4ylmethaiol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-methoxyphenylthio)propyllpiperid-4ylrnethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] -1-[cyclopentylmethyl Ipiperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (cyclopentyl) ethyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (cyclohexyl) -ethyllpiperid-4-ylmethanol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl (cyclopentylthio) -ethylllpiperid-4-ylmethanol 268 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl (cyclopentylthio) -propyllpiperid-4ylinethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (cyclohexyithia) -propyl Ipiperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (pyrid-2-yl) thioethyl] -piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (thien-2-yl )butyl] -piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (thien-2-yl) thiopropyl] -piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (thien-3-yl )propyl I-piperid-4-ylmethaiol S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (thien-3-yl)butyl] -piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (thien-2-yl) thioethyl] -piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (thien-3-yl) thioethyl] -piperid-4-ylmethanol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl )propyl (thien-3-yl) thiopropyl] -piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] 3-thiazol-2-yl)propyllpiperid-4ylrnethanol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl 3-thiazol-2-yl)butyllpiperid-4-ylmethanol 269 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 3-thiazol-2-yl) thioethyl]piperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-2-yl)propyl~piperid-4-ylrnethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-2-yl)butyllpiperid-4-yliethanol 4- S) -Fiuoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (pyrid-2-yl) thiopropyl ]piperid-4-ylmethaiol 4- (R,S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl] (pyrid-3-yl)propyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (pyrid-3-yl )butyl ]piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-3-yl) thioethyllpiperid-4-ylmethanol 4- SY-Fluoro-3- (3-chloro-6-methoxyquinolii-4yl) propyl] (pyrid-3-yl) thiopropyl Ipiperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl)propyllpiperid-4-ylmethanol 4- (R,S)-Fluoro-3- (3-chloro-6-methoxyquinolin-4y1)propyl (pyrid-4-yl)butyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl) thioethyllpiperid-4-ylmethaiol S) -Fluoro-3- (3-chloro-6-methoxyquinolii-4yl)propyl (pyrid-4-yl) thiopropyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-meth-oxyquinolin-4yl)propyl (pyrazin-2-yl)propyllpiperid-4-ylmethanol 270 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrazin-2-yl)butyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquiriolin-4yl) propyl] (pyrazin-2-yl) thioethyl.]piperid-4-ylmethanol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyll 3- (pyrazin-2-yl) thiopropyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-f luorophenyl)prop-2-yriyllpiperid-4ylmethaiol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 4-difluorophenyl)prop-2-ynyllpiperid-4ylmethaiol 4- S) -Fluoro-3- (3-chloro-6-methoxyquiaolin-4yl)propyl (2,4-difluorophenyl)prop-2-ynyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluoropherlyl)prop-2-ynyllpiperid- 4 -ylmethaiol 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4yl)propyl 6-trifluoropherayl)prop-2-ynyllpiperid- 4 -ylmethaiol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4-ylmethanol 271 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1- (4-chloro-3-fluorophenyl)prop-2yny.] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll-l-[3-(3-chloro-4-fluorophenyl)prop.2ynyl] piperid-4-ylmethanol 4 -[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4 yl)propyl]-1- (2-chloro-4-fluorophenyl)prop-2ynyl Ipiperid- 4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propylj-1- (3-chloro-5-fluoropheriyl)prop-2ynyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (4-chloro-2-fluorophenyl)prop-2ynyl] piperid-4-ylmethaiol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (3-f luoro-4-methylphenyl)prop-2ynyl] piperid-4-ylinethanol 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4yl)propyl]-l-[3-(3,5-bis(trifuoromethy)pheny)prop2ynyllIpiperid-4-ylmethaiol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (thien-2-yl) prop-2-ynyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (thien-3-yl) prop-2-yny. Ipiperid-4-ylmethanol 272 S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-1-[3-(1,3-thiazo1-2-yl)prop-2-ynyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl]-l-[3-(1,3-thiazol-4-yl)prop-2-ynyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyll-l-[3-(1,3-thiazol-5-yl)prop-2-yiyljpiperid-4ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl )propyl] (pyrid-2-yl )prop-2-ynyl ]piperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl) propyl] (pyrid-3-yl )prop-2-ynyl Ipiperid-4-ylmethanol 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4yl)propyl (pyrid-4-yl)prop-2-ynyljpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl )propyl] (phenyl )propyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperid-4ylmethanol 273 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamino) ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-l-[2-(3,5-difluorophenoxy)ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethy1]piperid-4ylmethanol 4-113- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenylthio)ethyljpiperid-4ylmethanol 4-13- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl) propyl] -1-12- (cyclopentylthio) ethyl Ipiperid-4-ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl] -1-12- (pyrid-2-yl) thioethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl )propyl] (thien-2-yl) thioethyl ]piperid-4-ylmethaiol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl )propyl] (thien-2-yl )prop-2-ynyl ]piperid-4-ylmethanol 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl )propyl] -1-[3-.(phenyl) propyl Ipiperid-4-ylmethanol 274 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propylll--[2- 5-difluorophenylamino) ethyllpiperid-4ylinethanol 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl] (2,3,-5-trifluorophenylamino) ethyllpiperid-4ylinethanol 4-[3-(R,S),-Fluoro-3-(3-fluoro-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperid-4ylrnethanol 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyll-l- 5-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylthio)ethyllpiperid-4ylinethanol 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl (cyclopentylthio) ethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl )propyl] (pyrid-2-yl) thioethyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl) propyl l-i- (thien-2-yl) thioethyl Ipiperid-4-ylmethanol 4-[3-(R,S)-Fluoro-3-(3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynylllpiperid- 4 -ylmethanol 275 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl) propyl] (thien-2-yl )prop-2-ynyl ]piperid-4-ylmethanol 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl] 2- (cyclohexyl) ethyllpiperid-4-ylmethanol 4- -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl) propyl] (phenyl) propyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl] 3- 5-trifluorophenyl)propyllpiperid-4ylmethano 1 4- -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamino)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4y1)propyl 5-difluorophenoxy) ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5-trifluorophenoxy)ethyllpiperid-4ylniethanol 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4y1)propyl] 5-trifluorophenylthio)ethyllpiperid-4ylrnethanol 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl )propyl] (cyclopentyithia) ethyl] piperid-4-ylmethanol 276 4- S) -Fluoro-3- (3-dimethylamcino-6-methoxyquinolin-4yl)propyll (pyrid-2-yl) thioethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl (thien-2-y.) thioethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-dimethylalnino-6-methoxyquinolin-4yl)propyl]-l- 5-trifluorophenyl)prop-2-ynyl]piperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl (thien-2-yl)prop-2-yny1]piperid-4-ylmethanol 4-13- S)-Fluoro-3- (3-hydroxyxnethyl-6-methoxyquinolin-4yl) propyl] (cyclohexyl) ethyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl )propyl] (phenyl) propyl ]piperid-4-ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperid-4ylmethanol S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperid-4ylmethano 1 4-13- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamino)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenoxy)ethyllpiperid-4ylmethanol 277 4-13- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl) propyl] -1-12- 5-trifluorophenoxy) ethyllpiperid-4y lmethanol 4-113- S) -Fluoro-3- (3-hydroxyrethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyllpiperid-4 ylmethano 1 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (cyclopentyithia) ethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyJ.-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl) propyl] (thien-2-yl) thioethyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)prop-2-ynyllpiperid- 4-ylmethanol 4- S) -Fluoro (3-hydroxymethyl-6-methoxyquinolin-4yl )propyl] (thien-2-y prop-2-ynyl] piperid-4-ylrnethanol 4-13- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperid-4-ylniethanol 4-113- -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl )propyl]-1-113- (phenyl )propyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4y1)propyl 5-trifluorophenyl)propyllpiperid-4ylmethano 1 4-113- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyllpiperid-4ylmethaiol 278 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamino) ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4y1)propyl]-1-[2-(3,5-difluorophenoxy)ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyllpiperid-4ylmethano 1 4- -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-f luoronethyl-6-methoxyquinolin-4yl )propyl] (cyclopentyithia) ethyl] piperid-4-ylmethanol 4- -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-y1) thioethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl )propyl] (thien-2-yl) thioethyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl )propyl] (thien-2-yl )prop-2-ynyl ]piperid-4-ylmethanol 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl )propyl] (cyclohexyl) ethyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-arrinomethyl-6-methoxyquinolin-4yl )propyl] (phenyl )propyl] piperid-4-ylmethanol 279 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-aminorethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyl]piperid-4ylmethaio 1 4- S) -Fluoro-3- (3-amiinorethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylanino) ethylj piperid-4ylmethanol 4- (R,S)-Fluoro-3- (3-aninomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-difluorophenoxy)ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenoxy)ethyl]piperid-4ylmethanol 4- S) -Fluoro-3- (3-axinomethyl-6-xethoxyquinolin-4yl)propyl]-1- 5-trifluorophenylthio)ethyljpiperid-4ylrnethanol 4- S) -Fluoro-3- (3-aminorethyl-6-methoxyquinolin-4yl)propyl (cyclopentyithia) ethyllpiperid-4-ylmethanol 4- S) -Fluoro-3- (3-axinorethyl-6-methoxyquinolin-4yl propyl] (pyrid-2-yl) thioethyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl )propyl] (thien-2-yl) thioethyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-axinorethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyl]piperid- 4-ylmethanol 280 4- S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl) propyl] (thien-2-yl) prop-2-ynyl] piperid-4-ylmethaiol 4- S) -Fluoro-3- (3-morpholinornethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperid-4-ylrnethanol 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl) propyl] -l-13- (phenyl) propyl] piperid-4-ylmethanol 4- S) -Fluoro-3- (3-morpholinoniethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-morpholinornethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyl]piperid-4ylmetihanol 4- S) -Fluoro-3- (3-morpholinornethyl-6-methoxyquinolin-4yl) propyl1-1- 5-trifluorophenylamino) ethyl] piperid-4ylmethanol 4-113-(R, S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenoxy) ethyllpiperid-4ylmethanol 4-113-(R, S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- 13- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenylthio)ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl) propyl] (cyclopentylthio) ethyl] piperid-4-ylmethanol 281 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl (pyrid-2-yl) thioethyllpiperid-4-ylmethanol 4- S) -Fluaro-3- (3-morpholinornethyl-6-methoxyquinolin-4yl)propyl (thien-2-yl) thioethyllpiperid-4-ylmethaiol 4-13- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,3,5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylrnethanol 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl) propyl] (thien-2-yl )prop-2-ynyl ]piperid-4-ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-triffluorophenyl)propyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)propylljpiperid-4ylmethanol 4- S) -Fluoro-3- (3-methyl-6-meth-oxyquinolin-4yl)propyll-l-[2-(2,4,6-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenylthio)ethyllpiperid-4ylmethano.
4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6-trifluorophenylamino)ethyllpiperid-4ylmethanol 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyquinolin-4y1)propyl 5-trifluorophenylamino)ethyllpiperid-4ylmethano 1 282 4-13- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,4,6-trifluorophenoxy)ethyllpiperid-4ylrnethano 1 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolii-4yl)propyl 6-trifluorophenyl)prop-2-ynyl~piperid- 4 -ylmethano 1 4- 13- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4yl)propyll-l-[3-(3,4,5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethaiol 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolii-4yl)propyl 6-trifluoropheriyl)propyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyl]piperid-4ylmethano 1 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyll-1-[2-(2,4,6-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenylthio)ethyllpiperid-4ylmethano 1 4-[3-(R,S)-Fluoro-3-(3-fluoro-6-methoxyquinolin-4yl)propyl 6-trifluorophenylamino) ethyllpiperid-4ylmethanol 283 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamrino)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyll-1-[2-(2,4,6-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyllpiperid-4ylmethanol2 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl]-l-[3-(2,4,6-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4-ylmethanol 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)propyllpiperid-4ylrnethanol 4- S) -Fluoro-3- (3-dimethylainino-6-methoxyquinolin-4yl)propylll-- 2- 6-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio)ethyllpiperid-4ylrnethanol 284 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propylll--[2- 6-trifluorophenylamino)ethyllpiperid-4yl~methano 1 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyll-1-'[2- 5-trifluorophenylainino)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-dimethylamino-,6-methoxyquinolin-4yl)propyl)-1- 6-trifluorophenoxy)ethyllpiperid-4ylmethaiol 4- S)-Fluoro-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy)ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-dimethylaxnino-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenyl)prop-2-ynyllpiperid- 4-ylmethaiol 4- S) -Fluoro-3- (3-dimethylanlino-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)propyllpiperid-4ylrnethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyll 5-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyllpiperid-4ylmethano 1 285 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[2- 5-trifluorophenylthio)ethyllpiperid-4ylxnethano 1 4- S) -Fluoro-3- (3-hydroxyxnethyl-6-methoxyquinolin-4yl)propyl]-l-[ 2 2 4 ,6-trifluorophenylarnino)ethyllpiperid-4 ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamino) ethyllpiperid-4y1methanol 4- (R,S)-Fluoro-3- (3-hydroxymethyl-6-methoxyqinolin-4yl)propyl]-l-[ 2 -(2,4,6-trifluorophenoxy)ethyllpiperid-4 ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-Inethoxyquinolin-4yl)propyl]-1- 5-trifluorophenoxy)ethyllpiperid-4ylinethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4-ylrnethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyl]piperid-4ylmethanol 286 4- S) -Fluoro-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,4,6-trifluorophenylthio)ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyll-l--r2-(3,4,5-trifluorophenylthio)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenylamino)ethyllpiperid-4ylmethaiol 4- -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamino) ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,4,6-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy)ethyl]piperid-4ylrnethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- 6-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1- 5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-aminorethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyl]piperid-4ylmethaiol 287 -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyljl--[3-(3,4,5-trifluorophenyl)propyllpiperid-4ylmethaaol 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyll-1-[2-(2,4,6-trifluorophenylthio)ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl)l--[2-(3,4,5-trifluorophenylthi,)ethyllpiperid-4yl~methanol 4- -Fluoro-3- (3-aninomethyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenylamino) ethyllpiperid-4ylrnethanol 4- S) -Fluoro-3- (3-arinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamino) ethyl]piperid-4ylmethaiol 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyllpiperid-4ylrnethanol S) -Fluoro-3- (3-axinomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 288 4- S) -Fluoro-3- (3-rorpholinomethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,4,6-trifluorophenyl)propyllpiperid-4ylinethano 1 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)propyl]piperid-4ylmethanol 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenylthio)ethyllpiperid-4ylmethano 1 4- S) -Fluoro-3- (3-morpholinomethyl-6-rnethoxyquinolin-4yl)propyll 5-trifluorophenylthio)ethyllpiperid-4ylmethaio 1 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propylll--[2- 6-trifluorophenylamino)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl )propyl] 5-trifluorophenylamnino) ethyl] piperid-4ylmethanol S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4y1)propyl]-1-[2-(2,4,6-trifluorophenoxy)ethyllpiperid-4ylmethanol 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyl]piperid-4ylmethanol 4- -Fluoro-3- (3-norpholinomethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(2,4,6-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethanol 289 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4yl)propyl (3,4,5-trifluorophenyl)prop-2-ynyllpiperid- 4 -ylmethaiol 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl] -1-heptyl piperidine-4-hydroxamic acid 4- (3-Chloro-6-Inethoxyquinolin-4-yl)propyl [4phenylbutyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propylj (2fluorophenyl)propyllpiperidine-4-hydroxanic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[4-(3fluorophenyl )propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4- .fluorophenyl )propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4fluorophenyl)butyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2,3ditluorophenyl)propyl]piperidine-4-hydroxanic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,3difluorophenyl)propyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-y1)propy1]-1-[3-(2,6difluorophenyl)propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,6difluorophenyl)propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl difluorophenyl )propyl]piperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3- 5-trifluorophenyl) propyllpiperidine-4-hydroxamic 290 acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3- 6-trifluorophenyl)propylllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3- 5-trifluorophenyl)propyl]piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquiriolin-4-yl)propyl [3phenyithiopropyl Ipiperidine-4-hydroxamic acid 4-[3--3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2fluorophenylthio)propylllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3fluorophenylthio)propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4fluorophenyithio) ethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4fluorophenylthio)propyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,3difluorophenylthio) ethylllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,3difluorophenylthio)propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyqiainolin-4-yl)propyl (2,6difluorophenyithia) ethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl]-1- [2- 5-trifluorophenylthio) ethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [2- 291 6-trifluorophenyithio) ethylllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylthio) ethyllpiperidine-4-hydroxanic acid 4- [3-(3-Chloro-6-methoxyquinoin-4-y)propy1]l1[2 5-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [2- 6-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4 -[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl1]l1q2-(3,5.
difluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyq-uinolin-4-yl)propyl [2- 5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4 -[3-(3-Chloro-6-methoxyquinolin-4-yl)propy1]-l1[2- 6-trifluorophenylanino) ethyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl>1[>(2 5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl] 6difluorophenylthio)propyl] piperidine-4-hydroxamic acid 292 4- (3-Chloro-6-methoxycpainolin-4-yl)propyl (2chiorophenyithia) ethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (2chlorophenylthio) propyllpiperidine-4-hydroxanic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3chiorophenyithio) ethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3chlorophenylthio) propyllpiperidine-4-hydroxanic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyll (4chlorophenylthio) ethyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4chlorophenylthio)propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-Inethoxyquinolin-4-yl)propyl (2methylpheriylthio) ethyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-1-[3-(2methylphenylthio) propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3methylphenylthio) ethyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3methylphenylthio) propyllpiperidine-4-hydroxamic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(4rnethylphenylthio) ethyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (4inethyiphenyithio) propyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2trifluoromethyiphenyithia) ethyl] piperidine-4-hydroxamic acid 293 4- (3-Chloro-6-methoxyquinolin-4-yljpropyl] (2trifluoromethylphenylthio) propyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (3trifluoromethylphenylthio) ethyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3trifluoromethylphenylthio) propyl] piperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(4trifluorornethylphenylthio) ethyl Ipiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4trifluoromethylphenylthio)propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquiriolin-4-yl)propyl (2rethoxyphenyithio) ethyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-y1)propyl]-l-[3-(2methoxyphenylthio)propyllpiperidine-4-hydroxamic acid 4- [3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3.
methoxyphenylthio) ethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3methoxyphenylthio)propyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (4methoxyphenyithia) ethyl~piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl]-l- (4methoxyphenylthio)propy1]piperidine-4-hydroxamic acid 294 (3-Chloro-6-methoxyquinolin-4-yl)propyl]-1- [cyclopentylrnethyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl [2- (cyclopentyl) ethyllipiperidine-4-hydroxamic acid (3-Chloro-6-methoxyquinolin-4-yl)propylj-1-[2- (cyclopentylthio) ethyllpiperidine-4-hydroxamic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl [3- (cyclopentyithia) propyllpiperidine-4-hydroxamic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3- (cyclohexylthio) propyl] piperidine-4-hydroxamic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[4- (thien-2-yl) butyl] piperidine-4-hydroxamic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3- (thien-2-yl) thiopropyl] piperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3- (thien-3-yl) propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [4- (thien-3-yl) butyllpiperidirie-4-hydroxamic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl [2- (thien-3-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [3- (thien-3-yl) thiopropyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl 13- (1,3thiazol-2-yl) propyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[4-(1,3thiazol-2-yl)butyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (1,3- 295 thiazol-2-yl) thioethyljpiperidine-4-hydroxamic acid (3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-l- [3- (pyrid-2-yl) propyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl] (pyrid-2-yl)butyllpiperidine-4-hydroxanic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-2-yl) thiopropyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [3- (pyrid-3 -yl) propyl 1piperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[4- (pyrid-3-yl )butylllpiperidine-4-hydroxanic acid 4-13- (3-Chloro-6-methoxyquinolin-4-yl)propyl]-1- [2- (pyrid-3-yl) thioethylljpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyqtiinolin-4-yl)propyl] (pyrid-3-yl) thiopropyllpiperidine-4-hydroxamic acid- 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [3- (pyrid-4-yl) propyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [4- (pyrid-4-yl)butyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[2- (pyrid-4-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl]-l- [3- (pyrid-4-yl) thiopropyllpiperidine-4-hydroxamic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl]-1- [3- (pyrazin-2-yl)propyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propylj-l- [4- (pyrazin-2-yl)butyl]piperidine-4-hydroxamic acid 296 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [2- (pyrazin-2-yl) thioethyllpiperidine-4-hydroxamic acid (3-Chloro-6-niethoxyquinolin-4-yl)propyll]-l-[3- (pyrazin-2-yl) thiopropyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-l-[3-(4fluorophenyl )prop-2-ynyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3,4difluorophenyl) prop-2-ynyllpiperidine-4-hydroxanic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2,4difluorophenyl )prop-2-ynyllpiperidine-4-hydroxamic acid (3-Chloro-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(4chloro-3-fluorophenyl) prop-2-ynyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] 3- (3chloro-4-fluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (2chloro-4-fluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic 297 acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)prapyl (3- )prop-2-ynyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(4chloro-2-fluorophenyl) prop-2-ynyl] piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3fluoro-4-methylphenyl) prop-2-ynyl Ipiperidine-4-hydroxamic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl bistrifluoromethyiphenyl )prop-2-ynyl ]piperidine-4hydroxamic acid 4-[3-(3-Chloro-6-rnethoxyquinolin-4-yl)propyl]-l-[3- (thien-2-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl [3- (thien-3-yl) -2-ynyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-rnethoxyquinolin-4-yl)propyl (1,3thiazol-2-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3-(1,3thiazol-4-yl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (1,3thiazol-5-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[3- (pyrid-2-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-3-yl)prop-2-yriyllpiperidine-4-hydroxamic acid 298 (3-Chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-4-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4-[3-(3-methyl-6-methoxyquinolin-4-yl)propyl]-1-[3- (phenyl )propyllpiperidine-4-hydroxanic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)propyl] piperidine-4-hydroxamic acid 4-[3-(3-methyl-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4-[3-(3-Methyl-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluoropheioxy) ethyllpiperidine-4-hydroxamic acid 4- (3-methyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4-[3-(3-methyl-6-methoxyquinolin-4-yl)propyl]-l-[2- (cyclopentyithio) ethyl] piperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- (pyrid-2-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4- 299 hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] (thien-2-yl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [2- (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- (phenyl) propyl] piperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl) [3- 5-trifluorophenyl )propyllpiperidine-4-hydroxamic acid (3-Fluoro-6-methoxyq-uinolin-4-yl)propyl difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [2- 3, 5-trifluorophenylamino) ethyl]piperidine-4-hydroxamic acid 4- [3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl difluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyq-uinolin-4-yl)propyl [2- 5-trifluorophenylthio) ethyllpiperidine-4-hydroxamic acid (3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l- [2- (cyclopentylthio) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoro-6-rnethoxyquinolin-4-yl)propyl]-1- [2- (pyrid-2-yl) thioethyllpiperidine-4-hydroxamic acid 300 4- (3-Fluoro-6-rnethoxyquinolin-4-yl)propyl] (thien-2-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynylllpiperidine-4hydroxarnic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- (thien-2-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4- (3-Direthylamino-6-methoxyquinolin-4-yl)propyl] -1- (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- (phenyl)propyl] piperidine-4-hydroxanic acid 4- (3-Dimethylamino-6-methoxyqiinolin-4-yl)propyl] -1- 5-trifluorophenyl)propyllpiperidine-4-hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- 5-difluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenylamino) ethyllpiperidine-4hydroxarnic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- 5-difluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-y1)propyl] -1- 5-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- 301 5-trifluoropherlylthio)ethyllpiperidine-4hydroxamic acid 4- (3-Dimethylamirio-6-methoxyquinolin-4-yl)propylI -1- (cyclopentylthio) ethyllpiperidine-4-hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- (pyrid-2-yl) thioethyllpiperidine-4-hydroxamic acid (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl1]l- (thien-2-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Dimethylarnino-6-methoxyquinolin-4-yl)propyl] -1- [3-(2,3,5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxarnic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propylj -1- (thien-2-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- (cyclohexyl)ethyljpiperidine-4-hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquiraolin-4-yl)propyl] -1- (phenyl) propyl] piperidine-4-hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyguinolin-4-yl)propyl] -1- 5-trifluorophenyl)propyllpiperidine-4-hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-difluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propylj -1- 2 ,3,5-trifluorophenylamino)ethyllpiperidine-4hydroxamic acid 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl] -1- 302 5-difluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4-13- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenoxy) ethyl]piperidine-4-hydroxamic acid 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenylthio) ethylllpiperidine-4hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- (cyclopentylthio) ethyllpiperidine-4-hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- (pyrid-2-yl) thioethyllpiperidine-4-hydroxamic acid (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl]-1- (thien-2-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Hydroxyrethyl-6-methoxyquinolin-4-yl)propyl] -1- (2,3,5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- (thien-2-yl)prop-2-ynyllpiperidine-4-hydroxamic acid (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] (cyclohexyl) ethyllpiperidine-4-hydroxamic acid (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-1-[3- (phenyl )propyl ]piperidine-4-hydroxanic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-1-[3- 5-trifluorophenyl)propyllpiperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 303 5-difluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-rnethoxyquinoliri-4-yl)propyl] 5-trifluorophenylanino) ethyl] piperidine-4-hydroxamic acid (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-1- [2- 5-difluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyll-1- [2- 5-trifluorophenoxy) ethyllpiperidine-4-hydroxanic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-1-[2- 5-trifluorophenylthio) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-rnethoxyquinolin-4-yl)propyl]-l- [2- (cyclopentylthio) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluorornethyl-6-Iethoxyquinolin-4-yl)propyl]-1- [2- (pyrid-2-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 2- (thien-2-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-1- [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- (thien-2-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4-[3-(3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-1- [2- (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyll-1- [3- 304 (phenyl) propyl] piperidine-4-hydroxamic acid 4-13- (3-Aminorethyl-6-methoxyquinolin-4-yl)propyl 13- 5-trifluorophenyl) propyl] piperidine-4-hydroxamic acid 4-13- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl] 5-difluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenylanino) ethyllpiperidine-4-hydroxamic acid 4- (3-Axinomethyl-6-methoxyquinolin-4-yl)propyl] 5-difluorophenoxy) ethyllpiperidine-4-hydroxamic acid (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-l- [2- 5-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4-13- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-1- [2- 5-trifluorophenylthio)ethyllpiperidine-4-hydroxanic acid (37Aiinomethyl-6-methoxyquinolin-4-yl)propyl]-1- [2- (cyclopentyithio) ethyl] piperidine-4-hydroxamic acid 4-13- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl] (pyrid-2-yl) thioethyllpiperidine-4-hydroxanic acid 4-13- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyllpiperidine-4-hydroxanic acid 4-[3-(3-Arninomethyl-6-methoxyquinolin-4-yl)propyl]-1-[3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 305 (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl [3- (thien-2-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1-12- (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] (phenyl)propyl] piperidine-4-hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1- 5-trifluorophenyl)propyllpiperidine-4hydroxamic acid 4-13- (3-Morpholinomethyl-6-methoxyquinolin-4-y1)propyl] 1- 5-difluorophenylamino) ethyllpiperidine-4hydroxamic acid 4-13- (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl] 1-12- 5-trifluorophenylamino) ethyllpiperidine-4hydroxamic acid 4-13- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1-12- 5-difluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1-[2-(2,3,5-trifluorophenoxy)ethyllpiperidine-4hydroxarnic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1- 5-trifluorophenylthio)ethyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1- (cyclopentyithiol) ethyllpiperidine-4-hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 306 1- (pyrid-2-yl) thioethyllpiperidine-4-hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1- (thien-2-yl) thioethyllpiperidine-4-hydroxanic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1-[3-(2,3..5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1- (thier-2-yl)prop-2-ynyllpiperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquiraolin-4-yl)propyl [3- 6-trifluorophenyl)propyl] piperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl) propyl] piperidine-4-hydroxamic acid 4-[3-(3-Methyl-6-methoxyq-uinolin-4-yl)propyl]-1-[2- 6-trifluorophenylthio) ethyllpiperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinoli'n-4-yl)propyl [2- 5-trifluorophenyithio) ethyllpiperidine-4-hydroxamic acid (3-Methyl-6-methoxyquinolin-4-yl)propyl]-1- [2- 6-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylanino) ethyllpiperidirie-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl] 307 6-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) ethyllpiperidine-4-hydroxanic .acid 4- (3-Methyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Methyl-6-methoxyquiriolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl)propyllpiperidine-4-hydroxamic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[3- 5-trifluorophenyl)propyl]piperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyll]-1- [2- 6-trifluorophenylthio) ethyllpiperidine-4-hydroxanic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenylthio) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyqtiinolin-4-yl)propyl [2- 6-trifluorophenylanino) ethyl] piperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [2- 308 5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [2- 6-trifiluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [2- 5-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid (3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3- 6-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4 hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- G-trifluorophenyl)propyllpiperidine-4-hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propylj -1- S-trifluorophenyl)propyllpiperidine-4-hydroxamic acid 4- 3 -Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- 2 ,4,6-trifluorophenylthio)ethyl]piperidine4-~ hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- 2 4 ,5-trifluorophenylthio)ethyllpiperidine-4hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- 309 6-trifluorophenylamino) ethyllpiperidine-4hydroxamic acid 4- (3-Diiethylarino-6-rethoxyquinolin-4-yl)propyl] -1- 5-trifluoro] henylamino) ethyllpiperidine-4hydroxamic acid 4- (3-Direthylamino-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenoxy)ethyllpiperidine-4-hydroxamic acid 4- (3-Dimethylamino-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Diiethylamino-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxarnic acid (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl]-1- 5-trifluorophenyl)propyllpiperidine-4-hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenylthio) ethyllpiperidine-4hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyguiriolin-4-yl)propyl] -1- (3,4,5-trifluorophenylthio)ethyllpiperidine-4hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- 310 6-trifluorophenylamino) ethyllpiperidine-4hydroxamic acid 4-13- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluoropheiylamino) ethyllpiperidine-4hydroxamic acid 4- (3-Hydroxyrnethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluoropheioxy) ethyl] piperidine-4-hydroxamic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propylj -1- 5-trifluorophenoxy) ethyllpiperidine-4-hydroxanic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- 6-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxarnic acid 4- (3-Hydroxymethyl-6-methoxyquinolin-4-yl)propyl] -1- 5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxanic acid 4-13- (3-Fluoromethyl-6-Inethoxyquinolin-4-yl)propyl] 6-trifluorophenyl)propyllpiperidine-4-hydroxamic acid 4- [3-(3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-1-[3- 4, 5-trifluorophenyl) propyl] piperidine-4-hydroxamic acid (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-1-[2- 6-trifluorophenyithia) ethyl]piperidine-4-hydroxamic acid (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-l-[2- 311 5-trifluorophenyithia) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-methoxyq-uinolin-4-yl)propyl]-l- [2- 6-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid (3-Fluoromethyl-6-rnethoxyquinolin--4-yl)propyl]-l- [2- 6-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-1- [2- 5-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl]-l-[3- 6-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Fluoromethyl-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxanic acid 4- (3-Axinomethyl-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl) propyllpiperidine-4-hydroxamic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-1- [3- 5-trifluorophenyl) propyllpiperidine-4-hydroxamic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl] 312 6-trifluorophenyithio) ethyllpiperidine-4-hydroxamic acid (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-1-[2- 5-trifluorophenylthio) ethyl] piperidine-4-hydroxamic acid (3-Aminomethyl-6-methoxyquinolin-4--yl)propyl]-1-[2- 6-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Arinomethyl-6-methoxyquinolin-4-yl)propyl]-1- [2- 5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- (3-Aminomethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4-[3-(3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-1-[2- 5-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- (3-Axinomethyl-6-methoxyquinolin-4-yl)propyl] 3- 6-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- [3-(3-Aminomethyl-6-methoxyquinolin-4-yl)propyl]-l- [3- 5-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl )propyl] l-[3-(2,4,6-trifluorophenyl)propyllpiperidine-4hydroxanic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 313 1-[3-(3,4,5-trifluorophenyl)propyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1- 6-trifluoropheriylthio)ethyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1-[2-(3,4,5-trifluorophenylthio)ethylllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl] 1- 6-trifluorophenylamino)ethyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl] 1- 5-trifluorophenylamino)ethyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1- 6-trifluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1- 5-trifluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 1-[3-(2,4,6-trifluorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (3-Morpholinomethyl-6-methoxyquinolin-4-yl) propyl] 1-[3-(3,4,5-trifluorophenyl)prop-2-yxyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) 314 propyl] -1-heptyl piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] -1-[4-phenylbutyl]piperidine-4-hydroxamic acid 4- -Hydroxy-3- (3-chloro-6-xnethoxyquinolin-4-yl) propyl] (phenyl)propylllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyqu~inolin-4-y1) propyl] (2-f luorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] (3-f luorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] (4-f luorophenyl )propyl] piperidine-4hydroxanic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (4-f luorophenyl)butyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 3-difluorophenyl)propyl]piperidine-4hydroxanic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) prop yl] 3-difluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 6-difluorophenyl)propyllpiperidine-4hydroxamic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) 315 propyl]-1- 6-difluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propylj-1-[3-(3,5-difluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1- 13-(2,3, 5-trifluorophenyl)propyl~piperidine-4hydroxanic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) .propyl [3-phenylthiopropyllpiperidine-4-hydroxamnic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (2-f luorophenylthio)propyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (3-f luorophenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-f luorophenylthio)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-f luorophenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1-[2- 3-difluorophenylthio)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyguinolin-4-yl) 316 propyl 3-difluorophenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyll 6-difluorophenylthio) ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 5-tritluorophenylthio) ethyllpiperidine- 4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl]-l- [2-(2,4,6-trifluorophenylthio)ethyllpiperidine- 4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyll 5-trifluorophenyithio) ethyl~piperidine- 4-hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-ntethoxyquinolin-4-yl)- *propyl (3,5-difluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1- [2-(2,3,5-trifluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenoxy) ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyllpiperidine-4hydroxamic acid -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) 317 propyl] 5-difluorophenylamino) ethyl Ipiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl 6-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Iydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l-[2-(3,4,5-trifluorophenylamino)ethyl]piperidine-4-hydroxamic acid 4- S) -H-ydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyll-1- 6-difluorophenylthio)propyl]piperidine-4hydroxamic acid 4 -[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyuinolin-4-yl)propyl] (2-chlorophenylthio)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (2-chlorophenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-niethoxyquinolin-4-yl) propyl] (3-chlorophenylthio)ethyl~piperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (3-chlorophenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) 318 propyll (4-chlorophenylthio) ethyllpiperidine-4hydroxamic acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propylll--[3- (4-chlorophenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (2-methylphenylthio) ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (2-methylphenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (3-methyiphenyithio) ethyl~piperidine-4hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin.4-yl)propyl] (3-methylphenylthio)propyl]piperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyguinolin-4-yl) propyl] (4-rethylphenylthio) ethyllpiperidine-4hydroxamic acid S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-methylphenylthio)propyl]piperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propylj-1-[2- (2-trifluoromethylphenylthio)ethyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) 319 propyl] (2-trifluoromethylphenylthio)propyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-nmethoxyquinolin-4-yl) propyl (3-trifluoromethylphenylthio) ethyl] piperidine-4-hydroxamic acid 4-13- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-y1) propyl] (3-trifluoromethylphenylthio)propyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-trifluoromethylphenylthio) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-trifluoromethylphenylthio)propyl] piperidine-4-hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-choro-6-methoxyuinolin4yl)propyl] (2-iethoxyphenyithia) ethyllpiperidirie-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (2-methoxyphenylthio) propyljpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (3-methoxypheriylthio) ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (3-methoxyphenylthio)propyl]piperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) 320 propyl] (4-methoxyphenylthio)ethyl]piperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquiriolin-4-yl) propyl] (4-methoxyphenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] -1-[cyclopentylmethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyq-uinolin-4-yl) propyl] (cyclopentyl) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (cyclohexyl) ethyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquiriolin-4-yl) propyl] (cyclopentylthio) ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-y l) propyl] 3-(cyclopentylthio)propyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-rnethoxyquinolin-4-yl)propyl] (cyclohexylthio)propyllpiperidine-4hydr~oxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-2-yl) thioethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (thien-2-yl)butyllpiperidine-4-hydroxamic 321 acid 4- -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l- [3-(thien-2-yl)thiopropyllpiperidine-4hydroxamic acid (R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (thien-3-yl)propyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (thien-3-yl)butyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l- [2-(thien-2-yl)thioethyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyllpiperidine-4hydroxarnic acid 4- (R,S)-Hydroxy-3- (3-chloro-6-methoxyquiriolin-4-yl)propyl]l--[3-(thien-3-yl)thiopropyllpiperidine-4hydroxamic acid 4- (R,S)-Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl)propyl] 3-thiazol-2-yl)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6--methoxyquinolin-4-yl) propyl] 3-thiazol-2-yl)butyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 3-thiazol-2-yl) thioethyllpiperidine-4- 322 hydroxamic acid- 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl (pyrid-2-yl)propylllpiperidine-4-hydroxamic acid -4-f3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyll (pyrid-2-yl)butylllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) ,propy1 (pyrid-2-yl) thiopropyllpiperidine-4- -hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolii-4-yl) propyl] (pyrid-3-yl)propyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) :,propyl (pyrid-3-yl)butyllpiperidine-4-hydroxamic ,.acid S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) ,propy1 (pyrid-3-yl) thioethyl~piperidine-4hydroxamic acid '4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyll-1- (pyrid-3-yl)thiopropyllpiperidine-4hydroxamic acid 4- -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] (pyrid-4-yl)propyllpiperidine-4-hydroxamic acid 4- -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] (pyrid-4-yl)butyllpiperidine-4-hydroxamic 323 acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-4-yl) thioethylllpiperidine-4hydroxamic acid (R,S)-Hydroxy-3-(3-chloro-6-nethoxyquinolin-4-yl) propyl] (pyrid-4-yl) thiopropyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-inethoxyquinolin-4-yl) propyl (pyrazin-2-yl)propyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrazin-2-yl)butyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3 7 -chloro-6-rnethoxyquinolin-4-yl) propyl]-1- (pyrazin-2-yl)thioethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] (pyrazin-2-yl) thiopropyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (4-f luorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 4-difluorophenyl)prop-2-ynyllpiperidine- 4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 4-difluorophenyl)prop-2-ynyllpiperidine- 324 4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyqiinolin-4-yl) propyl] 3- 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid (R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l- [3-(4-chloro-3-fluorophenyl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl]-1-[3-(3-chloro-4-fluorophenyl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1- [3-(2-chloro-4-fluorophenyl)prop-2-ynyllpiperidine-4-hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-l- [3-(3-chloro-5-fluorophenyl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] -1-[3-(4-chloro-2-fluorophenyl)prop-2-yiyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1- [3-(3-fluoro-4-methylphenyl)prop-2-ynyl]- 325 piperidine-4--hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 5-bistrifluoromethylpheiyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin4yl)propyl (thien-2-yl)prop-2-ynyllpiperidine-4hydroxarnic acid 4- S) -Iydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (thien-3-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l-[ 3 -(l,3-thiazol-2-yl)prop-2-ynyl]piperidine-4 hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l-[ 3 -(1,3-thiazol-4-yl)prop-2-ynyllpiperidine-4 hydroxanic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 3-thiazol-5-yl)prop.-2-ynyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-2-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-3-yl)prop-2--ynyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-4-yl)prop-2-yriyllpiperidine-4- 326 hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4-yl) propyl] (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-methyl-6-rnethoxyquinolin-4-yl)propyl] (phenyl) propylllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4-yl) propyl 5-trifluorophenyl)propyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-methyl-6-methoxyquinolin-4-yl)propyl 5-difluorophenylamino) ethyl]piperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 5-difluorophenoxy) ethyllpiperidine-4hydroxanic acid S) -Hydroxy-3- (3-methyl-6-methoxyguinolin-4-yl) propyl]-1-[2-(2,3,5-trifluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 4-hydroxanic acid 4-[3-(R,S)-Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl)propyl] (cyclopentyithia) ethyllpiperidine-4hydroxanic acid 327 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4-yl) propyl] (pyrid-2-yl) thioethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4-yl) propyl] -1-[2-(thien-2-yl)thioethyllpiperidine-4hydroxamic acid 4-13- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4-yl) propyl] 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid- (R,S)-Hydroxy-3-(3-methyl-6-methoxyquinolin-4-yl)propyl]-1- [3-(thien-2-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) propyl] (cyclohexyl) ethyllpiperidine-4-hydroxanic acid 4- -Hydroxy-3- (3-f luoro-6-methoxyquiriolin-4-yl) propyl] (phenyl)propyljpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolii-4-yl) propyl] 5-trifluorophenyl)propyllpiperidine-4hydroxaniic acid 4 -[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl] 5-difluoropheiylamino) ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) propyl]-l-[ 2 -(2,3,5-trifluorophenylamino)ethyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) 328 propyll 5-difluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-fluoro-6-rnethoxyquinolin-4-yl) propyl] 5-trifluorophenoxy) ethyl]piperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-fluoro-6-Inethoxyquinolin-4-yl) propyl] 5-trifluoropheiylthio) ethyllpiperidine- 4-hydroxamic acid 4- S) -Hydroxy-3- (3-fluoro-6-rnethoxyquinolin-4-yl) propyl]-1-[2-(cyclopentylthio)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-fluoro-6-rnethoxyquinolin-4-yl) propyll (pyrid-2-yl) thioethyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl] (thieri-2-yl) thioethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] (thien-2-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-direthylamino-6-methoxyquinolin- 4-yl)propyl] -1-[2-(cyclohexyl)ethyllpiperidine-4hydroxantic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 329 4-yl)propyl (phenyl)propyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylarnino-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenyl) propyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-rnethoxyquinolin- 4-yl)propyl 5-difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl]-l-[2-(2,3,5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl]-l- 4-hydroxamic acid 4- S) -Iydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenyithia) ethyllpiperidine-4-hydroxamic acid 4- S) -I-ydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl]-1-[2- (cyclopentylthio)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl]-l-[2-(pyrid-2-yl) thioethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 330 4-yl)propyl [2-(thien-2-yl)thioethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-direthylamino-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl]-1- [3-(thien-2-yl)prop-2-ynyllpiperidiie-4hydroxainic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl]-1-[2-(cyclohexyl)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl) propyl] (phenyl) propyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl] 5-trifluorophenyl) propyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl] 5-difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl] 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl]-l-[2- 4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin- 331 4-yl)propyl] 2- 5-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl] 5-trifluorophenylthio) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin- 4-yl)propyl (cyclopentylthio) ethyl Ipiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl]-l-[2- (pyrid-2-yl)thioethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl] (thien-2-yl) thioethylllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin- 4 -yl)propyll-l-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin- 4-yl)propyl]-1-[3- (thien-2-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- (R,S)-Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4-[3-(R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (phenyl)propylllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4- 332 yl)propyl] -1-13- 4-hydroxamic acid (R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(3,5-difluorophenylamino)ethyllpiperidine-4-hydroxamic acid 4-13- (R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 12- 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4-13- (R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(3,5-difluorophenoxy)ethylljpiperidine-4hydroxarnic acid 4-13- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenoxy) ethylipiperidine- 4-hydroxamic acid 4- (R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylthio)ethyl] piperidine-4-hydroxamic acid 4- (R,S)-Hydroxy-3- (3-f luoromethyl-6-rnethoxyquinolin-4yl)propyll-1-[2- (cyclopentylthio)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4y1)propyl (pyrid-2-yl) thioethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(thien-2-yl)thioethylllpiperidine-4hydroxamic acid 4- (R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4- 333 yl)propyl] 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid (R,S)-Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl) propyl] (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl (phenyl)propyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 4-hydroxamic acid (R,S)-Hydroxy-3- (3-aminomethyl-6-rnethoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminonethyl-6-methoxyquinolin-4yl)propyl]-1-[2- 5-difluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l-[2- 4-hydroxamic acid S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4- 334 yl)propyl 3, 5-trifluorophenyithio) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 2 -(cyclopentylthio)ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(pyrid-2-yljthioethyllpiperidine-4hydroxamic acid S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyll-l-[2-(thien-2-yl)thioethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-amiromethyl-6-methoxyquinolin-4yl)propyl] 5-trifluorophenyl)prop-2-ynylj piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1- 13- (thien-2-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinornethyl-6-methoxyquinolin-4-yl)propyl (cyclohexyl) ethyllpiperidine- 4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl (phenyl)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)propyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxy- 335 quinolin-4-yl)propyl] -1-12- 5-difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin- 4 -yl)propyl]-l-[2-(2,3,5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4-13- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl].-l-[12- 5-difluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- S) -Iydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-y1)propyl]-1-[2-(2,3,5-trifluorophenoxy)ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl 5-trifluorophenylthio) ethyl] piperidine-4-hydroxamic acid 4- (R,S)-I-ydroxy-3- (3-morpholinomethyl-6-methoxy- :quinolin-4-yl)propyl (cyclopentyithia) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyguinolin-4-yl)propyl] -1-12- (pyrid-2-yl) thioethyl] piperidine-4-hydroxamic acid 4-13- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl (thien-2-yl) thioethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,3,5-trifluorophenyl)prop2 ynyl ]piperidine-4-hydroxamic acid 4-113-(R, S) -Hydroxy-3- (3-morpholinornethyl-6-methoxy- 336 quinolin-4-yl)propyl]-l-[3-(thien-2-yl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propylll--[3- (2,4,6-trifluoropherwl)propyl]piperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propyl]-l- (3-(3,4,5-trifluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-rnethoxyquinolin-4-yl) propyl]-1-[2-(2,4,6-trifluorophenylthio)ethyllpiperidine- 4-hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propyl 5-trifluorophenylthio) ethyllpiperidine- 4-hydroxamic acid 4-[3-(R,S)-Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenoxy) ethyllpiperidine-4hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propyl]-l-[2-(3,4,5-trifluorophenoxy)ethyllpiperidine-4hydroxaniic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) 337 propyl]-l-[3-(2,4,6-trifluoropheny)prop2nyl]> piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic ~acid 4- -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenyl)propyl]piperidine-4hydroxainic acid 4- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4-yl) -propyl]-l-[ 3 3 ,4,5-trifluorophenyl)propyllpiperidine-4 hydroxamic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenylthio) ethyllpiperidine- 4-hydroxamic acid 4 -[3-(R,S)-Hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl) propyl] 4-hydroxanic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenylamiao) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) propyll-l-[2-(2,4,6-trifluorophenoxy)ethyllpiperidine.4hydroxamic acid 4- S) -I-ydroxy-3- (3-f luoro-6-methoxyquinolin-4-yl) 338 propyl]-1- (3,4,5-trifluorophenoxy)ethyllpiperidine-4hydraxamic acid S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxanic acid 4-13- S) -Hydroxy-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl]-1-[3-(2,4,6-trifluorophenyl)propyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenyl)propyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylainino-6-methoxyquinolin- 4-yl)propyl 6-trifluorophenyithio) ethyl] piperidine-4-hydroxamic acid 4- -Hydroxy-3- (3-dimethylamino-6-rnethoxyquinolin- 4-yl)propyl 5-trifluorophenylthio)ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl 6-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl]-1-[2-(3,4,5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4-13- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 339 4-yl)propyl 6-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenoxy) ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylamino-6-methoxyquinolin- 4-yl)propyl] -1-13- 6-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-dimethylarnino-6-methoxyquinolin- 4-yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenyl) propyl] piperidine-4-hydroxamic acid 4- -Hydroxy-3- (3-hydroxyrnethyl-6-methoxyquinolin- 4-yl)propyl] 6-trifluorophenyithic) ethylllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenylthio) ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl 6-trifiluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl]-1-[2-(3,4,5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 340 4-yl)propyl 6-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl 5-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4-yl)propyl 6-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-hydroxymethyl-6-methoxyquinolin- 4 -yl)propyl]-l-[3-(3,4,5-trifluorophenyl)prop-2-ynyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 6-trifluorophenyl)propyllpiperidine- 4-hydroxamic acid 4- (R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 4-hydroxamic acid 4- S) -Hydroxy-3- (3-f luorornethyl-6-rethoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyl] piperidine-4-hydroxamic acid 4- (R,S)-Hydroxy-3- (3-f luoromethyl-6-rnethoxyquinolin-4yl)p ropyl]-l-[2-(3,4,5-trifluorophenylthio)ethyl>piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-f luoromethyl-6-rnethoxyquinolin-4yl)propyl]-l-[2-(2,4,6-trifuorophenylanino)ethyl]jpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-fluoromethyl-6-methoxyquinolin-4- 341 yl)propyl]-l-[2-(3,4,5-trifluorophenylamino)ethyllpiperidine-4-hydroxamic acid (R,S)-Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenoxy) ethyl]piperidine- 4-hydroxamic acid 4-13- S) -Hydroxy-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyll 5-trifluorophenoxy) ethyllpiperidine- 4-hydroxamic acid 4-13- -Hydroxy-3- (3-f luoromethyl-6-methoxycjuinolin-4yljpropyl]-1-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-hydroxamic acid 4-[3-(R,S)-Hydroxy-3-(3-fluoromethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid (R,S)-Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propyllpiperidine- 4-hydroxamic acid 4-113-(R, S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 4-hydroxamic acid 4-13- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyll-1-112- 6-trifluorophenylthio)ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenylthio)ethyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4- 342 yl)propyl]-1-112-(2,4,6-trifluorophenylamino)ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamia) ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-arinomethyl-6-methoxyquinolin-4yl)propyl] 2- 4;6-trifluorophenoxy) ethyllpiperidine- 4-hydroxanic acid 4- S) -Hydroxy-3- (3-aiinomethyl-6-methoxyquinolin-4yl)propyl 4-hydroxamic acid 4- S) -Hydroxy-3- (3-arinomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl) prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(3,4,5-trifluorophenyl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinornethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenyl) propyl ]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenyl) propyl ]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,4,6-trifluorophenylthio)ethyl] piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinornethyl-6-methoxy- 343 quinolin-4-yl)propyl.I 5-trifluorophenyithio) ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl amino) ethyllpiperidine-4-hydroxamic acid S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,4,6-trifluorophenoxy)ethyllpiperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl 5-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- (R,S)-Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyll 6-trifluorophenyl)prop-2ynyl ]piperidine-4-hydroxamic acid 4- S) -Hydroxy-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl 5-trifluorophenyl)prop-2ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] -l-heptylpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxycjuinolin-4-yl) propyl] -1-[4-phenylbutyl]piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (phenyl) propyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) 344 propyl] 2 -fluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyguinolin-4-yl) propyl] (3-f luorophenyl)propyllpiperidine-4hydroxainic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-f luorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l- [4-(4-fluorophenyl)butyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 3-difluorophenyl)propyl]piperidine-4hydroxamic acid 4 -[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl).
propyll 3-difluoropheriyl)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-niethoxyquinolin-4-yl) propyl] 6-difluorophenyl)propyl]piperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l-[4- 6-difluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 5-difluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) 345 propyl]-1- (2,3,5-trifluorophenyl)propyllpiperidine-4hydroxarnic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1- (2,4,6-trifluorophenyl)propyl~piperidine-4hydroxarnic acid 4-13- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl 5-trifluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 3-phenyithiopropyl] piperidine-4-hydroxamic acid 4- (R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl).
propyl] (2-f luorophenylthio)propyllpiperidine-4hydroxanic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (3-f luorophenylthio) propyllpiperidine-4hydroxainic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-f luorophenylthio) ethyl]piperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6--methoxyquinolin-4-yl) propy1 (4-f luorophenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1- [2-(2,3-difluorophenylthio)ethyl]piperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4-yl) 346 propyl] 3-difluorophenylthio)propyllpiperidine-4 hydroxamic acid 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyljll--[2- 6-difluorophenylthio) ethyllpiperidine-4hydroxarnic acid 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 4-hydroxamic acid 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyll 6-trifluorophenyithia) ethyllpiperidine- 4-hydroxamic acid S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl 5-trifluorophenyithia) ethylipiperidine- 4-hydroxanic acid 4 -[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl).
propyl] 5-difluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- -Fluoro-3- (3-chIloro-6-methoxyquinolin-4-yl) propyl 5-trifluorophenoxy) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l-[ 2 -(3,4,5-trifluorophenoxy)ethyllpiperidine.4hydroxamic acid S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) 347 propyl] 5-difluorophenylamino) ethyllpiperidine-4hydroxarnic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l-[2-(3,4,5-trifluorophenylamino)ethyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl 6-difluorophenylthio)propyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Fluoro-3--(3-chloro-6-methoxyquinolin-4-yl)propyl] (2-chlorophenylthio) ethyl~piperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (2-chlorophenylthio)propyl]piperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1-[2-(3-chlorophenylthio)ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 3-(3-chlorophenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) 348 propyl.]-1- (4-chiorophenyithia) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (4-chlorophenylthio)propyllpiperidine-4hydroxamic acid -Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (2-methylphenylthio) ethyl]piperidine-4hydroxarnic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (2-methylphenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (3-methylphenylthio) ethyllpiperidine-4hydroxarnic acid (R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (3-methylphenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-methylphenylthio) ethyllpiperidine-4hydroxainic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-methylphenylthio) propyl] piperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (2-trifluoromethyiphenyithia) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) 349 propyl (2-trifluoromethylphenylthio)propyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (3-trifluoromethyiphenyithia) ethyl] piperidine-4-hydroxamic acid 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (3-trifluoromethylphenylthio)propyl] piperidine-4-hydroxanic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (4-trifluoromethyiphenyithio) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (4-trifluoromethylphenylthio)propyl] piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (2-methoxyphenylthio) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (2-methoxyphenylthio)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (3-methoxyphenylthio) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] (3-methoxyphenylthio)propyllpiperidine-4hydroxarnic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) 350 propyl] (4-methoxyphenyithia) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] (4-methoxyphenylthio)propyllpiperidine-4hydroxaiic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] -1-(cyclopentylmethyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (cyclopentyl) ethyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-y1) propyll (cyclohexyl) ethyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyguinolin-4-yl) -propyl] (cyclopentylthio)ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (cyclopentylthio)propyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-mrethoxyquinolin-4-yl)propyl]-l-[3- (cyclohexylthio)propyjjpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-2-yl) thioethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (thien-2-yl)butyllpiperidine-4-hydroxamic 351 acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (thien-2-yl) thiopropyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (thien-3-yl) propyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (thien-3-yl)butyllpiperidine-4-hydroxanic acid 4- S) -Fiuoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1- [2-(thien-2-yl~thioethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1-[2-(thien-3-yl)thioethyllpiperidine-4hydroxainic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (thien-3-yl) thiopropyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-nethoxyquinolin-4-yl)propyl]-1- [3-(1,3-thiazol-2-yl)propyllpiperidine-4hydroxanic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyguinolin-4-yl) propyl] 3-thiazol-2-yl)butyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-y1) propyl] 3-thiazol-2-yl) thioethyllpiperidine-4- 352 hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin--4-yl) propylll--[3- (pyrid-2-yl)propyllpiperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-2-yl)butyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propylJ]-1- (pyrid-2-yl) thiopropyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-3-yl)propyljpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-3-yl)butyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (pyrid-3-yl) thioethyllpiperidine-4hydroxarnic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-3-yl) thiopropylllpiperidine-4hydroxarnic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-4-yl)propyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-4-yl)butyllpiperidirie-4-hydroxamic 353 acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl (pyrid-4-yl) thioethyl]piperidine-4hydroxanic acid (R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl).
propyl] (pyrid-4-yl) thiopropyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyqiinolin-4-yl) propyl (pyrazin-2-yl)propyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrazin-2-yl)butyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1- [2-(pyrazir-2-yl)thioethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrazin-2-yl) thiopropyllpiperidine-4hydroxarnic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (4-f luorophenyl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4-yl) propyl] 4-difluorophenyl)prop-2-ynyllpiperidiie- 4-hydroxarnic acid 4- S) -Fluoro-3- (3-chloro-6-inethoxyquinolin-4-yl) propyl 4-difluorophenyl)prop-2-ynyl]piperidine- 354 4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinlin-4yl)propylll--[3- 6-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenyl)prop-2-ynylj piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l- (4-chloro-3-fluorophenyl)prop-2-yiyl]piperidirae-4-hydroxanic acid 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l-[3-(3-chloro-4-fluoropheny1)prop-2-yy]- .piperidine-4-hydroxamic acid S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1-[3-(2-chloro-4-fluorophenyl)prop2ynyl]> piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (3-chloro-5-fluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l- 3 -(4-chloro-2-fluorophenyl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (3-f luoro-4-methylphenyl)prop-2-ynyl] 355 piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] 5-bistrifluoromethylpheriyl)prop-2ynyl] piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolii-4-yl)propyl] (thien-2-yl)prop-2-ynylllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (thien-3-yl)prop-2-ynylllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-l-[3-(1,3-thiazol-2-yl)prop-2-ynyl]piperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-rnethoxyquinolin-4-yl) propylj-1-[3-(1,3-thiazol-4-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl]-1-[3-(1,3-thiazol-5-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4-13-(R,S)-Fluoro-3-(3-chloro-6-methoxyquinolin-4-yl)propyl] (pyrid-2-yl)prop-2-ynylllpiperidine-4hydroxainic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-3-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-chloro-6-methoxyquinolin-4-yl) propyl] (pyrid-4-yl)prop-2-ynyllpiperidiie-4- 356 hydroxamic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] (cyclohexyl) ethyl]piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyquinolin-4-yl)propyl] (phenyl)propyllpiperidine-4-hydroxanic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl]-1-[3- (2,3,5-trifluorophenyl)propyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyquinolin-4-yl)propyl] 5-difluorophenylamino) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenylamino)ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyll 5-ditluorophenoxy)ethyllpiperidine-4hydroxarnic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl]-l-[2-(2,3,5-trifluorophenoxy)ethyllpiperidine-4hydroxanic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyqiinolin-4-yl) propyl] 3, 5-trifluorophenylthio) ethyl] piperidine- 4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyquinolin-4-yl)propyl] (cyclopentylthio) ethyllpiperidine-4hydroxamic acid 357 S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propylll--[2- (pyrid-2-yl)thioethylllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-methyl-6-mrethoxyquinolin-4-yl) propyl (thien-2-yl)thioethyllpiperidine-4hydroxarnic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 3,'5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyquinolin-4-yl)propyl]-l- [3-(thien-2-yl)prop-2-ynylllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxycpiinolin-4-yl) propyl] (cyclohexyl) ethyllpiperidine-4-hydroxanic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquiiolin-4-yl) propyl] (phenyl) propyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-f 1uoro-6-methoxyquinolin-4-yl) propyl]-1-[3-(2,3,5-trifluorophenyl)propyllpiperidine-4hydroxanic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] 5-difluorophenylamino) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl]-l-[2-(2,3,5-trifluorophenylamino)ethyl]piperidine-4-hydroxamic acid 4- -Fluoro-3- (3-fluoro-6--methoxyquinolin-4-yl) 358 propyl 5-difluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenoxy) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4-yl) propyl 5-trifluorophenylthio) ethylilpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl (cyclopentyithia) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] (pyrid-2-yl) thioethyllpiperidine-4hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-fluoro-6-nethoxyquinolin-4-yl)propyl] (thien-2-yl) thioethyl]piperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl]-1- 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxanic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl]-1-[3-(thien-2-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-dimethylaniino-6-niethoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-direthylamino-6-methoxyquinolin-4- 359 yl) propyl] (phenyl) propyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino)ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3,5-trifluorophenylamino)ethyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1-[2- 5-difluorophenoxy)ethyllpiperidine-4hydroxamic acid 4-113- (R,S)-Fluoro-3-(3-dimethylarnino-6-methoxyquinolin-4yl)propyl]-1-112-(2,3, 4-hydroxamic acid 4-13- -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio)ethyl] piperidine-4-hydroxamic acid S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4y1)propyl (cyclopentylthio) ethyllpiperidine-4hydroxamic acid 4-13- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-l-[2- (pyrid-2-yl)thioethyllpiperidine-4hydroxarnic acid 4- -Fluoro-3- (3-dimethylamino-6-rnethoxyquinolin-4- 360 yl)propyl]-1- [2-(thien-2-yl)thioethyllpiperidiie-4hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-l-[3-(thien-2-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-hydroxamic acid S) -Fluoro-3- (3-hydroxyrnethyl-6-methoxyquinolin-4yl) propyl] (phenyl)propyllpiperidine-4-hydroxamic acid 4-13-(R,S)-Fluoro-3-(3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 4-hydroxanic acid 4- R, S)-Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-l-[2- 5-difluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-hydroxyrnethyl-6-rnethoxyquinolin-4- 361 yl)propyl 5-trifluorophenoxy) ethyl]piperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolii-4yl)propyl]-l-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxyrethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyll (pyrid-2-yl) thioethyllpiperidine-4hydroxainic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[2- (thien-2-yl)thioethyllpiperidine-4hydroxamic acid 4- (R,S)-Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-4hydroxamic acid 4- (R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4y1)propyl (phenyl)propylllpiperidine-4-hydroxamic acid 4- (R,S)-Fluoro-3- (3-f luorornethyl-6-methoxyquinolin-4- 362 yl)propyl]-1- (2,3,5-trifluorophenyl)propyl~piperidine- 4-hydroxamic acid (R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- (R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 3,'5-trifluorophenylamino~ethyll piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl] 5-difluorophenoxyl) ethyl]piperidine-4hydroxamic acid 4- (R,S)-Fluoro-3- (3-f luoromethyl-6-rnethoxyquinolin-4yl)propyl] 5-trifluorophenoxy) ethylipiperidine- 4-hydroxamic acid 4- (R,S)-Fluoro-3-(3-fluoromethyl-6-methoxyquinolin-4yl)propyll-l-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyll (cyclopentylthio) ethylllpiperidine-4hydroxamic acid 4- (R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(pyrid-2-yl)thioethyllpiperidine-4hydroxanic acid 4- (R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(thien-2-yl)thioethyllpiperidine-4hydroxamic acid 4- -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4- 363 yl)propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- -Fluoro-3- (3-fluoromethyl-6-methoxyquinolin-4yl)propyl]-l-[3-(thien-2-yl)prop-2-ynyllpiperidine-4hydroxainic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl (cyclohexyl) ethyl lpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl] (phenyl)propyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l-[3- 4-hydroxamic acid 4- (R,S)-Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l-[2-(2,3,5-trifluorophenylamino)ethyl]piperidine-4-hydroxamic acid 4- -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-difluorophenoxy) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-l-[2- 4-hydroxamic acid 4- S) -Fluoro-3- (3-aminoiethyl-6-methoxyquinolin-4- 364 yl)propyl 5-trifluorophenylthio)ethyl] piperidine-4-hydroxamic acid (R,S)-Fluoro-3- (3-aminorethyl-6-methoxyquinolin-4yl)propyl]-1- [2-(cyclopentylthio)ethyllpiperidiie-4hydroxarnic acid 4- S) -Fluoro-3- (3-aminorethyl-6-methoxyquinolin-4yl)propyl]-1- (pyrid-2-yl)thioethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyll-1-[2-(thien-2-yl)thioethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid (R,S)-Fluoro-3-(3-aminomethyl-6-methoxyquinolin-4yl)propyl] (thien-2-yl)prop-2-ynyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-rnethoxyquinolin-4-yl)propyl (cyclohexyl) ethyl]piperidine- 4-hydroxarnic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl]-1- [3-(phenyl)propyllpiperidine-4hydroxamic acid (R,S)-Fluoro-3-(3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)propyl] piperidine-4-hydroxanic acid 4- -Fluoro-3- (3-rorpholinomethyl-6-methoxy- 365 quinolin-4-yl)propyl 5-difluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl amino) ethyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 5-difluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinornethyl-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,3,5-trifluorophenoxy)ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl thio) ethyllpiperidine-4-hydroxamic acid -Fluoro-3- (3-morpholinornethyl-6-methoxyquinolin-4-yl)propyl] (cyclopentylthio) ethyl] piperidine-4-hydroxamic acid 4- S) -Pluoro-3- (3-morpholinornethyl-6-methoxyquinolin-4-yl)propyl (pyrid-2-yl) thioethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinornethyl-6-methoxyquinolin-4-yl)propyl (thien-2-yl) thioethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-rorpholinomethyl-6-methoxyquinolin-4-y1)propyl]-1-[3-(2,3,5-trifluoropheny1)prop-2ynyl] piperidine-4-hydroxamic acid 4- -Fluoro-3- (3-morpholinomethyl-6-methoxy- 366 quinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyquinoilin-4-yl)propyl]-1- 6-trifluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-methyl-6-inethoxyguinolin-4-yl) propyl] 5-trifluorophenyl)propyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquiraolin-4-yl) propyl]-l- 6-trifluorophenylthio)ethyllpiperidine- 4-hydroxamic acid 4-13- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenylthio) ethyllpiperidine- 4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-methyl-6-methoxyquinolin-4-yl)propyl] 6-trifluoropheiylamino) ethyl] piperidine-4-hydroxamic acid 4- -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenoxy) ethyllpiperidine-4hydroxarnic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyllpiperidine-4hydroxarnic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) 367 propyl] 6-trifluorophenyl) prop-2--ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-methyl-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl]-1-'[3- (2,4,6-trifluorophenyl)propyllpiperidine-4hydroxamic'acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl]-1-[3-(3,4,5-trifluorophenyl)propyl~piperidine-4 hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenylthio) ethyllpiperidine- 4-hydroxamic acid (R,S)-Fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenylthio) ethylilpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyguinolin-4-yl) propyl1-1- 4, 6-trifluorophenylamino) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4-yl) propyll 5-trifluorophenylanino) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-f luoro-6-methoxyquinolin-4-yl) propyl]-l-[2-(2,4,6-trifluorophenoxy)ethyllpiperidine-4hydroxamic acid 4- -Fluoro-3- (3-f luoro-6-methoxyquinolin-4-yl) 368 propyl] 5-trifluorophenoxy) ethyllpiperidine-4hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] 6-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl] 5-trifluorophenyl)prop-2-yiyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1-[3- 6-trifluorophenyl)propyllpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 4-hydroxamic acid 4- (R,S)-Fluoro-3-(3-dimethylamino-6-methoxyqu~inolin-4 yl)propyl]-1-[2-(2,4,6-trifluorophenythio)ethyl)j piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylaniino-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio) ethyl] piperidine-4-hydroxamic acid 4- -Fluoro-3- (3-direthylamino-6-rnethoxyquinolin-4yl)propyl] 6-trifluorophenylamino) ethyl] piperidine-4-hydroxanic acid 4- -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-l-[2-(3,4,5-trifluorophenylamino)ethyl].
piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4- 369 yl)propyl] 6-trifluorophenoxy) ethyllpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyll 5-trifluorophenoxy) ethyl jpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-dimethylamino-6-methoxyquinolin-4yl)propyl]-1-[3-(3,4,5-trifluorophenyl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-fluoro-6-methoxyquinolin-4-yl) propyl]-1- (2,4,6-trifluorophenyl)propyllpiperidine-4hydroxamic acid (R,S)-Fluoro-3-(3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxyniethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio)ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenylthio)ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6-trifluorophenylamino)ethyl]piperidine-4-hydroxamic acid -Fluoro-3- (3-hydroxymethyl-6-rnethoxyquinolin-4- 370 yl)propyl] -1-12- 5-trifluorophenylamino)ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl---[2- 6-trifluorophenoxy) ethyllpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propylll--[2- 5-trifluorophenoxy) ethyllpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl]-1-[3-(2,4,6-trifluorophenyl)prop-2-ynyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-hydroxymethyl-6-methoxyquinolin-4yl)propyl] -1-13- 5-trifluorophenyl)prop-2-ynyll piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-fluoromethyl-6-methoxyquinolin-4yl)propyl] -1-13- 6-trifluorophenyl)propyllpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-rnethoxyquinolin-4yl)propyl] 4-hydroxamic acid 4-[3-(R,S)-Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenylthio) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenylthio)ethyl]piperidine-4-hydroxamic acid 4- (R,S)-Fluoro-3-(3-fluoromethyl-6-methoxyquinolin-4- 371 yl)propyl 6-trifluorophenylamino)ethyl] piperidine-4-hydroxamic acid 4- S) -FJuoro-3- (3-f luoromethyl-6-rnethoxyquinolii-4yl)propyl 5-trifluorophenylamino)ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-f luoromethyl-6-methoxyquinolin-4yl)propyll 6-trifluorophenoxy) ethyl]piperidine- 4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-fluoromethyl-6-rnethoxyquinolin-4yl)propyl] 5-trifluorophenoxy) ethyllpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-tluoromethyl-6-rnethoxyquinolin-4yl)propyl 6-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-fluoromethyl-6-nethoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 6-trifluorophenyl)propylllpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1-[3- (3,4,5-trifluorophenyl)propyl~piperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl]-1-[2-(2,4,6-trifluorophenylthio)ethyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4- 372 yl)propyl]-1-[2-(3,4,5-trifluorophenylthio)ethyl]piperidirae-4-hydroxanic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propylll--[2- 6-trifluorophenylanino)ethyl] piperidine-4-hydroxamic acid S) -Fluoro-3- (3-aminomethyl-6-nethoxyquinolix-4yl)propylll-l-[2-(3,4,5-trifluorophenylamino)ethyl]piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyJ.-6-methoxyquinolin-4yl)propyl 6-trifluorophenoxy) ethyl IIpiperidine- 4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-methoxyquinolin-4yl)propyl 5-trifluorophenoxy) ethyl]piperidine- 4-hydroxamic acid 4-[3-(R,S)-Fluoro-3-(3-aminomethyl-6-methoxyquinolin-4yl)propyl 4,6-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-aminomethyl-6-inethoxyquinolin-4yl)propyl 5-trifluorophenyl)prop-2-ynyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,4,6-trifluorophenyl)propyll piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl]-l-[3-(3,4,5-trifluorophenyl)propyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxy- 373 quinolin-4-yl)propyl] 6-trifluorophenyithio) ethyl] piperidine-4-hydroxamic acid 4-13- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenylthio) ethyllpiperidine-4-hydroxanic acid 4- S) -Fluoro-3- (3-morpholinomethylL-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,4,5-trifluorophenylamino) ethyllpiperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 6-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid (R,S)-Fluoro-3- (3-morpholinomethyl-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenoxy) ethyl] piperidine-4-hydroxamic acid 4- S) -Fluoro-3- (3-morpholinornethyl-6-methoxyquinolin-4-yl)propyl]-l-[3-(2,4,6-trifluorophenyl)prop-2ynyl] piperidine-4-hydroxamic acid 4-13- S) -Fluoro-3- (3-morpholinomethyl-6-methoxyquiniolin-4-yl)propyl 13- 5-trifluorophenyl)prop-2ynyl] piperidine-4-hydroxamic acid 4-13- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] (2fluorophenyl)allyllpiperidine-4-carboxylic acid 4-13- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (3fluorophenyl) allyl] piperidine-4-carboxylic acid 374 4- (3-Fluoro-6-methoxyquinolin-4-yl)propy.]-1- (4fluorophenyl) allyllpiperidine-4-carboxylic acid 4- (3-Fluoro-6-Inethoxyquinolin-4-yl)propyl (2,3difluorophenyl) allyllpiperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,4difluorophenyl) allyl] piperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (2,6difluorophenyl) allyllpiperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl difluorophenyl)allyllpiperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl (3,4difluorophenyl) allyl~piperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[3- 5-trifluorophenyl) allyllpiperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[3- 4-trifluorophenyl) allyllpiperidine-4-carboxylic acid (3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[3- 6-trifluorophenyl) allyllpiperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)allyllpiperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- 6-trifluorophenyl) allyllpiperidine-4-carboxylic acid 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl [3- 5-trifluorophenyl)allyllpiperidine-4-carboxylic acid 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[3- 6-trifluorophenyl)allyllpiperidine-4-carboxylic acid The examples which follow, given in a non- 375 limiting manner, illustrate the present invention.
Example 1 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2- (thien-2-yl)thioethyl]-piperidine-4-carboxylic acid dihydrochloride.
A mixture of 0.6 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-4-carboxylate in 7.72 cm 3 of aqueous 6N hydrochloric acid is maintained at a temperature in the region of 100 0 C with stirring and under an inert atmosphere for 2 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0
C.
The residue obtained is taken up in 10 cm 3 of a dichloromethane/methanol mixture (90/10 by volume). The mixture is concentrated to dryness under the above conditions. 0.58 g of 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-4carboxylic acid dihydrochloride, is obtained in the form of a beige-colored foam melting at 130 0 C with decomposition.
H NMR spectrum (250 MHz, (CD 3 2 SO-d 6 at a temperature of 373 K, 6 in ppm): from 1.50 to 2.30 (mts: 8H in total); from 2.70 to 3.80 (mts: 10H in total); 3.99 3H); 7.09 (dd, J 5 and 3.5 Hz: 1H); 7.29 (broad d, 376 J 3.5 Hz: 1H); 7.40 J 2.5 Hz: 1H); 7.46 (dd, J 9 and 2.5 Hz: 1H); 7.64 (broad d, J 5 Hz: 1H); 7.99 (d, J 9 Hz: 1H); 8.67 1H).
Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- [2-(thien-2-yl)thioethyl]-piperidine-4-carboxylate A mixture of 0.6 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.36 g of 2-(2-bromoethylthio)thiophene and 0.22 g of potassium carbonate in 20 cm 3 of acetonitrile is heated for 16 hours at a temperature in the region of 80 0 C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 200C, the reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. A residue is obtained, which is purified by chromatography, under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-63 p; diameter 3.5 cm; height 28 cm), eluting with a mixture of dichloromethane/methanol (97.5/2.5 by volume) and collecting 35-cm 3 fractions. Fractions 15 to are combined and then concentrated to dryness under the above conditions. 0.67 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-4-carboxylate is obtained in the form of an orange-colored viscous oil.
Infra-red spectrum (CC1 4 2955; 1727; 1622; 1503; 1229; 1117; 833 and 698 cm 377 Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate.
1.27 cm 3 of trifluoroacetic acid are added, with stirring and under an inert atmosphere, at a temperature in the region of 20 0 C, to a solution of 2.05 g of benzyl 4 -[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate in 50 cm 3 of dichloromethane. After 30 minutes, a further 1.27 cm 3 of trifluoroacetic acid are added and, after a further 30 minutes, a further 1.27 cm 3 are added. The reaction is completed by a final addition of 1.27 cm 3 of trifluoroacetic acid. After one hour, the reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is taken up in 50 cm 3 of ethyl acetate and 20 cm 3 of water. After addition of 5 g of potassium carbonate and stirring for 5 minutes, phases are allowed to separate by settling and the organic phase separated out is washed with twice 10 cm 3 of distilled water and then with 20 cm 3 of aqueous 10% (by weight) sodium chloride solution. After drying over magnesium sulfate and then filtration, the organic solution is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography, under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-63 H; diameter cm; height 30 cm), eluting with a mixture of 378 dichloromethane/methanol/32% aqueous ammonia (89/10/1 by volume), and collecting 40-cm 3 fractions. Fractions 14 to 23 are combined and then concentrated to dryness under the above conditions. 1.36 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate are obtained in the form of a beige-colored solid melting at 0
C.
Infra-red spectrum (KBr) 2960; 1721; 1621; 1503; 1232; 1115; 829 and 744 cm-.
Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- (tert-butyloxycarbonyl)-piperidine-4-carboxylate.
1.98 g of benzyl 4-allyl-l-(tertbutyloxycarbonyl)piperidine-4-carboxylate are cooled to a temperature in the region of -30 0 C and 11.32 cm 3 of a solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran are added with stirring and under an inert atmosphere. After the addition, the temperature of the mixture is brought to about 20 0 C. The solution obtained is stirred for a further 4 hours, followed by addition of 40 cm 3 of dioxane, 0.183 g of diphenylphosphinoferrocenepalladium chloride, 2 g of 4-bromo-3chloro-6-methoxyquinoline and 3.0 g of tribasic potassium phosphate. After stirring for 16 hours at a temperature in the region of 600C, the reaction mixture is cooled to about 200C and then filtered. The insoluble material is washed with 3 times 20 cm 3 of ethyl acetate and the 379 filtrate and washing waters are then combined and stirred with 40 cm 3 of water and 100 cm 3 of ethyl acetate. The organic phase is separated out by settling, washed with twice 20 cm 3 of water and then with 40 cm 3 of aqueous (by weight) sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography, under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-63 Il; diameter cm; height 30 cm), eluting with a mixture of dichloromethane/methanol (98.5/1.5 by volume) and collecting 35-cm 3 fractions. Fractions 22 to 29 are combined and then concentrated under the above conditions. 2.09 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl) piperidine-4-carboxylate are obtained in the form of a thick yellow oil.
Infra-red spectrum (CC1 4 2930; 1728; 1695; 1622; 1503; 1230; 1172; 833 and 697 cm 1 Benzyl 4-allyl-l-(tert-butyloxycarbonyl)piperidine-4carboxylate.
15.4 g of potassium carbonate and then 10.6 cm 3 of benzyl bromide are added, at a temperature in the region of 20 0 C, with stirring and under an inert atmosphere, to a solution of 20 g of 4-allyl-l-(tert- 380 butyloxycarbonyl)piperidine-4-carboxylic acid in 200 cm 3 of dimethylformamide. The mixture is stirred for 16 hours at about 200C and then filtered. The insoluble material is washed with twice 100 cm 3 of ethyl acetate. The filtrate and the washing waters are combined, 250 cm 3 of water are added and the mixture is then extracted once with 500 cm 3 and once with 150 cm 3 of ethyl acetate. The organic extracts are combined, washed with twice 125 cm 3 of aqueous 10% (by weight) sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. An oil is obtained, which is purified by chromatography, under a pressure of 100 kPa of nitrogen, on a column of silica gel (particle size 40-63 p; diameter 7 cm; height 30 cm), eluting with a mixture of dichloromethane/methanol (99/1 by volume) and collecting 200-cm 3 fractions. Fractions 6 to 16 are combined and concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 400C. 25 g of benzyl 4allyl-l-(tert-butyloxycarbonyl)piperidine-4-carboxylate are obtained in the form of a pale yellow liquid.
Infra-red spectrum (CH 2 C1 2 2980; 1725; 1683; 1426; 1171; 1142; 974 and 924 cm 4-Allyl-- (tert-butyloxycarbonyl)piperidine-4-carboxylic acid.
4.44 cm 3 of water and then 30.62 g of ethyl 4- 381 allyl-1-(tert-butyloxycarbonyl)-piperidine-4-carboxylate predissolved in 150 cm 3 of tetrahydrofuran are added, with stirring and under an inert atmosphere, to a mixture of 48.52 g of potassium tert-butoxide in 350 cm 3 of tetrahydrofuran, cooled to a temperature in the region of 0°C. After allowing the temperature to return to the region of 20 0 C, the mixture is stirred for 24 hours at this temperature. 300 cm 3 of ice-cold water are added to the reaction mixture and the mixture is then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The aqueous residue is extracted with 300 cm 3 of diethyl ether. After leaving to stand for 16 hours, the aqueous phase is acidified at a pH in the region of 3-4 by addition of about 215 cm 3 of aqueous hydrochloric acid, and is then extracted with 3 times 300 cm 3 of diethyl ether. The ether extracts are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 400C. 26.1 g of 4-allyl-1- (tert-butyloxycarbonyl)piperidine-4-carboxylic acid are obtained in the form of an off-white solid.
Mass spectrum: El m/z=269 m/z=168 (M C5H902) m/z=124(m/z=168 CO2) m/z=57 C 4 H9 base peak 382 Ethyl allyl-1-(tert-butyloxycarbonyl)piperidine-4carboxylate.
cm 3 of a solution of butyllithium in hexane concentration) are added, with stirring and under an inert atmosphere, to 150 cm 3 of tetrahydrofuran cooled to a temperature in the region of -70 0 C, followed by addition of 50 cm 3 of tetrahydrofuran and 23 cm 3 of diisopropylamine predissolved in 300 cm 3 of tetrahydrofuran. After a further addition of 50 cm 3 of tetrahydrofuran, the mixture is stirred for 15 minutes at about -70 0 C, followed by addition of 45.15 g of ethyl de 1-(tert-butyloxycarbonyl)isonipecotate predissolved in 400 cm 3 of tetrahydrofuran, and finally 50 cm 3 of this same solvent. After stirring the mixture for 1 hour at a temperature in the region of -70 0 C, 16.7 cm 3 of allyl bromide predissolved in 150 cm 3 of tetrahydrofuran are added and the mixture is then warmed to about 20 0 C and stirred for 17 hours. The mixture is poured into 200 cm 3 of saturated aqueous ammonium chloride solution and then extracted with about 2 liters of ethyl acetate. The combined extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. An oil is obtained, which is purified by chromatography, under a nitrogen pressure of 100 kPa, on a column of silica gel (diameter 12 cm; height 50 cm), eluting with a mixture of dichloromethane/methanol (99.5/0.5 by volume) and 383 collecting 200-cm 3 fractions. Fractions 20 to 84 are combined and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. 27.85 g of ethyl 4-allyl-l-(tert-butyloxycarbonyl)-piperidine-4carboxylate are obtained in the form of a yellow oil.
Mass spectrum: El m/z=297 M m/z=240 (M C4H9) m/z=196(m/z=240 CO 2 m/z=168 (m/z=240 C0 2 Et) m/z=124 (m/z=168 C0 2 m/z=57 C 4
H
9 base peak Ethyl 1-(tert-butyloxycarbonyl)isonipecotate.
88.3 cm 3 of triethylamine are added over 1 hour, with stirring and under an inert atmosphere, to a solution of 100 g of ethyl isonipecotate in 1500 cm 3 of dichloromethane cooled to a temperature in the region of 0 C, followed, over the same time, by addition of 166.6 g of di-tert-butyl dicarbonate predissolved in 300 cm 3 of dichloromethane. The reaction mixture is stirred for 16 hours while allowing the temperature to return to the region of 20 0 C. After a further addition of 41.6 g of ditert-butyl dicarbonate dissolved in 70 cm 3 of dichloromethane, the reaction mixture is stirred for 3 hours at about 20 0 C and then washed with twice 600 cm 3 of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0
C.
384 171 g of ethyl l-(tert-butyloxycarbonyl)isonipecotate are obtained in the form of a brown oil.
Mass spectrum: DCI m/z=275 MNH4' base peak m/z=258 MH' 2-(2-Bromoethylsulfanyl)thiophene may be prepared according to Sadykhov, Aliev, S.M. and Seidov, M.M. Khim. Geterotsikl. Soedin, 3, 344-5 (1975).
4-Bromo-3-chloro-6-methoxyquinoline.
A mixture of 20 g of 3-chloro-4-hydroxy-6methoxyquinoline in 1000 cm 3 of acetonitrile, to which is added 80.8 g of triphenylphosphine bromide, is stirred for 2 hours 30 minutes at a temperature in the region of 0 C. The solution obtained is cooled to the region of 0 C and then stirred for 16 hours at this same temperature. The reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C and the evaporation residue is then taken up in 200 cm 3 of saturated aqueous sodium hydrogen carbonate solution and 200 cm 3 of ethyl acetate. The organic phase is separated out after settling has taken place and is washed with twice 200 cm 3 of distilled water. The aqueous phase is extracted once more with ethyl acetate and the organic extracts are then combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. A product is obtained, which is purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel 385 (diameter 7.5 cm; mass of silica 700 eluting with a mixture of cyclohexane/ethyl acetate (70/30 by volume).
The fractions corresponding to the expected product are collected. These fractions are combined and then concentrated under the same conditions as above. 20.7 g of 4-bromo-3-chloro-6-methoxyquinoline are obtained in the form of a white solid melting at 108 0
C.
Mass spectrum: El m/z=271 M base peak m/z=256 (M CH 3 m/z=228 (m/z=256 CO) m/z=149 (m/z=228 Br)* m/z=114(m/z=149 C1) 3-Chloro-4-hydroxy-6-methoxyquinoline.
14.26 g of N-chlorosuccinimide are added, at a temperature in the region of 200C and with stirring, to a mixture of 17 g of 4-hydroxy-6-methoxyquinoline in 700 cm 3 of acetic acid and the mixture is then heated at a temperature of between 50 and 70 0 C for 4 hours. The solution obtained is subsequently cooled to about 20 0
C
and then concentrated to dryness under reduced pressure kPa) at a temperature in the region of 400C. The solid residue is taken up in 250 cm 3 of saturated aqueous sodium hydrogen carbonate solution. The mixture is stirred for 1 hour. The insoluble material is filtered off and washed with 3 times 250 cm 3 of water. The crystals obtained are dried under reduced pressure Pa) for 3 hours at a temperature in the region of 386 200C. 20 g of 3-chloro-4-hydroxy-6-methoxyquinoline are obtained in the form of a yellow solid.
Mass spectrum: El m/z=209 M" base peak m/z=194 (M CH 3 m/z=166 (m/z=194 CO).
4-Hydroxy-6-methoxyquinoline.
A suspension of 53.5 g of 4-hydroxy-6-methoxyquinoline-3-carboxylic acid in 1000 cm 3 of diphenyl ether is heated with stirring, at a temperature of between 2500C and 260 0 C, for 2 hours 45 minutes. The reaction mixture is cooled to about 20 0 C. After stirring for 16 hours at this temperature, the mixture is poured with stirring into 1 liter of pentane and then filtered. The cake obtained is washed with 3 times 100 cm 3 of pentane and then with 3 times 100 cm 3 of diisopropyl ether. After drying in air, 37 g of 4-hydroxy-6-methoxyquinoline are obtained in the form of a beige-colored solid.
Mass spectrum: DCI m/z=176 MH base peak 4-Hydroxy-6-methoxyquinoline-3-carboxylic acid can be prepared according to B.R. Baker and Ray R.
Bramhall, J. Med. Chem. 15, 230 (1972).
Example 2 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluorophenoxy)ethyl]piperidine-4-carboxylic acid.
387 A mixture of 0.7 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine-4-carboxylate in 10 cm 3 of aqueous hydrochloric acid is stirred for 5 hours at a temperature in the region of 100 0 C. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 400C.
The residue obtained is purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-63 diameter 2.5 cm; height 35 cm), eluting with a mixture of dichloromethane/methanol/28% aqueous ammonia (89/10/1 by volume) and collecting 25-cm 3 fractions. Fractions 16 to 25 are collected. These fractions are combined and then concentrated under the above conditions. The evaporation residue obtained is slurried in 10 cm 3 of diisopropyl ether. The resulting crystalline product is filtered off, washed with twice cm 3 of the same solvent and air-dried. 0.37 g of 4-[3- (3-chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,5difluorophenoxy)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid melting at 2040C.
H NMR spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.20 to 2.15 (mt: 10H); 2,62 J 5.5 Hz: 2H); from 2.65 to 2.80 (mt: 2H); 3.18 (mt: 2H); 3.96 3H); 4.08 J 5.5 Hz: 2H); from 6.60 to 6.85 (mt: 3H); 7.38 J 2.5 Hz: 1H); 7.46 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.68 1H).
388 Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- [2-(3,5-difluorophenoxy)ethyl]piperidine-4-carboxylate.
A suspension composed of 1.36 g of benzyl 4-[3- (3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4carboxylate, 0.95 g of l-(2-bromoethoxy)-3,5-difluorobenzene (90 pure) and 0.5 g of potassium carbonate in cm 3 of acetonitrile is heated at a temperature in the region of 80 0 C for 16 hours, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20 0 C, the reaction mixture is filtered and the insoluble material is washed with acetonitrile. The filtrate and the washing waters are combined and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-63 p; diameter 3.5 cm; height 45 cm), eluting with a mixture of dichloromethane/methanol (97/3 by volume) and collecting 40-cm 3 fractions. Fractions 18 to 23 are collected. These fractions are combined and then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. 1.56 g of benzyl 4- [3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluorophenoxy)ethyl]piperidine-4-carboxylate are obtained in the form of an orange-colored oil.
Infra-red spectrum (CH 2 C1 2 2955; 1723; 1622; 1599; 1229; 1153; 1116 and 843 cm 389 Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 1.
Example 3 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-(2cyclohexylethyl)piperidine-4-carboxylic acid.
A mixture of 0.6 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-(2-cyclohexylethyl) piperidine-4-carboxylate in 9.6 cm 3 of aqueous hydrochloric acid is heated at a temperature in the region of 100 0 C with stirring for 5 hours. The solution obtained is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue obtained is slurried in diisopropyl ether. The resulting crystalline product is filtered off, washed with the same solvent and oven-dried at a temperature in the region of 60 0 C, under reduced pressure (10 Pa). A solid is obtained, which is purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-63 p; diameter 2.5 cm; height 40 cm), eluting with a mixture of dichloromethane/methanol/32% aqueous ammonia (89/10/1 by volume), and collecting 25-cm 3 fractions. Fractions 16 to 25 are combined and then concentrated under reduced pressure kPa) at a temperature in the region of 40 0 C. A 390 crystalline product is obtained, which is stirred in cm 3 of diisopropyl ether. The product obtained is filtered off, washed with the same solvent and air-dried.
0.33 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]- 1-(2-cyclohexylethyl)piperidine-4-carboxylic acid is obtained in the form of a white solid melting at 234 0
C.
1H NMR spectrum (300 MHz, CD30D-d 4 8 in ppm): from 0.95 to 2.20 2.42 from 2.90 to 3.15 and from 3.30 to 3.50 (respectively, mt, broad d, J 13.5 Hz, mt and mt: 29H in total); 4.11 3H); 7.52 (mt: 2H); 8.02 (broad d, J 9 Hz: 1H); 8.68 1H).
Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- (2-cyclohexylethyl)piperidine-4-carboxylate.
0.56 cm 3 of 2-cyclohexylethyl bromide and 0.5 g of potassium carbonate are added, with stirring and under an inert atmosphere, at a temperature in the region of 0 C, to a solution of 1.36 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate in 50 cm 3 of acetonitrile. The suspension obtained is heated at about 80 0 C for 16 hours and, after cooling to a temperature in the region of 200C, the reaction mixture is filtered and concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0
C.
The residue obtained is purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-63 g; diameter 3.5 cm; height 45 cm), 391 eluting with a mixture of dichloromethane/methanol (97/3 by volume) and collecting 40-cm 3 fractions. Fractions 22 to 30 are combined and concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. 1.33 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2-cyclohexylethyl)piperidine-4carboxylate are obtained in the form of an orange-colored oil.
Infra-red spectrum (CC1 4 2925; 1727; 1622; 1503; 1230; 1116; 833 and 697 cm Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate was prepared in Example 1.
Example 4 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-(3phenylpropyl)piperidine-4-carboxylic acid dihydrochloride.
0.5 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)-piperidine-4carboxylate in 8 cm 3 of 5M hydrochloric acid is heated at a temperature in the region of 100 0 C, with stirring, for hours. After cooling to about 20 0 C, the reaction mass is concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. The evaporation residue obtained is taken up in 6 cm 3 of a mixture of 392 dichloromethane/methanol (90/10 by volume) and the mixture is again concentrated to dryness under the above conditions. A foam is obtained, which is slurried in cm 3 of diisopropyl ether. The crystalline product formed is filtered off, washed with three times 5 cm 3 of the same solvent and dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 50 0
C.
0.46 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]- 1-(3-phenylpropyl)piperidine-4-carboxylic acid dihydrochloride is obtained in the form of a beigecolored solid.
H NMR spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.40 to 2.25 and from 2.50 to 3.60 (mts: 20H in total); 3.96 3H); from 7.10 to 7.45 (mt: 5H); 7.39 J 2.5 Hz: 1H); 7.47 (dd, J 9 and 2.5 Hz: 1H); 7.98 J 9 Hz: 1H); 8.70 1H); [lacuna] Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- (3-phenylpropyl)piperidine-4-carboxylate.
A mixture composed of 1.36 g of benzyl chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4carboxylate, 0.55 cm 3 of l-bromo-3-phenylpropane and g of potassium carbonate in 45 cm 3 of acetonitrile is heated with stirring and under an inert atmosphere for 16 hours at a temperature in the region of 80 0 C. After cooling, the reaction mixture is filtered and the insoluble material is then washed with acetonitrile. The 393 filtrate is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0
C.
An oil is obtained, which is purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-63p; diameter 3.5 cm; height cm), eluting with a mixture of dichloromethane/methanol (97/3 by volume) and collecting 40-cm 3 fractions. Fractions 21 to 25 are combined and then concentrated as above. 21 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-4-carboxylate are obtained in the form of an orange-colored viscous oil.
Infra-red spectrum (CH 2 C1 2 2948; 2812; 1722; 1622; 1504; 1229; 1118; 1029 and 834 cm Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 1.
Example 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2- (pyrid-2-yl)thioethyl]piperidine-4-carboxylic acid trihydrochloride.
A mixture of 0.4 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-l-[2-(pyrid-2-yl)thioethyl]piperidine-4-carboxylate in 7 cm 3 of aqueous hydrochloric acid is maintained at a temperature in the 394 region of 100 0 C, with stirring and under an inert atmosphere, for 4 hours. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0
C.
The residue obtained is taken up in 10 cm 3 of a mixture of dichloromethane/methanol (90/10 by volume). The mixture is concentrated to dryness under the above conditions. 0.45 g of 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]-l-[2-(pyrid-2-yl)thioethyl]piperidine-4carboxylic acid trihydrochloride is obtained in the form of a foam melting with decomposition at 132 0
C.
H NMR spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.59 (mt: 2H); from 1.65 to 1.95 (mt: 4H); 2.20 (broad d, J 13.5 Hz: 2H); 2.86 (mt: 2H); from 3.10 to 3.65 (mt: 8H); 3.99 3H); 7.19 (broad dd, J 7,5 and 4.5 Hz: 1H); from 7.35 to 7.50 (mt: 2H); 7.50 (dd, J 9 and 3 Hz: 1H); 7.71 (resolved t, J 7,5 and 1.5 Hz: 1H); 8.01 J 9 Hz: 1H); 8.48 (broad d, J 4.5 Hz: 1H); 8.74 1H); 10.70 (multiplet: 1H).
Ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2- (2-pyrid-2-yl)thioethyl]piperidine-4-carboxylate.
Ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-pyrid-2-yl)thioethyl]piperidine-4carboxylate is prepared by analogy with the method described in Example 1, starting with ethyl 395 chloro-6-methoxyquinolin-4-yl )propyl] piperidine-4carboxylate hydrochloride.
Infra-red spectrum (CCl 4 :2955; 1726; 1622; 1580; 1503; 1414; 1229; 1125; 1030 and 833 cm- 1 Ethyl 4- (3-chloro-6-methoxyquinolin-4-yl )propyl] piperidine-4-carboxylate hydrochloride.
A mixture of 2.6 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl) propyl] (ert-butyloxycarbonyl) piperidine-4-carboxylate in 40 cm 3 of dioxane, to which is added 14 cm 3 of 4 N hydrochloric dioxane, is stirred for 16 hours at a temperature in the region of 200C. The suspension obtained is diluted by addition of 100 cm 3 of diethyl ether, stirred at about 200W for 1 hour and then filtered. The cake is washed with twice 40 cm 3 of diethyl ether and then dried in a desiccator under reduced pressure (5 kPa). 1.9 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl) propyllpiperidine-4-carboxylate are obtained in the form of a white solid.
Infra-red spectrum 2965; 2474; 1720; 1620; 1584; 1416; 1241; 1119; 1019; 872 and 743 cm-.
Ethyl 4- (3-chloro-6-methoxyguinolin-4-yl)propyl] -1- (tert-butyloxycarbony piperidine-4-carboxylate.
30 cm 3 of a 0.5M solution of 9-borabicyclof3.3.1]nonane in tetrahydrofuran are added to a solution of 2.96 g of ethyl 4-allyl-l-(tert-butyloxycarbonyl)- 396 piperidine-4-carboxylate in 30 cm 3 of tetrahydrofuran, stirred at a temperature in the region of -100C under an inert atmosphere, while keeping the temperature below 0°C. After the addition, the temperature of the mixture is brought to about 20 0 C and the mixture is then stirred for a further 4 hours. 3.1 g of 4-bromo-3-chloro-6methoxyquinoline are added, followed by 50 cm 3 of dioxane, 6.4 g of tribasic potassium phosphate and 0.22 g of diphenylphosphinoferrocene palladium chloride. The reaction mixture is heated at a temperature in the region of 50 0 C for 16 hours. After cooling to a temperature in the region of 20 0 C, the mixture is filtered and the cake is then washed with 3 times 50 cm 3 of ethyl acetate. The filtrate is washed with 100 cm 3 of water and then with twice 50 cm 3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure kPa), at a temperature in the region of 40 0 C. A brown oil is obtained, which is purified by chromatography, under a pressure of 50 kPa of nitrogen, on a column of silica gel (particle size 20-45 p; diameter 4.5 cm; height 42 cm), eluting with a mixture of cyclohexane/ethyl acetate (80/20 by volume). The fractions containing the expected product are collected. These fractions are combined and then concentrated under reduced pressure kPa) at a temperature in the region of 40 0 C. 2.62 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-l- 397 (tert-butyloxycarbonyl)piperidine-4-carboxylate are obtained in the form of a yellow oil.
Infra-red spectrum: (CH 2 C1 2 1720; 1682; 1622; 1504; 1423; 1367; 1229; 1174; 1027 and 834 cm 1 Ethyl 4-allyl-l-(tert-butyloxycarbonyl)piperidine-4-carboxylate was prepared in Example 1.
Example 6 Sodium salt of 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]-l-heptylpiperidine-4-carboxylic acid.
A mixture of 0.48 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-l-heptylpiperidine-4carboxylate in 7 cm 3 of aqueous 5 M hydrochloric acid is maintaied at a temperature in the region of 100 0 C, with stirring and under an inert atmosphere, for 6 hours.
After cooling to about 200C, the reaction mixture is stirred for 24 hours and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40 0
C.
The residue obtained is purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-60 g; diameter 2.5 cm, height 35 cm), eluting with a mixture of dichloromethane/methanol/aqueous ammonia (84/15/1 by volume) and collecting 40-cm 3 fractions. Fractions 19 to 24 are combined and then concentrated as above. The solid obtained is stirred in cm 3 of diisopropyl ether, filtered and washed with 398 3 times 5 cm 3 of diisopropyl ether. 0.35 g of the sodium salt of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1heptylpiperidine-4-carboxylic acid is obtained in the form of a solid melting at 223 0
C.
H NMR spectrum (300 MHz, (CD 3 2 SO-d 6 E in ppm): 0.87 J 7 Hz: 3H); from 1.10 to 1.45 (mt: 12H); from 1.45 to 1.70 (mt: 4H); from 1.85 to 2.05 (mt: 2H); 1.97 (broad d, J 10.5 Hz: 2H); 2.17 (broad t, J 7.5 Hz: 2H); from 2.45 to 2.60 (mt: 2H); 3.15 (mt: 2H); 3.97 3H); 7.40 (mt: 1H); 7.44 (dd, J 9 and 3 Hz: 1H); 7.95 J 9 Hz: 1H); 8.66 1H) Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1heptylpiperidine-4-carboxylate.
1.36 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate and 0.5 g of potassium carbonate are added, at a temperature in the region of 20 0 C, with stirring and under an inert atmosphere, to a solution of 0.61 cm 3 of 1-iodoheptane in 45 cm 3 of acetonitrile. After heating for 18 hours at a temperature in the region of 80 0 C, a further 1.17 cm 3 of 1-iodoheptane are added. After heating for 40 hours at a temperature in the region of 800C, the reaction mixture is cooled to about 200C, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 500C. The residue obtained is purified by chromatography under a nitrogen pressure of 100 kPa, on a 399 column of silica gel (particle size 40-60 g; diameter cm; height 35 cm), eluting with a mixture of dichloromethane/methanol (95/05 by volume) and collecting 3 fractions. Fractions 18 to 26 are combined and then concentrated as above. 0.36 g of benzyl chloro-6-methoxyquinolin-4-yl)propyl]-1-heptylpiperidine- 4-carboxylate is obtained.
Infra-red spectrum (CH 2 C1 2 2957; 2931; 1722; 1622; 1504; 1229; 1159; 1118; [lacuna] Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared as described in Example 1.
Example 7 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2- (cyclopentylthio)ethyl]piperidine-4-carboxylic acid dihydrochloride.
A mixture of 0.55 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-4-carboxylate in 8 cm 3 of aqueous 6 N hydrochloric acid is heated at a temperature in the region of 100 0 C, with stirring and under an inert atmosphere, for 5 hours. After stirring for 18 hours at a temperature in the region of 20 0 C, the solution obtained is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation 400 residue obtained is taken up in 10 cm 3 of a mixture of dichloromethane/methanol (90/10 by volume) and then concentrated under the same conditions as above. 0.59 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-l-[2- (cyclopentylthio)ethyl]piperidine-4-carboxylic acid dihydrochloride is obtained in the form of a foam melting at 129 0 C with softening.
1 H NMR spectrum: (300 MHz, (CD 3 2 SO-d 6 E in ppm): from 1.30 to 2.10 (mt: 14H); 2.15 (broad d, J 13.5 Hz: 2H); from 2.65 to 3.00 (mt: 4H); from 3.05 to 3.40 (mt: 5H); 3.46 (broad d, J= 12 Hz: 2H); 3.97 (s: 3H); 7.42 J 2.5 Hz: 1H); 7.48 (dd, J 9 and Hz: 1H); 7.99 J 9 Hz: 1H); 8.72 1H); from 10.55 to 10.90 (multiplet: 1H).
Ethyl 4-[3-(3-chloro-6-methoxyguinolin-4-yl)propyl]-1-[2- (cyclopentylthio)ethyl]piperidine-4-carboxylate.
1.2 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.51 g of potassium carbonate and 0.61 g of potassium iodide are added, at a temperature in the region of 20 0 C, with stirring and under an inert atmosphere, to a solution of 0.607 g of (2-chloroethylthio)cyclopentane in 50 cm 3 of acetonitrile. After heating for 20 hours at a temperature in the region of 800C, the reaction mixture is cooled to about 20 0 C, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 0
C.
401 The residue obtained is purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-60 g; diameter 3.5 cm), eluting with a mixture of [lacuna] 35-cm 3 [lacuna]. Fractions 25 to 31 are combined and then concentrated as above. 0.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-l-[2- (cyclopentylthio)ethyl]piperidine-4-carboxylate is obtained.
Infra-red spectrum (CC1 4 958; 1726; 1622; 1503; 1229; 1117; 1030 and 833 cm Ethyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared as described in Example Example 8 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2thien-2-yl)thioethyl]piperidine-4-acetic acid.
Working in a manner analogous to that of the preceding examples, 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]-l-[2-(2-thien-2-yl)thioethyl]piperidine-4acetic acid is prepared.
'H NMR spectrum (300 MHz, (CD 3 2 SO-d 6 D in ppm): from 1.30 to 1.70 (mt: 8H); 2.14 2H); 2.33 (mt: 4H); from 2.45 to 2.60 (mt: 2H); 2.92 (broad t, J 7 Hz: 2H); 3.13 (mt: 2H); 3.96 3H); 7.05 (dd, J 5.5 and Hz: 1H); 7.18 (dd, J 3.5 and 1 Hz: 1H); 7.39 J 402 3 Hz: 1H); 7.44 (dd, J 9 and 3 Hz: 1H); 7.60 (dd, J= and 1 Hz: iH); 7.95 J 9 Hz: 1H); 8.66 1H).
Example 9 (3-Chloro-6-methoxyquinolin-4-yl)propyl [2- (cyclopentylthio) ethyl] piperidine-4-yllmethanol.
Working in a manner analogous to that of the preceding examples, (3-chloro-6-methoxyquinoiin-4yl)propy] (cyclopentylthio) ethyllpiperidine-4yilrnethanol is prepared.
1 H NMR spectrum (300 MHz, (CD 3 2 S0-d 6 C. in ppm): from 1.15 to 1.75 (mt: 14H); 1.95 (mt: 2H); from 2.20 to 2.40 (mt: 4H); 2.44 Cmt: 2H); 2.57 (mt: 2H); from 3.05 to 3.25 (mt: 5H); 3.97 3H); 4.38 J 5.5 Hz: 1H); 7.38 J 3 Hz: 1H); 7.45 (dd, J =9 and 3 Hz: 1H); 7.96 J =9 Hz: 1H); 8.68 1H) Example 4- (3-Chloro-6-methoxycauinolin-4-yl)propyl phenyipropyl )piperidine-4-yl ]methanol.
Working in a manner analogous to that of the preceding examples, 4- (3-chloro-6-methoxyquinolin-4yi)propyl] (3-phenylpropyl)piperidine-4--yllmethanol is prepared.
403 H NMR spectrum (300 MHz, (CD 3 2 SO-d 6 E in ppm): 1.59 (mt: 2H); from 1.65 to 1.95 (mt: 4H); 2.20 (broad d, J 13.5 Hz: 2H); 2.86 (mt: 2H); from 3.10 to 3.65 (mt: 8H); 3.99 3H); 7.19 (broad dd, J 7.5 and 4.5 Hz: 1H); from 7.35 to 7.50 (mt: 2H); 7.50 (dd, J 9 and 3 Hz: 1H); 7.71 (resolved t, J 7.5 and 1.5 Hz: 1H); 8.01 J 9 Hz: 1H); 8.48 (broad d, J 4.5 Hz: 1H); 8.74 1H); 10.70 (multiplet: 1H).
Example 11 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2- (thien-2-yl)thioethyl]piperidine-4-carboxylic acid A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-l-[2-(thien-2-yl)thioethyl]piperidine-4-carboxylate in 5 cm 3 of aqueous hydrochloric acid and 3 cm 3 of dioxane is maintained at a temperature in the region of 100 0 C with stirring and under an inert atmosphere for 20 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The mixture is filtered and then chromatographed, under atmospheric pressure, on a column of silica gel (particle size 40-63 g; diameter 1.5 cm; mass 55 eluting with a mixture of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and collecting 15-cm 3 fractions. Fractions 5 to 12 are 404 combined and then concentrated to dryness under the above conditions. 0.26 g of 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-4carboxylic acid is obtained in the form of a white crystalline solid melting at 180 0
C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 1.31 (very broad J 13 Hz: 2H); from 1.50 to 1.70 (mt: 4H); from 1.85 to 2.05 (mt: 4H); 2.45 (broad t, J 7 Hz: 2H); 2.60 (broad d, J 11 Hz: 2H); 2.91 (broad t, J 7 Hz: 2H); 3.04 (very broad t, J 6 Hz: 2H); 3.96 3H); 7.04 (dd, J 5 and 3.5 Hz: 1H); 7.17 (dd, J and 1 Hz: 1H); 7.35 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.60 (dd, J 5 and 1 Hz: 1H); 7.97 J 9 Hz: 1H); 8.70 (broad s: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyguinolin-4-yl)propyl]-1-[2- (thien-2-yl)thioethyl]piperidine-4-carboxylate A mixture of 0.8 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.6 g of 2-(2-bromoethylthio)thiophene and 1.5 g of potassium carbonate in 10 cm 3 of acetonitrile is heated for 18 hours at a temperature in the region of 80 0 C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in dichloromethane and water. The 405 organic phase is washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under the above conditions.
The residue is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 l; diameter 3 cm; mass 50 eluting with a mixture of ethyl acetate/petroleum ether (40-65 0 C) (75/25 by volume) and collecting 30-cm 3 fractions. Fractions 3 to 5 are combined and then concentrated to dryness under the above conditions. 0.7 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-l-[2-(thien-2yl)thioethyl]piperidine-4-carboxylate is obtained in the form of a thick colorless oil.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 0.99 J 7 Hz: 3H); 1.34 (very broad t, J 12 Hz: 2H); from 1.45 to 1.65 (mt: 4H); from 1.85 to 2.00 (mt: 4H); 2.44 (broad t, J 7 Hz: 2H); 2.59 (broad d, J 11.5 Hz: 2H); 2.89 (broad t, J 7 Hz: 2H); 3.03 (very broad t, J 6.5 Hz: 2H); 3.94 3H); 3.96 J 7 Hz: 2H); 7.02 (dd, J 5 and 3.5 Hz: 1H); 7.16 (dd, J and 1 Hz: 1H); 7.32 J 2.5 Hz: 1H); 7.39 (dd, J 9 and 2.5 Hz: 1H); 7.58 (dd, J 5 and 1 Hz: 1H); 7.96 J 9 Hz: 1H); 8.69 (broad s: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl] piperidine-4-carboxylate 2 cm 3 of trifluoroacetic acid are added, with stirring and under an inert atmosphere, at a temperature 406 in the region of 5 0 C, to a solution of 0.5 g of ethyl 4- [3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-(tertbutyloxycarbonyl)piperidine-4-carboxylate in 10 cm 3 of dichloromethane. After 45 minutes, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is taken up in diethyl ether and washed with a saturated potassium bicarbonate solution and then with a saturated potassium carbonate solution. The organic phase is washed with twice 5 cm 3 of water and then with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
0.26 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate is obtained in the form of a thick oil.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.02 J 7 Hz: 3H); 1.28 (mt: 2H); from 1.45 to 1.70 (mt: 4H); 1.90 (broad d, J 13.5 Hz: 2H); 2.46 (broad t, J 12 Hz: 2H); 2.79 (d mt, J 12 Hz: 2H); 3.06 (broad t, J 6 Hz: 2H); 3.95 3H); 3.98 J 7 Hz: 2H); 7.35 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.70 J 1 Hz: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyguinolin-4-yl)propyl]-1- (tert-butyloxycarbonyl)piperidine-4-carboxylate 1.4 g of ethyl 4-allyl-l-(tert-butyloxycarbonyl)piperidine-4-carboxylate are cooled to a 407 temperature in the region of -30 0 C and 11 cm 3 of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran are added, with stirring and under an inert atmosphere.
After the addition, the temperature of the mixture is returned to about 20 0 C. The solution obtained is stirred for a further 4 hours, followed by addition of 0.09 g of palladium diphenylphosphinoferrocene chloride, 1.4 g of 4-iodo-3-fluoro-6-methoxyquinoline and 2.5 g of tribasic potassium phosphate. After stirring for 16 hours at a temperature in the region of 600C, the reaction mixture is cooled to about 20 0 C and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in ethyl acetate and water, the phases are separated by settling and the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C.
The residue obtained is purified by chromatography, under atmospheric pressure, on a column of silica gel (particle size 70-200 g; diameter 4.5 cm; mass 125 eluting with a mixture of dichloromethane/ethyl acetate (98/2 by volume), and collecting 20-cm 3 fractions. Fractions 98 to 170 are combined and then concentrated to dryness under the above conditions. 1.5 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-l-(tertbutyloxycarbonyl)piperidine-4-carboxylate are obtained in the form of a thick brown oil.
408 IH NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.02 J 7 Hz: 3H); 1.30 (mt:2H); 1.39 9H); from 1.45 to 1.70 (mt: 4H); 1.92 (broad d, J 13.5 Hz: 2H); 2.81 (mt: 2H); 3.05 (broad t, J 6.5 Hz: 2H); 3.69 (broad d, J 13.5 Hz: 2H); 3.95 3H); 4.00 (q, J 7 Hz: 2H); 7.34 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.70 J 1 Hz: 1H).
4-Iodo-3-fluoro-6-methoxyquinoline 1.8 cm 3 of diisopropylamine in 80 cm 3 of tetrahydrofuran are cooled to a temperature in the region of -75 0 C and 7.7 cm 3 of a 1.6 M solution of butyl lithium in hexane are added, with stirring and under an inert atmosphere. After stirring for 20 minutes at a temperature in the region of -75 0 C, a solution of 2.2 g of 3-fluoro-6-methoxyquinoline in 20 cm 3 of tetrahydrofuran is added. The solution obtained is stirred for a further 4 hours, followed by addition of a solution of 3.3 g of double-sublimated iodine in 10 cm 3 of tetrahydrofuran. After stirring for 2 hours at a temperature in the region of 20 0 C, the reaction mixture is hydrolyzed with 200 cm 3 of a 90/10 tetrahydrofuran/water mixture and then 100 cm 3 of a saturated sodium chloride solution and 150 cm 3 of ethyl acetate. The mixture is washed with 3 times 80 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, 409 filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is purified by chromatography, under atmospheric pressure, on a column of silica gel (particle size 70-200 p; diameter 5 cm; height 35 cm), eluting with a mixture of 90/10 petroleum ether/ethyl acetate.
Fractions 66 to 95 are combined and then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. 0.9 g of 4-iodo-3-fluoro-6methoxyquinoline is obtained in the form of a creamcolored solid.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 4.00 3H); 7.31 J 2.5 Hz: 1H); 7.47 (dd, J 9 and 2.5 Hz: 1H); 8.01 J 9 Hz: 1H); 8.64 1H).
3-Fluoro-6-methoxyquinoline A mixture of 1.35 g of 4-chloro-3-fluoro-6methoxyquinoline, 1.1 cm 3 of triethylamine and 100 mg of palladium-on-charcoal in 23 cm 3 of methanol is stirred at a temperature in the region of 20 0 C under a pressure of 2 bar of hydrogen for 18 hours. The reaction mixture is filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 p; diameter 3 cm; mass 40 eluting with dichloromethane/ethyl acetate (95/5 by volume). The 410 fractions containing the product are combined and then concentrated to dryness according to the above conditions. 1 g of 3-fluoro-6-methoxyquinoline is obtained.
1 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 5 in ppm): 3.92 3H); 7.40 (mt: 2H); 8.07 J 9 Hz: 1H); 8.04 (dd, J 10 and 3 Hz: 1H); 8.77 J 3 Hz: 1H).
4-Chloro-3-fluoro-6-methoxyquinoline 1.3 cm 3 of diisopropylamine in 50 cm 3 of tetrahydrofuran are cooled to a temperature in the region of -75 0 C and 5.8 cm 3 of a 1.6 M solution of butyl lithium in hexane are added, with stirring and under an inert atmosphere. After stirring for 20 minutes at a temperature in the region of -75 0 C, a solution of 1.2 g of 4-chloro-6-methoxyquinoline in 20 cm 3 of tetrahydrofuran is added. The solution obtained is stirred for a further 4 hours, followed by addition of a solution of 2.9 g of N-fluorobenzene sulfonimide in 10 cm 3 of tetrahydrofuran. After stirring for 2 hours at a temperature in the region of 20 0 C, the reaction mixture is hydrolyzed with 200 cm 3 of a 90/10 tetrahydrofuran/water mixture and then 100 cm 3 of a saturated sodium chloride solution and 150 cm 3 of ethyl acetate. The mixture is washed with 3 times 80 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced 411 pressure (2 kPa) at a temperature in the region of 400C.
The residue obtained is purified by chromatography, under atmospheric pressure, on a column of silica gel (particle size 70-200 p; diameter 4 cm; mass 100 eluting with dichloromethane. The fractions containing the product are combined and then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 400C.
0.4 g of 4-chloro-3-fluoro-6-methoxyquinoline is obtained.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 4.01 3H); 7.43 J 2.5 Hz: 1H); 7.52 (dd, J 9 and 2.5 Hz: 1H); 8.07 J 9 Hz: 1H); 8.91 J 1 Hz: 1H).
4-Chloro-6-methoxyquinoline A mixture of 12 g of 4-hydroxy-6-methoxyquinoline in 50 cm 3 of [lacuna] oxychloride [lacuna] inert atmosphere, for 2 hours. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C and then hydrolyzed with ice and brought to pH 10 using a 5 N sodium hydroxide solution. The mixture is extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is chromatographed, under atmospheric pressure, on a column of silica gel 412 (particle size 70-200 eluting with a mixture of dichloromethane/methanol (85/15 by volume). The fractions containing the product are combined and then concentrated to dryness according to the above conditions. 12 g of 4chloro-6-methoxyquinoline are obtained in the form of a white solid melting at 82 0
C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 3.958 3H); 7.45 J 2.5 Hz: 1H); 7.53 (dd, J 9 and 2.5 Hz: 1H); 7.76 J 4.5 Hz: 1H); 8.04 J 9 Hz: 1H); 8.70 J 4.5 Hz: 1H).
The ethyl 4-allyl-l-(tert-butyloxycarbonyl)piperidine-4-carboxylate was prepared in Example 1.
The 4-hydroxy-6-methoxyquinoline was prepared as described in Example 1.
Example 12 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluoro-6-phenoxy)ethyl]piperidine-4-carboxylic acid A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluoro-6phenoxy)ethyl]piperidine-4-carboxylate in 6 cm 3 of aqueous 5N hydrochloric acid and 10 cm 3 of dioxane is maintained at a temperature in the region of 1000C, with stirring and under an inert atmosphere, for 20 hours.
After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at 413 a temperature in the region of 40 0 C. The residue obtained is chromatographed, at atmospheric pressure, on a column of silica gel (particle size 70-200 g; diameter 1.5 cm; mass 50 eluting with a mixture of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and collecting 15-cm 3 fractions. Fractions 10 to 15 are combined and then concentrated to dryness according to the above conditions. 0.2 g of 4-[3-(3-Fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluoro-6phenoxy)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid melting at 175 0
C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.33 (very broad t, J 13 Hz: 2H); from 1.50 to 1.70 (mt: 4H); 1.95 (broad d, J 13 Hz: 2H); 2.05 (broad t, J 11.5 Hz: 2H); 2.60 J 6 Hz: 2H); 2.69 (broad d, J 11.5 Hz: 2H); 3.04 (mt: 2H); 3.96 3H); 4.06 (t, J 6 Hz: 2H); from 6.65 to 6.85 (mt: 3H); 7.34 (d, J 2.5 Hz: 1H); 7.39 (dd, J 9 and 2.5 Hz: 1H); 7.96 J 9 Hz: 1H); 8.69 (broad s: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyguinolin-4-yl)propyl]-1-[2- (3,5-difluoro-6-phenoxy)ethyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl] piperidine-4-carboxylate, 0.3 g of 1-(2-bromoethoxy)-3,5-difluorobenzene, 0.18 g of potassium iodide and 0.74 g of potassium carbonate in cm 3 of acetonitrile is heated for 18 hours at a 414 temperature in the region of 75 0 C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in ethyl acetate and water. The organic phase is washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under the above conditions. The residue is purified by chromatography, under atmospheric pressure, on a column of silica gel (particle size 200 g; diameter 1.5 cm; mass 35 eluting with dichloromethane. Fractions 7 to 11 are combined and then concentrated to dryness according to the above conditions. 0.4 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluoro-6-phenoxy)ethyl]piperidine-4-carboxylate is obtained in the form of a thick colorless oil.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.00 J 7 Hz: 3H); 1.38 (very broad t, J 12 Hz: 2H); from 1.45 to 1.70 (mt: 4H); from 1.90 to 2.10 (mt: 4H); 2.60 J 6 Hz: 2H); 2.69 (very broad d, J 12 Hz: 2H); 3.05 (very broad t, J 6.5 Hz: 2H); 3.95 (s: 3H); 3.98 J 7 Hz: 2H); 4.06 J 6 Hz: 2H); from 6.65 to 6.85 (mt: 3H); 7.34 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.70 (broad s: 1H).
415 The ethyl 4-allyl-l-(tert-butyloxycarbonyl)piperidine-4-carboxylate is prepared in Example 1.
The 1-(2-bromoethoxy)-3,5-difluorobenzene may be obtained by applying the method described in Example 16.
Example 13 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2- (2,3,5-trifluoro-6-phenoxy)ethyl]piperidine-4-carboxylic acid dihydrochloride A mixture of 1 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluoro-6phenoxy)ethyl]piperidine-4-carboxylate in 50 cm 3 of aqueous 5N hydrochloric acid is maintained at a temperature in the region of 100 0 C with stirring for hours. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in 50 cm 3 of acetone, filtered, washed with 3 times 15 cm 3 of [lacuna] and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40 0 C. 0.88 g of chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluoro-6-phenoxy)ethyl]piperidine-4-carboxylic acid dihydrochloride is obtained in the form of a white solid melting at 170 0
C.
416 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.45 to 2.30 (mt:8H); from 2.85 to 3.70 (mt: 8H); 3.97 3H); 4.50 (mt: 2H); 7.15 (mt: 2H); 7.40 (d, J 3 Hz: 1H 7.46 (dd, J 9 and 3 Hz: 1H); 7.97 (d, J 9 Hz: 1H); 8.69 1H); 10.07 (unresolved peak: 1H); from 12.50 to 13.10 (broad unresolved peak: 1H).
Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- [2-(2,3,5-trifluoro-6-phenoxy)ethyl]piperidine-4carboxylate A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate hydrochloride, 0.9 g of 1-(2-bromoethoxy)-2,3,5-trifluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm 3 of acetonitrile is heated for 18 hours at a temperature in the region of 750C with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20 0 C, the reaction mixture is filtered and washed with 3 times 30 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 g; diameter 3 cm; height: 27 cm), eluting with ethyl acetate and collecting 50-cm 3 fractions. Fractions 9 to 23 are combined and then concentrated to dryness according to the above 417 conditions. 1.27 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl 5-trifluoro-6-phenoxy) ethyllpiperidine-4-carboxylate are obtained in the form of a thick yellow oil.
1 H NNR Spectrum (300 MHz, (CD 3 2 S0-d 6 8 in ppm) from 1.30 to 1.60 (mt: 4H); 1.72 (mt: 2H); from 1.95 to 2.15 (mt: 4H); 2.64 J 5.5 Hz: 2H); 2.71 (dunresolved peak, J 12 Hz: 2H); 3.13 (broad t, J Hz: 2H); 3.93 3H); 4.16 J 5.5 Hz: 2H); 5.04 (s: 2H); from 6.95 to 7.15 (mt: 2H); from 7.20 to 7.30 (mt: 7.34 J 3 Hz: 1H); 7.45 (dd, J 9 and 3 Hz: 1H); 7.97 J 9 Hz: 1H); 8.67 1H).
Benzyl 4- (3-chloro-6-methoxyquinolin-4-yl)propyl] piperidine-4 -carboxylate hydrochloride A mixture of 17.4 g of benzyl 1-tertbutyloxycarbonyl-4- (3-chloro-6-methoxyquinolin-4yl)propyllpiperidine-4-carboxylate in 75 cm 3 of hydrochloric acid dissolved in dioxane and 200 cm 3 of dioxane is stirred at a temperature in the region of 20 0
C
for 20 hours. 200 cm 3 of diethyl ether are added to the reaction mixture. The precipitate formed is filtered off to give 14.26 g of benzyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl) propyl] piperidine-4-carboxylate hydrochloride.
H NMR Spectrum (300 MHz, (CD 3 2 S0-d 6 8 in ppm): 1.49 (mt: 2H); from 1.65 to 1.85 (mt: 4H1); 2.11 418 (d-unresolved peak J 14 Hz: 2H); 2.78 (mt: 2H); from 3.10 to 3.25 (mt: 2H); 3.20 (broad t, J 7.5 Hz: 2H); 3.96 3H); 5.09 2H); 7.28 (mt: 5H); 7.43 (d, J 3 Hz: 1H); 7.53 (dd, J 9 and 3Hz: 1H); 8.06 (d, J 9 Hz: 1H); 8.80 1H); from 9.05 to 9.30 (unresolved peak: 2H).
1-(2-Bromoethoxy)-2,3,5-trifluorobenzene A mixture of 11.4 g of 2,3,5-trifluorophenol, 40.5 cm 3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 200 cm 3 of acetonitrile is heated for 18 hours at a temperature in the region of 75 0 C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20 0 C, the reaction mixture is filtered and washed with 4 times 50 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in 150 cm 3 of petroleum ether (40-65 0 filtered and washed with 3 times 30 cm 3 of petroleum ether (40-65 0 The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 g; diameter 5 cm; height: 33 cm), eluting with petroleum ether (40-650C) and collecting 100-cm 3 fractions. Fractions 28 to 63 are combined and then 419 concentrated to dryness according to the above conditions. 16.15 g of l-(2-bromoethoxy)-2,3,5trifluorobenzene are obtained in the form of a thick colorless oil.
1 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 3.83 (broad t, J 5.5 Hz: 2H); 4.45 (broad t, J Hz: 2H); from 7.00 to 7.15 (mt: 2H).
The benzyl 4-allyl-l-(tert-butyloxycarbonyl)piperidine-4-carboxylate was prepared in Example 1.
Example 14 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluoro-6-phenylthio)ethyl]piperidine-4-carboxylic acid A mixture of 1.3 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluoro-6- [lacuna]piperidine-4-carboxylate in 15 cm 3 of aqueous hydrochloric acid and 15 cm 3 of dioxane is maintained at a temperature in the region of 100 0 C with stirring and under an inert atmosphere for 20 hours. After cooling to about 20 0 C, the reaction mixture is evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up 4 times in toluene, evaporating between each washing. The oil obtained is taken up in a chloroform/methanol/aqueous ammonia mixture (12/3/0.5 by volume), the phases are separated by settling and the organic phase is washed 420 with water and then left to crystallize for 20 hours. The solid obtained is filtered off and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 400C. 0.6 g of chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluoro- 6-phenylthio)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white crystalline solid melting at 2050C.
H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.39 (unresolved peak: 2H); 1.55 (mt: 2H); 1.70 (mt: 2H); from 1.90 to 2.20 (mt: 4H); from 2.40 to 2.85 (broad unresolved peak: 4H); from 3.05 to 3.25 (mt: 2H); 3.17 (broad t, J 7.5 Hz: 2H); 3.96 3H); 7.07 (mt: 1H); 7.26 (mt: 1H); 7.33 (mt: 1H); 7.38 J 2.5 Hz: 1H); 7.46 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.68 1H); from 12.00 to 12.50 (unresolved peak: 1H).
Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- [2-(2,5-difluoro-6-phenylthio)ethyl]piperidine-4carboxylate A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.9 g of l-(2-bromoethylthio)-2,5-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm 3 of acetonitrile is heated for 18 hours at a temperature in the region of 750C, with stirring and under an inert atmosphere. After cooling to a temperature 421 in the region of 200C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is taken up in water and extracted with ethyl acetate.
The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness as above. The residue obtained is purified by chromatography, under atmospheric pressure, on a column of silica gel (particle size 70-200 g; diameter 2.5 cm; mass: 50 eluting with a mixture of ethyl acetate and dichloromethane (05/95 by volume) and collecting 15-cm 3 fractions. Fractions 21 to 100 are combined and then concentrated to dryness according to the above conditions. 1.35 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluoro-6phenylthio)ethyl]piperidine-4-carboxylate are obtained in the form of a white solid melting at 950C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.30 to 1.60 (mt: 4H); 1.71 (mt: 2H); from 1.85 to 2.05 (mt: 4H); from 2.40 to 2.60 (mt: 2H); 2.66 (d-unresolved peak, J 12 Hz: 2H); from 3.05 to 3.20 (mt: 2H); 3.11 (broad t, J 7.5 Hz: 2H); 3.92 3H); 5.03 2H); 7.04 (mt: 1H); from 7.15 to 7.35 (mt: 7H); 7.35 J 3 Hz: 1H); 7.44 (dd, J 9 and 3 Hz: 1H); 7.95 J 9 Hz: 1H); 8.66 1H).
1-(2-Bromoethylthio)-2,5-difluorobenzene 422 A mixture of 5.8 g of dimethyl thiocarbamate in 80 cm 3 of a 10% solution of potassium hydroxide in methanol is heated for 1 hour at a temperature in the region of 100 0 C with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in water, extracted with diethyl ether and then acidified with 40 cm 3 of 5N hydrochloric acid. The aqueous phase is extracted with twice 30 cm 3 of diethyl ether. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and then concentrated to dryness as above. The residue obtained is taken up in 30 cm 3 of 1,2-dibromoethane and 0.5 g of aliquat 336, followed by addition of 20 cm 3 of cold sodium hydroxide solution. The solution obtained is stirred for a further 18 hours at a temperature in the region of 20 0 C and then washed with twice 15 cm 3 of water. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and then concentrated to dryness as above. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 g; diameter 2.5 cm; mass: 75 eluting with petroleum ether and collecting 3 fractions. Fractions 4 to 13 are combined and then 423 concentrated to dryness according to the above conditions. 4.4 g of l-(2-bromoethylthio)-2,5-difluorobenzene are obtained in the form of a colorless fluid oil.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 3.50 (mt: 2H); 3.66 (mt: 2H); 7.15 (mt: 1H); 7.32 (doubled triplet, J 9 and 4.5 Hz: 1H); 7.42 (ddd, J 9-6.5 and 3 Hz: 1H).
Dimethyl 2 g of dimethyl carbamate are heated at a temperature in the region of 2350C for 40 minutes. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 p; diameter 3 cm; mass: eluting with a mixture of petroleum ether and dichloromethane (50/50 by volume) and collecting 15-cm 3 fractions. Fractions 6 to 11 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 1.25 g of dimethyl are obtained in the form of a white solid melting at 96 0
C.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 2.96 (unresolved peak: 3H); 3.08 (unresolved peak: 3H); from 7.35 to 7.50 (mt: 3H).
424 Dimethyl 14.1 g of dimethylthiocarbamate chloride and 13 g of 1,4-diaza[2.2.2]tricyclooctane are added with stirring to a solution of 7.5 g of 2,5-difluorophenol in 120 cm 3 of dimethylformamide. After stirring for 1 hour at a temperature in the region of 20 0 C, the reaction mixture is taken up in 1 dm 3 of water and 100 cm 3 of dry concentrated hydrochloric acid, and extracted with 400 cm 3 of diethyl ether. The organic phase is dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 v; diameter 10 cm; mass: 400 eluting with a mixture of petroleum ether and dichloromethane (50/50 by volume). The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 400C. 12.4 g of dimethyl O-(2,5)-difluorophenylthiocarbamate are obtained in the form of a solid melting at 620C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 3.35 3H); 3.40 3H); from 7.15 to 7.30 (mt: 2H); 7.42 (doubled triplet, J 9.5 and 5.5 Hz: 1H).
The benzyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate hydrochloride was prepared in Example 13.
425 Example 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,6difluorophenoxy)ethyl]piperidine-4-carboxylic acid dihydrochloride A mixture of 1 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,6-difluorophenoxy)ethyl]piperidine-4-carboxylate in 50 cm 3 of aqueous hydrochloric acid is maintained at a temperature in the region of 1000C, with stirring and under an inert atmosphere for 20 hours. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is taken up in 50 cm 3 of acetone and then stirred for 1 hour at a temperature in the region of 0 C. The mixture is filtered, washed with 3 times 15 cm 3 of acetone and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 400C. 0.86 g of 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1-[2-(2,6-difluorophenoxy)ethyl]piperidine-4carboxylic acid dihydrochloride is obtained in the form of a white solid melting at 218 0
C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm) 1.59 (mt: 2H); 1.75 (mt: 2H); 1.82 (very broad t, J 14 Hz: 2H); 2.22 (broad d, J 14 Hz: 2H); 2.98 (mt: 2H); 3.22 (broad t, J 7.5 Hz: 2H); from 3.45 to 3.70 (mt: 4H); 3.98 3H); 4.51 J 5 Hz: 2H); from 7.15 to 426 7.25 (mt: 3H); 7.42 J 3 Hz: 1H); 7.48 (dd, J 9 and 3 Hz: 1H); 7.99 J 9 Hz: 1H); 8.72 1H); 10.66 (unresolved peak: 1H).
Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- [2-(2,6-difluorophenoxy)ethyl]piperidine-4-carboxylate A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.82 g of 1-(2-bromoethoxy)-2,6-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm 3 of acetonitrile is heated for 18 hours at a temperature in the region of 75 0 C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 200C, the reaction mixture is filtered and washed with three times 30 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C.
The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 p; diameter 3 cm; height: 27 cm), eluting with ethyl acetate and collecting 50-cm 3 fractions. Fractions 7 to 17 are combined and then concentrated to dryness under the above conditions. 1.65 g of benzyl chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,6difluorophenoxy)ethyl]piperidine-4-carboxylate are obtained in the form of a thick yellow oil.
427 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.25 to 1.55 (mt: 4H); 1.70 (mt: 2H); from 1.90 to 2.10 (mt: 4H); 2.59 J 6 Hz: 2H); 2.66 (d-unresolved peak, J 12 Hz: 2H); 3.13 (broad t, J 7.5 Hz: 2H); 3.93 3H); 4.14 J 6 Hz: 2H); 5.03 2H); from 7.05 to 7.20 (mt: 3H); 7.35 (mt: 5H); 7.35 J 3 Hz: 1H); 7.46 (dd, J 9 and 3 Hz: 1H); 7.97 J 9 Hz: 1H); 8.67 1H).
1-(2-Bromoethoxy)-2,6-difluorobenzene A mixture of 10 g of 2,6-difluorophenol, 40.5 cm 3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 300 cm 3 of acetonitrile is heated for 18 hours at a temperature in the region of 75 0 C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20 0 C, the reaction mixture is filtered and washed with 3 times 30 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is taken up in 200 cm 3 of petroleum ether (40-650C), filtered and washed with 3 times 30 cm 3 of petroleum ether (40-65 0 The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 p; diameter 7 cm; height: 28 cm), eluting with 428 petroleum ether (40-65 0 C) and collecting 100-cm 3 fractions. Fractions 22 to 58 are combined and then concentrated to dryness under the above conditions.
14.5 g of l-(2-bromoethoxy)-2,6-difluorobenzene are obtained in the form of a thick colorless oil.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 3.76 (broad t, J 6 Hz: 2H); 4.42 (broad t, J 6 Hz: 2H); from 7.10 to 7.25 (mt: 3H).
The benzyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate hydrochloride was prepared in Example 13.
Example 16 4-[3-(3-Chloro-6-methoxyguinolin-4-yl)propyl]-1-[2-(2,5difluorophenoxy)ethyl]piperidine-4-carboxylic acid dihydrochloride A mixture of 1 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluorophenoxy)ethyl]piperidine-4-carboxylate in 50 cm 3 of 5N hydrochloric acid is maintained at a temperature in the region of 100 0 C, with stirring and under an inert atmosphere for 20 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is taken up in 50 cm 3 of acetone and then stirred for 1 hour at a temperature in the region of 429 0 C. The mixture is filtered, washed with 3 times 15 cm 3 of acetone and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 400C. 0.8 g of 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1- [2-(2,5-difluorophenoxy)ethyllpiperidine-4carboxylic acid dihydrochioride is obtained in the form of a white solid melting at 1800C.
IH NMR Spectrum (400 MHz, (CD 3 2 S0-d 6 6 in ppm): 1.58 (mt: 2H); 1.72 (mt: 2H); 1.84 (very broad t, J 14 Hz: 2H); 2.19 (broad d, J 14 Hz: 2H); 2.95 (mt: 2H); 3.22 (broad t, J 7.5 Hz: 2H); 3.53 (mt: 4H); 3.98 (s: 3H); 4.52 J =5 Hz: 2H); 6.84 (mt: 1H); 7.22 (ddd, J 9 -7and3 Hz: 1H);7.30 (ddd, J=l10.5 -9 and Hz: 1H); 7.42 J 2.5 Hz: 1H); 7.49 (dd, J 9 and 2.5 Hz: 1H); 8.00 J 9 Hz: 1H); 8.74 1H); 10.97 (unresolved peak: 1H).
Benzyl 4- (3-chloro-6-methoxyuiiolizi-4-yl )propyl] -1- 5-difluorophenoxy) ethyl] piperidine-4-carboxylate A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl )propyl] piperidine-4-carboxylate hydrochloride, 0.82 g of l-(2-bromoethoxy) benzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm 3 of acetonitrile is heated for 18 hours at a temperature in the region of 75 0 C with stirring and under an inert atmosphere. After cooling to a temperature in the region of 2000, the reaction mixture 430 is filtered and washed with 3 times 30 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 p; diameter 2.4 cm; height: 26 cm), eluting with ethyl acetate and collecting 3 fractions. Fractions 7 to 14 are combined and then concentrated to dryness under the above conditions. 1.6 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]- 1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylate are obtained in the form of a thick yellow oil.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): from 1.35 to 1.60 (mt: 4H); 1.73 (mt: 2H); from 1.95 to 2.15 (mt: 4H); 2.63 J 5.5 Hz: 2H); 2.72 (dunresolved peak, J 12 Hz: 2H); 3.14 (broad t, J Hz: 2H); 3.92 3H); 4.12 J 5.5 Hz: 2H); 5.04 (s: 2H); 6.75 (tripled triplet, J 9 and 3 Hz: 1H); 7.13 (ddd, J 10.5 7.5 and 3 Hz: 1H); from 7.20 to 7.30 (mt: 6H); 7.34 J 3 Hz: 1H); 7.45 (dd, J 9 and 3 Hz: 1H); 7.97 J 9 Hz: 1H); 8.67 1H).
1-(2-Bromoethoxy)-2,5-difluorobenzene A mixture of 10 g of 40.5 cm 3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 200 cm 3 of acetonitrile is heated for 18 hours at a temperature in the region of 75 0 C, with 431 stirring and under an inert atmosphere. After cooling to a temperature in the region of 200C, the reaction mixture is filtered and washed with 4 times 50 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in 150 cm 3 of petroleum ether (40-650C), filtered and washed with 3 times 30 cm 3 of petroleum ether (40-650). The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 p; diameter 7 cm; height: 49 cm), eluting with petroleum ether (40-65 0 C) and collecting 100-cm 3 fractions. Fractions 29 to 88 are combined and then concentrated to dryness under the above conditions.
13.5 g of l-(2-bromoethoxy)-2,5-difluorobenzene are obtained in the form of a colorless fluid oil.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 3.85 (broad t, J 6 Hz: 2H); 4.44 (broad t, J 6 Hz: 2H); 6.82 (mt: 1H); 7.18 (ddd, J 9 7 and 3 Hz: 1H); 7.29 (ddd, J 11 9 and 5 Hz: 1H).
The benzyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate hydrochloride was prepared in Example 13.
432 Example 17 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3difluorophenoxy)ethyl]piperidine-4-carboxylic acid dihydrochloride A mixture of 1 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,3-difluorophenoxy)ethyl]piperidine-4-carboxylate in 50 cm 3 of aqueous hydrochloric acid is maintained at a temperature in the region of 1000C, with stirring and under an inert atmosphere for 20 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C.
The residue obtained is taken up in 50 cm 3 of acetone and then stirred for 1 hour at a temperature in the region of 0 C. The mixture is filtered, washed with 3 times 15 cm 3 of acetone and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 400C. 0.9 g of 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1-[2-(2,3-difluorophenoxy)ethyl]piperidine-4carboxylic acid dihydrochloride is obtained in the form of a white solid melting at 2590C.
1H NMR Spectrum (400 MHz (CD 3 2 SO-d 6 8 in ppm): from 1.45 to 1.65 (mt: 2H); 1.73 (mt: 2H); 1.81 (very broad t, J 14 Hz: 2H); 2.20 (broad d, J 14 Hz: 2H); 2.97 (mt: 2H); 3.22 (broad t, J 7.5 Hz: 2H); from 3.45 to 3.60 (mt: 4H); 3.98 3H); 4.54 J 5 Hz: 2H); 433 7.09 (mt: 2H); 7.20 (mt: 1H); 7.42 J 2.5 Hz: 1H); 7.48 (dd, J 9 and 2.5 Hz: 1H); 7.99 J 9 Hz: 1H); 8.72 1H); 10.70 (unresolved peak: 1H); from 12.40 to 13.30 (broad unresolved peak: 1H).
Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- [2-(2,3-difluorophenoxy)ethyl]piperidine-4-carboxylate A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate hydrochloride, 0.82 g of 1-(2-bromoethoxy)-2,3-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm 3 of acetonitrile is heated for 18 hours at a temperature in the region of 750C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 200C, the reaction mixture is filtered and washed with 3 times 30 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 p; diameter 2.7 cm; height: 32 cm), eluting with ethyl acetate and collecting 3 fractions. Fractions 7 to 21 are combined and then concentrated to dryness under the above conditions. 1.6 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]- 1-[2-(2,3-difluorophenoxy)ethyl]piperidine-4-carboxylate are obtained in the form of a thick yellow oil.
434 1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.35 to 1.55 (mt: 4H); 1.72 (mt: 2H); from 1.95 to 2.15 (mt: 4H); 2.64 J 6 Hz: 2H); 2.72 (d-unresolved peak, J 12 Hz: 2H); 3.13 (broad t, J 7.5 Hz: 2H); 3.93 3H); 4.15 J 6 Hz: 2H); 5.04 2H); from 6.90 to 7.20 (mts: 3H); 7.25 (mt: 5H); 7.35 J 3 Hz: 1H); 7.46 (dd, J 9 and 3 Hz: 1H); 7.97 J 9 Hz: 1H); 8.67 1H).
1-(2-Bromoethoxy)-2,3-difluorobenzene A mixture of 10 g of 2,3-difluorophenol, 40.5 cm 3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 200 cm 3 of acetonitrile is heated for 48 hours at a temperature in the region of 75 0 C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 200C, the reaction mixture is filtered and washed with 6 times 30 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 p; diameter 7 cm; height: 42 cm), eluting with a mixture of dichloromethane and ethyl acetate (90/10 by volume) and collecting 100-cm 3 fractions. Fractions 4 to 10 are combined and then concentrated to dryness under the above conditions. The residue obtained is purified by chromatography under 435 atmospheric pressure, on a column of silica gel (particle size 20-45 p; diameter 5 cm; height: 30 cm), eluting with petroleum ether (40-650C) and collecting 100-cm 3 fractions. Fractions 34 to 82 are combined and then concentrated to dryness under the above conditions.
13.6 g of l-(2-bromoethoxy)-2,3-difluorobenzene are obtained in the form of a colorless fluid oil.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 3.85 (broad t, J 6 Hz: 2H); 4.44 (broad t, J 6 Hz: 2H); 6.82 (mt: 1H); 7.18 (ddd, J 9 7 and 3 Hz: 1H); 7.29 (ddd, J 11 9 and 5 Hz: 1H).
The benzyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate hydrochloride was prepared in Example 13.
Example 18 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-(2thiazole-2-thioethyl)piperidine-4-carboxylic acid A mixture of 0.3 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-(2-thiazole-2thioethyl)piperidine-4-carboxylate in 6 cm 3 of aqueous hydrochloric acid is maintained at a temperature in the region of 100 0 C, with stirring and under an inert atmosphere for 6 hours. After cooling and stirring for 16 hours at a temperature in the region of 200C, the reaction mixture is concentrated to dryness under reduced 436 pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is taken up in 10 cm 3 of dichloroethane containing 10% methanol, and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 40-60 p; diameter 2.5 cm; height: 30 cm), eluting with a dichloroethane/methanol/aqueous ammonia mixture (89/10/1 by volume). Fractions 18 to 41 are combined and then concentrated to dryness under the above conditions. The residue obtained is taken up in 5 cm 3 of isopropyl ether, filtered and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 400C. 0.24 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2thiazole-2-thioethyl)piperidine-4-carboxylic acid is obtained in the form of a white solid melting at 200 0
C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.34 (mt: 2H); 1.55 (mt: 2H); 1.69 (mt: 2H); from 1.85 to 2.15 (mt: 4H); 2.59 (broad t, J 7 Hz: 2H); 2.67 (dunresolved peak, J 12 Hz: 2H); 3.17 (broad t, J 6 Hz: 2H); from 3.20 to 3.50 (mt: 2H); 3.96 3H); 7.38 (broad s: 1H); 7.45 (broad dd, J 9 and 2.5 Hz: 1H); 7.63 J 3 Hz: 1H); 7.71 J 3 Hz: 1H); 7.96 (d, J 9 Hz: 1H); 8.68 1H); from 11.90 to 12.55 (very broad unresolved peak: 1H).
437 Ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2thiazole-2-thioethyl)piperidine-4-carboxylate 0.28 g of 2-mercaptothiazole, 0.33 g of potassium carbonate and 0.39 g of potassium iodide are added to a solution of 0.9 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-l-(2-chloroethyl)piperidine- 4-carboxylate in 50 cm 3 of acetonitrile at a temperature in the region of 20 0 C, with stirring and under an inert atmosphere. After heating for 20 hours at a temperature in the region of 80 0 C, the reaction mixture is cooled to about 20 0 C, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The residue obtained is purified by chromatography under a pressure of 100 kPa of nitrogen, on a column of silica gel (particle size 40-60 p; diameter 3.5 cm; height 35 cm), eluting with a dichloromethane/methanol mixture (95/0.5 by volume) and collecting 40-cm 3 fractions. The fractions containing the product are combined and then purified by chromatography under a pressure of 100 kPa of nitrogen, on a column of silica gel (particle size 40-60 p; diameter 3.5 cm; height 30 cm), eluting with an ethyl acetate/cyclohexane mixture (75/25 by volume) and collecting 30-cm 3 fractions. Fractions 23 to 40 are combined and then concentrated to dryness as previously. 0.75 g of ethyl 4- [3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2- 438 thiazole-2-thioethyl)piperidine-4-carboxylate is obtained.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.05 J 7 Hz: 3H); 1.38 (mt: 2H); 1.52 (mt: 2H); 1.68 (mt: 2H); from 1.90 to 2.05 (mt: 4H); 2.59 J 7 Hz: 2H); 2.68 (broad d, J 12 Hz: 2H); 3.17 (broad t, J 7.5 Hz: 2H); from 3.25 to 3.40 (mt: 2H); 3.97 (s: 3H); 4.00 J 7 Hz: 2H); 7.38 J 2.5 Hz: 1H); 7.46 (dd, J 9 and 2.5 Hz: 1H); 7.63 J 3.5 Hz: 1H); 7.71 J 3.5 Hz: 1H); 7.96 J 9 Hz: 1H); 8.68 1H).
Ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2chloroethyl)piperidine-4-carboxylate 1.21 cm 3 of thionyl chloride are added to a solution of 1.8 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2-hydroxyethyl)piperidine-4carboxylate in 40 cm 3 of dichloromethane with stirring, at a temperature in the region of 20 0 C. After stirring for 48 hours at a temperature in the region of 20 0 C, the reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 0 C. The residue is taken up in 50 cm 3 of water and 50 cm 3 of ethyl acetate with vigorous stirring at a temperature in the region of 20 0 C, followed by addition of 10 g of potassium carbonate. The organic phase is washed with 25 cm 3 of water and then with 25 cm 3 of saturated sodium chloride 439 solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 0 C. 1.8 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2chloroethyl)piperidine-4-carboxylate are obtained.
Infra-red Spectrum (CC1 4 2957; 1726; 1622; 1503; 1230; 1116; 1029 and 833 cm 1 Ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2hydroxyethyl)piperidine-4-carboxylate 3.9 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate and 2.07 g of potassium carbonate are added to a solution of 1.17 cm 3 of 2-iodoethanol in 80 cm 3 of acetonitrile, at a temperature in the region of 200C with stirring and under an inert atmosphere. After heating for 23 hours at a temperature in the region of 80 0 C, a further 1.17 cm 3 of 2-iodoethanol are added. After heating for 40 hours at a temperature in the region of 80 0 C, the reaction mixture is cooled to about 20 0 C, filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50 0 C. The residue obtained is purified by chromatography under a pressure of 100 kPa of nitrogen, on a column of silica gel (particle size 40-60 p; diameter 4 cm; height 60 cm), eluting with a dichloromethane/methanol/aqueous ammonia mixture (89/10/1 by volume) and collecting 50-cm 3 fractions. Fractions 14 440 to 17 are combined and then concentrated as previously.
1.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2-hydroxyethyl)piperidine-4-carboxylate are obtained.
Infra-red Spectrum (CC1 4 2439; 2952; 1726; 1622; 1503; 1230; 1116; 1029 and 833 cm 1 Example 19 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthioethyl)piperidin-4-yl]methanol dihydrochloride A mixture of 0.6 g of {4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidin-4yl}methanol dihydrochloride, 0.24 g of l-bromo-2- (cyclopentylthio)ethyl, 0.22 g of potassium iodide and 0.9 g of potassium carbonate in 25 cm 3 of acetonitrile is heated with stirring for 20 hours at a temperature in the region of 75 0 C. After cooling to a temperature in the region of 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in 20 cm 3 of water and then extracted with 3 times 20 cm 3 of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness as above. The residue obtained is purified by chromatography under a pressure of 50 kPa of nitrogen, on 441 a column of silica gel (particle size 20-45 g; diameter 3 cm; height: 18 cm), eluting with a dichloromethane/methanol mixture (90/10 by volume). The fractions containing the expected product are combined and then concentrated to dryness under the above conditions. The residue obtained is taken up in 5 cm 3 of acetone and then acidified with 3 cm 3 of a 1N solution of hydrogen chloride in diethyl ether. The suspension obtained is diluted with 20 cm 3 of diethyl ether, stirred at a temperature in the region of 20 0 C for 3 hours, filtered, washed with diethyl ether and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 400C. 0.4 g of 4-[3-(R,S)-hydroxy-3-(3-chloro- 6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthioethyl)piperidin-4-yl]methanol dihydrochloride is obtained in the form of a pale yellow solid melting at 120 0
C.
H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CD 3 COOD-d 4 at a temperature of 373K, 6 in ppm): from 1.20 to 2.15 (mt: 16H); 2.93 (broad t, J 7.5 Hz: 2H); from 3.10 to 3.30 (mt: 7H); 3.33 (broad s: 2H); 3.91 3H); 5.49 (mt: 1H); 7.41 (dd, J 9 and 3 Hz: 1H); 7.93 J 9 Hz: 1H); 8.22 (d, J 3 Hz: 1H); 8.60 1H).
442 (3-Chloro-6-methoxyquinolin-4-yl) CR,S) hydroxypropyl] piperidin-4 -yllmethanol dihydrochioride A mixture of 1.5 g of tert-butyl 4-(tertbutyldimethylsilanyloxymethyl) (3-chloro-6-methoxyquinolin-4-yl)-3-(R,S) -hydroxypropylilpiperidine-1carboxylate in 6.5 cm 3 of 5N hydrochloric acid dissolved in dioxane and 30 cm 3 of dioxane is stirred at a temperature in the region of 20 0 C for 17 hours. 100 cm 3 of diethyl ether are added to the reaction mixture. The precipitate formed is filtered off to give 1.24 g of {4- (3-chloro-6-methoxyquinolin-4-yl) S) -hydroxypropyl] piperidin-4-yllmethanol dihydrochloride in the form of a pale yellow solid.
1 H NNP. Spectrum (300 MHz, (CD 3 2 S0-d 6 8 in ppm): 1.20 to 2.10 (mt: 8H); from 2.85 to 3.10 (mt: 4H); 3.26 (broad s: 2H); 3.91 3H); 5.45 (mt: l1H); 7.47 (dd, J =9 and 3Hz:H); 7.98 J =9Hz:H);8.23 (d, J 3 Hz: 1H); from 8.60 to 8.80 (unresolved peak: 2H); 8.69 1H).
tert-Eutyl 4- (tert-butyldimethylsilanyloxymethyl) [3- (3-chloro-6-methoxyquinolin-4-yl) CR,B) -hydroxypropyl] piperidine-l-carboxylate A solution of 5.26 g of tert-butyl 4-(tertbutyldimethylsilanyloxymethyl) (3-chloro-6-methoxyquinolin-4-yl)propyllpiperidine-l-carboxylate in 300 cm 3 of dimethyl sulf oxide and 75 cm 3 of tert-butanol is 443 stirred under an oxygen-saturated atmosphere at a temperature in the region of 200C. After 5 minutes, a solution of 2.1 g of potassium tert-butoxide in 30 cm 3 of tert-butanol is added to the reaction mixture. After sparging with oxygen for 1 and a half hours, the reaction mixture is poured carefully onto a mixture of 300 g of ice, 300 cm 3 of water and 1.1 cm 3 of acetic acid. The aqueous phase is extracted with 3 times 300 cm 3 of dichloromethane. The organic phases are combined, washed with twice 300 cm 3 of water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under a pressure of 50 kPa of nitrogen, on a column of silica gel (particle size 20-45 diameter 4 cm; height: 27 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and then concentrated to dryness under the above conditions. 3.4 g of tert-butyl 4-(tertbutyldimethylsilanyloxymethyl)-4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]piperidine-l-carboxylate are obtained in the form of a white foam.
Mass spectrum: El m/z 578 M' m/z 521 C 26
H
38 ClN 2 05Si m/z 465 C 22
H
3 0ClN 2 05Si m/z 421 C 21
H
3 0ClN 2 0 3 Si base peak m/z 57 C 4
H
9 444 DCI m/z 579 MH' m/z 523 C 26
H
4 0ClN 2 05Si tert-Butyl 4-(tert-butyldimethylsilanyloxymethyl)-4-[3- (3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-lcarboxylate A mixture of 0.45 g of tert-butyl chloro-6-methoxyquinolin-4-yl)propyl]-4-hydroxymethylpiperidine-l-carboxylate, 0.3 g of tert-butyldimethylsilyl chloride, 0.17 cm 3 of triethylamine and 0.04 g of dimethylaminopyridine in 20 cm 3 of dichloromethane is stirred under an inert atmosphere at a temperature in the region of 20 0 C. After stirring for 18 hours, 0.3 g of tert-butyldimethylsilyl chloride, 0.04 g of dimethylaminopyridine and 0.2 cm 3 of triethylamine are added. The reaction mixture is taken up in 20 cm 3 of water. The aqueous phase is extracted with twice 20 cm 3 of dichloromethane. The organic phases are combined, washed with twice 300 cm 3 of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under a pressure of 50 kPa of nitrogen, on a column of silica gel (particle size 20-45 g; diameter 2.5 cm; height: 15 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined 445 and then concentrated to dryness under the above conditions. 0.48 g of tert-butyl 4-(tert-butyldimethylsilanyloxymethyl)-4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-l-carboxylate is obtained in the form of a colorless lacquer.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): -0.04 6H); 0.76 9H); 1.29 (mt: 4H); 1.39 9H); 1.58 (mt: 4H); 3.19 (mt: 2H); from 3.20 to 3.45 (mt: 6H); 3.95 3H); 7.41 J 3 Hz: 1H); 7.45 (dd, J 9 and 3 Hz: 1H); 7.95 J 9 Hz: 1H); 8.67 1H).
tert-Butyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]- 4-hydroxymethylpiperidine-l-carboxylate 1.05 g of lithium aluminum hydride is added portionwise, with stirring and under an inert atmosphere, to a solution of 12.3 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate in 250 cm 3 of tetrahydrofuran, at a temperature in the region of -20 0 C. After stirring for 2 hours at a temperature in the region of 200C, 0.5 g of lithium aluminum hydride is added to the reaction mixture at a temperature in the region of -20 0 C. After 1 and a half hours, the reaction mixture is cooled to 0°C and is then hydrolyzed by successive addition of 1.8 cm 3 of water, 1.3 cm 3 of 5N sodium hydroxide and 5.7 cm 3 of water. After stirring for 30 minutes at a temperature in the region of 20 0 C, the reaction mixture is filtered and 446 then washed with 400 cm 3 of ethyl acetate. The filtrate is washed with 200 cm 3 of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 10.9 g of tert-butyl 4- (3-chloro-6-methoxyquinolin-4-yl)propyl] -4-hydroxymethylpiperidine-l-carboxylate are obtained.
1 H MR Spectrum (300 M~Hz, (CD 3 2 S0-d 6 8 in ppm): 1.23 (mt: 2H); 1.32 (mt: 2H); 1.39 9H); 1.58 (mt: 4H); from 3.10 to 3.40 (mt: 6H); 3.22 J 5 Hz: 2H); 3.96 3H); 4.50 J 5 Hz: 1H); 7.40 J 3 Hz: 1H); 7.45 (dd, J 9 and 3 Hz: lH); 7.96 J 9 Hz: 1H); 8.68 lH).
The ethyl 4- (3-chloro-6-methoxyquinolin-4yl) propyl] -1-(tert-butyloxycarbonyl )piperidine-4carboxylate was prepared in Example Example 4-[3-(3-Chloro-6-methoxyquiziolin-4-yl)-3-(R,S)fluoropropyl (3 -phenyipropyl )piperidin-4-carboxylic acid A mixture of 0.5 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl) S) -fluoropropyl] -1-(3-phenylpropyl)piperidine-4-carboxylate in 8 cm 3 of aqueous hydrochloric acid is maintained at a temperature in the region of 100 0 C, with stirring for 6 hours. After 447 stirring for 18 hours at a temperature in the region of 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is taken up in 10 cm 3 of dichloromethane and filtered. The filtrate is concentrated to dryness as above, taken up in diisopropyl ether and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 0 C. The residue obtained is purified by chromatography under a pressure of 60 kPa of nitrogen, on a column of silica gel (particle size 20-45 diameter 2.5 cm; height: 40 cm); eluting with a mixture of dichloromethane/methanol/aqueous ammonia (83/15/2).
Fractions 13 to 20 are combined and then concentrated to dryness under the above conditions. 0.24 g of chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1- (3-phenylpropyl)piperidin-4-carboxylic acid is obtained in the form of a white solid melting at 2400C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.20 to 2.35 and from 2.40 to 2.70 (mts: 18H in total); 3.94 (broad s: 3H); 6.36 (2 mts, JHF 48 Hz: 1H); from 7.10 to 7.35 (mt: 5H); 7.52 (broad d, J 9 Hz: 1H); 7.57 (broad s: 1H); 8.02 (broad d, J 9 Hz: 1H); 8.75 (broad s: 1H).
448 Methyl 4 -[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)fluoropropyl]-1-(3-phenylpropyl)piperidine-4-carboxylate 0.31 cm 3 of diethylaminosulfur trifluoride is added to a solution of 0.66 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-(3-phenylpropyl)piperidine-4-carboxylate in 40 cm 3 of dichloromethane, with stirring and under an inert atmosphere, at a temperature in the region of -150C.
After stirring for 3 hours at a temperature in the region of 200C, 0.31 cm 3 of diethylaminosulfur trifluoride is added to the reaction mixture, followed by 20 cm 3 of saturated sodium hydrogen carbonate solution. The aqueous phase is extracted with 20 cm 3 of dichloromethane. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is purified by chromatography under a pressure of 100 kPa of nitrogen, on a column of silica gel (particle size 20-45 p; diameter 3.5 cm; height: 35 cm), eluting with a dichloromethane/methanol mixture Fractions 15 to 21 are combined and then concentrated to dryness according to the above conditions. 0.5 g of methyl 4-[3- (3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]- 1-(3-phenylpropyl)piperidine-4-carboxylate is obtained in the form of a brown oil.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 449 from 1.30 to 2.35 and from 2.50 to 2.80 (mts: 18H in total); 3.54 3H); 3.93 3H); 6.36 (ddd, JHF 48and 4.5 Hz: 1H); 7.19 (mt: 3H); 7.29 (broad t, J Hz: 2H); 7.52 (mt: 2H); 8.04 J 9 Hz: 1H); 8.75 (broad s: 1H).
Methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]-1-(3-phenylpropyl)piperidine-4-carboxylate A mixture of 1 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidine-4carboxylate, 0.58 g of l-bromo-3-phenylpropane and 0.53 g of potassium carbonate in 50 cm 3 of acetonitrile is heated for 22 hours at a temperature in the region of 0 C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20 0 C, the reaction mixture is filtered and washed with acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under a pressure of 100 kPa of nitrogen, on a column of silica gel (particle size 70-200 L; diameter 3.5 cm; height: 40 cm), eluting with dichloromethane/methanol (95/05). Fractions 21 to 48 are combined and then concentrated to dryness under the above conditions. 0.7 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-l-(3phenylpropyl)piperidine-4-carboxylate is obtained.
450 IH NMR Spectrum (300 MHz, (CD 3 2 S0-d 6 8 in ppm): from 1.20 to 2.35 and from 2.45 to 2.75 (mts: 18H in total); 3.48 3H); 3.88 3H); 5.40 (mt: 1H); 6.07 J 4 Hz: 1H); from 7.20 to 7.25 (mt: 3H); 7.27 (broad t, 1 7.5 Hz: 2H); 7.44 (dd, J 9 and 3 Hz: 1H); 9.96 J =9 Hz: 1H); 8.14 J 3 Hz: lH); 8.66 (s: 1H).
The methyl 4- (3-chloro-6-methoxyquinolin-4yl) -hydroxypropyllpiperidine-4-carboxylate was prepared in Example 49.
Example 21 Benzyl 4- (3-chloro-6-methoxyquinolin- 4-yl)propyl] 5-difluorophenylamino)ethylj piperidine-4-carboxylate is prepared in the form of a yellow oil.
1NMR Spectrum (300 MHz, (CD 3 2 S0-d 6 8 in ppm): from 1.35 to 1.60 (mt: 4H); 1.74 (mt: 2H); from 1.95 to 2.10 (mt: 4H); 2.40 J 7 Hz: 2H); from 2.60 to 2.75 (mt: 2H); 3.07 (mt: 2H); 3.15 (broad t, J 7.5 Hz: 2H); 3.94 3H); 5.05 2H); 6.05 (broad t, J 5 Hz: 1H); from 6.15 to 6.30 (mt: 3H); 7.27 (mt: 5H); 7.36 J= Hz: 1H); 7.47 (dd, J 9 and 2.5 Hz: 1H); 7.98 (d,J 9 Hz: 1H); 8.68 1H).
451 4-[3-(3-Chloro-6-methoxyuinolin-4-yl)propyl]-1-[2-(3,5difluorophenylamino)ethyl]piperidin-4-carboxylic acid A mixture of 0.73 g of benzyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylamino)ethyl]piperidine-4-carboxylate in 12 cm 3 of aqueous 5N hydrochloric acid is maintained at a temperature in the region of 1000C with stirring for hours. After cooling to about 20 0 C, the reaction mixture is evaporated under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The evaporation residue obtained is taken up in 50 cm 3 of acetone and is then concentrated to dryness under the same conditions as above. The foam obtained is purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 20-45 diameter 2.5 cm; height 38 cm), eluting with a mixture.of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume).
Fractions 31 to 46 are combined and then concentrated to dryness under .the same conditions as above. The powder obtained is dried in an oven under reduced pressure (0.1 kPa) at a temperature in the region of 400C. 0.28 g of 4 -[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-l-[2- (3,5-difluorophenylamino)ethyl]piperidin-4-carboxylic acid is obtained in the form of a pink-white solid melting at 210 0
C.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.45 (broad t, J 12.5 Hz: 2H); 1.56 (mt: 2H); 1.68 (mt: 452 2H); from 1.90 to 2.10 (mt: 4H); 2.41 J 6.5 Hz: 2H); 2.66 (broad d, J 12 Hz: 2H); 3.08 (mt: 2H); 3.18 (broad t, J 7.5 Hz: 2H); 3.97 3H); 6.08 (broad t, J Hz: 1H); from 6.15 to 6.30 (mt: 3H); 7.38 J 2.5 Hz: 1H); 7.45 (dd, J 9 and 2.5 Hz: 1H); 7.96 J 9 Hz: 1H: 1H); 8.68 1H).
Example 22 4-[3-(R,S)-Hydroxy-3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidin-4-yl methanol A mixture of 0.6 g of {4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidin-4yl} methanol dihydrochloride, 0.34 g of 2-(2-bromoethylthio)thiophene, 0.95 g of potassium carbonate and 0.23 g of potassium iodide in 25 cm 3 of acetonitrile is heated for 17 hours at a temperature in the region of 800C, with stirring and under an inert atmosphere. After cooling to a temperature in the region of 200C, the reaction mixture is diluted with 30 cm 3 of water and is then extracted with twice 30 cm 3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The oil obtained is purified by chromatography under a pressure of 50 kPa of argon, on a column of 453 silica gel (particle size 20-45 l; diameter 3 cm; height 27 cm), eluting with a mixture of dichloromethane/methanol (93/7 by volume). The fractions containing the product are combined and then concentrated to dryness under the above conditions. The oil obtained is acidified with 2 cm 3 of 1N hydrochloric ether, diluted with 20 cm 3 of diethyl ether and stirred for 1 hour at a temperature in the region of 20 0 C. The solid is filtered off, washed with diethyl ether and then dried in an oven under reduced pressure (10 kPa) at a temperature in the region of 40 0 C. 0.28 g of 4-[3-(R,S)-hydroxy-3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-thien-3-yl)thioethyl]piperidin-4-yl} methanol hydrochloride is obtained in the form of a yellow solid melting at 118 0 C and becoming pasty.
H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 8 in ppm).
A mixture of two diastereoisomers in 50/50 approximate proportions is observed.
from 1.35 to 2.10 (mt: 8H); from 2.85 to 3.60 (mt: 10H); 3.86 and 3.87 (2s: 3H in total); 5.41 (mt: 1H); from 5.80 to 6.30 (broad unresolved peak: 1H); 7.10 (mt: 1H); 7.29 (mt: 1H); 7.43 J 9 and 3 Hz: 1H); 7.70 (mt: 1H); 7.94 J 9 Hz: 1H); 8.19 (broad s: 1H); 8.64 1H); 9.48 (unresolved peak: 1H).
{4-[3-(3-Chloro-6-methoxyquinolin-4-yl)-3- (R,S)-hydroxypropyllpiperidin-4-yl} methanol dihydrochloride was prepared in Example 19.
454 Example 23 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-(3phenylpropyl)piperidine-4-carboxamide 15.6 cm 3 of a 0.5N solution of aqueous ammonia in dioxane, 0.26 g of l-hydroxybenzotriazole hydrate, 0.75 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 0.55 cm 3 of triethylamine are added to a mixture of 0.75 g of 4-[3-(3-chloro-6-methoxyquinolin- 4-yl)propyl]-1-(3-phenylpropyl)piperidine-4-carboxylic acid in the form of the sodium salt, in 20 cm 3 of dichloromethane. The suspension obtained is stirred for 17 hours at a temperature in the region of 200C. The reaction mixture is diluted with 25 cm 3 of water and stirred, and the phases are then separated by settling.
The aqueous phase is extracted with twice 25 cm 3 of dichloromethane and the organic extracts are combined, washed with 25 cm of brine, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The evaporation residue obtained is purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 20-45 p; diameter 3 cm; height 21 cm), eluting with a mixture of dichloromethane/methanol (90/10 by volume). The fractions containing the product are combined and then concentrated to dryness under the above conditions. 0.22 g of 455 chloro-6-methoxyquinolin-4-yl)propyl (3-phenyipropyl) piperidine-4-carboxamide is obtained in the form of a white solid melting at 160 0
C.
H NMR Spectrum (400 MHz, (CD 3 2 S0-d 6 6 in ppm): 1.33 (broad t, J 12 Hz: 2H); 1.53 (mt: 2H); 1.67 (mt: 4H); 1.98 (mt: 4H); 2.20 J 7.5 Hz: 2H); from 2.40 to 2.60 (mt: 4H); 3.15 J 7.5 Hz: 2H); 3.97 3H); 6.87 1H); 7.10 1H); 7.17 (mt: 1H); 7.20 (broad d, J 7.5 Hz: 2H); 7.27 (broad t, J 7.5 Hz: 2H); 7.37 (d, J =2.5 Hz: 1H); 7.45 (dd, J 9 and 2.5 Hz: 1H); 7.96 J 9 Hz: lH); 8.68 1H).
The (3-chloro-6-methoxyquinolin-4-yl)propyl (3-phenylpropyl)piperidine-4-carboxylic acid dihydrochloride was prepared in Example 4.
Example 24 4- (3-Chloro-6, 7-dimethoxyquinolin-4-yl)propyl] (thiophen-2-ylthio) ethyl] piperidine-4-carboxylic acid 26 cm 3 of aqueous 5N sodium hydroxide and 20 cm 3 of methanol are added to a solution of 1.47 g of ethyl 4- [3-(3-chloro-6,7-dimethoxyquinolin-4-yl)propyl]-1-[2- (thiophen-2-ylthio) ethyllpiperidine-4-carboxylate in cm 3 of dioxane, with stirring and at a temperature in the region of 20 0 C, and the mixture is then maintained at a temperature of about 700C for 21 hours. The reaction mixture is concentrated to dryness under reduced pressure 456 (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 40-63 p; mass 60 eluting with a mixture of dichloromethane/methanol/aqueous ammonia (12/3/0.5 by volume). Fractions 11 to 25 are-combined and then concentrated to dryness under the above conditions.
1.03 g of 4 -[3-(3-chloro-6,7-dimethoxyquinolin-4-yl)propyl]-l-[2-(thiophen-2-ylthio)ethyl]piperidine-4- .carboxylic acid is obtained in the form of a white solid melting at 214 0
C.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 1.27 (very broad t, J 12 Hz: 2H); from 1.45 to 1.75 (mt: 4H); from 1.85 to 2.10 (mt: 4H); 2.44 (mt: 2H); from 2.50 to 2.65 (mt: 2H); 2.89 (broad t, J 7.5 Hz: 2H); 3.13 (mt: 2H); 3.93 3H); 3.96 3H); 7.02 (dd, J 5.5 and 3.5 Hz: 1H); 7.15 (dd, J 3.5 and 1 Hz: 1H); 7.30 (broad s: 1 7.38 (broad s: 1H); 7.58 (dd, J 5.5 and 1Hz: 1H); 8.58 1H).
Ethyl 4-[3-(3-chloro-6,7-dimethoxyquinolin-4-yl)propyl]- 1-[2-(thiophen-2-ylthio)ethyl]piperidine-4-carboxylate A mixture of 1.65 g of ethyl 4-[3-(3-chloro- 6,7-dimethoxyquinolin-4-yl)piperidine-4-carboxylate, 1.16 g of 2-(2-bromoethylthio)thiophene, 1.63 g of potassium carbonate and 0.685 g of potassium iodide in cm 3 of acetonitrile is stirred for 23 hours at a 457 temperature in the region of 20 0 C. The suspension is filtered and the filtrate is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The evaporation residue is taken up in 50 cm 3 of ethyl acetate, washed with twice 50 cm 3 of water and with 40 cm 3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under the above conditions. The oil obtained is purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 40-63 p; diameter 4 cm), eluting with a mixture of dichloromethane/methanol/acetonitrile (95/2.5/2.5 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 1.47 g of 4-[3-(3-chloro-6,7-dimethoxyquinolin-4-yl)propyl]-1-[2-(thiophen-2-ylthio)ethyl]piperidine-4-carboxylic acid are obtained in the form of an oil.
1 H NMR spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 1.05 J 7 Hz: 3H); 1.37 (broad t, J 12 Hz: 2H); 1.52 (mt: 2H); from 1.60 to 1.75 (mt: 2H); from 1.85 to 2.05 (mt: 4H); 2.46 (mt: 2H); 2.61 (broad d, J 12 Hz: 2H); 2.91 (mt: 2H); 3.15 (broad t, J 7.5 Hz: 2H); 3.95 3H); 3.97 3H); 4.00 J 7 Hz: 2H); 7.04 (dd, J 5.5 and 3.5 Hz: 1H); 7.17 (dd, J 3.5 and 1 Hz: 1H); 7.31 (broad s: 1H); 7.40 (broad s: 1H); 7.60 (dd, J 458 and 1 Hz: 1H); 8.61 1H).
Ethyl 4-[3-(3-chloro-6,7-dimethoxyguinolin-4-yl)piperidine-4-carboxylate 3 cm 3 of trifluoroacetic acid are added dropwise to a mixture of 2.05 g of ethyl 4-[3-(3-chloro- 6,7-dimethoxyquinolin-4-yl)propyl]-l-(tertbutyloxycarbonyl)piperidine-4-carboxylate in 20 cm 3 of dichloromethane, with stirring and at a temperature in the region of 20 0 C. After 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is taken up in 20 cm 3 of water and 10 cm 3 of ethyl acetate, and then extracted with twice 10 cm 3 of aqueous 1N hydrochloric acid solution. The aqueous phase is basified with an aqueous 30% sodium hydroxide solution until the pH is about 10, and then extracted with 3 times 30 cm 3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness as above. 1.65 g of ethyl 4-[3-(3-chloro-6,7dimethoxyquinolin-4-yl)piperidine-4-carboxylate are obtained in the form of a yellow oil.
Mass Spectrum: El m/z 420 M+ m/z 364 C 19
H
23 C1N0 4 m/z 264 C 14 HisClNO 2 m/z 237
C
12
H
2 C1N0 2 base peak m/z 184 CloHiBN02 459 Ethyl 4-[3-(3-chloro-6,7-dimethoxyguinolin-4-yl)propyl]- 1-(tert-butyloxycarbonyl)piperidine-4-carboxylate 21 cm 3 of 0.5M 9-borabicyclo[3.3.1]nonane solution are cooled to a temperature in the region of 0OC and 2.61 g of ethyl 4-allyl-l-(tert-butyloxycarbonyl)piperidine-4-carboxylate in 26 cm 3 of tetrahydrofuran are added dropwise, with stirring and under an inert atmosphere, while maintaining the temperature at about 0°C. After the addition, the temperature of the mixture is returned to about 20 0 C. The solution obtained is stirred for a further 4 hours at this temperature, followed by addition of 37 cm 3 of dioxane, 0.19 g of palladiumdiphenylphosphinoferrocene chloride, 3.05 g of 4-bromo-3-fluoro-6-methoxyquinoline and 5.58 g of tribasic potassium phosphate. After stirring for 24.75 hours at a temperature in the region of 60 0 C, the reaction mixture is cooled to about 20 0 C and filtered, and the filtrate is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in 100 cm 3 of ethyl acetate and 100 cm 3 of water, the phases are separated by settling and the organic phase is then washed with 100 cm 3 of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The oil obtained is purified by chromatography, 460 under a pressure of 50 kPa of argon, on a column of silica gel (particle size 40-63 g; volume 690 cm 3 eluting with a dichloromethane/methanol/acetonitrile mixture (98/1/1 by volume). The fractions containing the product are combined and then concentrated to dryness according to the same conditions as above. 2.16 g of ethyl 4-[3-(3-chloro-6,7-dimethoxyquinolin-4-yl)propyl]- 1-(cert-butyloxycarbonyl)piperidine-4-carboxylate are obtained in the form of a yellow gel.
1 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.06 J 7 Hz: 3H); from 1.25 to 1.45 (mt: 2H); 1.39 9H); 1.53 (mt: 2H); 1.69 (mt: 2H); 1.93 (broad d, J 13.5 Hz: 2H), 2.82 (unresolved peak: 2H); 3.14 (broad t, J 7.5 Hz: 2H); 3.69 (broad d, J 13.5 Hz: 2H); 3.94 3H); 3.97 3H); 4.03 J 7 Hz: 2H); 7.31 (broad s: 1H); 7.40 (broad s: 1H); 8.61 1H).
4-Bromo-3-chloro-6,7-dimethoxyquinoline 19 g of triphenylphosphine dibromide are added to a solution of 5.39 g of 3-chloro-4-hydroxy-6,7dimethoxyquinoline in 270 cm 3 of acetonitrile, with stirring and at a temperature in the region of 20 0 C. The reaction mixture is heated at about 80 0 C for 8.25 hours.
After cooling to a temperature in the region of 20 0 C, the insoluble material is filtered off. 5.67 g of 4-bromo-3chloro-6,7-dimethoxyquinoline are obtained in the form of a gray solid.
461 Mass spectrum: DCI m/z 302 MH' 3-Chloro-4-hydroxy-6,7-dimethoxyquinoline 5.45 g of N-chlorosuccinimide are added to a solution [lacuna] of 6,7-dimethoxyquinolin-4-ol in 300 cm 3 of acetic acid, with stirring and at a temperature in the region of 20 0 C. The reaction mixture is heated at a temperature in the region of 50 0 C for 6 hours. After cooling to about 20 0 C and stirring for 18 hours at this same temperature, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 100 cm 3 of sodium hydrogen carbonate solution are added dropwise to the evaporation residue and the suspension is then stirred for 24 hours in the region of 20 0 C. The insoluble material is filtered off and then dried in an oven under reduced pressure (20 Pa). 5.39 g of 3-chloro-4-hydroxy- 6,7-dimethoxyquinoline are obtained in the form of a dark green solid.
Mass spectrum: DCI m/z 240 MH' 6,7-Dimethoxy-4-hydroxyquinoline A mixture of 9.24 g of 4-hydroxy-6,7dimethoxyquinoline-3-carboxylic acid in 185 cm 3 of diphenyl ether is maintained, with mechanical stirring, at a temperature in the region of 250 0 C for 1.3 hours.
After cooling the reaction mixture to about 20 0 C, 100 cm 3 462 of diisopropyl ether are added. The suspension is stirred for 8 hours and filtered, and the filter cake is washed with 3 times 100 cm 3 of diisopropyl ether. 7.96 g of 6,7dimethoxyquinolin-4-ol are obtained in the form of a brown solid.
Infra-red spectrum (KBr): 3242; 1605; 1548; 1500; 1273; 1239; 1220; 1075 and 822 cm n 4-Hydroxy-6,7-dimethoxyguinoline-3-carboxylic acid 10.2 g of phosphorus pentoxide are added cautiously, with mechanical stirring, to a mixture of 21.1 g of diethyl 2-[(3,4-dimethoxyphenylamino)methylene]malonate in 42 cm 3 of nitrobenzene. The reaction mixture is maintained at a temperature in the region of 1500C for 4 hours. After cooling to about 20 0
C
and stirring for 18 hours at this same temperature, 14 cm 3 of water are added dropwise and the reaction mixture is then heated to about 110 0 C for 7 hours. After cooling to a temperature in the region of 200C, 42 cm 3 of ethyl acetate are added. The suspension is stirred under these conditions for 18 hours, the phases are then separated by settling, the organic phase is filtered and the filter cake is washed with 3 times 40 cm 3 of ethyl acetate, 40 cm 3 of ethanol and 40 cm 3 of water. 9.25 g of 4-hydroxy-6,7-dimethoxyquinoline-3-carboxylic acid are obtained in the form of a cream-colored solid.
Infra-red spectrum (KBr): 2842; 1673; 1631; 463 1590; 1503; 1437; 1279; 1220; 1006; 807; 586 and 357 cm-.
Diethyl 2- 4-dimethoxyphenylamino)methylene] malonate A mixture of 10 g of 3,4-dimethoxyaniline in 13.2 cm 3 of diethyl ethoxymethylenemalonate is stirred for 1.5 hours at a temperature in the region of 110 0
C.
After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. 21.1 g of diethyl 2- 4-dimethoxyphenylamino)methylene)malonate are obtained in the form of a brown solid.
Mass spectrumi: DCI m/z 324 M4H+ The ethyl 4-allyl-1- (tert-butyloxycarbonyl) piperidine-4-carboxylate was prepared in Example 1.
Example 4- (3-Chloro-6-methoxyquinolin-4-yl) S) hydroxypropyl] 5-difluorophenylthio)ethyl] piperidine-4-carboxylic acid monohydrochioride cm 3 of aqueous 5N sodium hydroxide are added to a solution of 0.6 g of (R,S)-3-(3-chloro-6methoxyquinolin-4-yl) 5-difluorophenylthio) ethyl]-2-oxa-9-azaspirol5.Sllundecan-l-one in 50 cm 3 of acetone, with stirring and at a temperature in the region of 20 0 C. After 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at 464 a temperature in the region of 40 0 C. The evaporation residue is slurried in 10 cm 3 of diethyl ether and filtered, and the filter cake is washed with diethyl ether and then dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 500C. The solid is taken up in water and acidified with aqueous IN hydrochloric acid solution until the pH is equal to 3.
Dichloromethane is added at a temperature in the region of 20 0 C with moderate stirring and the solid is then filtered off. 0.32 g of 4-[3-(3-chloro-6-methoxyquinolin- 4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-4-carboxylic acid monohydrochloride is obtained in the form of a white solid.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.30 to 2.35 (mt: 8H); 2.84 (unresolved peak: 2H); from 3.05 to 3.70 (mt: 6H); 3.90 (broad s: 3H); 5.43 (unresolved peak: 1H); 6.16 (unresolved peak: 1H); 7.14 (unresolved peak: 1H); 7.33 (unresolved peak: 1H); 7.46 (mt: 2H); 7.96 (broad d, J 9 Hz: 1H); 8.16 (broad s: 1H); 8.67 (broad s: 1H); from 10.20 to 10.60 (broad unresolved peak: 1H).
3-(3-Chloro-6-methoxyquinolin-4-yl)-9-[2-(2,5-difluorophenylthio)ethyl]-2-oxa-9-azaspiro[5.5]undecan-l-one A mixture of 1.75 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-(R,S)-propyl]piperidine-4- 465 carboxylate dihydrochloride, 0.95 g of 2-(2bromoethylthio)-1,4-difluorobenzene, 0.62 g of potassium iodide and 3.11 g of potassium carbonate in 30 cm 3 of acetonitrile and 20 cm 3 of dimethylformamide is heated with stirring for 18 hours at a temperature in the region of 85 0 C. After cooling to about 200C, the reaction mixture is filtered through Celite and the filtrate is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in water and diethyl ether.
The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness as above. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 g; diameter 4 cm), eluting with a dichloromethane/methanol mixture (97.5/2.5 by volume).
The fractions containing the product are combined and then concentrated to dryness under the above conditions.
0.6 g of 3-(3-chloro-6-methoxyquinolin-4-yl)-9-[2-(2,5difluorophenylthio)ethyl]-2-oxa-9-azaspiro[5.5]undecan-lone is obtained.
Mass spectrum: El m/z 532 M m/z 373 C20H 22 ClN 2 03 base peak The 2-(2-bromoethylthio)-1,4-difluorobenzene was prepared in Example 14.
The methyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)-3-(R,S)-hydroxypropyl]piperidine-4-carboxylate was 466 prepared in Example 49.
Example 26 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)fluoropropyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine- 4-carboxylate A mixture of 0.4 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(3,5difluorophenoxy)ethyl]piperidine-4-carboxylate in 6.6 cm 3 of aqueous 5N hydrochloric acid is maintained at a temperature in the region of 100 0 C with stirring for 6 hours. After cooling to about 200C, the reaction mixture is stirred for 20 hours at this same temperature and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is taken up in a dichloromethane/methanol mixture (90/10 by volume) and is then concentrated to dryness again under the above conditions. The evaporation residue is purified by chromatography under a pressure of 60 kPa of argon, on a column of silica gel (particle size A; diameter 2.5 cm; height 41 cm), eluting with a dichloromethane/methanol/28% aqueous ammonia mixture (83/15/2 by volume) and collecting 30-cm 3 fractions.
Fractions 16 to 22 are combined and then concentrated to dryness under the above conditions. The residue is slurried in 10 cm 3 of diisopropyl ether, filtered and 467 dried. 0.21 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)- 3-(R,S)-fluoropropyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine-4-carboxylic acid is obtained in the form of an off-white solid melting at 205 0
C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.20 to 1.70 (mt: 3H); from 1.80 to 2.40 (mt: 7H); from 2.30 to 2.80 (mt: 2H); 2.61 J 6 Hz: 2H); 3.92 3H); 4.17 J 6 Hz: 2H); 6.36 (d mt, JHF 48 Hz: 1H); from 6.65 to 6.85 (mt: 3H); 7.51 (dd, J 9 and Hz: 1H); 7.55 (broad s: 1H); 8.02 J 9 Hz: 1H); 8.74 1H).
Methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)fluoropropyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine- 4-carboxylate 0.4 cm 3 of diethylaminosulfur trifluoride is added to a solution of 1.1 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(3,5difluorophenoxy)ethyl]piperidine-4-carboxylate in 50 cm 3 of dichloromethane, with stirring and under an inert atmosphere, at a temperature in the region of -10 0
C.
After stirring for 4 hours at a temperature in the region of 20 0 C, 0.4 cm 3 of diethylaminosulfur trifluoride is added to the reaction mixture and the mixture is then stirred for 20 hours at this same temperature. 20 cm 3 of saturated aqueous sodium hydrogen carbonate solution are added. The aqueous phase is extracted with 25 cm 3 of 468 dichloromethane. The organic phase is washed with twice cm 3 of aqueous 10% (by weight) sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The oil obtained is purified by chromatography under a pressure of 100 kPa of argon, on a column of silica gel (particle size 40-60 g; diameter 3.5 cm; height: 35 cm), eluting with a dichloromethane/methanol mixture (97/3) and collecting 35-cm 3 fractions. Fractions 20 to 21 are combined and then concentrated to dryness under the above conditions.
0.62 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)- 3-(R,S)-fluoropropyl]-l-[2-(3,5-difluorophenoxy)ethyl]piperidine-4-carboxylate is obtained in the form of an orange-colored oil.
Infra-red spectrum: (CH 2 C1 2 2953; 1725; 1622; 1599; 1504; 1466; 1234; 1152; 1117 and 837 cm Methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine-4-carboxylate 0.47 cm 3 of thionyl chloride is added dropwise, with stirring and under an inert atmosphere, to a mixture of 1.1 g of 3-(3-chloro-6-methoxyquinolin-4-yl)-9-[2- (3,5-difluorophenoxy)ethyl]-2-oxa-9-azaspiro[5.5]undecan- 1-one in 20 cm 3 of methanol cooled to -20 0 C, and the mixture is then stirred for 24 hours at a temperature in 469 the region of 20 0 C. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is taken up in 30 cm 3 of ethyl acetate and 15 cm 3 of water. After addition of 5 g of potassium carbonate and vigorous stirring for 5 minutes, the mixture is allowed to settle and the organic phase is separated out and washed with 3 times 15 cm 3 of aqueous 10% (by weight) sodium chloride solution. After drying over magnesium sulfate and then filtration, the organic solution is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 1.12 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(3,5difluorophenoxy)ethyl]piperidine-4-carboxylate are obtained in the form of a brown lacquer.
Infra-red spectrum (CC1 4 3615; 2952; 1732; 1622; 1600; 1466; 1233; 1154; 1117; 841 and 671 cm 1 3-(3-Chloro-6-methoxyquinolin-4-yl)-9-[2-(3,5difluorophenoxy)ethyl]-2-oxa-9-azaspiro[5.5]undecan-l-one A mixture of 1 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidine-4carboxylate, 0.8 g of 1-(2-bromoethoxy)-3,5-difluorobenzene and 0.42 g of potassium carbonate in 45 cm 3 of acetonitrile is maintained at a temperature of 80 0 C with stirring and under an argon atmosphere for 20 hours. The suspension is filtered, the insoluble material is washed 470 with ethyl acetate and the filtrate is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is purified by chromatography under a pressure of 100 kPa of argon, on a column of silica gel (particle size 40-60 |t; diameter 3.5 cm; height: 38 cm), eluting with a dichloromethane/methanol mixture (97/4 by volume) and collecting 35-cm 3 fractions. Fractions 9 to 20 are combined and then concentrated to dryness under the above conditions. 1.1 g of 3-(3-chloro-6-methoxyquinolin-4-yl)- 9-[2-(3,5-difluorophenoxy)ethyl]-2-oxa-9-azaspiro[5.5]undecan-l-one are obtained.
Infra-red spectrum (CC1 4 2940; 1735; 1622; 1600; 1503; 1467; 1233; 1153; 1117; 841 and 671 cm-.
The methyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)-3-hydroxypropyl]piperidine-4-carboxylate was prepared in Example 49.
The 1-(2-bromoethoxy)-3,5-difluorobenzene may be obtained by applying the method described in Example 16.
Example 27 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluorophenoxy)ethyl]piperidine-4-carboxamide 13.4 cm 3 of a 0.5N solution of aqueous ammonia in dioxane, 0.229 g of 1-hydroxybenzotriazole hydrate, 0.64 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 0.46 cm 3 of triethylamine are added, with stirring and under an inert atmosphere, to a mixture of 0.69 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine-4carboxylic acid in 30 cm 3 of dichloromethane. The suspension obtained is stirred for 17 hours at a temperature in the region of 20 0 C. The reaction mixture is diluted with 50 cm 3 of water, stirred and the phases are separated by settling. The aqueous phase is extracted with twice 25 cm 3 of dichloromethane and the organic extracts are combined, washed with 25 cm 3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The solid is taken up in 20 cm 3 of diisopropyl ether, stirred and then filtered. 0.52 g of 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine-4-carboxamide is obtained.
1 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.34 (broad t, J 12.5 Hz: 2H); 1.54 (mt: 2H); 1.66 (mt: 2H); 2.02 (broad d, J 12.5 Hz: 2H); 2.12 (broad t, J 11 Hz: 2H); from 2.55 to 2.75 (mt: 4H); 3.16 (broad t, J 7.5 Hz: 2H); 3.97 3H); 4.08 J 6Hz: 2H); from 6.65 to 6.85 (mt: 3H); 6.91 (broad s: 1H); 7.15 (broad s: 1H); 7.37 J 3 Hz: 1H); 7.45 (dd, J 9 and 3 Hz: 1H); 7.97 J 9 Hz: 1H); 8.68 1H).
472 The 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine-4carboxylic acid was prepared in Example 2.
Example 28 Sodium salt of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(cinnamyl)piperidine-4-carboxylic acid A mixture of 0.72 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-(cinnamyl)piperidine-4carboxylate in 14 cm 3 dioxane, 14 cm 3 of methanol and 14 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 20 0 C. After 2 hours, a further 14 cm 3 of aqueous 5N sodium hydroxide solution are added, followed by a further 14 cm 3 after a further 18 hours. The reaction mixture is maintained at a temperature in the region of 70 0 C for 21 hours. After cooling to about 200C, the reaction mass is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in 15 cm 3 of distilled water, filtered and then dried in the open air for 18 hours. 0.49 g of the sodium salt of sodium salt of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(cinnamyl)piperidine-4-carboxylic acid is obtained in the form of a white solid melting at about 2300C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 473 1.16 (very broad t, J 12 Hz: 2H); from 1.45 to 1.70 (mt: 4H); from 1.95 to 2.20 (mt: 4H); from 2.45 to 2.60 (mt: 2H); 2.99 J 6.5 Hz: 2H); 3.14 (broad t, J 7 Hz: 2H); 3.99 3H); 6.28 (dt, J 15.5 and 6.5 Hz: 1H); 6.48 J 15.5 Hz: 1H); 7.24 (broad t, J Hz: 1H); 7.33 (broad t, J 7.5 Hz: 2H); from 7.40 to 7.50 (mt: 4H); 7.95 J 9 Hz: 1H); 8.66 1H).
Ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- (cinnamyl)piperidine-4-carboxylate A mixture of 1 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.551 g of cinnamyl bromide, 0.42 g of potassium iodide and 1.05 g of potassium carbonate in 20 cm 3 of acetonitrile is stirred for 18.5 hours at a temperature in the region of 20 0 C. The reaction mixture is filtered and the insoluble material is rinsed with 20 cm 3 of acetonitrile and with twice 30 cm 3 of dichloromethane.
The filtrate is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 40-63 p; diameter 2.5 cm; mass 35 g), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume) and then with a cyclohexane/ethyl acetate mixture (60/40 by volume) and collecting 20-cm 3 474 fractions. The fractions containing the product are combined and then concentrated to dryness under the conditions described above. 0.72 g of ethyl chloro-6-methoxyquinolin-4-yl)propyl]-1-(3-phenylallyl)piperidine-4-carboxylate is obtained in the form of a viscous orange oil.
Mass spectrum: El m/z 506 M' m/z 415 C 23
H
28 ClN 2 03 m/z 300 C19H 26 NO2 m/z 117 C 9
H
9 base peak The ethyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in the form of the monohydrochloride in Example Example 29 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5difluorophenoxy)ethyl]piperidine-4-acetic acid A mixture of 0.18 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-l-[2-(3,5difluorophenoxy)ethyl]piperidin-4-yl}carboxylate in cm 3 of dioxane, 10 cm 3 of methanol and 0.99 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 75 0 C for 17 hours. After cooling to about 45 0 C, the reaction mixture is concentrated to dryness under a pressure gradually reduced to 9 kPa at a temperature in the region of 40 0
C.
475 The pasty residue is taken up in 3 cm 3 of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and the organic phase is then purified by chromatography under atmospheric pressure, on a column of silica gel (Bond Elut; particle size 70-200 g; diameter 2 cm; mass 5 g), eluting with a chloroform/methanol/aqueous ammonia mixture (12/3/0.5 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C and the product is dried in an oven under reduced pressure (50 kPa) at a temperature in the region of 50 0 C. 0.15 g of 4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine-4acetic acid is obtained.
1 H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 6 in ppm): 1.39 (mt: 2H); 1.50 (mt: 2H); 1.61 (mt: 4H); 2.15 (broad s: 2H); from 2.30 to 2.60 (mt: 4H); 2.63 (broad t, J Hz: 2H); 3.12 (unresolved peak: 2H); 3.94 3H); 4.06 (broad t, J 5.5 Hz: 2H); from 6.65 to 6.75 (mt: 3H); 7.36 (broad s: 1H); 7.41 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.64 1H).
Methyl (4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- [2-(3,5-difluorophenoxy)ethyl]piperidin-4-yl}acetate A mixture of 0.35 g of methyl {4-[3-(3-chloro- 6-methoxyquinolin-4-yl)propyl]piperidin-4-yl}acetate, 0.318 g of l-(2-bromoethoxy)-3,5-difluorobenzene, 0.15 g 476 of potassium iodide and 0.62 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 0 C, the reaction mixture is filtered through a silica cartridge (Bond Elut) and then rinsed with twice 2 cm 3 of acetonitrile. The organic phase is concentrated to dryness under reduced pressure (2.4 kPa) at a temperature in the region of 45 0 C. The evaporation residue obtained is dissolved in 12 cm 3 of dimethylformamide and then purified by injection of 4 times 3 cm 3 per chromatography onto an SCX silica gel cartridge (mass 1 eluting with a gradient of from pure methanol to a mixture of 4N ammoniacal methanol. The fractions containing the product are combined and then concentrated to dryness under compressed air at a temperature in the region of 45 0
C.
The evaporation residue obtained is taken up in dichloromethane and dried in the open air for 48 hours and then oven-dried under reduced pressure (10 kPa) at a temperature in the region of 500C. 0.195 g of methyl {4- [3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,5difluorophenoxy)ethyl]piperidin-4-yl}acetate is obtained.
H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 at a temperature of 353 K, 8 in ppm): from 1.45 to 2.70 (mt: 16H); 3.17 (mt: 2H); 3.51 3H); 3.96 3H); 4.24 (unresolved peak: 2H); from 6.60 to 6.70 (mt: 3H); 7.38 (broad s: 1H); 7.42 (broad d, J 9 Hz: 1H); 7.94 (d, J 9 Hz: 1H); 8.62 (broad s: 1H).
477 Methyl {4-[3-(3-chloro-6-methoxyguinolin-4-yl)propyl]piperidin-4-yl}acetate A mixture of 17 g of tert-butyl 4-[3-(3-chloro- 6-methoxyquinolin-4-yl)propyl]-4-cyanomethylpiperidine-1carboxylate in 100 cm 3 of aqueous 12N hydrochloric acid (concentrated to dryness) is gradually brought to a temperature in the region of 100 0 C with stirring over 18 hours. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 60 0 C. The oil obtained is taken up in acetone and the precipitate is filtered off and washed with acetone. 20.4 g of {4-[3-(3-chloro-6-methoxyquinolin-4yl)propyl]piperidin-4-yl}acetic acid dihydrochloride are obtained in the form of a grayish solid melting at 181 0
C
and becoming sticky. The above product is dissolved in 400 cm 3 of methanol and 10 cm 3 of dry concentrated sulfuric acid, stirred and heated in the region of 100 0
C
for 1.5 hours. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The oil obtained is taken up in 300 cm 3 of water with stirring, neutralized with sodium hydrogen carbonate, basified with potassium carbonate and extracted with ethyl acetate. The organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The aqueous phase is 478 basified to pH 8 with aqueous 5N sodium hydroxide solution and extracted with ethyl acetate, the phases are separated by settling and the organic extracts are washed, dried with magnesium sulfate and concentrated to dryness according to the conditions described above. All the organic evaporation residues are combined and purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 20-43 i; mass 200 eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume). The fractions containing the product are combined and concentrated to dryness as under the above conditions. 7.6 g of methyl {4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidin-4-yl}acetate are obtained in the form of orange-colored oil.
Mass spectrum: El m/z 390 M' m/z 207 C 11 HioClNO m/z 184 CloH 18 NO2 tert-Butyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]- 4-cyanomethylpiperidine-l-carboxylate A mixture of 30.58 g of tert-butyl chloro-6-methoxyquinolin-4-yl)propyl]-4-methanesulfonyloxymethylpiperidine-l-carboxylate and 15.1 g of potassium cyanide in 436 cm 3 of dimethyl sulfoxide is heated with stirring at a temperature in the region of 1000C for 48 hours and is then stirred in the region of 0 C for 24 hours. 2 000 cm 3 of ice-water are added to 479 the reaction mixture, the suspension is stirred for 1 hour at a temperature in the region of 20 0 C and then filtered, and the filter cake is washed with 3 times 200 cm 3 of water and then dried in the open air. The residue is purified by chromatography under a pressure of kPa of argon, on a column of silica gel (particle size 20-45 p; diameter 9 cm; height 45 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume).
Fractions 40 to 100 are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 45 0 C. 19.25 g of tert-butyl chloro-6-methoxyquinolin-4-yl)propyl]-4-cyanomethylpiperidine-l-carboxylate are obtained in the form of a yellow solid melting at 160 0
C.
Infra-red spectrum (KBr): 2968; 2924; 2235; 1684; 1622; 1505; 1414; 1230; 1166; 1151; 826 and 738 cm 1 tert-Butyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]- 4-methanesulfonyloxymethylpiperidine-l-carboxylate A mixture of 24.8 g of tert-butyl chloro-6-methoxyquinolin-4-yl)propyl]-4-hydroxymethylpiperidine-1-carboxylate in 400 cm 3 of dichloromethane and 12.9 cm 3 of triethylamine is cooled to about 0°C with stirring and under an inert atmosphere. Methanesulfonyl chloride, dissolved beforehand in 125 cm 3 of dichloromethane, is added dropwise and the reaction 480 mixture is then stirred for 18 hours at a temperature in the region of 20 0 C. 200 cm 3 of water are added to the reaction mass, followed by a further addition of 3 000 cm 3 of water. The phases are separated by settling and the aqueous phase is extracted with 200 cm 3 of dichloromethane. The organic extracts are washed with 300 cm 3 of aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 45 0 C. 30.6 g of tert-butyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-4-methanesulfonyloxymethylpiperidine-l-carboxylate are obtained in the form of an orange-colored oil.
Mass spectrum: DCI m/z 507 MH' m/z 431 M-CH 3
SO
3 m/z 397 431-C1 m/z 375 431-tBu m/z 331 431-BOC The 1-(2-bromoethoxy)-3,5-difluorobenzene was prepared in Example 16.
The tert-butyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-4-hydroxymethylpiperidine-lcarboxylate was prepared in Example 19.
Example {4-[3-(3-chloro-6-methoxyguinolin-4-yl)propyl]-l-[2-(2,5difluorophenoxy)ethyl]piperidin-4-yl)acetic acid A mixture of 0.35 g of methyl {4-[3-(3-chloro- 6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluorophenoxy)ethyl]piperidin-4-yl}acetate in 10 cm 3 of dioxane, 10 cm 3 of methanol and 1.91 cm 3 of aqueous sodium hydroxide solution is stirred at a temperature in the region of 750C for 17 hours. After cooling to about 0 C, the reaction mixture is concentrated to dryness under a pressure gradually reduced to 9 kPa at a temperature in the region of 40 0 C. The pasty residue is taken up in 3 cm 3 of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and the organic phase is then purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 g; diameter 2 cm; mass 5 eluting with a chloroform/methanol/aqueous ammonia mixture (12/3/0.5 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 400C and the product is dried in an over under reduced pressure (50 Pa) at a temperature in the region of 50 0 C. 0.27 g of chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluorophenoxy)ethyl]piperidin-4-yl}acetic acid is obtained.
1H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.39 (mt: 2H); 1.50 (mt: 2H); 1.60 (mt: 4H); 2.15 (broad 482 s: 2H); from 2.30 to 2.60 (mt: 4H); 2.67 J 6 Hz: 2H); 3.12 (unresolved peak: 2H); 3.93 3H); 4.12 (t, J 6 Hz: 2H); 6.72 (mt: 1H); 7.11 (mt: 1H); 7.21 (mt: 1H); 7.37 (broad s: 1H); 7.41 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.64 1H).
Methyl {4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1- [2-(2,5-difluorophenoxy)ethyl]piperidin-4-yl}acetate A mixture of 0.35 g of methyl {4-[3-(3-chloro- 6-methoxyquinolin-4-yl)propyl]piperidin-4-yl}acetate, 0.32 g of 2-(2-bromoethoxy)-1,4-difluorobenzene, 0.15 g of potassium iodide and 0.62 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 700C. After cooling to about 200C, the reaction mixture is filtered through a silica cartridge (Bond Elut) and then rinsed with twice 2 cm 3 of acetonitrile. The organic phase is concentrated to dryness under reduced pressure (2.4 kPa) at a temperature in the region of 45 0 C. The evaporation residue obtained in dissolved in 12 cm 3 of dimethylformamide and then purified by injection of 4 times 3 cm 3 per chromatography onto an SCX silica gel cartridge (mass 1 eluting with a gradient of from pure methanol to a mixture of 4N ammoniacal methanol. The fractions containing the product are combined and then concentrated to dryness under compressed air at a temperature in the region of 450C.
The evaporation residue obtained is taken up in 483 dichioromethane and dried in the open air for 48 hours and then oven-dried under reduced pressure (10 Pa) at a temperature in the region of 50 0 C. 0.38 g of methyl {4- (3-chloro-6-methoxyquinolin-4-yl)propyl difluorophenoxy) ethyllpiperidin-4-yllacetate is obtained.
1H NNR Spectrum (500 MHz, (CD 3 2 S0-d 6 8 in ppm): from 1.30 to 1.65 (mt: 8H); 2.25 (broad s: 2H); from 2.30 to 2.60 (mt: 4H); 2.69 (mt: 2H); 3.14 (mt: 2H); 3.47 (broad s: 3H); 3.95 (broad s: 3H); 4.12 (mt: 2H); 6.72 (mt: 1H); 7.11 (mt: 1H); 7.21 (mt: 1H); 7.38 (broad s: 1H); 7.43 (broad d, J 9 Hz: 1H); 7.94 (broad d, J 9 Hz: 1H); 8.66 (broad s: 1H).
The 2- (2-bromoethoxy) 4-difluorobenzene was prepared in Example 16.
The methyl (3-chloro-6-methoxyqiinolin-4yl)propylljpiperidin-4-yl~acetate was prepared in Example 29.
Example 31 1- (2-Cyclopentylthioethyl) (3-f luoro-6-methoxyquiziolin-4-yl )propyl] piperidine-4-carboxylic acid A mixture of 0.4 g of ethyl l-(2cyclopentylthioethyl) (3-fluoro-6-methoxyquinolin-4yl)propyllpiperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 2.4 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the 484 region of 70 0 C for 17 hours. After cooling to about 20 0
C,
the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (13/3/0.5).
The fractions containing a precipitate are combined, filtered and then washed with methanol. The solid obtained is recrystallized from 15 cm 3 of boiling methanol, cooled, filtered, washed with methanol and oven-dried under reduced pressure (10 Pa) in the region of 20 0 C. The filtration liquors are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The liquors, once concentrated to dryness, and the solid obtained above are combined to give 0.179 g of l-(2-cyclopentylthioethyl)-4- [3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4carboxylic acid in the form of a white solid.
H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 8 in ppm): 1.41 (mt: 2H); from 1.50 to 1.75 (mt: 8H); from 1.90 to 2.05 (mt: 4H); 2.20 (broad d, J 14 Hz: 2H); from 2.75 to 2.90 485 (mt: 4H); from 3.10 to 3.25 (mt: 1H); 3.16 J 7 Hz: 2H); 3.29 (mt: 2H); 3.50 (broad d, J 14 Hz: 2H); 3.99 3H); 7.47 J 2.5 Hz: 1H); 7.55 (dd, J 9 and Hz: 1H); 8.06 J 9 Hz: 1H); 8.98 (broad s: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate A mixture of 0.5 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.253 g of (2-chloroethylthio)cyclopentane, 0.25 g of potassium iodide and 0.92 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 700C. After cooling to about 0 C, the reaction mixture is filtered and then rinsed with twice 3 cm 3 of acetonitrile. The organic phase is concentrated to dryness under reduced pressure (2.4 kPa) at a temperature in the region of 450C. The evaporation residue obtained is dissolved in a mixture of ethyl acetate/40-60 0 C petroleum ether (8/2 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass 10 eluting with a mixture of ethyl acetate/40-60 0 C petroleum ether (8/2 by volume). Fractions 5 to 14 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. 0.43 g of ethyl 4- [3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4- 486 carboxylate is obtained.
H NNR Spectrum (500 MHz, (CD 3 2 S0-d 6 8 in ppm): 0.98 J 7 Hz: 3H); 1.36 (mt: 4H); from 1.40 to 1.70 (mt: 8H); from 1.80 to 2.00 (rnt: 6H); from 2.30 *to 2.65 (mt: 6H); 3.02 (mt: 2H); 3.09 (mt: 1H); 3.92 3H); 3.94 J 7 Hz: 2H); 7.31 (broad s: 1H); 7.37 (broad d, J 9 Hz: 1H); 7.94 J 9 Hz: 1H); 8.66 (broad s: 1H).
The ethyl 4- (3-fluoro-6-methoxyquinolin-4yl)propylljpiperidine-4-carboxylate was prepared in Example 11.
Example 32 l-(2-Cyclohexylethyl) -4-.3-(3-fluoro-6-methoxyquinolin-4- -yl)propyl] piperidirie-4-carboxylic acid .A mixture of 0.2 g of ethyl l-(2-cyclohexylethyl)-4-[3- (3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate in 3 :cm 3 of dioxane, 3 cm 3 Of methanol and 1.2 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 700C for 22 hours. After cooling to about 20 0 C, the reaction mixture is evaporated under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 450C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol /aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by 487 chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (13/3/0.5).
The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.14 g of l-(2-cyclohexylethyl)-4- [3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4carboxylic acid is obtained in the form of a white solid.
H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 8 in ppm): from 0.80 to 1.00 (mt: 2H); from 1.05 to 1.35 (mt: 5H); from 1.40 to 1.75 (mt: 12H); 2.19 (broad d, J 14 Hz: 2H); 2.78 (broad t, J 12.5 Hz: 2H); 3.07 (mt: 2H); 3.20 (broad t, J 6.5 Hz: 2H); 3.45 (broad d, J 12.5 Hz: 2H); 4.00 3H); 7.52 J 2.5 Hz: 1H); 7.60 (dd, J 9 and Hz: 1H); 8.10 J 9 Hz: 1H); 9.10 J 2 Hz: 1H).
Ethyl 1-(2-cyclohexylethyl)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.245 g of l-bromo-2-cyclohexylethane, 0.18 g of potassium iodide and 0.737 g of potassium carbonate in 488 cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 L; mass 12 eluting with a mixture of ethyl acetate/40-60 0
C
petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.23 g of ethyl 1-(2-cyclohexylethyl)-4- [3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4carboxylate is obtained.
H NMR Spectrum (500 MHz, (CD 3 2 SO-ds, 8 in ppm): 0.84 (mt: 2H); 0.98 J 7 Hz: 3H); from 1.00 to 2.65 (mt: 25H); 3.02 (mt: 2H); 3.93 3H); 3.95 J 7 Hz: 2H); 7.31 (broad s: 1H); 7.35 (broad d, J 9 Hz: 1H); 7.94 J 9 Hz: 1H); 8.67 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
Example 33 l-(2-Cyclohexylthioethyl)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl) propyl]piperidine-4-carboxylic acid 489 A mixture of 0.3 g of ethyl 1-(2-cyclohexylthioethyl)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 1.7 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 0 C for 17 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 450C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (13/3/0.5).
The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.25 g of 1-(2-cyclohexylthioethyl)- 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine- 4-carboxylic acid is obtained in the form of a white solid.
H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 6 in ppm): from 1.15 to 1.35 (mt: 5H); from 1.50 to 1.75 (mt: 8H); from 1.80 to 2.05 (mt: 3H); 2.20 (broad d, J 14 Hz: 2H); from 490 2.65 to 2.90 (mt: 5H); 3.20 (broad t, J 7 Hz: 2H); 3.25 (mt: 2H); 3.50 (broad d, J 12 Hz: 2H); 4.00 3H); 7.50 J 2.5 Hz: 1H); 7.59 (dd, J 9 and 2.5 Hz: 1H); 8.09 J 9 Hz: 1H); 9.07 J 2.5 Hz: 1H).
Ethyl 1-(2-cyclohexylthioethyl)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.23 g of 2-chloroethylthiocyclohexane, 0.18 g of potassium iodide and 0.74 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass 12 eluting with a mixture of ethyl acetate/40-60 0
C
petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.32 g of ethyl l-(2-cyclohexylethyl)-4- [3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4carboxylate is obtained.
H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 8 in ppm): 0.97 J 7 Hz: 3H); from 1.05 to 1.70 (mt: 14H); from 491 1.75 to 2.00 (mt: 6H); from 2.25 to 2.60 (mt: 6H); 2.62 (mt: 1H); 3.01 (mt: 2H); 3.91 3H); 3.94 J 7 Hz: 2H); 7.30 (broad s: 1H); 7.37 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.66 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
Example 34 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-(3phenylpropyl)piperidine-4-carboxylic acid A mixture of 0.1 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 0.6 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 700C for 17 hours. After cooling to about 200C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass eluting with a mixture of dichloromethane/methanol/aqueous ammonia (40/5/0.5 by volume) and then 492 with a chloroform/methanol/aqueous ammonia mixture The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C and dried in a desiccator (10 Pa). 0.25 g of 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-4-carboxylic acid is obtained in the form of a white solid.
1 H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 8 in ppm): from 1.50 to 1.75 (mt: 6H); from 1.85 to 2.05 (mt: 2H); 2.19 (broad d, J 14 Hz: 2H); 2.60 J 7.5 Hz: 2H); 2.81 (broad t, J 12.5 Hz: 2H); 3.07 (mt: 2H); 3.20 (broad t, J Hz: 2H); 3.47 (broad d, J 12.5 Hz: 2H); 3.99 (s: 3H); from 7.15 to 7.35 (mt: 5H); 7.51 J 2.5 Hz: 1H); 7.59 (dd, J 9 and 2.5 Hz: 1H); 8.10 J 9 Hz: 1H); 9.08 J 2 Hz: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyguinolin-4-yl)propyl]-1-(3phenylpropyl)piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.25 g of l-bromo-3-phenylpropane, 0.181 g of potassium iodide and 0.74 g of potassium carbonate in 15 cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 700C. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced 493 pressure (5 kPa) at a temperature in the region of 40 0
C.
The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 g; mass 12 eluting with a mixture of ethyl acetate/40-60 0 C petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
0.1 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-4-carboxylate is obtained.
H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 8 in ppm): 0.97 J 7 Hz: 3H); from 1.25 to 2.00 (mt: 12H); from 2.25 to 2.70 (mt: 6H); 3.01 (mt: 2H); 3.91 3H); 3.94 (broad q, J 7 Hz: 2H); 7.15 (mt: 3H); 7.24 (broad t, J 7.5 Hz: 2H); 7.30 (broad s: 1H); 7.36 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.66 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
Example 1-[2-(2,5-Difluorophenylthio)ethyl]-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid A mixture of 0.26 g of ethyl difluorophenylthio)ethyl]-4-[3-(3-fluoro-6-methoxy- 494 quinolin-4-yl)propyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 1.4 cm 3 of aqueous sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 17 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass 10 eluting with a mixture of dichloromethane/methanol/aqueous ammonia (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C and dried in a desiccator (10 kPa). 0.3 g of difluorophenylthio)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 8 in ppm): from 1.50 to 1.75 (mt: 6H); 2.21 (broad d, J 14 Hz: 2H); 2.89 (broad t, J 12.5 Hz: 2H); 3.16 (mt: 2H); from 3.25 to 3.50 (mt: 4H); 3.54 (broad d, J 12.5 Hz: 2H); 3.99 (s: 495 3H); 7.14 (mt: 1H); 7.30 (doubled triplet, J 9 and Hz: 1H); 7.39 (mt: 1H); 7.47 J 2.5 Hz: 1H); 7.54 (dd, J 9 and 2.5 Hz: 1H); 8.07 J 9 Hz: 1H); 8.97 J 2 Hz: 1H).
Ethyl 1-[2-(2,5-difluorophenylthio)ethyl]-4-[3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.324 g of 2-(2-bromoethylthio)-1,4-difluorobenzene, 0.181 g of potassium iodide and 0.74 g of potassium carbonate in 15 cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass 12 eluting with a mixture of ethyl acetate/40-60 0 C petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
0.27 g of ethyl l-[2-(2,5-difluorophenylthio)ethyl]-4-[3- (3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4carboxylate is obtained.
1H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 6 in ppm): 496 0.97 J 7 Hz: 3H); 1.31 (broad t, J 11 Hz: 2H); from 1.40 to 1.60 (mt: 4H); from 1.80 to 2.00 (mt: 4H); from 2.35 to 2.70 (mt: 4H); 3.01 (mt: 2H); 3.07 (broad t, J 7 Hz: 2H); 3.91 3H); 3.94 J 7 Hz: 2H); 7.00 (mt: 1H); 7.21 (mt: 1H); 7.26 (mt: 1H); 7.30 (broad s: 1H); 7.37 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.66 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
The 1-(2-bromoethylthio)-2,5-difluorobenzene was prepared in Example 14.
Example 36 l-[2-(2,5-Difluorophenoxy)ethyl]-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid A mixture of 0.38 g of ethyl difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 2.1 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 17 hours. After cooling to about 200C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 450C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia 497 mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 g; mass eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.36 g of difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 1.32 (broad t, J 13 Hz: 2H); from 1.50 to 1.70 (mt: 4H); 1.96 (broad d, J 13 Hz: 2H); 2.09 (broad t, J 11.5 Hz: 2H); 2.64 J 6 Hz: 2H); 2.70 (broad d, J 11.5 Hz: 2H); 3.05 (very broad t, J 6.5 Hz: 2H); 3.96 3H); 4.13 J 6 Hz: 2H); 6.75 (mt: 1H); 7.14 (mt: 1H); 7.24 (mt: 1H); 7.34 J 2.5 Hz: 1H); 7.41 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.69 (broad s: 1H).
Ethyl 1-[2-(2,5-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 498 0.30 g of 2 -(2-bromoethoxy)-1,4-difluorobenzene, 0.181 g of potassium iodide and 0.74 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 g; mass 12 eluting with a mixture of ethyl acetate/40-60 0
C
petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.4 g of ethyl difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl]piperidine-4-carboxylate is obtained.
H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 8 in ppm): 0.97 J 7 Hz: 3H); 1.36 (broad t, J 11.5 Hz: 2H); from 1.40 to 1.60 (mt: 4H); from 1.80 to 2.10 (mt: 4H); 2.61 (broad t, J 5.5 Hz: 2H); 2.69 (broad d, J 11 Hz: 2H); 3.02 (mt: 2H); 3.92 3H); 3.94 J 7 Hz: 2H); 4.09 (mt: 2H); 6.71 (mt: 1H); 7.10 (mt: 1H); 7.19 (mt: 1H); 7.29 (broad s: 1H); 7.37 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.66 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
499 The 2-(2-bromoethoxy)-1,4-difluorobenzene was prepared in Example 16.
Example 37 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2- (2,3,5-trifluorophenoxy)ethyl]piperidine-4-carboxylic acid A mixture of 0.42 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenoxy)ethyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 2.3 cm 3 of aqueous sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 17 hours. After cooling to about 200C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass 10 eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C and dried 500 in a desiccator (10 kPa). 0.39 g of 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenoxy)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
1 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 1.32 (very broad t, J 12.5 Hz: 2H); 1.60 (mt: 4H); 1.95 (broad d, J 12.5 Hz: 2H); 2.09 (broad t, J 11 Hz: 2H); 2.64 J 5.5 Hz: 2H); 2.70 (broad d, J 11 Hz: 2H); 3.04 (very broad t, J 6 Hz: 2H); 3.96 3H); 4.16 J 5.5 Hz: 2H); from 6.95 to 7.15 (mt: 2H); 7.34 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.96 J 9 Hz: 1H); 8.69 (broad s: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2- (2,3,5-trifluorophenoxy)ethyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.33 g of l-(2-bromoethoxy)-2,3,5-trifluorobenzene, 0.181 g of potassium iodide and 0.74 g of potassium carbonate in 15 cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 700C. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 l; mass 12 g; volume 25 cm 3
I
501 eluting with a mixture of ethyl acetate/40-60 0 C petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.43 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl] 5-trifluorophenoxy) ethyllpiperidine-4-carboxylate is obtained.
H NMR Spectrum (500 MHz, (CDA) 2 S0-d 6 6 in ppm): 0.98 J 7 Hz: 3H); 1.34 (broad t, J =11.5 Hz: 2H); from 1.45 to 1.60 (mt: 4H); from 1.85 to 2.10 (mt: 4H); from 2.50 to 2.70 (mt: 4H); 3.02 (mt: 2H); 3.92 3H); 3.94 J 7 Hz: 2H); 4.14 (mt: 2H); 7.02 (mt: 2H); 7.30 (broad s: lIH); 7.37 (broad d, J 9 Hz: 1H); 7.94 J 9 Hz: 1H); 8.66 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
The 1- (2-bromoethoxy) was prepared as described in Example 13.
Example 38 (3-Fluoro-6-methoxyquinolin-4-yl)propylJ -1heptylpiperidine-4-carboxylic acid A mixture of 0.16 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl) propyl] -1-heptylpiperidine-4carboxylate in 3. cm 3 of dioxane, 3 cm 3 of methanol and 502 1 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 17 hours.
After cooling to about 200C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (13/3/0.5).
The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.07 g of 4 3 -(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-heptylpiperidine-4-carboxylic acid is obtained in the form of a white solid.
'H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 8 in ppm): 0.85 (t, J 7 Hz: 3H); from 1.15 to 1.35 (mt: 8H); from 1.50 to 1.75 (mt: 8H); 2.19 (broad d, J 14 Hz: 2H); 2.78 (broad t, J 12.5 Hz: 2H); 3.02 (mt: 2H); 3.19 (broad t, J 7 Hz: 2H); 3.45 (broad d, J 12.5 Hz: 2H); 4.00 3H); 7.50 J 2.5 Hz: 1H); 7.58 (dd, J 9 and 2.5 Hz: 1H); 8.09 J 9 Hz: 1H); 9.04 J 2 Hz: 1H).
503 Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1heptylpiperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.23 g of 1-bromoheptane, 0.18 g of potassium iodide and 0.737 g of potassium carbonate in 15 cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 0 C. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (particle size 200 g; mass 12 eluting with a mixture of ethyl acetate/40-60 0 C petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.2 g of ethyl 4-[3- (3-fluoro-6-methoxyquinolin-4-yl)propyl]-1heptylpiperidine-4-carboxylate is obtained.
IH NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 8 in ppm) 0.84 J 7 Hz: 3H); 0.98 J 7 Hz: 3H); from 1.10 to 1.30 (mt: 8H); 1.33 (mt: 4H); from 1.40 to 1.60 (mt: 4H); 1.83 (broad t, J 11 Hz: 2H); 1.93 (broad d, J 13 Hz: 2H); 2.13 (mt: 2H); from 2.35 to 2.55 (mt: 2H); 3.01 (mt: 2H); 3.89 3H); 3.94 (mt: 2H); 7.31 (broad s: 1H); 7.37 (broad d, J 9 Hz: 1H); 7.94 J 9 Hz: 1H); 8.67 (broad s: 1H).
504 The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
Example 39 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-(2phenylthioethyl)piperidine-4-carboxylic acid A mixture of 0.39 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-l-(2phenylthioethyl)piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 2.3 cm 3 of aqueous sodium hydroxide solution is stirred at a temperature in the region of 700C for 17 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 450C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 L; mass 10 eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure 505 (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.3 g of 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-4-carboxylic acid is obtained in the form of a white solid.
1 H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 6 in ppm): from 1.50 to 1.75 (mt: 6H); 2.20 (broad d, J 14 Hz: 2H); 2.87 (broad t, J 13 Hz: 2H); 3.16 (mt: 2H); 3.41 4H); 3.53 (broad d, J 13 Hz: 2H); 4.00 3H); 7.25 (broad t, J 7.5 Hz: 1H); from 7.30 to 7.45 (mt: 4H); 7.48 (d, J 2.5 Hz: 1H); 7.54 (dd, J 9 and 2.5 Hz: 1H); 8.07 J 9 Hz: 1H); 8.97 J 2 Hz: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2phenylthioethyl)piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.28 g of 2-bromoethyl phenyl sulfide, 0.181 g of potassium iodide and 0.74 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass 506 12 eluting with a mixture of ethyl acetate/40-60 0
C
petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.4 g of ethyl 4 -[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl] -1-(2-phenylthioethyl)piperidine-4carboxylate is obtained.
H NMR Spectrum (500 MHz, (CD 3 2 S0-d 6 6 in ppm): 0.97 J 7 Hz: 3H); 1.33 (broad t, J 12.5 Hz: 2H); from 1.45 to 1.65 (mt: 4H); from 1.85 to 2.00 (tnt: 4H); from 2.30 to 2.70 (mt: 4H); 3.01 (mt: 4H); 3.92 3H); 3.94 (mt: 2H); 7.15 (tnt: 1H); from 7.20 to 7.35 (mt: 7.37 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.66 (broad s: 1H).
The ethyl 4-113- (3-fluoro-6-methoxyquinolin-4yl)propyllpiperidine-4-carboxylate was prepared in Example 11.
Example 4- (3-Fluoro-6-methoxyquinolin-4-yl)propyl] 2- (3fluorophenylthio) ethyl] piperidine-4-carboxylic acid A mixture of 0.2 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl (2-phenylthioethyl) piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 1.1 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 507 0 C for 17 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 l; mass eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.18 g of 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-4-carboxylic acid is obtained.
1 H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 8 in ppm): from 1.50 to 1.75 (mt: 6H); 2.20 (broad d, J 14 Hz: 2H); 2.89 (broad t, J 12.5 Hz: 2H); 3.18 (mt: 2H); from 3.25 to 3.45 (mt: 4H); 3.54 (broad d, J 12.5 Hz: 2H); 3.99 (s: 3H); 7.05 (doubled triplet, J 9 and 2.5 Hz: 1H); from 7.15 to 7.30 (mt: 2H); 7.38 (mt: 1H); 7.48 J Hz: 1H); 7.55 (dd, J 9 and 2.5 Hz: 1H); 8.08 J 9 Hz: 1H); 9.00 J 2 Hz: 1H).
508 Ethyl 4-[ 3 -(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-(2phenylthioethyl)piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.30 g of 3-fluoro-2-bromoethyl phenyl sulfide, 0.18 g of potassium iodide and 0.74 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure of argon, on a cartridge of silica gel (Bond Elut; particle size 200 g; mass 12 eluting with a mixture of ethyl acetate/40-60 0 C petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.22 g of ethyl 4- 3 -fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-4-carboxylate is obtained.
H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 8 in ppm): 0.98 J 7 Hz: 3H); 1.33 (broad t, J 12 Hz: 2H); from 1.45 to 1.65 (mt: 4H); from 1.85 to 2.00 (mt: 4H); from 2.30 to 2.70 (mt: 4H); 3.02 (mt: 2H); 3.07 J 6.5 Hz: 2H); 3.92 3H); 3.94 J 7 Hz: 2H); 6.94 (broad t, J 8.5 Hz: 1H); from 7.05 to 7.20 (mt: 2H); from 7.25 to 7.35 (mt: 2H); 7.37 (broad d, J 9 Hz: 1H); 509 7.94 J 9 Hz: 1H); 8.66 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
The 3-fluoro-2-bromoethyl phenyl sulfide was prepared according to the method described in Example 14.
Example 41 1-[2-(3,4-Difluorophenoxy)ethyl]-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid A mixture of 0.38 g of ethyl difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin- 4 -yl)propyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 2.1 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 17 hours. After cooling to about 20 0
C,
the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 IA; mass 10 eluting with a mixture of dichloromethane/methanol/aqueous ammonia (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture 510 (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.3 g of 1-[2-(3,4-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
1 H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 6 in ppm): from 1.50 to 1.75 (mt: 6H); 2.21 (broad d, J 14 Hz: 2H); 2.96 (broad t, J 13 Hz: 2H); 3.19 (broad t, J 6.5 Hz: 2H); from 3.50 to 3.65 (mt: 4H); 4.00 3H); 4.31 J Hz: 2H); 6.82 (mt: 1H); 7.11 (mt: 1H); 7.35 (mt: 1H); 7.50 J 2.5 Hz: 1H); 7.57 (dd, J 9 and 2.5 Hz: 1H); 8.09 J 9 Hz: 1H); 9.03 J 2 Hz: 1H).
Ethyl 1-[2-(3,4-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.3 g of 4-(2-bromoethoxy)-1,2-difluorobenzene, 0.18 g of potassium iodide and 0.74 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 400C. The evaporation residue is purified by 511 chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass 12 eluting with a mixture of ethyl acetate/40-60 0
C
petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.4 g of ethyl difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl]piperidine-4-carboxylate is obtained.
IH NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 6 in ppm): 0.98 J 7 Hz: 3H); 1.36 (broad t, J 12 Hz: 2H); from 1.45 to 1.65 (mt: 4H); 1.93 (broad d, J 12 Hz: 2H); 2.00 (broad t, J 11.5 Hz: 2H); from 2.40 to 2.70 (mt: 4H); 3.02 (mt: 2H); 3.92 3H); 3.94 J 7 Hz: 2H); 3.99 (mt: 2H); 6.73 (mt: 1H); 7.03 (mt: 1H); from 7.25 to 7.35 (mt: 2H); 7.37 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.66 (broad 1H).
4-(2-Bromoethoxy)-1,2-difluorobenzene A mixture of 15 g of 3,4-difluorophenol, 23.5 g of potassium carbonate and 60 cm 3 of 1,2-dibromoethane in 250 cm 3 of acetonitrile is stirred at a temperature in the region of 70 0 C for 18 hours. After cooling to about 0 C, the reaction mixture is filtered through Celite and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under 512 atmospheric pressure, on a column of silica gel (particle size 70-200 g; diameter 8 cm; mass 400 eluting with 40-600C petroleum ether. The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) in the region of 400C.
15.7 g of 4-(2-bromoethoxy)-l,2-difluorobenzene are obtained in the form of an oil.
Infra-red spectrum (CC1 4 1609; 1516; 1264; 1253; 1215; 1206; 1162; 1019; 854 and 834 cm-.
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
Example 42 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2phenoxyethyl)piperidine-4-carboxylic acid A mixture of 0.39 of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(2-phenoxyethyl)piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 2.4 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 700C for 17 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia 513 mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass eluting with a mixture of dichloromethane/methanol/aqueous ammonia (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.33 g of 4- [3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2phenoxyethyl)piperidine-4-carboxylic acid is obtained in the form of a white solid.
IH NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 8 in ppm): 1.36 (broad t, J 12.5 Hz: 2H); from 1.50 to 1.70 (mt: 4H); 1.96 (broad d, .J 12.5 Hz: 2H); 2.08 (broad t, J 11.5 Hz: 2H); 2.62 J 6 Hz: 2H); 2.71 (broad d, J 11.5 Hz: 2H); 3.05 (broad t, J 6.5 Hz: 2H); 3.97 3H); 4.03 J 6 Hz: 2H); from 6.85 to 7.00 (mt: 3H); 7.29 (broad t, J 8 Hz: 2H); 7.35 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.70 (broad s: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-(2phenoxyethyl)piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6- 514 methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.26 g of 2-bromoethyl phenyl ether, 0.181 g of potassium iodide and 0.737 g of potassium carbonate in 15 cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 400C.
The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 g; mass 12 eluting with a mixture of ethyl acetate/40-60 0 C petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
0.4 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenoxyethyl)piperidine-4-carboxylate is obtained.
H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 6 in ppm): 0.99 J 7 Hz: 3H); 1.37 (mt: 2H); from 1.45 to 1.65 (mt: 4H); from 1.85 to 2.10 (mt: 4H); from 2.35 to 2.75 (mt: 4H); 3.03 (mt: 2H); 3.93 3H); 3.96 J 7 Hz: 2H); 4.02 (mt: 2H); 6.90 (mt: 3H); 7.26 (broad t, J Hz: 2H); 7.32 (broad s: 1H); 7.38 (broad d, J 9 Hz: 1H); 7.95 J 9 Hz: 1H); 8.68 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
515 Example 43 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3fluorophenoxy)ethyl]piperidine-4-carboxylic acid A mixture of 0.415 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenoxy)ethyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 2.4 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 17 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a. dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 g; mass eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.34 g of 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenoxy)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
516 1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CF 3 COOD, 8 in ppm): 1.34 (broad t, J 12.5 Hz: 2H); from 1.50 to 1.70 (mt: 4H); 1.96 (broad d, J 12.5 Hz: 2H); 2.08 (broad t, J 11 Hz: 2H); 2.63 J 6 Hz: 2H); 2.70 (broad d, J 11 Hz: 2H); 3.05 (broad t, J 6.5 Hz: 2H); 3.97 3H); 4.06 J 6 Hz: 2H); from 6.70 to 6.90 (mt: 3H); from 7.25 to 7.40 (mt: 1H); 7.35 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.70 (broad s: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2- (3-fluorophenoxy)ethyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.281 g of l-(2-bromoethoxy)-3-fluorobenzene, 0.181 g of potassium iodide and 0.737 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 700C. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass 12 eluting with a mixture of ethyl acetate/40-600C petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness 517 under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.43 g of ethyl 4 -[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3-fluorophenoxy)ethyl]piperidine-4-carboxylate is obtained.
1H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 8 in ppm): 0.98 J 7 Hz: 3H); 1.35 (broad t, J 12 Hz: 2H); from 1.45 to 1.65 (mt: 4H); 1.92 (broad d, J 12 Hz: 2H); 2.00 (broad t, J 11.5 Hz: 2H); from 2.30 to 2.70 (mt: 4H); 3.02 (mt: 2H); 3.91 3H); 3.94 J 7 Hz: 2H); 4.01 (mt: 2H); from 6.65 to 6.80 (mt: 3H); from 7.20 to 7.30 (mt: 1H); 7.28 (broad s: 1H); 7.36 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.65 (broad s: 1H).
1-(2-Bromoethoxy)-3-fluorobenzene A mixture of 8.6 g of 3-fluorophenol, 15.3 g of potassium carbonate and 40.5 cm 3 of 1,2-dibromoethane in 200 cm 3 of acetonitrile is stirred, under an inert atmosphere, at a temperature in the region of 70 0 C for hours. After cooling to about 200C, the suspension is filtered, the insoluble material is rinsed with 3 times cm 3 of acetonitrile and the filtrate is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is taken up in 50 cm 3 of diethyl ether and then filtered, and the filtration liquors are concentrated to dryness as under the previous conditions. The oil obtained by evaporation is purified by chromatography under a 518 pressure of 50 kPa of argon on a column of silica gel (particle size 20-45 diameter 4.5 cm; height 22 cm), eluting with 40-60 0 C petroleum ether. Fractions 8 to are combined and then concentrated to dryness under reduced pressure (2 kPa) in the region of 40 0 C. 7.67 g of 1-(2-bromoethoxy)-3-fluorobenzene are obtained.
Infra-red spectrum (CC1 4 1616; 1596; 1492; 1279; 1265; 1168; 1140; 1025; 853; 834 and 679 cm The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
Example 44 l-[2-(2,6-Difluorophenoxy)ethyl]-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid A mixture of 0.39 g of ethyl difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 2.2 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 17 hours. After cooling to about 20 0
C,
the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 450C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by 519 chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 t; mass eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.3 g of difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.33 (broad t, J 12.5 Hz: 2H); from 1.50 to 1.65 (mt: 4H); 1.91 (broad d, J 12.5 Hz: 2H); 2.05 (broad t, J 11 Hz: 2H); 2.60 J 6 Hz: 2H); 2.63 (mt: 2H); 3.05 (mt: 2H); 3.97 3H); 4.16 J 6 Hz: 2H); from 7.05 to 7.20 (mt: 3H); 7.35 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.70 (broad s: 1H).
Ethyl l-[2-(2,6-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.304 g of 1-(2-bromoethoxy)-3-fluorobenzene, 0.181 g of potassium iodide and 0.74 g of potassium carbonate in 520 cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 70 0 C. After cooling to about 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 p; mass 12 eluting with a mixture of ethyl acetate/40-60 0
C
petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.4 g of ethyl l-[2-(2,6-difluorophenoxy)ethyl]-4-[ 3 -(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate is obtained.
1 H NMR Spectrum (500 MHz, (CD 3 2 SO-d 6 8 in ppm): 0.97 J 7 Hz: 3H); 1.26 (broad t, J 125 Hz: 2H); from 1.40 to 1.60 (mt: 4H); 1.88 (broad d, J 12 Hz: 2H); 1.98 (broad t, J 11 Hz: 2H); from 2.30 to 2.65 (mt: 4H); 3.00 (mt: 2H); 3.92 3H); 3.94 (mt: 2H); 4.11 (mt: 2H); from 6.95 to 7.10 (mt: 3H); 7.30 (broad s: 1H); 7.37 (broad d, J 9 Hz: 1H); 7.93 J 9 Hz: 1H); 8.66 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
The 1-(2-bromoethoxy)-3-fluorobenzene was prepared according to the method described in Example 521 Example l-[2-(2,3-Difluorophenoxy)ethyl]-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylic acid A mixture of 0.42 g of ethyl difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin- 4 -yl)propyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 2.4 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 17 hours. After cooling to about 20 0
C,
the reaction mixture is concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45 0 C. The residue is taken up in 5 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and is then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 g; mass eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and dried in a desiccator (10 kPa). 0.32 g of difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin- 4 -yl)propyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
522 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.34 (broad t, J 12.5 Hz: 2H); from 1.50 to 1.70 (mt: 4H); 1.96 (broad d, J 12.5 Hz: 2H); 2.09 (broad t, J 11.5 Hz: 2H); 2.65 J 6 Hz: 2.71 (broad d, J 11.5 Hz: 2H); 3.05 (mt: 2H); 3.97 3H); 4.16 J 6 Hz: 2H); from 6.90 to 7.20 (mt: 3H); 7.34 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.70 (broad s: 1H).
Ethyl 1-[2-(2,3-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.3 g of 1-(2-bromoethoxy)-2,3-difluorobenzene, 0.181 g of potassium iodide and 0.74 g of potassium carbonate in cm 3 of acetonitrile is stirred for 18 hours at a temperature in the region of 700C. After cooling to about 0 C, the reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 400C. The evaporation residue is purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200 l; mass 12 eluting with a mixture of ethyl acetate/40-60 0
C
petroleum ether (8/2 by volume). The fractions containing the product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. 0.43 g of ethyl 523 difluorophenoxy) ethyl] (3-fluoro-6-methoxyquinolin- 4-yl)propyllpiperidine-4-carboxylate is obtained.
I MR Spectrum (500 MHz, (CD 3 2 S0-d 6 8 in ppm): 0.99 (mt: 3H); 1.34 (mt: 2H); from 1.40 to 1.60 (mt: 4H); 1.93 (broad d, J 12.5 Hz: 2H); from 1.95 to 2.10 (mt: 2H); from 2.45 to 2.70 limt: 4H); 3.02 (int: 2H); 3.93 3H); 3.95 (int: 2H); 4.12 (mt: 2H); from 6.85 to 7.05 (mt: 2H); 7.09 (int: 1H); 7.31 (broad s: 1H); 7.37 (broad d, J 9 Hz: 1H); 7.94 J 9 Hz: 1H); 8.66 (broads: 1H).
The ethyl 4- (3-f luoro-6-methoxyquinolin-4yl)propyllpiperidine-4-carboxylate was prepared in Example 11.
The 1- (2-bromoethoxy) 3-difluorobenzene was prepared in Example 17.
Example 46 4- (3-Fluoroquinolin-4-yl)propylj (thien-2-yl) thioethyl] piperidine-4-carboxylic acid A mixture of 1.29 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl (thien-2-yl) thioethyl] piperidine-4-carboxylate in 65 cm 3 of dioxane, 65 cm 3 of methanol and 8 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 0 C for 20 hours. 8 cm 3 of aqueous 5N sodium hydroxide solution are added to the reaction mixture, which is 524 stirred in the region of 700C for a further 6 hours.
After cooling to about 20 0 C, the reaction mass is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The residue is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 L; diameter 6 cm; height 30 cm), eluting with a chloroform/methanol/aqueous ammonia mixture (12/3/0.5 by volume) and collecting 100-cm 3 fractions. Fractions 8 to 24 are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C.
The white solid is taken up in 60 cm 3 of diisopropyl ether and stirred for 18 hours at a temperature in the region of 20 0 C. The suspension is filtered, washed with 3 times 15 cm 3 of diisopropyl ether, spin-filtered and then dried under reduced pressure (10 kPa) at about 500C.
0.8 g of 4 -[3-(3-fluoroquinolin-4-yl)propyl]-1-[2-(thien- 2-yl)thioethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid melting at 1800C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 1.27 (mt: 2H); 1.56 (mt: 4H); from 1.85 to 2.05 (mt: 4H); 2.44 (broad t, J 7 Hz: 2H); 2.57 (mt: 2H); 2.90 (broad t, J 7 Hz: 2H); 3.06 (unresolved peak: 2H); 7.04 (dd, J 5.5 and 3.5 Hz: 1H); 7.17 (dd, J 3.5 and 1.5 Hz: 1H); 7.60 (dd, J 5.5 and 1.5 Hz: 1H); 7.71 (broad t, J 7.5 Hz: 1H); 7.77 (broad t, J 7.5 Hz: 1H); 8.08 (broad d, J 7.5 Hz: 1H); 8.15 (broad d, J 7.5 Hz: 525 1H); 8.89 J 1.5 Hz: 1H).
Ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-1-[2-(thien-2yl)thioethyl]piperidine-4-carboxylate A mixture of 1.8 g of ethyl 1-(2-chloroethyl)- 4-[3-(3-fluoroquinolin-4-yl)propyl]piperidine-4carboxylate monohydrochloride, 0.48 cm 3 of thiophene-2thiol, 2.8 g of potassium carbonate and 0.75 g of potassium iodide in 200 cm 3 of anhydrous acetonitrile is stirred under an inert atmosphere for 18 hours at a temperature in the region of 70 0 C. After cooling to about 0 C, the suspension is filtered, washed with 3 times cm 3 of acetonitrile and the filtrate is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size p; diameter 6 cm; height 30 cm), eluting with ethyl acetate and collecting 50-cm 3 fractions. Fractions 25 to 52 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 1.3 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-1-[2-(thiophen-2-ylthio)ethyl]piperidine- 4-carboxylate are obtained in the form of a viscous orange-colored oil.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 0.99 J 7 Hz: 3H); 1.34 (very broad t, J 13 Hz: 526 2H); 1.56 (mt: 4H); from 1.85 to 2.00 (mt: 4H); 2.45 (broad t, J 7 Hz: 2H); 2.59 (broad d, J 11.5 Hz: 2H); 2.90 (broad t, J 7 Hz: 2H); 3.07 (broad t, J 6.5 Hz: 2H); 3.95 J 7 Hz: 2H); 7.04 (dd, J 5.5 and Hz: 1H); 7.17 (dd, J 3.5 and 1.5 Hz: 1H); 7.60 (dd, J 5.5 and 1.5 Hz: 1H); 7.70 (broad t, J 7.5 Hz: 1H); 7.77 (doubled triplet, J 7.5 and 1.5 Hz: 1H); 8.08 (broad d, J 7.5 Hz: 1H); 8.13 (broad d, J 7.5 Hz: 1H); 8.89 J 1 Hz: 1H).
Ethyl 1-(2-chloroethyl)-4-[3-(3-fluoroquinolin-4-yl)propyl]piperidine-4-carboxylate hydrochloride 1.2 cm 3 of thionyl chloride in 5 cm 3 of dichloromethane are added to a solution of 1.55 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-1-(2-hydroxyethyl)piperidine-4-carboxylate in 35 cm 3 of dichloromethane, with stirring at a temperature in the region of 0 C. After stirring for 42 hours at a temperature in the region of 200C, the reaction mixture is concentrated to dryness under reduced pressure (1.2 kPa) at about 50 0
C.
The foam obtained is taken up in 3 times 100 cm 3 of cyclohexane, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C and oven-dried under reduced pressure (10 kPa) at a temperature in the region of 20 0 C. 1.8 g of ethyl 1-(2chloroethyl)-4-[3-(3-fluoroquinolin-4-yl)propyl]piperidine-4-carboxylate monohydrochloride are obtained 527 in the form of a cream-colored solid.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 5 in ppm): 1.03 J 7 Hz: 3H); from 1.45 to 2.10 (mt: 6H); 2.16 (broad d, J 14 Hz: 2H); from 2.70 to 3.00 (mt: 2H); 3.12 (mt: 2H); from 3.40 to 3.55 (mt: 4H); from 3.95 to 4.10 (mt: 4H); 7.72 (broad t, J 7.5 Hz: 1H); 7.79 (broad t, J 7.5 Hz: 1H); 8.09 (broad d, J 7.5 Hz: 1H); 8.18 (broad d, J 7.5 Hz: 1H); 8.92 (broad s: 1H); from 10.10 to 10.35 (unresolved peak: 1H).
Ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-l-(2-hydroxyethyl)piperidine-4-carboxylate 1.14 cm 3 of 2-iodoethanol and 1.9 g of potassium carbonate are added to a solution of 4.4 g of ethyl 4-[ 3 -(3-fluoroquinolin-4-yl)propyl]piperidine-4carboxylate in 100 cm 3 of anhydrous acetonitrile, with vigorous stirring and under an inert atmosphere. The reaction mixture is stirred for 18 hours in the region of 0 C, filtered and washed with 3 times 30 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 p; diameter 5 cm; height 32 cm), eluting with dichloromethane/methanol/aqueous ammonia (40/5/0.5 by volume) and collecting 100-cm 3 fractions. Fractions 8 to 12 are combined and then 528 concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 3.5 g of ethyl 4-[3- (3-fluoroquinolin-4-yl)propyl]-1-(2-hydroxyethyl)piperidine-4-carboxylate are obtained in the form of a viscous orange-colored oil.
IH NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 0.99 J 7 Hz: 3H); 1.36 (mt: 2H); 1.57 (mt: 4H); from 1.85 to 2.05 (mt: 4H); 2.29 .J 6.5 Hz: 2H); 2.61 (d mt, J 12 Hz: 2H); 3.08 (broad t, J 6 Hz: 2H); 3.45 (mt: 2H); 3.96 J 7 Hz: 2H); 4.31 J Hz: 1H); 7.70 (broad t, J 7.5 Hz: 1H); 7.77 (doubled triplet, J 7.5 and 1.5 Hz: 1H); 8.08 (dd, J 7.5 and Hz: 1H); 8.14 (dd, J 7.5 and 1.5 Hz: 1H); 8.89 (d, J 1 Hz: 1H).
.Ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]piperidine-4carboxylate cm 3 of a solution of hydrogen chloride in dioxane at a concentration of 4M are added cautiously to a .solution of 8.7 g of ethyl 4-[3-(3-fluoroquinolin-4yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4carboxylate in 150 cm 3 of anhydrous dioxane, and the temperature is maintained below 300C during the addition.
After stirring for 18 hours in the region of 200C, the suspension is diluted with 250 cm 3 of diethyl ether, filtered and washed with 5 times 50 cm 3 of diethyl ether, and the solid is dried in a desiccator under reduced 529 pressure (2 kPa) and at a temperature in the region of 0 C. The solid is taken up in 50 cm 3 of water and aqueous 5N sodium hydroxide solution is added so that the pH is at about 10, and the mixture is then extracted with 5 times 100 cm 3 of diethyl ether. The organic phases are combined, dried over magnesium sulfate, taken up with plant charcoal filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. 4.7 g of ethyl 4-[3-(3-fluoroquinolin-4yl)propyl]piperidine-4-carboxylate are obtained in the form of a viscous orange-colored oil.
Mass spectrum: El m/z 344 M' m/z 288 C 17 H19FN02" m/z 184 CloHi 8
NO
2 base peak m/z 161 CloH 8
FN
Ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-l-(tertbutyloxycarbonyl)piperidine-4-carboxylate 17.7 g of ethyl 4-allyl-l-(tert-butyloxycarbonyl)piperidine-4-carboxylate in 200 cm 3 of tetrahydrofuran are cooled to a temperature in the region of -30 0 C and 135 cm 3 of a 0.5M solution of 9-borabicyclo- [3.3.1]nonane in tetrahydrofuran are added with stirring and under an inert atmosphere. After the addition, the temperature of the mixture is returned to about 20 0 C and the mixture is stirred for 2 hours. 14.8 g of 3-fluoro-4iodoquinoline in 430 cm 3 of tetrahydrofuran, 1.3 g of palladium diphenylphosphinoferrocene chloride and 29.8 g 530 of tribasic potassium phosphate are added. The reaction mixture is then heated at a temperature in the region of 0 C for 20 hours. After cooling to a temperature in the region of 20 0 C, the reaction mass is filtered and washed with 3 times 100 cm 3 of tetrahydrofuran. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The evaporation residue is taken up in 500 cm 3 of diethyl ether, the insoluble material is washed with 3 times 100 cm 3 of diethyl ether and the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The oil obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 L; diameter 6 cm; height 45 cm), eluting with a dichloromethane/ethyl acetate mixture (90/10 by volume) and collecting 120-cm 3 fractions. Fractions 30 to 76 are combined and then concentrated to dryness under the same conditions as above. 13.7 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate are obtained in the form of a viscous orange-colored oil.
Mass spectrum: El m/z 444 m/z 388 [M tBu]'' m/z 343 [M BOC] m/z 288 C 17
H
19 FN0 2 4 m/z 184
C
1 oH 1 8 N02' m/z 161 CloHsFN m/z 57 C 4 H9" 531 3-Fluoro-4-iodoquinoline 17.3 cm 3 of diisopropylamine in 650 cm 3 of tetrahydrofuran are cooled to a temperature in the region of -750C and 76 cm 3 of a 1.6M solution of butyl lithium in hexane are added, with stirring and under an inert atmosphere, while maintaining the temperature at about 0 C. After stirring for 20 minutes at a temperature in the region of -75 0 C, a solution of 11.9 g of 3-fluoroquinoline in 200 cm 3 of tetrahydrofuran is added. The solution obtained is stirred for a further 4 hours at -750C, followed by addition of a solution of 32.2 g of double-sublimed iodine in 150 cm 3 of tetrahydrofuran.
After stirring for 2 hours at a temperature in the region of -400C, the reaction mixture is hydrolyzed with 200 cm 3 of a tetrahydrofuran/water mixture (90/10 by volume) and then with 200 cm 3 of saturated sodium chloride solution.
In the region of 200C, the mixture is diluted with 300 cm 3 of ethyl acetate and washed with twice 250 cm 3 of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 l; diameter 10 cm; height 30 cm), eluting with dichloromethane and collecting 100-cm 3 fractions.
Fractions 45 to 80 are combined and then concentrated to 532 dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. 15.1 g of 3-fluoro-4-iodoquinoline are obtained in the form of a cream-colored solid melting at 1100C.
Mass spectrum: El m/z 273 M' base peak m/z 146 [M I]' 3-Fluoroquinoline 23.5 g of 3-aminoquinoline and 12.1 g of sodium nitrite in 20 cm 3 of distilled water are added cautiously to 100 cm 3 of tetrafluoroboric acid cooled to about 0°C, with vigorous stirring, and the reaction mixture is thus stirred for 30 minutes. The suspension is filtered, spinfiltered, washed with 3 times 30 cm 3 of ice-cold tetrafluoroboric acid, 50 cm 3 of ice-cold ethanol and 4 times 30 cm 3 of diethyl ether. The solid is dried in a desiccator (2 kPa) in the region of 200C and then taken up in 200 cm 3 of toluene and heated at a temperature in the region of 900C for 1 hour with stirring. After cooling to about 200C, the phases of the reaction mass are separated by settling and the insoluble oil is washed with 3 times 100 cm 3 of toluene and taken up in 110 cm 3 of water, which is basified by slow addition of sodium hydrogen carbonate so that the pH is at about 8. The aqueous phase is extracted with 5 times 100 cm 3 of diethyl ether and the organic phases are combined, washed with twice 50 cm 3 of water, dried over magnesium sulfate 533 and taken up with vegetable charcoal filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 45 0 C. The oil is taken up in 50 cm 3 of a 40-60 0 C petroleum ether/ethyl acetate mixture (90/10 by volume) and the insoluble material is filtered off, rinsed with twice 25 cm 3 of a 40-60 0
C
petroleum ether/ethyl acetate mixture (90/10 by volume) and dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20 0 C. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 i; diameter 5 cm; height 45 cm), eluting with a 40-60 0
C
petroleum ether/ethyl acetate mixture (90/10 :by volume) and collecting 100-cm 3 fractions. Fractions 20 to 31 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
13 g of 3-fluoroquinoline are obtained in the form of a colorless liquid.
Mass spectrum: El m/z 147 base peak m/z 127 [M HF]"m/z 120 [M HCN] The ethyl 4-allyl-l-(tert-butoxycarbonyl)piperidine-4-carboxylate was prepared in Example 1.
Example 47 534 Ethyl 4- (3-chloro--6-methoxyquinolin-4-yl) propyl] (pyridin-2-yloxy) ethyllpiperidine-4carboxylate is prepared in the form of a viscous colorless oil.
H NMR Spectrum (300 MHz, (CD 3 2 S0-d 6 8 in ppm) 1.04 J 7 Hz: 3H); 1.39 (very broad t, J 12 Hz: 2H); 1.51 (mt: 2H); 1.68 (mt: 2H); from 1.90 to 2.15 (mt: 4H); 2.60 J 6 Hz: 2H); 2.70 (broad d, J 12 Hz: 2H); 3.16 (broad t, J 7.5 Hz: 2H); 3.95 3H); 3.99 J 7 Hz: 2H); 4.31 J 6 Hz: 2H); 6.78 (d, J 8 Hz: 1H); 6.96 (broad dd, J 7.5 and 5 Hz: 1H); 7.37 J 2.5 Hz: 1H); 7.45 (dd, J 9 and 2.5 Hz: 1H); 7.69 (ddd, J 8-7.5 and 2 Hz: 1H); 7.96 J 9 Hz: 1H); 8.14 (broad dd, J 5 and 2 Hz: 1H); 8.67 (s: 1H).
4- (3-Chloro-6-methoxyquinolin-4-yl)propy1] (pyridin-2-yloxy) ethyl] piperidipe-4-carboxylic acid A mixture of 0.12 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl (pyridin-2-yloxy) ethyllpiperidine-4-carboxylate in 5 cm 3 of dioxane, 5 cm 3 of methanol and 1 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 0 C for 21 hours. After cooling to about 20 0 C, the reaction mass is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 60 0
C.
The residue is taken up in 5 cm 3 of a 535 dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 p; diameter 1.5 cm; mass 20 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume). The fractions containing the product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The foam is taken up in 2 cm 3 of methanol, filtered, washed with 1 cm 3 of methanol and 2 cm 3 of diethyl ether and then oven-dried under reduced pressure (10 kPa) at about 50 0 C. 0.115 g of chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2yloxy)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid melting at about 70 0 C and becoming sticky.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.20 to 1.80 (mt: 6H); 1.98 (very broad d, J 13.5 Hz: 2H); 2.09 (very broad t, J 11 Hz: 2H); 2.60 J 6 Hz: 2H); 2.67 (mt: 2H); 3.16 (mt: 2H); 3.98 3H); 4.32 J 6 Hz: 2H); 6.80 J 8 Hz: 1H); 6.96 (ddd, J 7.5-5 and 1 Hz: 1H); 7.39 (broad s: 1H); 7.45 (dd, J 9 and 2.5 Hz: 1H); 7.70 (ddd, J 8-7.5 and 2 Hz: 1H); 7.97 J 9 Hz: 1H); 8.16 (broad dd, J and 2 Hz: 1H); 8.67 1H).
Example 48 536 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)-3-(R,S)fluoropropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylic acid A mixture of 0.07 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 0.9 cm 3 of aqueous sodium hydroxide solution is maintained at a temperature in the region of 70 0 C for 4 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is chromatographed under atmospheric pressure, on a column of silica gel (particle size 70-200 t; mass 10 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume). Fractions 10 to 15 are combined and then concentrated to dryness under the same conditions as above. 0.04 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): from 1.20 to 2.60 (mt: 12H); 2.66 (mt: 2H); 3.03 J 7 Hz: 2H); 3.93 3H); 6.38 (mt, JHF 48 Hz: 1H); 7.05 (mt: 1H); from 7.20 to 7.40 (mt: 2H); 7.52 (dd, J 9 and Hz: 1H); 7.56 J 2.5 Hz: 1H); 8.04 J 9 Hz: 1H); 8.75 (broad s: 1H); from 12.30 to 12.70 (broad 537 unresolved peak: 1H).
Methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)fluoropropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate 0.1 cm 3 of diethylaminosulfur trifluoride is added to a solution of 0.25 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-4-carboxylate in 10 cm 3 of dichloromethane, with stirring and under an inert atmosphere, at a temperature in the region of 5 0
C.
After stirring for 7 hours at a temperature in the region of 200C, saturated sodium hydrogen carbonate solution is added to the reaction mixture. The aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 g; mass: eluting with 60 cm 3 of dichloromethane, then with cm 3 of a mixture of ethyl acetate/dichloromethane (1/9 by volume), then with 30 cm 3 of a mixture of ethyl acetate/dichloromethane (2/8 by volume) and then with 210 cm 3 of a mixture of ethyl acetate/dichloromethane (3/7 by volume) and then with ethyl acetate. Fractions 24 to 26 are combined and then concentrated to dryness 538 according to the same conditions as above. 0.08 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)fluoropropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate is obtained in the form of a thick yellow oil.
H NMR Spectrum (400 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.20 to 2.60 (mt: 12H); from 2.55 to 2.75 (mt: 2H); 3.11 J 7 Hz: 2H); 3.54 3H); 3.93 3H); 6.36 (mt, JHF 48 Hz: 1H); 7.05 (mt: 1H); from 7.15 to 7.35 (mt: 2H); from 7.45 to 7.55 (mt: 2H); 8.03 J 9 Hz: 1H); 8.75 1H).
Methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate A mixture of 1.75 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate dihydrochloride, 0.95 g of 2-(2-bromoethylthio)-1,4difluorobenzene, 0.622 g of potassium iodide and 3.11 g of potassium carbonate in 30 cm 3 of acetonitrile and cm 3 of dimethylformamide is heated with stirring for 18 hours at a temperature in the region of 85 0 C. After cooling to about 20 0 C, the reaction mixture is filtered through Celite and the filtrate is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is taken up in water and diethyl ether. The organic phase is dried 539 over magnesium sulfate, filtered and then concentrated to dryness as above. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 p; diameter 4 cm), eluting with a dichloromethane/methanol mixture (97.5/2.5 by volume). The fractions containing the product are combined and then concentrated to dryness according to the same conditions as above. 0.6 g of methyl chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1- [2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate is obtained.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): from 1.20 to 2.15 (mt: 10H); from 2.45 to 2.55 (mt: 2H); 2.64 (mt: 2H); 3.12 J 7 Hz: 2H); 3.47 3H); 3.87 3H); 5.41 (mt: 1H); 6.10 (unresolved peak: 1H); 7.04 (mt: 1H); from 7.15 to 7.35 (mt: 2H); 7.45 (dd, J 9 and Hz: 1H); 7.97 J 9 Hz: 1H); 8.13 (very broad d, J 2.5 Hz: 1H); 8.66 1H).
The 2-(2-bromoethylthio)-1,4-difluorobenzene may be obtained by applying the method described in Example 14.
The methyl 4-[3-(3-chloro-6-methoxyquinolin-4yl)-3-(R,S)-hydroxypropyl]piperidine-4-carboxylate was prepared in Example 49.
Example 49 540 4-[3-(3-Chloro-6-methoxyquinolin-4-yl)-3-(R,S)fluoropropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine- 4-carboxylic acid A mixture of 0.15 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5difluorophenoxy)ethyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 1 cm 3 of aqueous sodium hydroxide solution is maintained at a temperature in the region of 700C for 4 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is chromatographed under an atmospheric pressure of 60 kPa, on a Bond Elut of 60 cm 3 of silica gel (particle size 70-200 C; mass 25 g), eluting with 60 cm 3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then with a dichloromethane/methanol/aqueous ammonia mixture (40/5/2 by volume). The fractions containing the expected product are combined and then concentrated to dryness according to the same conditions as above. 0.04 g of chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1- [2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): from 1.20 to 2.40 (mt: 10H); 2.65 J 6 Hz: 2H); 2.72 (mt: 2H); 3.93 3H); 4.03 J 6 Hz: 2H); 6.37 (mt, JHF 48 Hz: 1H); 6.75 (mt: 1H); 7.14 (mt: 1H); 7.25 (mt: 541 1H); 7.52 (dd, J 9 and 2.5 Hz: 1H); 7.56 J Hz: 1H); 8.03 J 9 Hz: 1H); 8.75 J 1 Hz: 1H).
Methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)fluoropropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine- 4-carboxylate 0.2 cm 3 of diethylaminosulfur trifluoride is added to a solution of 0.5 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(2,5difluorophenoxy)ethyl]piperidine-4-carboxylate in 20 cm 3 of dichloromethane, with stirring and under an inert atmosphere, at a temperature in the region of 3 0 C. After stirring for 7 hours at a temperature in the region of 0 C, saturated sodium hydrogencarbonate solution is added to the reaction mixture. The aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 4; diameter 1.5 cm; mass: 15 eluting with a mixture of ethyl acetate/petroleum ether (40-60 0 C) (8/2 by volume).
Fractions 9 to 11 are combined and then concentrated to dryness under the above conditions. 0.21 g of methyl 4- [3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4- 542 carboxylate is obtained in the form of a thick yellow oil.
Mass spectrum: DCI m/z 551 MH Presence of an impurity m' 532.
Methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylate A mixture of 1.55 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-hydroxypropyl]piperidine-4carboxylate, 1.03 g of l-(2-bromoethoxy)-2,5difluorobenzene, 0.65 g of potassium iodide and 2.7 g of potassium carbonate in 30 cm 3 of acetonitrile and 20 cm 3 of dimethylformamide is heated with stirring at a temperature in the region of 850C for 17 hours. After cooling to a temperature in the region of 200C, the suspension is filtered through Celite and the filtrate is concentrated to dryness under reduced pressure (2 kPa) in the region of 40 0 C. The evaporation residue is taken up in dichloromethane and water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness as under the above conditions. The residue is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200 p; diameter 4 cm), eluting with a mixture of dichloromethane/methanol (97/3 by volume). The fractions containing the product are combined and then concentrated to dryness under 543 reduced pressure (2 kPa), at a temperature in the region of 40 0 C and under the same conditions as above. 0.5 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylate is obtained.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): from 1.20 to 2.20 (mt: 10H); from 2.60 to 2.80 (mt: 2H); 2.64 J 6:Hz: 2H); 3.48 3H); 3.88 3H); 4.12 J 6 Hz: 2H); 5.40 (mt: 1H); 6.10 (broad s: 1H); 6.74 (mt: 1H); 7.13 (mt: 1H); 7.24 (mt: 1H); 7.44 (dd, .J 9 and 2.5 Hz: 1H); 7.96 J 9 Hz: 1H); 8.14 J Hz: 1H); 8.66 1H).
Methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]piperidine-4-carboxylate A mixture of 2.95 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]-(tertbutyloxycarbonyl)piperidine-carboxylate and 2.3 cm 3 of sulfuric acid in 100 cm 3 of methanol is heated at a temperature in the region of 80 0 C for 1 and a half hours.
After cooling, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is taken up in 10 cm 3 of water, basified to pH 11 with saturated sodium bicarbonate solution and then with saturated sodium carbonate solution and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 544 0 C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 g; diameter 2 cm; volume 80 cm 3 eluting with a mixture of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume). Fractions 8 to 20 are combined and then concentrated to dryness under the same conditions as above. 1.37 g of methyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]piperidine-4carboxylate are obtained in the form of a cream-colored foam.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.10 to 1.45 (mt: 3H); from 1.55 to 1.75 (mt: 1H); from 1.80 to 2.05 (mt: 4H); 2.40 (mt: 2H); 2.72 (mt: 2H); 3.50 3H); 3.90 3H); 5.42 (broad t, J 6.5 Hz: 1H); 6.09 (mt: 1H); 7.45 (dd, J 9 and 3 Hz: 1H); 7.97 J 9 Hz: 1H); 8.15 J 3 Hz: 1H); 8.67 1H).
Methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]-(tert-butyloxycarbonyl)piperidine carboxylate A solution of 5 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)-propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate in 400 cm 3 of dimethyl sulfoxide and 120 cm 3 of tert-butanol is stirred under an oxygensaturated atmosphere at a temperature in the region of 0 C. After 5 minutes, a solution of 2.8 g of potassium tert-butoxide in 30 cm 3 of tert-butanol is added to the 545 reaction mixture. After sparging with oxygen for 2 hours, 300 cm 3 of ice-cold water and 3.5 cm 3 of acetic acid are added cautiously. The aqueous phase is extracted with twice 200 cm 3 of dichloromethane. The organic phases are combined and washed with 4 times 1 dm 3 of water. The organic phase is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue is taken up in 200 cm 3 of diethyl ether, filtered, washed with 20 cm 3 of diethyl ether and then dried in a dessicator under reduced pressure (0.1 kPa) at a temperature in the region of 40 0 C. 3 g of methyl 4-[3- (3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)hydroxypropyl]- (tert-butyloxycarbonyl)piperidine carboxylate are obtained in the form of a white solid melting at 222 0
C.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): from 1.10 to 1.50 (mt: 3H); 1.39 9H); 1.70 (mt: 1H); from 1.80 to 2.10 (mt: 4H); 2.81 (mt: 2H); 3.69 (mt: 2H); 3.89 3H); 5.41 (dd, J 9 and 5 Hz: 1H); from 5.80 to 6.30 (broad unresolved peak: 1H); 7.44 (dd, J 9 and 3 Hz: 1H); 7.95 J 9 Hz: 1H); 8.16 J 3 Hz: 1H); 8.65 1H); from 12.00 to 12.90 (broad unresolved peak: 1H).
The 1-(2-bromoethoxy)-2,5-difluorobenzene was prepared in Example 16.
The ethyl 4-[3-(3-chloro-6-methoxyquinolinyl)propyl]-1-(tert-butoxycarbonyl)piperidine-4-carboxylate was prepared in Example 546 Example Ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(thiazol-2-yloxy)ethyl]piperidine-4carboxylate is prepared.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.05 J 7 Hz: 3H); 1.40 (very broad t, J 12 Hz: 2H); 1.53 (mt: 2H); 1.69 (mt: 2H); from 1.90 to 2.15 (mt: 4H); 2.64 J 5.5 Hz: 2H); 2.70 (broad d, J 11.5 Hz: 2H); 3.16 (broad t, J 7.5 Hz: 2H); 3.96 3H); 4.01 J 7 Hz: 2H); 4.42 J 5.5 Hz: 2H); 7.04 (d, J 3.5 Hz: 1H); 7.17 J 3.5 Hz: 1H); 7.37 (d, J 2.5 Hz: 1H); 7.46 (dd, J 9 and 2.5 Hz: 1H); 7.97 (d, J 9 Hz: 1H); 8.67 1H).
4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2- (thiazol-2-yloxy)ethyl]piperidine-4-carboxylic acid A mixture of 0.68 g of ethyl 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl] [2-(thiazol-2-yloxy)ethyl]piperidine-4-carboxylate in 7 cm 3 of dioxane, 9 cm 3 of methanol and 2 cm 3 of aqueous 5N sodium hydroxide solution is maintained at a temperature in the region of 600C for 20 hours. After cooling to about 200C, the reaction mass is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C.
The residue obtained is chromatographed under a pressure of 50 kPa of argon, on a column of silica gel (particle size 20-45 R; diameter 2.2 cm; mass 20 eluting with a 547 mixture of dichloromethane/methanol (70/30 by volume). The fractions containing the expected product are combined and then concentrated to dryness under the above conditions.
The residue obtained is taken up in 5 cm 3 of ethyl acetate, stirred for 1 hour at room temperature and then filtered and rinsed with 3 times 3 cm 3 of ethyl acetate and then 3 times 3 cm 3 of pentane. 0.27 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thiazol-2-yloxy)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid melting at 188 0
C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d6, 8 in ppm): 1.39 (broad t, J 12 Hz: 2H); from 1.50 to 1.65 (mt: 2H); 1.71 (mt: 2H); 1.98 (broad d, J 12 Hz: 2H); 2.12 (unresolved peak: 2H); from 2.60 to 2.85 (mt: 4H); 3.17 (broad t, J 7.5 Hz: 2H); 3.96 3H); 4.45 (very broad t, J 5.5 Hz: 2H); 7.05 J 3.5 Hz: 1H); 7.18 J Hz: 1H); 7.37 J 2.5 Hz: 1H); 7.46 (dd, J 9 and Hz: 1H); 7.97 J 9 Hz: 1H); 8.68 1H); from 11.80 to 12.70 (broad unresolved peak: 1H).
Example 51 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(4,5dihydrothiazol-2-ylthio)ethyl]piperidine-4-carboxylic acid A mixture of 0.15 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(4,5-dihydrothiazol-2ylthio)ethyl]piperidine-4-carboxylate in 5 cm 3 of dioxane, 548 cm 3 of methanol and 1 cm 3 of aqueous 5N sodium hydroxide solution is maintained at a temperature in the region of 0 C for 20 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (Bond Elut; particle size 70-200 l; mass 7 eluting with a mixture of dichloromethane/methanol/aqueous ammonia (40/5/0.5 by volume). The fractions containing the product are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C
and then oven-dried under reduced pressure (10 kPa) at about 50 0 C. 0.1 g of 4 -[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(4,5-dihydrothiazol-2-ylthio)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 1.33 (very broad t, J 11.5 Hz: 2H); 1.61 (mt: 4H); from 1.90 to 2.10 (mt: 4H); from 2.45 to 2.60 (mt: 2H); 2.63 (broad d, J 11.5 Hz: 2H); 3.05 (mt: 2H); 3.19 J Hz: 2H); 3.44 J 8 Hz: 2H); 3.97 3H); 4.15 J 8 Hz: 2H); 7.35 (broad s: 1H); 7.40 (broad d, J 9 Hz: 1H); 7.97 (broad d, J 9 Hz: 1H); 8.69 (broad s: 1H).
549 Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2- (4,5-dihydrothiazol-2-ylthio)ethyl]piperidine-4carboxylate A mixture of 0.7 g of ethyl 1-(2-chloroethyl)-4- [3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4carboxylate dihydrochloride, 0.18 g of 2-mercaptothiazoline and 0.63 cm 3 of triethylamine in 10 cm 3 of dimethylformamide is stirred under an inert atmosphere for 23 hours at a temperature in the region of 80 0 C. After cooling to about 20 0 C, the reaction mixture is taken up in water, extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The evaporation residue is added to a solution of 0.18 g of 2-mercaptothiazoline and 0.06 g of 10% sodium hydride in cm 3 of dimethylformamide, and the mixture is then heated at a temperature in the region of 80 0 C for 15 hours. After cooling to about 20 0 C, the reaction mixture is taken up in water, extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under atmospheric pressure on a column of silica gel (particle size 70-200 g; 550 diameter 2 cm; mass 40 eluting with a mixture of dichloromethane/ethanol (95/5 by volume) and collecting 3 fractions. Fractions 11 to 24 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. 0.15 g of ethyl 4-[3- (3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(4,5-dihydrothiazol-2-ylthio)ethyl]piperidine-4-carboxylate is obtained in the form of a brown oil.
1 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 with addition of a few drops of CD 3 COOD d4, 8 in ppm): 1.06 (t, J 7 Hz: 3H); 1.41 (mt: 2H); from 1.50 to 1.70 (mt: 4H); 1.98 (broad d, J 13.5 Hz: 2H); 2.14 (broad t, J 11.5 Hz: 2H); 2.66 J 7 Hz: 2H); 2.80 (very broad d, J 11.5 Hz: 2H); 3.04 (broad t, J 6.5 Hz: 2H); 3.21 J 7 Hz: 2H); 3.42 J 8 Hz: 2H); 3.94 3H); 3.97 (q, J 7 Hz: 2H); 4.12 J 8 Hz: 2H); 7.32 J Hz: 1H); 7.38 (dd, J 9 and 2.5 Hz: 1H); 7.96 J 9 Hz: 1H); 8.66 J 1.5 Hz: 1H).
Ethyl 1-(2-chloroethyl)-4-[3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl]piperidine-4-carboxylate dihydrochloride 5.73 cm 3 of thionyl chloride are added dropwise to a suspension of 0.6 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(2-hydroxyethyl)piperidine- 4-carboxylate in 10 cm 3 of dichloromethane with stirring in the region of 20 0 C, and the mixture is stirred for 24 hours at a temperature in the region of 20 0 C. The reaction 551 mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is taken up in 3 times 30 cm 3 of cyclohexane and evaporated to dryness as under the above conditions.
0.67 g of ethyl 1-(2-chloroethyl)-4-[3-(3-fluoro-6methoxyquinolin-4-yl) propyl] piperidine-4-carboxylate dihydrochioride is obtained in the form of a beige-colored solid.
1H NNR Spectrum (300 MHz, (CD 3 2 S0-d 6 8 in ppm): 1.05 J =7 Hz: 3H); from 1.45 to 2.00 (mt: 6H); 2.19 (broad d, J =14 Hz: 2H); from 2.75 to 2.95 (mt: 2H); 3.09 (mt: 2H); from 3.40 to 3.60 (mt: 4H); from 3.95 to 4.15 (mt: 2H); 3.96 3H); 4.05 J 7 Hz: 2H); 7.37 (d, J 2.5 Hz: 1H); 7.42 (dd, J 9 and 2.5 Hz: 1H); 7.99 (d, J 9 Hz: 1H); 8.73 (broad s: 10.00 (unresolved peak: iH).
The ethyl 4- (3-f luoro-6-methoxyquinolin-4yl)propyl] -1-(2-hydroxyethyl)piperidine-4-carboxylate is prepared by analogy with the method described in Example 46.
Example 52 4- (3-fluoro-6-methoxyquinolin-4-yl)propyl] trifluorophenoxy) ethyl] piperidine-4-carboxylic acid A mixture of 0.8 g of ethyl 4-113-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluoro- 552 phenoxy)ethyl]piperidine-4-carboxylate in 50 cm 3 of dioxane, 50 cm 3 of methanol and 4.4 cm 3 of aqueous sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 18 hours. A further 4.4 cm 3 of aqueous 5N sodium hydroxide solution are added to the reaction mixture, which is stirred for 6 hours in the region of 70 0 C. After cooling to about 20 0 C, the reaction mass is concentrated to dryness under reduced pressure (1.1 kPa) at a temperature in the region of 50 0 C. The residue is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size L; diameter 4 cm; height 20 cm), eluting with a mixture of chloroform/methanol/aqueous ammonia (12/3/0.5 by volume) and collecting 60-cm 3 fractions. Fractions 8 to 19 are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C
and oven-dried under reduced pressure (10 kPa) at about 0 C. 0.59 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyl]piperidine-4carboxylic acid is obtained in the form of a white solid melting at about 120 0
C.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.32 (very broad t, J 12 Hz: 2H); 1.59 (mt: 4H); 1.95 (broad d, J 12 Hz: 2H); 2.07 (broad t, J 11 Hz: 2H); 2.59 J 5.5 Hz: 2H); 2.68 (very broad d, J 11 Hz: 2H); 3.04 (mt: 2H); 3.95 3H); 4.03 J 5.5 Hz: 2H); 6.97 (mt: 2H); 7.34 J 2.5 Hz: 1H); 7.39 (dd, 553 J 9 and 2.5 Hz: 1H); 7.96 J 9 Hz: 1H); 8.69 (broad s: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2- (3,4,5-trifluorophenoxy)ethyl]piperidine-4-carboxylate A mixture of '0.62 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.505 g of 5-(2-bromoethoxy)-1,2,3-trifluorobenzene, 0.34 g of potassium iodide and 1.14 g of potassium -carbonate in 80 cm 3 of.acetonitrile is stirred under an inert atmosphere for 18 hours at a temperature in the region of 70 0 C. After cooling to about 20 0 C, the suspension is filtered and the insoluble material is washed with 3 times 30 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size jp; diameter 3 cm; height 21 cm), eluting with ethyl acetate and collecting 40-cm 3 fractions. Fractions 9 to 24 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 0 C. 0.8 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyl]piperidine- 4-carboxylate is obtained in the form of a pale yellow viscous oil.
554 H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 0.99 J 7 Hz: 3H); 1.37 (very broad t, J 12 Hz: 2H); from 1.45 to 1.70 (mt: 4H); from 1.90 to 2.10 (mt: 4H); 2.59 J 5.5 Hz: 2H); 2.69 (broad d, J 12 Hz: 2H); 3.04 (broad t, J 7 Hz: 2H); 3.94 3H); 3.97 (q, J 7 Hz: 2H); 4.03 J 5.5 Hz: 2H); 6.97 (mt: 2H); 7.33 J 2.5 Hz: 1H); 7.39 (dd, J 9 and 2.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.69 (broad s: 1H).
The ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-4-carboxylate was prepared in Example 11.
The 5-(2-bromoethoxy)-1,2,3-trifluorobenzene was prepared by applying the method described in Example 13.
Example 53 4-[3-(3-fluoro-6-methoxyguinolin-4-yl)propyl]-1-[2- (thiazol-2-ylthio)ethyl]piperidine-4-carboxylic acid A mixture of 0.15 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(thiazol-2-ylthio)ethyl]piperidine-4-carboxylate in 3 cm 3 of dioxane, 3 cm 3 of methanol and 1 cm 3 of aqueous 5N sodium hydroxide solution is stirred at a temperature in the region of 70 0 C for 18 hours. After cooling to about 20 0 C, the reaction mass is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The residue is taken up in twice 20 cm 3 of toluene and then concentrated 555 to dryness as under the above conditions. The solid is purified by chromatography under atmospheric pressure, on a column of silica gel (Bond Elut; particle size 70-200 g; mass 7 eluting with a mixture of chloroform/methanol/aqueous ammonia (84/14/2 by volume) and collecting 5-cm 3 fractions. Fractions 8 to 19 are combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and then oven-dried under reduced pressure (to 10 kPa) at about 50 0 C. 0.114 g of fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thiazol-2-ylthio)ethyl]piperidine-4-carboxylic acid is obtained in the form of a white solid.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 6 in ppm): 1.31 (broad t, J 12 Hz: 2H); 1.45 to 1.70 (mt: 4H); from 1.90 to 2.10 (mt: 4H); 2.58 J 7 Hz: 2H); 2.65 (broad d, J 12 Hz: 2H); 3.04 (mt: 2H); from 3.25 to 3.45 (mt, 2H); 3.95 3H); 7.34 J 2.5 Hz: 1H); 7.39 (dd, J 9 and 2.5 Hz: 1H); 7.63 J 3.5 Hz: 1H); 7.71 (d, J 3.5 Hz: 1H); 7.96 J 9 Hz: 1H); 8.68 J 1 Hz: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2- (thiazol-2-ylthio)ethyl]piperidine-4-carboxylate A mixture of 0.65 g of ethyl 1-(2-chloroethyl)- 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4carboxylate dihydrochloride, 0.183 g of 2-mercaptothiazole, 0.21 g of potassium iodide and 0.88 g of 556 potassium carbonate in 50 cm 3 of acetonitrile is stirred under an inert atmosphere for 18 hours at a temperature in the region of 70 0 C. After cooling to about 200C, the suspension is filtered and the insoluble material is washed with acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The evaporation residue is taken up in a mixture of ethyl acetate/40-60 0 C petroleum ether (8/2 by volume) and filtered, and the filtrate is purified by chromatography under atmospheric pressure on a column of silica gel (particle size 70-200 diameter 1.5 cm; mass 100 eluting with ethyl acetate/40-60 0 C petroleum ether (8/2 by volume) and collecting 15-cm 3 fractions. The fractions 41 to 100 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. 0.15 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-l-[2-(thiazol-2-ylthio)ethyl]piperidine-4-carboxylate is obtained in the form of a thick yellow oil.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.00 J 7 Hz: 3H); 1.36 (broad t, J 11.5 Hz: 2H); from 1.45 to 1.70 (mt: 4H); from 1.85 to 2.10 (mt: 4H); 2.59 J 7 Hz: 2H); 2.68 (broad d, J 12 Hz: 2H); 3.05 (very broad t, J 7 Hz: 2H); 3.33 (mt: 2H); 3.96 (s: 3H); 3.98 J 7 Hz: 2H); 7.35 J 2.5 Hz: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.64 J 3.5 Hz: 1H); 557 7.72 J 3.5 Hz: 1H); 7.97 J 9 Hz: 1H); 8.70 (d, J 1 Hz: 1H).
The ethyl 1-(2-chloroethyl)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate dihydrochloride was prepared in Example 51.
Example 54 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-(3phenylallyl)piperidine-4-carboxylic acid A mixture of 0.13 g of ethyl 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(3-phenylallyl)piperidine- 4-carboxylate in 2 cm 3 of dioxane, 2 cm 3 of methanol and 1.32 cm 3 of aqueous 5N sodium hydroxide solution is maintained at a temperature in the region of 700C for 18 hours. After cooling to about 200C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The residue obtained is taken up in 10 cm 3 of water, acidified with acetic acid and extracted with ethyl acetate, allowed to separate by settling and then filtered and rinsed with twice 10 cm 3 of ethanol. 0.12 g of 4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(3-phenylallyl)piperidine- 4-carboxylic acid is obtained in the form of a white solid melting at 240 0
C.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.35 (broad t, J 11.5 Hz: 2H); from 1.50 to 1.75 (mt: 558 4H); from 1.85 to 2.10 (mt: 4H); 2.63 (broad d, J 11.5 Hz: 2H); from 2.95 to 3.15 (mt: 4H); 3.96 3H); 6.26 (dt, J 16 and 7 Hz: 1H); 6.50 J 16 Hz: 1H); from 7.10 to 7.50 (mt: 7H); 8.06 J 9 Hz: 1H); 8.69 (broad s: 1H).
Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(3- :phenylallyl)piperidine-4-carboxylate 77 mg of borane-pyridine complex are added to a :mixture of 0.31 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate and 0.1 cm 3 of trans-cinnamaldehyde in 10 cm 3 of ethanol. The reaction mixture is maintained at a temperature in the region of 77 0 C for 22 hours. After cooling to about 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0
C.
The residue obtained is taken up in 10 cm 3 of water, extracted with twice 10 cm 3 of dichloromethane, dried over magnesium sulfate, filtered and then concentrated to dryness under the above conditions. The residue obtained is chromatographed under a pressure of 60 kPa of argon, on a column of silica gel (particle size 70-200 i; diameter cm; mass 20 eluting with 500 cm 3 of a mixture of ethyl acetate/cyclohexane (40/60 by volume) and then of a mixture of dichloromethane/methanol (95/5 by volume). The fractions containing the expected product are combined and then concentrated to dryness under the above conditions.
559 0.13 g of ethyl 4 -[3-(3-fluoro-6-methoxyquinolin-4-y.)propyl] 3 -phenylallyl)piperidine-4-carboxylate is obtained in the form of a viscous oil.
IH NMR Spectrum (300 M'flz, (CD 3 2 S0-d 6 8 in ppm): 1.01 J 7 Hz: 3H); 1.40 (broad t, J 11.5 Hz: 2H); from 1.45 to 1.75 (mt: 4H); from 1.90 to 2.05 (mt: 4H); 2.65 (very broad d, J =12 Hz: 2H); 3.02 J 7 Hz: 2H); 3.05 (mt: 2H); 3.96 3H); 3.97 J 7 Hz: 2H); 6.25 (dt, J 16 and 7 Hz: 1H); 6.51 J 16 Hz: 1H); from 7.15 to 7.50 (mt: 7H); 7.96 J 9 Hz: lH); 8.70 J 1 Hz: 1Hi).
The ethyl 4- (3-f luoro-6-methoxyquinolin-4yl)propyllpiperidine-4-carboxylate was prepared in Example 11.
Example 4- (3-Chloro-6-methoxyquinolin-4-yl)propyl (3phenyipropyl )piperidine-4 -hydroxamic acid A solution of 0.1 g of 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl (3-phenylpropyl) piperidine-4-tert-butoxycarboxamide in 2 cm 3 Of trifluoroacetic acid is left for 60 days at a temperature in the region of 20 0 C. The solution is evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and then purified by chromatography under atmospheric pressure on Bond Elut silica (particle size 560 70-200 L; volume 25 cm 3 eluting with a mixture of dichloromethane/methanol/aqueous ammonia (40/5/0.3 by volume). The fractions containing the product are combined and then evaporated under the conditions described above. 0.036 g of 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-l-(3-phenylpropyl)piperidine-4-hydroxamic acid is obtained in the form of a colorless oil.
1H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.33 (mt: 2H); 1.51 (mt: 2H); from 1.60 to 1.80 (mt: 4H); from 1.90 to 2.10 (mt: 4H); 2.18 J 7 Hz: 2H); from 2.45 to 2.65 (mt: 4H); 3.12 (broad t, J 7.5 Hz: 2H); 3.96 3H); from 7.15 to 7.25 (mt: 3H); 7.28 (t mt, J Hz: 2H); 7.36 J 2.5 Hz: 1H); 7.45 (dd, J 9 and 2.5 Hz: 1H); 7.96 J 9 Hz: 1H); 8.56 (unresolved peak: 1H); 8.67 1H); 10.37 (unresolved peak: 1H).
4-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-(3phenylpropyl)piperidine-4-tert-butoxyamide A mixture of 0.5 g of 4-[3-(3-chloro-6methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-4-carboxylic acid, 0.175 g of 1-hydroxybenzotriazole hydrate, 0.498 g of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 0.58 cm 3 of triethylamine and 0.4 g of O-tert-butylhydroxylamine is stirred for 48 hours at a temperature in the region of 0 C. The reaction medium is diluted with 50 cm 3 of 561 water, stirred and the phases are then separated by settling. The aqueous phase is extracted with twice cm 3 of dichloromethane and the organic extracts are combined, dried over magnesium sulfate, filtered and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45 g; diameter 2.5 cm; mass 18 eluting with a mixture of dichloromethane/methanol/aqueous ammonia (40/5/0.2 by volume). The fractions containing the product are combined and then evaporated under the conditions described above. 0.27 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-4tert-butoxyamide is obtained.
H NMR Spectrum (300 MHz, (CD 3 2 SO-d 6 8 in ppm): 1.09 9H); 1.35 (mt: 2H); 1.54 (mt: 2H); 1.67 (mt: 4H); 1.95 (broad t, J 11 Hz: 2H); 2.08 (broad d, J 13.5 Hz: 2H); 2.19 J 7 Hz: 2H); from 2.50 to 2.65 (mt: 4H); 3.14 (broad t, J 7.5 Hz: 2H); 3.98 3H); from 7.10 to 7.25 (mt: 3H); 7.27 (broad t, J 7.5 Hz: 2H); 7.36 (d, J Hz: 1H); 7.45 (dd, J 9 and 2.5 Hz: 1H); 7.96 (d, J 9 Hz: 1H); 8.68 1H); 10.06 (broad s: 1H).
4-[3-(-3-Chloro-6-methoxyquinoline-4yl)propyl]-1-(3-phenylpropyl)piperidine-4-carboxylic acid dihydrochloride was prepared in Example 4.
Benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)- 562 propyl (3-phenyipropyl) piperidine-4-carboxylate was prepared in Example 4.
Example 56 4- (3-Fluoro-6-methoxyquiziolin-4-yl)propyl difluorophanyl )prop-2-enylJ piperidine-4-carboxylic acid hydrochloride Working in a manner analogous to that of Example 54, 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl 5-difluorophenyl)prop-2-enyllpiperidine- 4-carboxylic acid hydrochloride is prepared.
1NMER Spectrum (400 MHz, (CD 3 2 S0-d 6 with addition of a few drops of CD 3 COOD-d 4 at a temperature of 383 K, 8 in ppm): 1.73 (mt: 6H); 2.22 (broad d, J 14 Hz: 2H); 3.01 (unresolved peak: 2H); 3.11 (broad t, J 7 Hz: 2H); 3.42 (very broad d, J 12 Hz: 2H); 3.94 J 7 Hz: 2H); 3.98 (s 3H) 6.48 (dt, J 16.5 and 7 Hz: 1H); 6.93 J 16.5 Hz: 1H); from 7.10 to 7.30 (mt: 2H1); 7.35 (broad s: 1H); 7.40 (dd, J 9 and 2.5 Hz: 1H); 7.44 (mt: 1H); 7.98 J 9 Hz: 1H); 8.64 (broad s: 1H).
Example 57 4-[3-(3-Fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2,5difluorophenoxy) ethyl] piperidine-4-hydroxamic acid 563 Working in a manner analogous to that of Example 55, 4- (3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2- 5-difluorophenoxy)ethyllpiperidine-4hydroxamic acid is prepared.
1HNMR Spectrum (300 MHz, (CD 3 2 S0-d 6 8 in ppm): 1.31 (very broad t, J 12.5-Hz: 2H); from 1.45 to 1.70 (mt: 4H); 2.02 (broad d, J =12.5.Hz: 2H); 2.10 (broad t, J 11 Hz: 2H); from 2.55 to 2.75 (mt: 4H); 3.00 (mt: 2H); 3.97 3H); 4.12 J 5.'5"Hz: 2H); 6.75 (mt: 1H); 7.14 1H) 7.24 (mt: 1H); 7.33 J 3.Hz: 1H); 7.40 (dd, J 9 and 3 Hz: 1H); 7.96 J 9 Hz: 1H); 8.63 (unresolved peak: 1H); 8.70 J 0.5 Hz: 1H); 10.40 (unresolved peak: 1H).
Example 58 1-Cinnamyl-4- (3-f luoro-6-methoxyquinolin-4-yl)propyl] -piperidine-4-hydroxaiic acid Working in a manner analogous to that of -Example 55, l-cinnamyl-4-[13- (3-f luoro-6-methoxyquinolin- 4-yl) propyl] -piperidine-4-hydroxamic acid is prepared.
1 H NMR Spectrum (400 MHz, (CD 3 2 S0-d 6 with addition of a few drops of CD 3 COOD-d 4 at a temperature of 373 K, 8 in ppm): from 1.50 to 1.75 (mt: 6H); 2.23 (broad d, J 14 Hz: 2H); 2.81 (broad t, J 11.5 Hz: 2H); 3.04 (mt: 2H); 3.22 (broad d, J 11.5 Hz: 2H); 3.69 J 7 Hz: 2H); 3.97 3H); 6.24 (dt, J 16 and 7 Hz: 1H); 564 6.78 J =16 Hz: 1H); from 7.20 to 7.50 (mt: 7ff); 7.96 J 9 Hz: 1H); 8.62 (broad s: 211).
Example 59 Sodium 4- (3-chloro-6-trifluoromethylquinolin-4yl)propyl] 5-difluorophenoxy)ethyllpiperidine-4carboxylate Working in a manner analogous to that of Example 1, sodium 4-[3-(3-chloro-6trifluoromethylquinolin-4-yl)propyl difluorophenoxy) ethyllpiperidine-4-carboxylate was prepared.
1H NMR Spectrum (300 MHz, (CD 3 2 S0-d 6 8 in ppm): 1.09 (very broad t, J 11.5 Hz: 2H); from 1.40 to 1.70 (mt: 4H); 1.98 (broad d, J 11.5 Hz: 2H); 2.14 J 10.5 Hz: 2H); from 2.50 to 2.70 (mt: 4H); 3.22 (broad t, J 7 Hz: 2H); 4.10 J 5.5 Hz: 2H); 6.74 (mt: 1H); 7.12 (mt: 1H); 7.23 (mt: 1H); 8.06 (broad d, J 9 Hz: 1H); 8.26 J 9 Hz: 1H); 8.26 J 9 Hz: 1H); 8.54 (broad s: 1H); 9.00 1H).
The present invention also relates to pharmaceutical compositions containing at least one heterocyclylalkylpiperidine derivative according to the invention, where appropriate in the form of a salt, in pure form or in the form of a combination with one or 565 more compatible and pharmaceutically acceptable diluents and/or adjuvants.
The compositions according to the invention may be used orally, parenterally, topically, rectally or as aerosols.
Solid compositions for oral administration which may be used include tablets, pills, gel capsules, powders or granules. In these compositions, the active product according to the invention is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions may comprise substances other than diluents, for example a lubricant such as magnesium stearate or a coating intended for controlled release.
Liquid compositions for oral administration which may be used include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or liquid paraffin. These compositions may also comprise substances other than diluents, for example wetting, sweetening or flavoring products.
The compositions for parenteral administration may be sterile solutions or emulsions. Solvents or vehicles which may be used include water, propylene glycol, a polyethylene glycol, plant oils, in particular olive oil, and injectable organic esters, for example ethyl oleate. These compositions may also contain 566 adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers.
The sterilization may be carried out in several ways, for example using a bacteriological filter, by irradiation or by heating. The compositions may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other injectable sterile medium.
The compositions for topical administration may be, for example, creams, ointments, lotions or aerosols.
The compositions for rectal administration are suppositories or rectal capsules which contain, besides the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
The compositions may also be aerosols. For use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be inhaled directly, the active principle is finely divided and combined with a water-soluble solid diluent or vehicle with a particle size of from 30 to 80 pn, for example dextran, mannitol or lactose.
In human therapy, the novel heterocyclylalkylpiperidine derivatives according to the invention are particularly useful in the treatment of 567 infections of bacterial origin. The doses depend on the desired effect and on the duration of the treatment. The doctor will determine the dosage he considers most appropriate as a function of the treatment, depending on the age, weight, degree of infection and other factors specific to the individual to be treated. Generally, the doses are between 750 mg and 3 g of active product taken 2 or 3 times a day orally or between 400 mg and 1.2 g intravenously for an adult.

Claims (14)

1. A heterocyclylalkylpiperidine derivative of general formula: (CH N-R 3 I (I) X2 X4 X3 N for which: X 1 X 2 X 3 X 4 and X 5 represent, respectively, >C-R'I to >C-R' 5 or alternatively not more than one of them represents a nitrogen atom, RI, R' 1 R' 2 R' 3 R' 4 and R' 5 are identical or different and represent a hydrogen or halogen atom or an alkyl, cycloalkyl, phenyl, phenylthio, mono- or bicyclic aromatic heterocyclyl or heterocyclylthio, hydroxyl, alkyloxy, trifluoromethoxy, alkylthio, trifluoro- methylthio, cycloalkyloxy, cycloalkylthio, cyano, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, -NRaRb or -CONRaRb radical (for which Ra and Rb can represent hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6- membered heterocycle which can optionally contain another heteroatom chosen from O, S and N and, where appropriate, bearing an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent on the nitrogen atom or, where appropriate, the sulfur atom of which is oxidized in the 569 form of sulfinyl or sulfonyl), or represent a methylene radical substituted with fluoro, hydroxyl, alkyloxy, alkylthio, cycloalkyloxy, cycloalkylthio, phenyl, mono- or bicyclic aromatic heterocyclyl, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, -NRaRb or -CONRaRb for which Ra and Rb are defined as above, or represent phenoxy, heterocyclyloxy, benzyloxy, heterocyclylmethyloxy, or alternatively RI can also represent difluoromethoxy, or a radical of structure -CmF2m+1, -SCmF2m+1 or -OCmF2m+i for which m is an integer from 1 to 6, or alternatively R' 5 can also represent trifluoroacetyl, R 2 represents carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, cyano, -CONRaRb (for which Ra and Rb represent, respectively, hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic aromatic heterocyclyl, or Ra or Rb represents hydroxyl, alkyloxy, cycloalkyloxy, or Ra and Rb form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle which can optionally contain another heteroatom chosen from O, S and N and, where appropriate, bearing an alkyl, phenyl or mono- or bicyclic aromatic heterocyclyl substituent on the nitrogen atom or, where appropriate, the sulfur atom of which is oxidized in the form of sulfinyl or sulfonyl), or R 2 represents hydroxymethyl, alkyl containing 1 or 2 carbon atoms substituted with carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, cyano or 570 -CONRaRb for which Ra and Rb are defined as above, or R 2 represents a radical of structure -CF 2 -Rc, -C(CH 3 2 -Rc, -CO-Rc, -CHOH-Rc, -C(cycloalkyl)-Rc, or -CH=CH-Rc for which Rc is carboxyl, alkyloxycarbonyl, cycloalkyloxy- carbonyl, or -CONRaRb for which Ra and Rb are defined as above, R 3 represents a phenyl, mono- or bicyclic aromatic heterocyclyl or alk-R 0 3 radical for which alk is an alkyl radical and R 0 3 represents hydrogen, halogen, hydroxyl, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylamino, N-cycloalkyl- N-alkylamino, (cycloalkyl) 2 acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylamino, N-alkyl-N-phenylamino, N-cycloalkyl-N-phenylamino, (phenyl) 2 phenylalkyloxy, phenylalkylthio, phenylalkylsulfinyl, phenylalkylsulfonyl, phenylalkylanino, N-alkyl-N- phenylaminoalkyl, N-cycloalkyl-N-phenylalkylamino, benzoyl, mono- or bicyclic aromatic heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, heterocyclylamino, N-alkyl-N-heterocyclylamino, N-cycloalkyl- N-heterocyclylamino, heterocyclylcarbonyl, heterocyclylalkyloxy, heterocyclylalkylthio, heterocyclylalkylsulfinyl, heterocyclylalkylsulfonyl, 571 heterocyclylalkylamino, N-alkyl-N-heterocyclylaminoalkyl, N-cycloalkyl-N-heterocyclylaminoalkyl, (the heterocyclyl portions mentioned above being mono- or bicyclic aromatic), carboxyl, alkyloxycarbonyl, -NRaRb or -CO-NRaRb for which Ra and Rb are defined as above in the definition of R 2 or alternatively R 0 3 represents -CR'b=CR'c-R'a for which R'a represents phenyl, phenylalkyl, heterocyclyl or heterocyclylalkyl in which the heterocyclyl portion is mono- or bicyclic aromatic, phenoxyalkyl, phenylthioalkyl, phenylsulfinylalkyl, phenylsulfonylalkyl, phenylaminoalkyl, N-alkyl-N- phenylaminoalkyl, heterocyclyloxyalkyl, heterocyclylthioalkyl, heterocyclylsulfinylalkyl, heterocyclylsulfonylalkyl, heterocyclylaminoalkyl, N- alkyl-N-heterocyclylaminoalkyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, (the heterocyclyl portions mentioned above being mono- or bicyclic aromatic), phenylthio, phenylsulfinyl, phenylsulfonyl, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or alternatively R 0 3 represents a radical -C=C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, mono- or bicyclic aromatic heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, heterocyclylthioalkyl, heterocyclylaminoalkyl, N-alkyl-N-heterocyclylaminoalkyl, (the heterocyclyl portions mentioned above being mono- or bicyclic 572 aromatic), or alternatively R 0 3 represents a -CF 2 -phenyl or mono- or bicyclic aromatic -CF 2 -heterocyclyl radical, Y represents a radical >CH-Re for which Re is hydrogen, fluoro, hydroxyl, alkyloxy, cycloalkyloxy, carboxyl, alkyloxycarbonyl, cycloalkyloxycarbonyl, -NRaRb or -CO-NRaRb for which Ra and Rb are defined as above for R 2 or one represents a hydrogen atom and the other represents an alkyloxycarbonyl, acyl, cycloalkylcarbonyl, benzoyl or heterocyclylcarbonyl radical in which the heterocyclyl portion is mono- or bicyclic aromatic, or alternatively Y represents a difluoromethylene, carbonyl, hydroxyiminomethylene, alkyloxyiminomethylene or cycloalkyloxyiminomethylene radical or a 1,1- cycloalkylene radical containing 3 to 6 carbon atoms, and n is an integer from 0 to 4, it being understood that the phenyl, benzyl, benzoyl or heterocyclyl radicals or portions mentioned above may optionally be substituted on the ring with 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, alkyloxyalkyl, haloalkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, carboxyl, alkyloxycarbonyl, cyano, alkylamino, -NRaRb for which Ra and Rb are defined as above, phenyl, hydroxyalkyl, alkylthioalkyl, alkylsulfinylalkyl and alkylsulfonylalkyl, it being understood that the alkyl or acyl radicals and portions contain (except where especially mentioned) 1 to 573 carbon atoms in a straight or branched chain and that the cycloalkyl radicals contain 3 to 6 carbon atoms, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and/or, where appropriate, in their syn or anti form or a mixture thereof, as well as the salts thereof.
2. A heterocyclylalkylpiperidine derivative as claimed in claim 1, characterized in that X 1 X 2 X 3 X 4 and Xs represent, respectively, >C-R' 1 to >C-R' 5 or alternatively not more than one of.them represents a nitrogen atom, R I R'i, R' 2 R'3, R' 4 and R' 5 are identical or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a methylene radical substituted with alkyloxy, R 2 represents carboxyl, alkyloxycarbonyl or -CONRaRb (for which Ra represents a hydrogen atom and Rb represents a hydrogen atom or a hydroxyl radical) or R 2 represents hydroxymethyl, alkyl containing 1 or 2 carbon atoms substituted with carboxyl, or alkyloxycarbonyl, R 3 represents a radical alk-R 0 3 for which alk. is an alkyl radical and R 0 3 represents hydrogen, cycloalkyl, cycloalkylthio, phenyl, phenoxy, phenylthio, phenylamino, heterocyclyloxy or heterocyclylthio or alternatively R 0 3 represents -CR'b=CR'c-R'a for which R'a represents phenyl, and for which R'b and R'c represent hydrogen, 574 Y represents a radical >CH-Re for which Re is hydrogen, fluoro or hydroxyl, n is an integer from 2 to 3, it being understood that the phenyl or heterocyclyl radicals or portions mentioned above may optionally be substituted on the ring with 1 to 4 halogens, and it being understood that the alkyl or acyl radicals and portions contain (except where especially mentioned) 1 to 10 carbon atoms in a straight or branched chain and that the cycloalkyl radicals contain 3 to 6 carbon atoms, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and/or, where appropriate, in their syn or anti form or a mixture thereof, as well as the salts thereof.
3. A heterocyclylalkylpiperidine derivative as claimed in claim 1, characterized in that it is 4-[3- (3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2- yl)thioethyl]piperidine-4-carboxylic acid, as well as the salts thereof.
4. A heterocyclylalkylpiperidine derivative as claimed in claim 1, characterized in that it is 4-[3- (3-chloro-6-methoxyquinolin-4-yl)propyl]-l-[2-(3,5- difluorophenoxy)ethyl]piperidine-4-carboxylic acid, as well as the salts thereof.
5. A heterocyclylalkylpiperidine derivative as claimed in claim 1, characterized in that it is 4-[3- (3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(2-thiazol-2- 575 thioethyl)piperidine-4-carboxylic acid, as well as the salts thereof.
6. A heterocyclylalkylpiperidine derivative as claimed in claim 1, characterized in that it is 1-(2- cyclopentylthioethyl)-4-[3-(3-fluoro-6-methoxyquinolin-4- yl)propyl]piperidine-4-carboxylic acid, as well as the salts thereof.
7. A heterocyclylalkylpiperidine derivative as claimed in claim 1, characterized in that it is fluoro-6-methoxyquinolin-4-yl)propyl]-1-(3- phenylallyl)piperidine-4-carboxylic acid, as well as the salts thereof.
8. A process for preparing a heterocyclylalkylpiperidine derivative as claimed in claim 1, characterized in that the chain R 3 defined in claim 1 is coupled with the heterocyclylalkylpiperidine derivative of general formula: S(CH 2 )n y/ R^ NH X2 N in which X 1 X 2 X 3 X 4 X 5 R 1 R 2 Y and n are defined as above, and R 2 being protected when it bears a carboxyl or amino radical, optionally followed by removal of the acid-protecting or amine-protecting radical, optional 576 separation of the enantiomeric or diastereoisomeric forms and/or, where appropriate, of the syn or anti forms and optional conversion of the product obtained into a salt.
9. A process as claimed in claim 8, characterized in that the coupling of the chain R 3 with the piperidine is carried out by the action of a derivative of general formula: R 3 -X in which R 3 is defined as above and X represents a halogen atom, a methylsulfonyl radical, a trifluoromethylsulfonyl radical or a p-toluenesulfonyl radical.
A process as claimed in either of claims 8 and 9, characterized in that, when R 3 represents a radical -alk-R°3 for which alk is an alkyl radical and R 0 3 represents a radical -C=C-Rd in which Rd is phenyl, phenylalkyl, heterocyclyl or mono- or bicyclic aromatic heterocyclylalkyl, the reaction is preferably carried out by coupling an alkynyl halide: HC=C-alk-X for which alk is defined as above and X is a halogen atom, and then substitution of the chain with a phenyl, phenylalkyl, heterocyclyl or heterocyclylalkyl radical.
11. A process as claimed in either of claims 8 and 9, characterized in that, when R 3 represents a radical -alk-R 0 3 for which alk is an alkyl radical and R 0 3 represents a phenoxy, phenylthio, phenylamino, heterocyclyloxy, heterocyclylthio or heterocyclylamino 577 Sradical in which the heterocyclyl portion is aromatic, the reaction is preferably carried out by constructing the chain stepwise by first condensing a chain HO-alk-X for ln which X is a halogen atom, and then by converting the C hydroxyalkyl chain obtained into a haloalkyl, 00 methanesulfonylalkyl or p-toluenesulfonylalkyl chain, and Sfinally by reacting in basic medium with an aromatic (C derivative of structure Ar-ZH for which Ar is a phenyl or aromatic heterocyclyl radical and Z is a sulfur, oxygen or nitrogen atom.
12. A pharmaceutical composition, characterized in that it contains at least one derivative as claimed in claim 1, in pure form or in combination with one or more compatible and pharmaceutically acceptable diluents and/or adjuvants.
13. A method for the treatment of a bacterial infection in a human, the method comprising administering to a human in need of such treatment an effective amount of the heterocyclylalkylpiperidine derivative according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.
14. Use of the heterocyclylalkylpiperidine derivative according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of a bacterial infection in a human. A heterocyclylalkylpiperidine derivative substantially as hereinbefore described according to the examples.
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