WO2012041860A1 - Benzazole derivatives as histamine h4 receptor ligands - Google Patents

Benzazole derivatives as histamine h4 receptor ligands Download PDF

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Publication number
WO2012041860A1
WO2012041860A1 PCT/EP2011/066782 EP2011066782W WO2012041860A1 WO 2012041860 A1 WO2012041860 A1 WO 2012041860A1 EP 2011066782 W EP2011066782 W EP 2011066782W WO 2012041860 A1 WO2012041860 A1 WO 2012041860A1
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WIPO (PCT)
Prior art keywords
yloxy
met
methyl
methylpiperidin
benzimidazol
Prior art date
Application number
PCT/EP2011/066782
Other languages
French (fr)
Inventor
Isabelle Berrebi-Bertrand
Xavier Billot
Thierry Calmels
Marc Capet
Denis Danvy
Stéphane Krief
Olivier Labeeuw
Jeanne-Marie Lecomte
Nicolas Levoin
Xavier Ligneau
Philippe Robert
Jean-Charles Schwartz
Original Assignee
Bioprojet
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP11761383.6A priority Critical patent/EP2621916B1/en
Priority to RS20160297A priority patent/RS54737B1/en
Application filed by Bioprojet filed Critical Bioprojet
Priority to SI201130817A priority patent/SI2621916T1/en
Priority to CN201180057036.8A priority patent/CN103228643B/en
Priority to US13/825,989 priority patent/US8802664B2/en
Priority to JP2013529673A priority patent/JP5922128B2/en
Priority to PL11761383T priority patent/PL2621916T3/en
Priority to CA2812686A priority patent/CA2812686C/en
Priority to MX2013003479A priority patent/MX339460B/en
Priority to ES11761383T priority patent/ES2571335T3/en
Priority to DK11761383.6T priority patent/DK2621916T3/en
Publication of WO2012041860A1 publication Critical patent/WO2012041860A1/en
Priority to HK13111288.3A priority patent/HK1183867A1/en
Priority to US14/317,024 priority patent/US9029357B2/en
Priority to HRP20160398TT priority patent/HRP20160398T1/en
Priority to SM201600262T priority patent/SMT201600262B/en

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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Definitions

  • the present patent application concerns new ligands of the H4-receptor, their process of preparation and their therapeutic use.
  • H1 receptor and H1 receptor antagonists have found large therapeutic applications in allergic manifestations like the anaphylactic shock, allergic rhinitis, dermatitis, pruritus, etc.
  • H4R histamine H4 receptor
  • the recent discovery of the histamine H4 receptor (H4R) has modified this landscape (reviewed in Thurmond et al, Nature Rev. Drug Disc, 2008, 7, 41 ).
  • the H4R belongs to the superfamily of G-protein coupled heptahelical receptors and is expressed on the plasma membranes of a variety of immunocompetent/inflammatory cells, e.g. eosinophils, basophils, mast-cells or dendritic cells.
  • the H4R has a chimiotactic role, controlling the afflux of e.g.
  • H4R Blockade of the H4R by antagonists or inverse agonists should therefore constitute a novel therapeutic approach in diseases like asthma, emphysema, allergic rhinitis, nasal congestion, bronchitis, chronic obstructive pulmonary disease, dermatitis, arthritis, psoriasis, colitis, etc. in which they could be used alone or in association with already used other classes of anti-inflammatory medications, namely H1 R antagonists.
  • H4R antagonists/inverse agonists are also of potential interest in a variety of autoimmune diseases e.g. type I diabetes, Crohn's disease, multiple sclerosis, lupus, etc...
  • the itch-preventing effect of some H4R antagonists in a rodent model also suggests the use of these agents in pruritus, a manifestation only imperfectly controlled by available medications, namely H1 R antagonists.
  • H4R antagonists/inverse agonists have not yet reached clinical uses and there is therefore a need for compounds displaying high potency and safety.
  • a novel chemical class of H4R ligands is disclosed.
  • the instant invention thus relates to novel benzazoles derivatives as H4 receptor ligands, to their preparation and to their application in therapeutics.
  • the present invention concerns new compounds of formula (I):
  • X represents NR', S or O
  • HetAr represents a phenyl or heteroaryl, optionally substituted with one or more substituents chosen from halogen, OR" alkyl, cyano, NR"R"', -COR", -COOR", - CONR"R” ⁇ aryl, -alkylaryl;
  • R represents a lower alkyl or H
  • R' represents H, lower alkyl, alkoxyalkyl or alkoxycarbonyl
  • HET representing a non aromatic monocyclic heterocycle containing at least one nitrogen atom, which is linked to R;
  • B represents a single bond or an -alkyl- group
  • A represents O, NH or S
  • Ar is a mono or polycyclic aromatic or a mono or polycyclic heteroaromatic which can be optionally substituted with one or more of:
  • alkyl • alkyl; alkoxy; alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy; alkenylsulfanyl; alkynylsulfanyl; cycloalkoxy; cycloalkylalkyl;
  • alkyl, alkenyl, alkynyl or cycloalkyl part can be substituted with one or more of halo, hydroxy, polyhydroxy, alkoxy, hydroxyalkoxy, cyano, amino, aminoalkyl, alkylamino, dialkylamino, aminoalkylamino, aminoalkylaminocarbonyl, alkoxycarbonylamino, diarylmethylimino (where aryl is optionally substituted with one or more of hydroxy or halo), cycloalkenylimino (where cylalkenyl is optionally substituted with one or more of alkyl, OH), alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkyl, polycycloalkyl, cycloalkenyl, polycycloalkenyl, guanidino, alkylcarbonylguanidino, acylguanidino, cyanoguani
  • ⁇ aminocarbonyl which can be N-substituted with one or two of alkyl, aryl, arylalkyl;
  • (hetero)aryl part can be substituted with one or more of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, nitro, cyanoalkyi, or fused with a non aromatic heterocycle;
  • heterocycle can be substituted with one or more of halogenoalkyl, acylamino, acyloxy, amino, alkyl, alkylamino, dialkylamino, aminoalkyl, oxo, carbamimidoyl, halo, hydroxy, hydroxyalkyl, hydroxymethyl, alkoxcarbonyl;
  • Halo or halogen refers to fluorine, chlorine, bromine or iodine atom.
  • Halogenoalkyl refers to a C1 -C9-alkyl moiety wherein one or more hydrogen atoms and refers in particular to perhaloalkyl.
  • Perhaloalkyl represents a C1 -C9-alkyl moiety wherein all hydrogen atoms are substituted with same or different halogen atoms, for example, -CF 3 , -CHF 2 , -CCI 3 , -CF 2 CI, -CH 2 CI, -CH 2 CF 2 -CF 3 .
  • Perhaloalkoxy represents a perhaloalkyl linked via an oxygen atom, for example, -O-CF 3 , -0-CHF 2 , -0-CH 2 CF 3 .
  • Alkyl represents an aliphatic-hydrocarbon group which may be straight or branched having 1 to 20 carbon atoms in the chain unless specified otherwise. Preferred alkyl groups have 1 to 12 carbon atoms, more preferably have 1 to 6 carbon atoms in the chain; lower alkyls have preferably 1 to 4 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n- pentyl, 3-pentyl, octyl, nonyl, decyl.
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having 2 to 15 carbon atoms in the chain unless specified otherwise.
  • Preferred alkenyl groups have 2 to 12 carbon atoms in the chain; and more preferably about 2 to 6 carbon atoms in the chain.
  • Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, nonenyl, decenyl.
  • Alkynyl refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having 2 to 15 carbon atoms in the chain unless specified otherwise.
  • Preferred alkynyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 4 carbon atoms in the chain.
  • Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methyl-1 -butynyl, n-pentynyl, 4,4-dimethyl-2-pentynyl, heptynyl, octynyl and decynyl.
  • Carbocycle refers to a saturated orsaturatedon unsaturated non aromatic mono- or multicyclic hydrocarbon ring system of 3 to 10 carbon atoms, preferably of 4 to 10 carbon atoms.
  • Cycloalkyi refers to a saturated non-aromatic mono- or multicyclic hydrocarbon ring system of 3 to 10 carbon atoms, preferably of 4 to 10 carbon atoms. Preferred ring sizes of rings of the ring system include 4 to 6 ring atoms.
  • Exemplary monocyclic cycloalkyi include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Exemplary multicyclic cycloalkyi include 1 -decalin, norbornyl, adamant-(1 - or 2-)yl.
  • Aryl refers to an aromatic monocyclic or multicyclic hydrocarbon ring system of 6 to 14 carbon atoms, preferably of 6 to 10 carbon atoms.
  • Exemplary aryl groups include phenyl, naphthyl, indenyl, phenanthryl, biphenyl.
  • heterocycle or “heterocyclic” refer to a saturated or partially unsaturated non aromatic stable 3 to 14, preferably 5 to 10-membered mono, bi or multicyclic rings wherein at least one member of the ring is a hetero atom.
  • heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, selenium, and phosphorus atoms.
  • Preferable heteroatoms are oxygen, nitrogen and sulfur.
  • Suitable heterocycles are also disclosed in the Handbook of Chemistry and Physics, 76th Edition, CRC Press, Inc., 1995-1996, pages 2-25 to 2-26, the disclosure of which is hereby incorporated by reference.
  • Preferred non aromatic heterocyclic include, but are not limited to oxetanyl, tetraydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidyl, morpholinyl, imidazolidinyl, pyranyl.
  • Preferred saturated heterocycles are chosen from tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidyl, morpholinyl, imidazolidinyl, more preferably tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl.
  • heteroaryl refers to a 5 to 14, preferably 5 to 10 membered aromatic mono-, bi- or multicyclic ring wherein at least one member of the ring is a hetero atom.
  • heteroaryl examples include pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purinyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1 ,2,4-thiadiazolyl, isothiazolyl, triazoyl, tetrazolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, carbazolyl, benzimidazolyl, isoxazolyl.
  • acyl means an H-CO- or alkyl-CO- group wherein the alkyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
  • Alkyl also refers to the corresponding "alkylene”, “cycloalkylene”, “alkenylene”, “alkynylene”, “arylene”, “heteroarylene”, “heterocyclene” which are formed by the removal of two hydrogen atoms.
  • a first group of compounds according to the invention may be defined as follows:
  • X represents NR' or S
  • HetAr represents a phenyl, optionally substituted with one or more substituents chosen from hydrogen, halogen, amino, alkyl;
  • R represents H or a lower alkyl
  • R' represents H, alkyl, alkoxyalkyl, alkoxycarbonyl
  • HET representing a non aromatic 5 or 6 membered heterocycle containing one nitrogen atom, which is linked to R;
  • B represents a single bond or a -CH 2 - group
  • A represents O, NH or S
  • Ar is a thienyl, phenyl or naphtyl or 5 to 6 membered heteroaromatic where the phenyl can be optionally substituted with one or more of:
  • alkoxy alkylsulfanyl; alkenyl; alkenylsulfanyl;alkynyl; alkenyloxy; alkenyloxy; cycloalkoxy; cyloalkylalkyl
  • alkyl, alkenyl, alkynyl or or cycloalkyl part can be substituted with one or more of halo, hydroxy, alkoxy, hydroxyalkoxy, cyano, amino, aminoalkyl, alkylamino, aminoalkylamino, dialkylamino, aminoalkylaminocarbonyl, alkoxycarbonylamino, diarylmethylimino (where aryl is optionally substituted with one or more of hydroxy or halo), cycloalkenylimino (where cylalkenyl is optionally substituted with one or more of alkyl, OH), alkylsulfanyl, alkylsulfonyl, cycloalkyl, (poly)cycloalkenyl, guanidino, alkylcarbonylguanidino, acylguanidino, alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino
  • alkyl can be substituted with one or more of halo; • aminocarbonyl which can be N-substituted with one or two of alkyl, aryl, arylalkyl;
  • heterocycle can be substituted with one or more of halo, halogenoalkyl, acylamino, acyloxy, amino, alkyl, alkylamino, dialkylamino, aminoalkyl, oxo, carbamimidoyl, hydroxy, hydroxyalkyi;
  • X represents NH or S
  • HetAr represents a phenyl
  • R represents methyl
  • HET represents a piperidine or pyrrolidine
  • HET represents a piperidine
  • A represents O or NH
  • Ar is a phenyl which can be optionally substituted with one or more of:
  • alkoxy alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy;
  • alkyl; alkenyl or alkynyl part can be substituted with one or more of halo, hydroxy, alkoxy, hydroxyalkoxy, cyano, amino, alkylamino, aminoalkylamino, alkylsulfanyl, alkylsulfonyl, cycloalkyi, (poly)cycloalkenyl, guanidino, acylguanidino, alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxy- carbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl, heterocyclyl, heterocyclylamino, hydrazinocarbonyl, N-alkyl(thioureido), phtalimido, ureido,
  • aminocarbonyl which can be N-substituted with one or two of alkyl, aryl, arylalkyi;
  • aryl part can be substituted with one or more of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, nitro, cyanoalkyl, or is fused with a non aromatic heterocycle;
  • heterocycle can be substituted with one or more of acylamino, acyloxy, amino, alkyl, carbamimidoyl, hydroxy, hydroxyalkyl;
  • Ar is defined as above; and/or i is 0, 1 , 2, or 3; and/or
  • j is 0, 1 , 2, or 3;
  • Y is chosen from halo, hydroxy, alkyl, perhalogenoalkyi, alkoxy; and/or
  • Z is chosen from halo, hydroxy, alkyl, alkoxy.
  • i 1 , 2 or 3 and Y is chosen from halo, hydroxy, alkyl, perhalogenoalkyi, alkoxy; and/or
  • the present invention provides a compound selected from the group consisting of:
  • the compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
  • the compounds of the invention may also comprise tautomeric forms which are all encompassed by the present invention.
  • the compounds of formula (I) can be provided in the form of a free base or in the form of addition salts with acids, which also form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but salts with other acids, useful for example for the purification or for the isolation of the compounds of formula (I), also form part of the invention.
  • the term "patient” refers to a warm-blooded animal such as a mammal, preferably a human or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and conditions described herein.
  • a "therapeutically effective amount” refers to an amount of a compound of the present invention which is effective in reducing, eliminating, treating or controlling the symptoms of the herein-described diseases and conditions.
  • controlling is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment and chronic use.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propanoic, succinic, tartaric, citric, methanesulfonic, benzenesulfonic, glucuronic, glutamic, benzoic, salicylic, toluenesulfonic, oxalic, fumaric, maleic, and the like.
  • Further addition salts include ammonium salts such as tromethamine, meglumine, epolamine, etc., metal salts such as sodium, potassium, calcium, zinc or magnesium. Hydrochloride and oxalate salts are preferred.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • the compounds of the general formula (I) having geometrical and stereomers are also a part of the invention.
  • the present invention is also concerned with the process of preparation of the compounds of formula (I).
  • the compounds and process of the present invention may be prepared in a number of ways well known to those skilled in the art.
  • the compounds can be synthesized, for example, by application or adaptation of the methods described below, or variations thereon as appreciated by the skilled artisan.
  • the appropriate modifications and substitutions will be readily apparent and well known or readily obtainable from the scientific literature to those skilled in the art.
  • the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms.
  • optically active or racemic forms all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • optically active forms mixtures of stereomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.
  • Some reactions may be carried out in the presence of a base.
  • a base There is no particular restriction on the nature of the base to be used in this reaction, and any base conventionally used in reactions of this type may equally be used here, provided that it has no adverse effect on other parts of the molecule.
  • suitable bases include: sodium hydroxide, potassium carbonate, triethylamine, alkali metal hydrides, such as sodium hydride and potassium hydride; alkyllithium compounds, such as methyllithium and butyllithium; and alkali metal alkoxides, such as sodium methoxide and sodium ethoxide.
  • Suitable solvents include: hydrocarbons, which may be aromatic, aliphatic or cycloaliphatic hydrocarbons, such as hexane, cyclohexane, methylcyclohexane, toluene and xylene; amides, such as A/,A/-dimethylformamide; alcohols such as ethanol and methanol and ethers, such as diethyl ether, methyl fert-butyl ether, methyl cyclopentyl ether and tetrahydrofuran.
  • hydrocarbons which may be aromatic, aliphatic or cycloaliphatic hydrocarbons, such as hexane, cyclohexane, methylcyclohexane, toluene and xylene
  • amides such as A/,A/-dimethylformamide
  • alcohols such as ethanol and methanol and ethers, such as diethyl ether, methyl fert-butyl
  • the reactions can take place over a wide range of temperatures. In general, we find it convenient to carry out the reaction at a temperature of from 0°C to ⁇ ⁇ 50°C (more preferably from about room temperature to l OCO).
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 3 hours to 20 hours will usually suffice.
  • the compound thus prepared may be recovered from the reaction mixture by conventional means.
  • the compounds may be recovered by distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the residue into water followed by extraction with a water-immiscible organic solvent and distilling off the solvent from the extract.
  • the product can, if desired, be further purified by various well-known techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
  • This etherification reaction can be performed in acidic medium (toluenesulfonic acid, methanesulfonic acid) in an inert solvent (toluene, dichlorobenzene, dichloroethane) at a temperature between room temperature and about 160 ⁇ .
  • acidic medium toluenesulfonic acid, methanesulfonic acid
  • inert solvent toluene, dichlorobenzene, dichloroethane
  • Compounds of formula (II) can be prepared by condensing a benzothiazole or a benzimidazole derivative with an aldehyde ArCHO, by condensing an organometallic derivative ArMetal with an optionally substituted benzimidazole-2-carboxaldehyde or an optionally substituted benzothiazole-2-carboxaldehyde, or by condensing a hydroxy acid ArCHOHCOOH with an optionally substituted orho-phenylenediamine or an optionally substituted 2-aminothiophenol or 2-aminophenol
  • This reduction can be performed by hydrogenation with dihydrogen or transfer hydrogenation (formic acid, formic acid / triethylamine, ammonium formate) in the presence of a catalyst (palladium on charcoal) in an inert solvent (methanol, ethanol, ethyl acetate) at a temperature comprised between room temperature and about 150°C.
  • a catalyst palladium on charcoal
  • an inert solvent methanol, ethanol, ethyl acetate
  • This condensation can be performed in the presence of an acid (titanium tetraisopropoxide) in an inert solvent (tetrahydrofurane) at a temperature comprised between room temperature and reflux of the medium.
  • an acid titanium tetraisopropoxide
  • an inert solvent tetrahydrofurane
  • This oxidation can be performed with an oxidizing agent (potassium permanganate, barium permanganate, manganese dioxide) in an inert solvent (dioxane, acetonitrile) at a temperature comprised between room temperature and reflux of the medium.
  • an oxidizing agent potassium permanganate, barium permanganate, manganese dioxide
  • an inert solvent dioxane, acetonitrile
  • This condensation can be performed in the presence of a transition metal catalyst such as dichloro(pentamethylcyclopentadienyl)iridium(lll) dimer, in the presence of a base such as sodium hydrogenocarbonate in an inert solvent such as toluene at a temperature comprised between about 80 and 150°C.
  • a transition metal catalyst such as dichloro(pentamethylcyclopentadienyl)iridium(lll) dimer
  • a base such as sodium hydrogenocarbonate
  • an inert solvent such as toluene
  • compounds of formula (I) in which A and X are NH can be prepared by condensing an organometallic re ompound of formula (VI):
  • This addition can be performed by adding a Grignard reagent onto an imine in an inert solvent (tetrahydrofurane) at a temperature comprised between room temperature and reflux of the medium.
  • an inert solvent tetrahydrofurane
  • This alkylation can be performed by reductive method using a carbonylated compound and a reducing agent such as a borohydride, a cyanoborohydride, a triacetoxyborohydride, hypophosphonous acid, formic acid, formic acid / triethylamine or hydrogen, a catalyst such as palladium can be added for this transformation when hydrogen or hydrogen donnors are used.
  • a reducing agent such as a borohydride, a cyanoborohydride, a triacetoxyborohydride, hypophosphonous acid, formic acid, formic acid / triethylamine or hydrogen
  • a catalyst such as palladium can be added for this transformation when hydrogen or hydrogen donnors are used.
  • HET, B, X, HetAr and Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom.
  • Prot is a ferf-butoxycarbonyl group
  • the transformation is usually performed in acidic medium such a trifluoroacetic diluted with dichloromethane or in a solvent (ethyl acetate, ethanol, isopropanol) containing HCI.
  • acidic medium such as trifluoroacetic diluted with dichloromethane or in a solvent (ethyl acetate, ethanol, isopropanol) containing HCI.
  • this deprotection is performed at a temperature between O'C and the refluxing temperature of the medium.
  • Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom can be prepared by condensing an acid of formula (IX):
  • HET, B and Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom
  • This condensation can be performed by reacting the two compounds in acidic medium, or by first forming the amide bond with usual bond forming reagents, then dehydrating in acidic medium (acetic acid, hydrochloric acid) at a temperature comprised between room temperature and reflux.
  • Acids of formula (IX) in which HET, B and Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom can be prepared by hydrolysis of their esters. This hydrolysis can be performed in basic medium or in acidic medium at a temperature comprised between 0 °C and reflux of the medium.
  • Esters of the acid of formula (IX) in which HET, B, X and Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom can be prepared by condensing an ester of the acid (X)
  • This condensation can be performed in the presence of a metal catalyst such as rhodium acetate dimer in an inert solvent such a dichloromethane or dichloroethane, at a temperature comprised between 0 °C and reflux of the medium.
  • a metal catalyst such as rhodium acetate dimer in an inert solvent such a dichloromethane or dichloroethane
  • Esters of the acid of formula (X) can be prepared from esters of an acid ArCH2COOH with a diazo transfer reagent such as tosylazide in the presence of a base such as 1 ,8-diazabicyclo[5.4.0]undec-7-ene in an inert solvent such as acetonitrile at a temperature comprised between -20 °C and 40 °C.
  • a diazo transfer reagent such as tosylazide
  • a base such as 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • an inert solvent such as acetonitrile
  • compounds of formula (I) can be prepared from compounds of formula (I) by group interconversion or group transformation.
  • Such reaction include, but are not limited to, reaction on aromatic or heteroaromatic groups such as halogen exchange reaction, Sonogashira reaction, Heck reaction, Suzuki reaction, sulfide condensation, triflate displacement with grignard reagents, copper catalysed ether formation, metal catalysed amine aromatic substitution, aromatic carbonylation reaction; reaction on reactive groups such as acylation, alcoxycarbonylation of nitrogen containing groups such as amines, amidines, guanidines; substitution of hydroxy with nucleophile (Mitsunobu reaction or activation and nucleophilic substitution); hydrogenation of unsaturation (alkenyl to alkyl, alkynyl to alkenyl, alkynyl to alkyl); Staudinger reduction of azido group.
  • the process of the invention may comprise the additional step of isolating the desired compound of formula (I).
  • the starting products and/or reagents may be commercially available, or may be readily prepared by the skilled person by applying or adapting the procedures disclosed in the experimental part below.
  • the present invention is also concerned with pharmaceutical compositions comprising a compound of formula (I) as defined above with a pharmaceutically acceptable excipient.
  • the compounds of the invenion are antagonists and/or inverse agonists of H4 R.
  • compositions and compounds of the invention may thus be useful for use in the treatment and/or prevention of a disease associated with H 4 dysfunction, such as inflammatory disorders.
  • Said disease includes adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, conjunctivitis, nasal congestion, allergic congestion; disorders of the genito-urinary tract such as female and male sexual dysfunction, overactive bladder conditions, urinary incontinence, bladder overactivity, benign prostate hyperplasia and lower urinary tract symptoms; dermatological diseases such as dermatitis and psoriasis and treatment of itchy skin; diseases of the cardiovascular system including thromboembolic diseases, atherosclerosis, myocardial infarction, angina pectoris, myocardial ischaemia and arrhythmia, peripheral arterial occlusive diseases, pulmonary embolisms
  • Xanthines such as theophylline and aminophylline
  • Non-steroidal antiinflammatories such as sodium cromoglycate and nedocromil sodium
  • the present invention also concerns combinations comprising a compound of formula (I) of the invention with a H1 R antagonist, such as cetirizine, desloratadine, bepotastine or doxepin.
  • a H1 R antagonist such as cetirizine, desloratadine, bepotastine or doxepin.
  • the present invention is also concerned with a compound of formula (I) for the above conditions to be administered to a patient in the need thereof.
  • the present invention also concerns the methods of treatment comprising administering an effective amount of a compound of the invention for treating and/or preventing the above conditions or disorders.
  • a therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • determining the therapeutically effective amount a number of factors are considered by the attending diagnostician, including, but not limited to: the species of subject; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • the amount of a compound of formula (I), which is required to achieve the desired biological effect will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g. hydrophobicity) of the compounds employed, the potency of the compounds, the type of disease, the diseased state of the patient, and the route of administration.
  • the compounds of this invention may be provided in an aqueous physiological buffer solution containing 0.1 to 10% w/v compound for parenteral administration.
  • Typical dose ranges are from 1 ⁇ g kg to 0.1 g/kg of body weight per day; a preferred dose range is from 0.01 mg/kg to 10 mg/kg of body weight per day.
  • a preferred daily dose for adult humans includes 1 , 5, 50, 100 and 200 mg, and an equivalent dose in a human child.
  • the preferred dosage of drug to be administered is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
  • unit dose means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition, as described hereinafter.
  • typical daily dose ranges are from 0.01 to 10 mg/kg of body weight.
  • unit doses for humans range from 0.1 mg to 1000 mg per day.
  • the unit dose range is from 1 to 500 mg administered one to four times a day, and even more preferably from 1 mg to 300 mg, once a day.
  • compositions can be formulated into pharmaceutical compositions by admixture with one or more pharmaceutically acceptable excipients.
  • Such compositions may be prepared for use in oral administration, particularly in the form of tablets or capsules; or parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, for example, topically or via trans-dermal patches or ocular administration, or intravaginal or intra-uterine administration, particularly in the form of pessaries or by rectal administration.
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington: The Science and Practice of Pharmacy, 20 th ed.; Gennaro, A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000.
  • Pharmaceutically compatible binding agents and/or adjuvant materials can be included as part of the composition.
  • Oral compositions will generally include an inert diluent carrier or an edible carrier.
  • the tablets, pills, powders, capsules, troches and the like can contain one or more of any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, or methyl salicylate.
  • a binder such as microcrystalline cellulose, or gum tragacanth
  • a diluent such as starch or lactose
  • a disintegrant such as starch and cellulose derivatives
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • a flavoring agent
  • Capsules can be in the form of a hard capsule or soft capsule, which are generally made from gelatin blends optionally blended with plasticizers, as well as a starch capsule.
  • dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.
  • Other oral dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes, colorings, and flavorings.
  • the active compounds may be incorporated into fast dissolve, modified-release or sustained-release preparations and formulations, and wherein such sustained-release formulations are preferably bi-modal.
  • Preferred formulations include pharmaceutical compositions in which a compound of the present invention is formulated for oral or parenteral administration, or more preferably those in which a compound of the present invention is formulated as a tablet.
  • Preferred tablets contain lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc in any combination. It is also an aspect of the present disclosure that a compound of the present invention may be incorporated into a food product or a liquid.
  • Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • the liquid compositions may also include binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring agents, and the like.
  • Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, acrylate copolymers, vegetable oils such as olive oil, and organic esters such as ethyl oleate.
  • Aqueous carriers include mixtures of alcohols and water, hydrogels, buffered media, and saline.
  • biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds.
  • Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like.
  • Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • formulations for inhalation which include such means as dry powder, aerosol, or drops. They may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for buccal administration include, for example, lozenges or pastilles and may also include a flavored base, such as sucrose or acacia, and other excipients such as glycocholate.
  • Formulations suitable for rectal administration are preferably presented as unit-dose suppositories, with a solid based carrier, such as cocoa butter, and may include a salicylate.
  • Formulations for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which can be used include petroleum jelly, lanolin, polyethylene glycols, alcohols, or their combinations.
  • Formulations suitable for transdermal administration can be presented as discrete patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • Alternative administrations include also solutions, ointments or other formulations acceptable for ocular administration.
  • Benzothiazol-2-yl(3-propoxyphenyl)methanol can be prepared as described in example 1 B.
  • a mixture of 2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole (200mg), phenylboronic acid (70mg), palladium acetate (4.8mg) and 1 ,1 - bis(diphenylphosphino)ferrocene is placed in a round-bottom flask and purged with argon.
  • a 1 M aqueous degased solution of potassium carbonate (1 .51 ml.) and degased tetrahydrofuran (2ml_) are introduced.
  • the mixture is heated at 95°C for 30min, cooled back to room temperature and filtered over a celite pad.
  • the cake is rinsed with ethyl acetate and water.
  • the pooled phases are decanted.
  • the organic phase is dried over magnesium sulfate and concentrated.
  • the residue is purified by column chromatography (gradient dichloromethane / methanol from 98 / 2 to 90 / 10) to give the crude base which is then converted to the oxalate in acetone to give 2-[biphenyl-3-yl ⁇ 1 -methylpiperidin-4- yloxy)methyl]benzothiazole, oxalate as a beige amorphous solid.
  • reaction mixture is cooled to 0°C and a 10N sodium hydroxide solution is added dropwise to reach pH 1 .
  • the aqueous phase is extracted with ethyl acetate.
  • the pooled organic phases are washed with brine; dried on magnesium sulphate and concentrated to dryness under reduced pressure.
  • the residual solid is re-crystallized from hot toluene to give (3-bromophenyl)hydroxyacetic acid.
  • the first enantiomer has a retention time of 6.7min.
  • the second enantiomer has a retention time of 8.2min. Collection affords [benzothiazol-2-yl(3-propoxyphenyl)methyl](1 -methylpiperidin-4- yl)amine enantiomer B with a chromatographic enantiomeric purity of 98.8%.
  • 1 /-/-Benzimidazole-2-carboxaldehyde (781 mg, can be prepared according to Fegy, K. Angewandte Chemie Int Ed, 1998, vol. 37, 1270-1273), 4-amino-1 -methylpiperidine (781 mg) and 4A molecular sieves (15g) in ethanol (1 OOmL) are heated under reflux for 4h. The mixture is then filtered and the filtrate concentrated under reduced pressure to yield (1 - -benzimidazol-2-ylmethylene)(1 -methylpiperidin-4-yl)amine as a beige solid.
  • the mixture is purified by chromatography over silica gel (eluant dichloromethane / methanol : 98 / 2) to give the crude base, which is transformed to the oxalate in acetone to give [benzothiazol-2-yl(3-butoxyphenyl)methyl](1 - methylpiperidin-4-yl)amine oxalate melting at M6°C.
  • Benzothiazol-2-yl(3-butoxyphenyl)methanol can be obtained as described in example 1 B.
  • Benzothiazol-2-yl(3-pent-4-enyloxy-phenyl)methanol can be prepared as follows: to a 1 M solution of 3-pent-4-enyloxy-phenylmagnesium bromide in tetrahydrofurane (2.2ml_) diluted with the same solvent (6ml_) cooled at -50°C is added benzothiazole-2- carboxaldehyde (326mg). After stirring at -50°C for 1 h, the mixture is allowed to warm at room temperature, then hydrolyzed with aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure.
  • 1 -Pyrrolidin-1 -ylmethyl-1 H-benzimidazole can be prepared as described by Katritzky, Alan R.; Asian, Diana C; Leeming, Peter; Steel, Peter J. Tetrahedron: Asymmetry, 1997, 8, p. 1491 - 1500.
  • the pooled extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure.
  • the residue is purified by column chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 to 90 / 10 1 ) and salified with oxalic acid to give 5- ⁇ 3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenoxy ⁇ pentylamine, oxalate melting at 141 °C.

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Abstract

The present patent application concerns new Iigands of the H4-receptor of formula (I), their process of preparation and their therapeutic use.

Description

BENZAZOLE DERIVATIVES AS HISTAMINE H4 RECEPTOR LIGANDS
The present patent application concerns new ligands of the H4-receptor, their process of preparation and their therapeutic use.
Until recently, the pro-inflammatory actions of histamine were thought to be essentially mediated by the H1 receptor and H1 receptor antagonists have found large therapeutic applications in allergic manifestations like the anaphylactic shock, allergic rhinitis, dermatitis, pruritus, etc.
However these drugs essentially prevent the occurrence of major symptoms of these manifestations without modifying clearly the progressive development of the inflammatory process leading to chronic diseases like asthma in which, however, histamine release from mast-cells might represent an important trigger (reviewed in Galli et al, Nature, 2008, 454, 445).
The recent discovery of the histamine H4 receptor (H4R) has modified this landscape (reviewed in Thurmond et al, Nature Rev. Drug Disc, 2008, 7, 41 ). The H4R belongs to the superfamily of G-protein coupled heptahelical receptors and is expressed on the plasma membranes of a variety of immunocompetent/inflammatory cells, e.g. eosinophils, basophils, mast-cells or dendritic cells. The H4R has a chimiotactic role, controlling the afflux of e.g. mast-cells or eosinophils to inflammatory sites that is elicited by histamine release and, thereby plays a major role in the development of chronic inflammatory disorders.lt also controls the activity of eosinophils and some classes of lymphocytes. Blockade of the H4R by antagonists or inverse agonists should therefore constitute a novel therapeutic approach in diseases like asthma, emphysema, allergic rhinitis, nasal congestion, bronchitis, chronic obstructive pulmonary disease, dermatitis, arthritis, psoriasis, colitis, etc. in which they could be used alone or in association with already used other classes of anti-inflammatory medications, namely H1 R antagonists. In addition the utilisation of H4R antagonists/inverse agonists is also of potential interest in a variety of autoimmune diseases e.g. type I diabetes, Crohn's disease, multiple sclerosis, lupus, etc... The itch-preventing effect of some H4R antagonists in a rodent model (Bell et al, Br J Pharmacol, 2004, 142, 374) also suggests the use of these agents in pruritus, a manifestation only imperfectly controlled by available medications, namely H1 R antagonists.
H4R antagonists/inverse agonists have not yet reached clinical uses and there is therefore a need for compounds displaying high potency and safety. In the present application a novel chemical class of H4R ligands is disclosed. The instant invention thus relates to novel benzazoles derivatives as H4 receptor ligands, to their preparation and to their application in therapeutics.
According to a first object, the present invention concerns new compounds of formula (I):
Figure imgf000004_0001
wherein:
X represents NR', S or O;
HetAr represents a phenyl or heteroaryl, optionally substituted with one or more substituents chosen from halogen, OR" alkyl, cyano, NR"R"', -COR", -COOR", - CONR"R"\ aryl, -alkylaryl;
R represents a lower alkyl or H;
R' represents H, lower alkyl, alkoxyalkyl or alkoxycarbonyl;
R", R'" identical or different independently represent H or alkyl;
HET representing a non aromatic monocyclic heterocycle containing at least one nitrogen atom, which is linked to R;
B represents a single bond or an -alkyl- group;
A represents O, NH or S;
Ar is a mono or polycyclic aromatic or a mono or polycyclic heteroaromatic which can be optionally substituted with one or more of:
• halo; azido; cyano; hydroxy; nitro;
• alkyl; alkoxy; alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy; alkenylsulfanyl; alkynylsulfanyl; cycloalkoxy; cycloalkylalkyl;
whose alkyl, alkenyl, alkynyl or cycloalkyl part can be substituted with one or more of halo, hydroxy, polyhydroxy, alkoxy, hydroxyalkoxy, cyano, amino, aminoalkyl, alkylamino, dialkylamino, aminoalkylamino, aminoalkylaminocarbonyl, alkoxycarbonylamino, diarylmethylimino (where aryl is optionally substituted with one or more of hydroxy or halo), cycloalkenylimino (where cylalkenyl is optionally substituted with one or more of alkyl, OH), alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkyl, polycycloalkyl, cycloalkenyl, polycycloalkenyl, guanidino, alkylcarbonylguanidino, acylguanidino, cyanoguanidino, alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylalkylcycloalkyl, alkoxycarbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroaryl, heterocyclyl (heterocyclyl being optionally substituted with one or more of oxo, amino, imino), heteroaryloxy, heterocyclyloxy, heteroarylamino, heterocyclylamino, hydrazinocarbonyl, hydroxyalkylcycloalkyl, N-alkyl(thioureido), phtalimido, ureido, oxocycloalkenylamino substituted with amino, carbamimidoylheterocyclyl;
• amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfinyl; alkylsulfonyl; alkylsulfonyloxy
whose alkyl can be substituted with one or more of halo;
· aminocarbonyl which can be N-substituted with one or two of alkyl, aryl, arylalkyl;
• aryl; arylalkyl; aryloxy; arylalkoxy; arylalkylamino; arylalkylsulfanyl; heteroaryl; heteroaryloxy
whose (hetero)aryl part can be substituted with one or more of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, nitro, cyanoalkyi, or fused with a non aromatic heterocycle;
• heterocyclyl; heterocyclyloxy; heterocyclylalkoxy
whose heterocycle can be substituted with one or more of halogenoalkyl, acylamino, acyloxy, amino, alkyl, alkylamino, dialkylamino, aminoalkyl, oxo, carbamimidoyl, halo, hydroxy, hydroxyalkyl, hydroxymethyl, alkoxcarbonyl;
or
• fused with a non aromatic heterocycle (optionally substituted with one or more of halogens) or carbocycle;
as well as their enantiomers, diastereomers, mixtures thereof and pharmaceutically acceptable salts, tautomers, hydrates and solvates.
Unless specified otherwise, the terms used hereabove or hereafter have the meaning ascribed to them below:
"Halo" or "halogen" refers to fluorine, chlorine, bromine or iodine atom.
Halogenoalkyl refers to a C1 -C9-alkyl moiety wherein one or more hydrogen atoms and refers in particular to perhaloalkyl.
"Perhaloalkyl" represents a C1 -C9-alkyl moiety wherein all hydrogen atoms are substituted with same or different halogen atoms, for example, -CF3, -CHF2, -CCI3, -CF2CI, -CH2CI, -CH2CF2-CF3. "Perhaloalkoxy" represents a perhaloalkyl linked via an oxygen atom, for example, -O-CF3, -0-CHF2, -0-CH2CF3.
"Alkyl" represents an aliphatic-hydrocarbon group which may be straight or branched having 1 to 20 carbon atoms in the chain unless specified otherwise. Preferred alkyl groups have 1 to 12 carbon atoms, more preferably have 1 to 6 carbon atoms in the chain; lower alkyls have preferably 1 to 4 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n- pentyl, 3-pentyl, octyl, nonyl, decyl.
"Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having 2 to 15 carbon atoms in the chain unless specified otherwise. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain; and more preferably about 2 to 6 carbon atoms in the chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, nonenyl, decenyl.
"Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having 2 to 15 carbon atoms in the chain unless specified otherwise. Preferred alkynyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methyl-1 -butynyl, n-pentynyl, 4,4-dimethyl-2-pentynyl, heptynyl, octynyl and decynyl.
"Carbocycle" refers to a saturated orsaturatedon unsaturated non aromatic mono- or multicyclic hydrocarbon ring system of 3 to 10 carbon atoms, preferably of 4 to 10 carbon atoms. "Cycloalkyi" refers to a saturated non-aromatic mono- or multicyclic hydrocarbon ring system of 3 to 10 carbon atoms, preferably of 4 to 10 carbon atoms. Preferred ring sizes of rings of the ring system include 4 to 6 ring atoms. Exemplary monocyclic cycloalkyi include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Exemplary multicyclic cycloalkyi include 1 -decalin, norbornyl, adamant-(1 - or 2-)yl. "Aryl" refers to an aromatic monocyclic or multicyclic hydrocarbon ring system of 6 to 14 carbon atoms, preferably of 6 to 10 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, indenyl, phenanthryl, biphenyl. The terms "heterocycle" or "heterocyclic" refer to a saturated or partially unsaturated non aromatic stable 3 to 14, preferably 5 to 10-membered mono, bi or multicyclic rings wherein at least one member of the ring is a hetero atom. Typically, heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, selenium, and phosphorus atoms. Preferable heteroatoms are oxygen, nitrogen and sulfur. Suitable heterocycles are also disclosed in the Handbook of Chemistry and Physics, 76th Edition, CRC Press, Inc., 1995-1996, pages 2-25 to 2-26, the disclosure of which is hereby incorporated by reference. Preferred non aromatic heterocyclic include, but are not limited to oxetanyl, tetraydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidyl, morpholinyl, imidazolidinyl, pyranyl. Preferred saturated heterocycles are chosen from tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidyl, morpholinyl, imidazolidinyl, more preferably tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl.
The term "heteroaryl" refers to a 5 to 14, preferably 5 to 10 membered aromatic mono-, bi- or multicyclic ring wherein at least one member of the ring is a hetero atom. Examples include pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purinyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1 ,2,4-thiadiazolyl, isothiazolyl, triazoyl, tetrazolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, carbazolyl, benzimidazolyl, isoxazolyl.
"Acyl" means an H-CO- or alkyl-CO- group wherein the alkyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl. "Alkyl", "cycloalkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl", "heterocycle" also refers to the corresponding "alkylene", "cycloalkylene", "alkenylene", "alkynylene", "arylene", "heteroarylene", "heterocyclene" which are formed by the removal of two hydrogen atoms.
As used herein, "carbamimidoyl" also refers to "amidino".
A first group of compounds according to the invention may be defined as follows:
Figure imgf000008_0001
wherein:
X represents NR' or S;
HetAr represents a phenyl, optionally substituted with one or more substituents chosen from hydrogen, halogen, amino, alkyl;
R represents H or a lower alkyl;
R' represents H, alkyl, alkoxyalkyl, alkoxycarbonyl;
HET representing a non aromatic 5 or 6 membered heterocycle containing one nitrogen atom, which is linked to R;
B represents a single bond or a -CH2- group;
A represents O, NH or S;
Ar is a thienyl, phenyl or naphtyl or 5 to 6 membered heteroaromatic where the phenyl can be optionally substituted with one or more of:
• halo; azido; cyano; hydroxy; nitro; alkyl;
• alkoxy; alkylsulfanyl; alkenyl; alkenylsulfanyl;alkynyl; alkenyloxy; alkenyloxy; cycloalkoxy; cyloalkylalkyl
whose alkyl, alkenyl, alkynyl or or cycloalkyl part can be substituted with one or more of halo, hydroxy, alkoxy, hydroxyalkoxy, cyano, amino, aminoalkyl, alkylamino, aminoalkylamino, dialkylamino, aminoalkylaminocarbonyl, alkoxycarbonylamino, diarylmethylimino (where aryl is optionally substituted with one or more of hydroxy or halo), cycloalkenylimino (where cylalkenyl is optionally substituted with one or more of alkyl, OH), alkylsulfanyl, alkylsulfonyl, cycloalkyl, (poly)cycloalkenyl, guanidino, alkylcarbonylguanidino, acylguanidino, alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxy- carbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl, heterocyclyl (heterocyclyl being optionally substituted with one or more of oxo, amino, imino), heterocyclylamino, hydrazinocarbonyl, N-alkyl(thioureido), phtalimido, ureido, oxocycloalkenylamino substituted with amino, carbamimidoylheterocyclyl;
• amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfonyl; alkylsulfonyloxy
whose alkyl can be substituted with one or more of halo; • aminocarbonyl which can be N-substituted with one or two of alkyl, aryl, arylalkyl;
• aryl; arylalkyl; aryloxy; arylalkoxy; arylalkylsulfanyl; heteroaryl; heteroaryloxy whose (hetero)aryl part can be substituted with one or more of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyi, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, nitro, cyanoalkyl, or is fused with a non aromatic heterocycle;
• heterocyclyloxy; heterocyclylalkoxy; heterocyclyl
whose heterocycle can be substituted with one or more of halo, halogenoalkyl, acylamino, acyloxy, amino, alkyl, alkylamino, dialkylamino, aminoalkyl, oxo, carbamimidoyl, hydroxy, hydroxyalkyi;
or
• fused with a non aromatic heterocycle (optionally substituted with one or more of halogens) or carbocycle;
as well as their enantiomers, diastereomers, mixtures thereof and pharmaceutically acceptable salts, tautomers, hydrates and solvates.
Further group of compounds are those of formula (I) where:
X represents NH or S; and/or
HetAr represents a phenyl; and/or
R represents methyl; and/or
HET represents a piperidine or pyrrolidine; and/or
HET represents a piperidine; and/or
B represents a single bond; and/or
A represents O or NH;
Ar is a phenyl which can be optionally substituted with one or more of:
• halo; azido; cyano; hydroxy; nitro; alkyl;
• alkoxy; alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy;
whose alkyl; alkenyl or alkynyl part can be substituted with one or more of halo, hydroxy, alkoxy, hydroxyalkoxy, cyano, amino, alkylamino, aminoalkylamino, alkylsulfanyl, alkylsulfonyl, cycloalkyi, (poly)cycloalkenyl, guanidino, acylguanidino, alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxy- carbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl, heterocyclyl, heterocyclylamino, hydrazinocarbonyl, N-alkyl(thioureido), phtalimido, ureido, oxocycloalkenylamino substituted with amino, carbamimidoylheterocyclyl; • amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfonyl; alkylsulfonyloxy
whose alkyl can be substituted with one or more of halo;
• aminocarbonyl which can be N-substituted with one or two of alkyl, aryl, arylalkyi;
• aryl; aryloxy; arylalkoxy; arylalkylsulfanyl; heteroaryl
whose aryl part can be substituted with one or more of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, nitro, cyanoalkyl, or is fused with a non aromatic heterocycle;
• heterocyclyloxy; heterocyclylalkoxy
whose heterocycle can be substituted with one or more of acylamino, acyloxy, amino, alkyl, carbamimidoyl, hydroxy, hydroxyalkyl;
or
• fused with a non aromatic heterocycle;
as well as their enantiomers, diastereomers, mixtures thereof and pharmaceutically acceptable salts, tautomers, hydrates and solvates.
In particular, the compounds of formula (I) may be chosen from those of formula (Γ) below:
Figure imgf000010_0001
Figure imgf000010_0002
where
Ar is defined as above; and/or i is 0, 1 , 2, or 3; and/or
j is 0, 1 , 2, or 3; and/or
Y is chosen from halo, hydroxy, alkyl, perhalogenoalkyi, alkoxy; and/or
Z is chosen from halo, hydroxy, alkyl, alkoxy.
More particularly, in formula (Γ) and ( ):
i is 1 , 2 or 3 and Y is chosen from halo, hydroxy, alkyl, perhalogenoalkyi, alkoxy; and/or
j is 0.
In one preferred embodiment, the present invention provides a compound selected from the group consisting of:
2-[(1 -methylpiperidin-4-yloxy)phenylmethyl]benzothiazole
2-[(1 -methylpyrrolidin-3-yloxy)phenylmethyl]benzothiazole
- 2-[(4-fluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(4-chlorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(3-fluorophenyl)(1 -methylpiperidin-4-yloxymethyl]benzothiazole
2-[(2-fluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)-p-tolylmethyl]benzothiazole
- 2-[(1 -methylpiperidin-4-yloxy)(m-tolyl)methyl]benzothiazole
(benzothiazol-2-yl-phenylmethyl)(1 -methylpiperidin-4-yl)amine
2-[(2,3-dihydrobenzo[1 ,4]dioxin-6-yl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole
2-[(3-methoxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
- 2-[(2,4-difluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)thiophen-2-ylmethyl]benzothiazole
2-[(4-methoxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(3,5-difluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)thiophen-3-ylmethyl]benzothiazole
- 2-[(1 -methylpiperidin-4-yloxy)naphthalen-1 -ylmethyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)naphthalen-2-ylmethyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)(5-methylthiophen-2-yl)methyl]benzothiazole
2-[benzo[1 ,3]dioxol-5-yl(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
[(benzothiazol-2-yl)(m-tolyl)methyl](1 -methylpiperidin-4-yl)amine
- 2-[(3-allyloxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)(3-trifluoromethoxyphenyl)methyl]benzothiazole 2-[(1-met ylpiperidin-4-yloxy)(4-trifluoromet oxyp enyl)met yl]benzot iazole
[benzot iazol-2-yl(3-met oxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(1-methylpiperidin-4-yloxy)(3-propoxy-phenyl)methyl]benzothiazole
2-[(3-bromo-p enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(1-met ylpiperidin-4-yloxy)(3-p enoxy-p enyl)met yl]benzot iazole
5-met yl-2-[(1-met ylpiperidin-4-yloxy)p enylmet yl]benzot iazole
2-[(1 -met ylpiperidin-4-yloxy)p enylmet yl]-1 H-benzimidazole
2-[(1-met ylpiperidin-4-yloxy)(3-trifluoromet ylphenyl)met yl]benzot iazole
2-[(2,3-di ydrobenzofuran-5-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
5-fluoro-2-[(1-met ylpiperidin-4-yloxy)p enylmet yl]benzot iazole
2-[(4 luoro-3-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
[benzot iazol-2-yl(4 luoro-3-met yl-phenyl)met yl](1-met ylpiperidin-4-yl)amine
(benzot iazol-2-yl-p-tolylmet yl)(1-met ylpiperidin-4-yl)amine
[(benzofuran-2-yl)(benzot iazol-2-yl)met yl](1-met ylpiperidin-4-yl)amine
2-[(3 luoro-5-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
[(1 H-benzimidazol-2-yl)phenylmet yl](1-met ylpiperidin-4-yl)amine
2-[(3-fluoro-5-met oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(3-iodop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[benzot iazol-2-yl(3 luoro-5-met oxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
[benzot iazol-2-yl(3 luoro-5-met ylphenyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(3-benzyloxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[benzofuran-5-yl(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(3-et oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
[benzot iazol-2-yl(3-iodop enyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(1-met ylpiperidin-4-yloxy)(3-propoxyp enyl)met yl]-1 --benzimidazole
[(1 H-benzimidazol-2-yl)(3-propoxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(3-iodop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
(benzot iazol-2-ylpyridin-3-ylmet yl)(1-met ylpiperidin-4-yl)amine
2-[bip enyl-3-yl(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
{3'-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxymet yl]bip enyl-3-yl}rTiet anol
2-[(3-isopropoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[benzot iazol-2-yl(1 --pyrrol-2-yl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-trifluoromet ylphenyl)met yl](1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-trifluoromet oxyp enyl)met yl](1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-et ylphenyl)met yl](1-met ylpiperidin-4-yl)amine 3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenol
2-[(1-met ylpiperidin-4-yloxy)(3-pyridin-3-ylp enyl)met yl]benzot iazole
[(1 H-benzimidazol-2-yl)(3-bromop enyl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-benzyloxyp enyl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-isopropylp enyl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-isobutoxyp enyl)met yl](1-met ylpiperidin-4-yl)amine {(1 H-benzimidazol-2-yl)[3-(3-met ylbutoxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-butoxyp enyl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-met oxyp enyl)met yl](1-met ylpiperidin-4-yl)amine trifluoromet anesulfonic acid 3-[benzot iazol-2-yl(1 -met ylpiperidin-4- yloxy)methyl]phenyl ester
trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]phenyl ester
[(1 H-benzimidazol-2-yl)(3-cyclohexylmetrioxyprienyl)metriyl](1-metriylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3 luorophenyl)metriyl](1-metriylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-metriylsulfanylphenyl)metriyl](1-metriylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-riexylprienyl)metriyl](1-metriylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3-isopropoxyphenyl)metriyl](1-metriylpiperidin-4-yl)amine
2-[(3-bromophenyl)(1-metriylpiperidin-4-yloxy)metriyl]-1 H-benzimidazole
3'-[benzothiazol-2-yl(1-metriylpiperidin-4-yloxy)metriyl]biprienyl-3-ylamine
2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)metriyl]-1 H-benzimidazole
[benzothiazol-2-yl(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine
[(1 --benzimidazol-2-yl)(3-ethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1 --benzimidazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine
[(1 --benzimidazol-2-yl)(3-phenoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
{3'-[(1 --benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3- yljmethanol 3'-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]bip enyl-3-ylamine [benzothiazol-2-yl(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine 2-[(1-met ylpiperidin-4-yloxy)(3-pyridin-3-ylp enyl)met yl]-1 H-benzimidazole 1 -{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-ylamino)met yl]phenyl}et anone [benzot iazol-2-yl(3-butoxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(3-butoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
[benzot iazol-2-yl(3-cyclo exylmet oxyp enyl)met yl](1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)bip enyl-3-ylmet yl](1-met ylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3-pentyloxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(2'-met oxybip enyl-3-yl)(1-met ylpiperidiri-4-yloxy)rTiet yl]benzot iazole
2-[(1-met ylpiperidin-4-yloxy)(3'-nitrobip enyl-3-yl)met yl]benzot iazole
{S'^benzothiazol^-y I-methylpiperidin^-yloxyJmethy biphenyl-S-ylJacetonitrile
2-[(3'-met oxybip enyl-3-yl)(1-met ylpiperidiri-4-yloxy)rTiet yl]benzot iazole
2-[(4'-met oxybip enyl-3-yl)(1-met ylpiperidiri-4-yloxy)rTiet yl]benzot iazole
[benzot iazol-2-yl(3-benzyloxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
(benzot iazol-2-ylbip enyl-3-ylmet yl)(1-met ylpiperidin-4-yl)amine
{(1 H-benzimidazol-2-yl)[3-(4-fluorobenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-benzylsulfanylphenyl)met yl](1-met ylpiperidin-4- yl)amine
{(1 H-benzimidazol-2-yl)[3-(3-fluorobenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
{(1 H-benzimidazol-2-yl)[3-(2-phenoxyet oxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[benzot iazol-2-yl(3-benzylsulfanylphenyl)met yl](1-met ylpiperidin-4-yl)amine 1 -{3'-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]biphenyl-4- yljethanone
2-[(3'-fluoro-bip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 1 -{3'-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]biphenyl-3- yljethanone
[benzot iazol-2-yl(3-met ylsulfanylphenyl)met yl](1-met ylpiperidin-4-yl)amine [(3-allyloxyp enyl)(1 --benzimidazol-2-yl)met yl](1-met ylpiperidin-4-yl)amine {(1 H-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine 2-[(1-met ylpiperidin-4-yloxy)(2'-met ylsulfanylbip enyl-3-yl)met yl]-1 H- benzimidazole
2-[(4'-fluorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 --benzimidazole
2-[(1-met ylpiperidin-4-yloxy)(3'-met ylsulfanylbip enyl-3-yl)met yl]-1/-/- benzimidazole
2-[(3-iodop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(3-iodop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(1 -met ylpiperidin-4-yloxy)(4'-trifluoromethylbip enyl-3-yl)met yl]-1 H- benzimidazole
{(1/-/-benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1- met ylpiperidin-4-yl)amine
2-[(2'-c lorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
2- [(3',4'-dic lorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole {3'-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]bip enyl-2- yljmethanol
{(1 /-/-benzimidazol-2-yl)[3-(4-met oxybenzyloxy)p enyl]met yl}(1-met ylpiperidin- 4-yl)amine
{(1 /-/-benzimidazol-2-yl)[3-(3-met oxybenzyloxy)p enyl]met yl}(1-met ylpiperidin- 4-yl)amine
3- [(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-ylamino)met yl]phenol
{3'-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]bip enyl-2-yl}met anol 2-[(1-met ylpiperidin-4-yloxy)(3'-met ylsulfanylbip enyl-3-yl)met yl]benzot iazole {(1 /-/-benzimidazol-2-yl)[3-(2-met ylbenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
{(1/-/-benzimidazol-2-yl)[3-(4-met ylbenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[(1 /-/-benzimidazol-2-yl)(3-nitrop enyl)met yl](1-met ylpiperidin-4-yl)amine
[(3-azidop enyl)(1/-/-benzimidazol-2-yl)met yl](1-met ylpiperidin-4-yl)amine
2-[(3',4'-dic lorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
{(1/-/-benzimidazol-2-yl)[3-(2-et oxyet oxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[(1 /-/-benzimidazol-2-yl)(3-pent-4-enyloxyp enyl)met yl](1-met ylpiperidin-4- yl)amine
2-[(4'-fluorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(2'-fluorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole {3'-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]bip enyl-4- yljcarbamic acid ferf-butyl ester
2-[(3'-fluorobip enyl-3-yl)(1-metriylpiperidin-4-yloxy)metriyl]benzotriiazole
2 (1-met ylpiperidin-4-yloxy)(4'-trifluoromet ylbip enyl-3-yl)metriyl]benzotriiazole 2 (1-met ylpiperidin-4-yloxy)(2,,3,,4,-trifluorobiprienyl-3-yl)metriyl]benzotriiazole 2-[(2'-fluorobip enyl-3-yl)(1-metriylpiperidin-4-yloxy)metriyl]-1 H-benzimidazole {3' benzothiazol-2-yl(1-methylpiperidin-4-yloxy)rTiethyl]biphenyl-4-yl}carbamic acid ferf-butyl ester
[(1 H-benzimidazol-2-yl)(3 uran-2-ylphenyl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-but-3-enyloxyp enyl)metriyl](1-metriylpiperidin-4- yl)amine
{(1 H-benzimidazol-2-yl)[3-(4-met ylpentyloxy)p enyl]met yl}(1-metriylpiperidin-4- yl)amine
2-[(1-methylpiperidin-4-yloxy)(3-pyrazol-1-ylphenyl)methyl]benzothiazole
2-[(3-benzylsulfanylphenyl)(1-met ylpiperidin-4-yloxy)metriyl]benzotriiazole {(1 H-benzimidazol-2-yl)[3-(2,5-difluoro-benzyloxy)phenyl]methyl}(1- met ylpiperidin-4-yl)amine
2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole 2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
2-[(3-et ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(3-et ylsulfanylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}acetic acid methyl ester
2-[(3-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
2-[[3-(2,5-difluorobenzyloxy)phenyl](1-methylpiperidin-4- yloxy)methyl]benzothiazole
2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethanol
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol 2-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid methyl ester
2-[[3-(2,3-difluorobenzyloxy)phenyl](1-methylpiperidin-4- yloxy)methyl]benzothiazole
{(1H-benzimidazol-2-yl)[3-(2,3-difluoro-benzyloxy)phenyl]methyl}(1- methylpiperidin-4-yl)amine 2-[[3-(2-fluoroet oxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole 2-[(1-met ylpiperidin-4-yloxy)(m-tolyl)met yl]-1 --benzimidazole
5,6-dic loro-2-[(1-met ylpiperidin-4-yloxy)p enyl-met yl]-1 /-/-benzimidazole 5-fluoro-2-[(1-met ylpiperidin-4-yloxy)p enyl-met yl]-1 /-/-benzimidazole
2-[(2-fluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
2-[(1-met ylpiperidin-4-yloxy)(3-pent-4-enyloxy-p enyl)met yl]benzot iazole 2-{(1-methylpiperidin-4-yloxy)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}benzothiazole 5-bromo-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1 /-/-benzimidazole
2- [[3-(3-fluorobenzyloxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole
3- [(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]benzonitrile
2-[[3-(furan-2-ylmet ylsulfanyl)phenyl](1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
((1 H-benzimidazol-2-yl)-{3-[3-(2-methyl-[1 ,3]dioxolan-2-yl)- propoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine
{(1 /-/-benzimidazol-2-yl)[3-(4,4,4-trifluoro-butoxy)p enyl]met yl}(1-met ylpiperidin-
4- yl)amine
2-[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole 2-[(1-met ylpiperidin-4-yloxy)-p-tolyl-met yl]-1 /-/-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(3,3,3-trifluoro- propoxy)phenyl]methyl}benzothiazole
2-[(4-fluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
{(1 /-/-benzimidazol-2-yl)[3-(2-fluoro-et oxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2- yl)et oxy]p enyl}met yl)(1-met ylpiperidin-4-yl)amine
2-[(1-met ylpiperidin-4-yloxy)(4'-trifluoromet oxy-bip enyl-3-yl)met yl]-1/-/- benzimidazole
2-[(4'-met oxybip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole 2-[(3-benzo[1 ,3]dioxol-5-ylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
2-[[3-(3-met oxybenzyloxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole
5- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentan-2-one 2-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl- benzyloxy)p enyl]met yl}benzot iazole
4-[benzot iazol-2-yl(3-bromo-p enyl)met oxy]-1 ,1-dimethylpiperidinium 2- (3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2- ynyl)isoindole-1 ,3-dione
3- {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}prop-2-yn-1 - ol
4- {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}but-3-yn-1 -ol
5- {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}pent-4-yn-1 - ol
2- [(1 -methylpiperidin-4-yloxy)-o-tolyl-methyl]-1 /-/-benzimidazole
3- {3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2- ynylamine
2-[(3-ethynylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole
2- {(1 -met ylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)p enyl]met yl}benzot iazole
3- [benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]benzonitrile
2- {(1 -methylpiperidin-4-yloxy)[3-(1 H-[1 ,2,3]triazol-4-yl)phenyl]methyl}-1 H- benzimidazole
3- [benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]benzoic acid methyl ester 2-[(1 -methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ylamine
2-[(1 -methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]benzothiazole 2-[(1 -methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]-1 /-/-benzimidazole 2-[(3-methanesulfonylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2- [(4-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole
3- {3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}acrylic acid tert- butyl ester
3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]benzoic acid ethyl ester {3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}methanol
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}propionic acid tert- butyl ester
2-[[3-(2-benzenesulfonylvinyl)phenyl](1 -methylpiperidin-4- yloxy)methyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ol
[benzothiazol-2-yl(4'-methoxy-biphenyl-3-yl)methyl](1 -methylpiperidin-4-yl)amine 2-[[3-(2-methanesulfonylvinyl)phenyl](1 -methylpiperidin-4- yloxy)methyl]benzothiazole
2-[(2-chloro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole 5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}pyrimidin-2-ol 2-[(3-ferf-butylsulfanylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole 2- [(1-met ylpiperidin-4-yloxy)(3-pyrimidin-5-yl-p enyl)met yl]benzot iazole
3- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}acrylonitrile
2- [(1-met ylpiperidin-4-yloxy)(3-vinyl-phenyl)met yl]benzot iazole
3- [benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]-A/-benzyl-A/- met ylbenzamide
3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]-A/-propylbenzamide
2- [(2,4-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole [(1 H-benzimidazol-2-yl)(4'-met oxy-bip enyl-3-yl)rTiet yl](1-rTiet ylpiperidiri-4- yl)amine
3- [benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]-A/-met yl-A/- phenylbenzamide
3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenylamine 2-[(3-c lorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
2- [(4-c lorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol 3-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxymet yl}- phenylamine
2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}et anol 2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}et anol 2-[(3-azidop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
2-{(1-met ylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-et ylsulfanyl)phenyl]met yl}-1H- benzimidazole
2- {(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl- ethylsulfanyl)phenyl]methyl}benzothiazole
{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}benzyl-amine
3- {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}-3- methyl-butan-1-ol
4- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}but-3-yn-1-ol
5- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4-yn-1-ol 4-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}butan-1-ol (1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanylmet yl}- cyclopropyl)acetic acid methyl ester
2-{(1 -methylpiperidin-4-yloxy)[3-(2-[1 ,2,3]triazol-2-yl- ethylsulfanyl)phenyl]methyl}benzothiazole
2-{(1 -methylpiperidin-4-yloxy)[3-(2-[1 ,2,3]triazol-1 -yl- ethylsulfanyl)phenyl]methyl}benzothiazole 3-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}-3-met yl- butan-1-ol
2-[(1-met ylpiperidin-4-yloxy)(3-morpholin-4-yl-phenyl)met yl]benzot iazole 2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}et anol
2- [(1-met ylpiperidin-4-yloxy)(3-vinyl-phenyl)met yl]-1 --benzimidazole
3- {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)
methyl]phenylsulfanyl}propan-1-ol
1 -{3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)
methyl]phenylsulfanyl}propan-2-ol
4- {3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}butan-1-ol
2-{3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanyl}et ylamine
2-{(1-methylpiperidin-4-yloxy)[3-(2-methylsulfanyl- ethoxy)phenyl]methyl}benzothiazole
2-[(1-met ylpiperidin-4-yloxy)(2-trifluoromet oxy-p enyl)met yl]-1 /-/-benzimidazole 2-[(1-met ylpiperidin-4-yloxy)-p-tolylmet yl]-1 /-/-benzimidazole
2- [(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1 /-/-benzimidazole
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1- ol
1- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2- ol
4- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}butan-1-ol
2- (1 -{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propan-1-ol 2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}-/V- methylacetamide
2-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole 2-[(3-bromo-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole 2-[(2-bromop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid hydrazide
2-{(1-met ylpiperidin-4-yloxy)[3-(pyridin-4-ylmet oxy)p enyl]met yl}benzot iazole
4- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}butan-1-ol 2-[[3-(furan-2-ylmet oxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-(1-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanylmet yl}- cyclopropyl)ethanol
2-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}et ylamine
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]benzyloxy}propan-2-one
2- {3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}et ylamine 2-[(1-met ylpyrrolidin-3-yloxy)p enyl-met yl]-1 --benzimidazole
[(1 H-benzimidazol-2-yl)-p-tolyl-met yl](1-met ylpiperidin-4-yl)amine
2-[(3-et ylsulfanyl-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)- propan-2-one
1- (3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)- propan-2-ol
2- [[3-(2-met oxyet oxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole Λ/-(2-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
(2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}et yl)met yl- amine
2-[(1-met ylpiperidin-4-yloxy)(3-trifluoromet oxy-p enyl)met yl]-1 /-/-benzimidazole 2-[(2-c lorop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
4-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}but-3-ynyl amine 2-{(1-met ylpiperidin-4-yloxy)[3-(pyridin-2-ylmet oxy)p enyl]met yl}benzot iazole 2-{(1-met ylpiperidin-4-yloxy)[3-(pyridin-3-ylmet oxy)p enyl]met yl}benzot iazole
2- [(3-Cyclo exylmet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
4- {3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}but-3- ynylamine
5- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4-ynylamine
3- {3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}propane-1 ,2-diol
5- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pentylamine 2-{3-[benzot iazol-2-yl(1-et yl-piperidin-4-yloxy)met yl]phenoxy}et ylamine 2-{3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenoxy}et ylamine
6- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}hexan-1-ol
4- {3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}butylamine 5- {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4- ynylamine
6- {3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanyl}hexan-1-ol
3- {3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}prop-2-ynylamine 2-[benzo[1 ,3]dioxol-5-yl(1 -met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole (2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-urea
(2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-thiazol-2-yl)amine
2- [(2,3-di ydrobenzo[1 ,4]dioxin-6-yl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
4- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}butylamine A/-(2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
3- {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}propylamine A/-ferf-butoxycarbonyl-/V-(2-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
5- {3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}pentylamine
2-[{3-[2-(1 -met yl-1 --imidazol4-yl)et yl]phenyl}(1 -met ylpiperidin-4- yloxy)met yl]benzot iazole
A/-ferf-butoxycarbonyl-N'-(4-{3-[(1 --benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenyl}but-3-ynyl)guanidine
Λ/-(4-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}butyl)guanidine
A/-ferf-butoxycarbonyl-N'-(4-{3-[(1 --benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenyl}butyl)guanidine
2- {(1-met ylpiperidin-4-yloxy)[3-(pyridin-2-ylmet oxy)p enyl]met yl}-1 H- benzimidazole
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine 5-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}pentylamine A/-ferf-butoxycarbonyl-N'-(3-{3-[(1 --benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenyl}propyl)guanidine
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}propylamine 2-{(1 -methylpiperidin-4-yloxy)[3-(4-[1 ,2,3]triazol-2-yl- butoxy)phenyl]methyl}benzothiazole
2-{(1 -methylpiperidin-4-yloxy)[3-(4-[1 ,2,4]triazol-1 -yl- butoxy)phenyl]methyl}benzothiazole
(2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanyl}et yl)(4,5-di ydro-1 --imidazol-2-yl)amine
Λ/-(2-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-N'-cyanoguanidine
6-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}hex-5-ynyl amine
Λ/-(3-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}propyl)guanidine
Λ/-(3-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}propyl)guanidine
2- {(1-met ylpiperidin-4-yloxy)[3-(4-morpholin-4-yl- butoxy)phenyl]methyl}benzothiazole
(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-2- yl)methanol
(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-2- yl)methanol
6-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}hexylamine 4-{3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanyl}butylamine
3- {3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenoxy}propylamine
4- (2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4- yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid ferf-butyl ester
4-(2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4- yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid ferf-butyl ester
2-{(1 -methylpiperidin-4-yloxy)[3-(2-piperazin-1 -yl- ethoxy)phenyl]methyl}benzothiazole
4-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenoxy}butylamine
2-{(1-met ylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)p enyl]metriyl}-1 -- benzimidazole
2-{(1 -met ylpiperidin-4-yloxy)[3-(4-piperidin-1 -yl-butoxy)p enyl]met yl}-1 H- benzimidazole
2-[(2-fluoro-3-iodop enyl)(1-metriylpiperidin-4-yloxy)metriyl]-1 --benzimidazole A/-ferf-butoxycarbonyl-/V-(-{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenyl}pentyl)guanidine
A/-ferf-butoxycarbonyl-/V-(3-{3-[(1 - -benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenyl}prop-2-ynyl)guanidine
6-{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}hex-5- ynylamine
2-{(1 -methylpiperidin-4-yloxy)[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1 H- benzimidazole
A/-ferf-butoxycarbonyl-/V-(5-{3-[(benzothiazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-5-ynyl)guanidine
A/-(5-{3-[benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]phenyl}pent-4- ynyl)guanidine
A/-ferf-butoxycarbonyl-/V-(6-{3-[(benzothiazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenyl}hex-5-ynyl)guanidine
A/-(6-{3-[benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]phenyl}hex-5- ynyl)guanidine
4-(4-{3-[(1 - -benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}butyl)piperazine-1 -carboxylic acid ferf-butyl ester
6-{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}hexylamine
A/-feA -butoxycarbonyl-A/,-(6-{3-[(1 H-benzimidazol-2-yl)(1 -metriylpiperidin-4- yloxy)met yl]phenyl}hex-5-ynyl)guanidine
Λ/-(6-{3-[(1 H-benzimidazol-2-yl)(1 -metriylpiperidin-4-yloxy)metriyl]phenyl}hex-5- ynyl)guanidine
1 -(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-3-isopropyl-thiourea
2-{(1 -methylpiperidin-4-yloxy)[3-(3-[1 ,2,4]triazol-1 -yl- propoxy)phenyl]methyl}benzothiazole
2-{(1 -methylpiperidin-4-yloxy)[3-(3-[1 ,2,3]triazol-2-yl- propoxy)phenyl]methyl}benzothiazole
2-{(1 -met ylpiperidin-4-yloxy)[3-(3-morpholin-4-yl- propoxy)phenyl]methyl}benzothiazole
4-(3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]phenoxy}propyl)piperazine-1 -carboxylic acid ferf-butyl ester
2-{3-[(1 H-benzimidazol-2-yl)(1 -metriylpiperidin-4-yloxy)metriyl]-2-fluoro- phenylsulfanyl}et ylamine 4-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}-3,6-di ydro- 2H-pyridine-1 -carboxamidine
2-[[3-(2-c loroet oxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole Λ/-(6-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenyl}hexyl)guanidine
2- {(1 -met ylpiperidin-4-yloxy)[3-(2-piperidin-1 -yl-et oxy)p enyl]met yl}-1 H- benzimidazole
A/-ferf-butoxycarbonyl-/V-(5-{3-[(1 --benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynyl)guanidine
Λ/-(5-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4- ynyl)guanidine
4-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}butylamine 4-(3-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic acid ferf-butyl ester
(2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}ethylamino)acetic acid ferf-butyl ester
4-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic acid ferf-butyl ester
A/-(6-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)metriyl]phenyl}hexyl)guanidine
A/-feA-butoxycarbonyl-A/,-(6-{3-[(1H-benzimidazol-2-yl)(1-metriylpiperidin-4- yloxy)met yl]phenyl}hexyl)guanidine
A/-(5-{3-[benzot iazol-2-yl(1-metriylpiperidin-4- yloxy)methyl]phenyl}pentyl)guanidine
4-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)metriyl]phenyl}butylamine
[[3-(4-aminobutoxy)p enyl](1 H-benzimidazol-2-yl)met yl](1-met ylpiperidin-4- yl)amine
3- {3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}propylamine
4- (2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid ferf-butyl ester
(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenoxy}ethylamino)acetic acid ferf-butyl ester
5- {3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}pentylamine A-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3- ynyl)guanidine A/-(3-{3 benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2- ynyl)guanidine
A/-(4-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}butyl)guanidine
(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenoxy}pentylamino)acetic acid ferf-butyl ester
2-[(1 -methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1 H- benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4- ylmet oxy)prienyl]metriyl}benzotriiazole
2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-3- ylmet oxy)prienyl]metriyl}benzotriiazole
2-[[3-(1-metriylpiperidin-3-ylmetrioxy)prienyl](1-metriylpiperidin-4- yloxy)met yl]benzotriiazole
2-[(1 -methylpiperidin-4-yloxy)(3-piperidin-3-ylethynyl-phenyl)methyl]-1 H- benzimidazole
5-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}pentylamine
2-{(1-metriylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)prienyl]metriyl}benzotriiazole
2- {(1-metriylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)prienyl]metriyl}benzotriiazole 5-{3 benzot iazol-2-yl(1-metriylpiperidin-4-yloxy)metriyl]phenyl}pent-4-en-1-ol
3- amino-4-(2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione
[[3-(6-amino ex-1 -ynyl)phenyl](1 --benzimidazol-2-yl)met yl](1 -met ylpiperidin-4- yl)amine
{[3-(4-aminobutoxy)p enyl]benzot iazol-2-yl-met yl}(1-met ylpiperidin-4-yl)amine 2-[(3-azetidin-3-ylet ynylphenyl)(1-metriylpiperidin-4-yloxy)metriyl]-1 H- benzimidazole
5-{3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)metriyl]phenyl}pent-4-en-1 - ol
5-{3 benzot iazol-2-yl(1-metriylpiperidin-4-yloxy)metriyl]phenyl}pent-4-en-1-ol
4- (5-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic acid ferf-butyl ester
2-[[3-(2-azetidin-3-ylethyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1 -- benzimidazole
Λ/-(4-{3-[(1 H-benzimidazol-2-yl)(1-metriylpiperidin-4-yloxy)metriyl]phenyl}but-3- ynyl)guanidine 4- {3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}piperidine-1 - carboxamidine
2-{(1-met ylpiperidin-4-yloxy)[3-(2-piperidin-2-yl-et ylsulfanyl)phenyl]met yl}-1 -- benzimidazole
2-{(1-met ylpiperidin-4-yloxy)[3-(2-piperidin-4-yl-et yl)phenyl]met yl}-1 -- benzimidazole
Λ/-(5-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pentyl)guanidine
2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]- 1 --benzimidazole
A/-ferf-butoxycarbonyl-/V-(4-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4- yloxy)methyl]phenyl}but-3-ynyl)guanidine
5- {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}pentylamine
N-acetyl-N'-(2-{3-[(1 --benzimidazol-2-yl)(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
2-[[3-(azetidin-3-yloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole 1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}azetidin-3-ol (1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)methanol
1-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}piperidin-4-ylamine 1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3-ol
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3-ol A/-(1-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)acetamide
2- [[3-(5-imidazol-1 -ylpent-1 -ynyl)phenyl](1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
2-{(1 -methylpiperidin-4-yloxy)[3-(5-pyrazol-1 -yl-pent-1 -ynyl)phenyl]methyl}-1 H- benzimidazole
1- {3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}piperidin-4-ol
2- [{3-[2-(1 H-imidazol-4-yl)et yl]phenyl}(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
acetic acid 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenyl}piperidin-4-yl ester
2-[(3-bromo-p enyl)(1-met yl-pyrrolidin-3-ylmet oxy)met yl]-1H-benzimidazole 2-{(1-met ylpiperidin-4-yloxy)[3-(piperidin-4-yloxy)p enyl]metriyl}benzotriiazole 2-{(1 -methylpiperidin-4-yloxy)[3-(5-[1 ,2,3]triazol-2-yl-pent-1 -ynyl)phenyl]methyl}- 1 --benzimidazole
2-{(1 -methylpiperidin-4-yloxy)[3-(5-[1 ,2,3]triazol-1 -yl-pent-1 -ynyl)phenyl]methyl}- 1 /-/-benzimidazole
A/-(3-{3-[(1/-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}prop-2- ynyl)guanidine
Λ/1 -(5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenoxy}pentyl)butane-1,4-diamine
{[3-(6-amino ex-1-ynyl)phenyl]benzot iazol-2-yl-met yl}(1-met ylpiperidin-4- yl)amine
5-{3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4- enylamine
4-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}but-2-en-1-ol
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- ylamine
2- [(2,5-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
2- [(2-fluoro-5-iodo-p enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
3- {3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenylet ynyl}azetidine-1-carboxamidine
4- {3-[(5-fluoro-1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}butan-1-ol
2-{3-[(5-fluoro-1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanyl}et ylamine
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- ylamine
2- [[3-(3-fluoropyrrolidin-1 -yl)phenyl](1 -methylpiperidin-4- yloxy)met yl]benzot iazole
4-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}but-2-enylamir
2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]-1/-/- benzimidazole
2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]-1/-/- benzimidazole (enantiomer A)
2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole (enantiomer B)
N-(2-aminoethyl)-2-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}acetamide N-(2-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
2-(5-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1 ,3-dione
6-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}hex- 5-ynylamine oxalate
4- {3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}butylamine oxalate
N-(3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}propyl)guanidine, dihydrochloride
1 - {3 benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3-one, oxalate
N-(4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}butyl)guanidine, dihydrochloride
5- {3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}pentan-1 -ol
N-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-N-(2,2-dimethylpropionyl)guanidine
2- [(1 -methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1 H-benzimidazole
2-{(1 -methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl}benzothiazole, oxalate
2-[(3-bromophenyl)(1 -methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1 H- benzimidazole, oxalate
4-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]aniline
4-[(1 H-benzimidazol-2-yl)(piperidin-4-yloxy)methyl]aniline, hydrochloride
N-(2-amino-ethyl)-2-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}acetamide
1 - {3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}-3- trifluoromethylpyrrolidin-3-ol, oxalate
2- [[3-(4,5-dihydro-1 H-imidazol-2-ylmethylsulfanyl)phenyl](1 -methylpiperidin-4- yloxy)methyl]-1 H-benzimidazole
2-[[3-(4,5-dihydro-1 H-imidazol-2-ylmethylsulfanyl)phenyl](1 -methylpiperidin-4- yloxy)methyl]-5-fluoro-1 H-benzimidazole
2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1 H- benzimidazole 2-[(3-iodop enyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 -methyl- 1 H-benzimidazole, dioxalate
2-amino-5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanylmethyl}-1 ,5-dihydroimidazol-4-one
2- [(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5,6,7-trifluoro-1 H- benzimidazole
1 -(2-ethoxyethyl)-2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, dioxalate
3- [(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]benzaldehyde
4- {3-[(1 H-benzimidazol-2-yl)(1 -methylazetidin-3- ylmethoxy)methyl]phenylsulfanyl}butylamine, oxalate
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]benzoxazole, oxalate
{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}methanol. dimethylsulfoxonium ylide of 3-bromophenylacetic acid methyl ester
2-[(2-fluoro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, enantiomer B
2-[(2,6-difluoro-3-methoxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
ethyl (6-{3-[(1 -methyl-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}hex-5-ynyl)carbamate, oxalate
2-[(1 H-indol-6-yl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, oxalate 2-[benzo[b]thiophen-6-yl(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, oxalate
2-[(2,6-difluoro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, enantiomer B
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol
2-[(1 H-benzimidazol-2-yl)hydroxymethyl]phenol
2-[(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol
5- (6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1 -enol
2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, enantiomer B
5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4- ynylamine, enantiomer A 5- {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)metriyl]phenyl}pent-4- ynylamine, enantiomer B
2-[(3-bromop enyl)(1-met ylpiperidin-4-yloxy)met yl]-5-fluoro-1 H-benzimidazole, enantiomer A
2-[(3-bromop enyl)(1-met ylpiperidin-4-yloxy)met yl]-5-fluoro-1 H-benzimidazole, enantiomer B
2-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-4-met ylphenol 2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenol enantiomer A
2- [(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenol enantiomer B
6- [(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2-fluoro-3- met ylphenol enantiomer A
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2-fluoro-3- met ylphenol enantiomer B
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2,3-difluorop enol enantiomer A
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2,3-difluorop enol enantiomer B
5-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-4- fluorophenyl}pent-4-ynylamine, dioxalate
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenoxy}cyclopentylamine, oxalate
2-{[3-(3-fluoropyrrolidin-1 -yl)phenyl](1 -methylpiperidin-4- yloxy)methyl}benzothiazole, oxalate
5-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -met ylpyrrolidin-3- ylmethoxy)methyl]phenyl}pent-4-ynylamine, oxalate
2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole, oxalate (one epimer)
2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole, oxalate (50/50 mixture of two epimers)
2-{(1-methylpiperidin-4-yloxy)[3-(octahydrocyclopenta[c]pyrrol-5- yloxy)phenyl]methyl}benzothiazole, dioxalate
(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)methylamine, dioxalate
4- {3-[(5,6-difluoro-1 H-benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}butan-1-ol 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenyl}octahydrocyclopenta[c]pyrrol-5-ylamine, dioxalate
2-{[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H- benzimidazole, oxalate
2-{[3-(2-fluoroet oxy)p enyl](1-met ylpiperidin-4-yloxy)met yl}-1 H- benzimidazole, oxalate
4-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}cyclo exylamine, oxalate
6-{3-[(1 -methyl-1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenyl}hex-5-ynylamine, dioxalate
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-2- ylmethylamine, oxalate
(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)(methyl)amine, oxalate
(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)(dimethyl)amine, oxalate
2- {[3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)phenyl](1-methylpiperidin-4- yloxy)methyl}benzothiazole, dioxalate
2- [(2-fluoro-5-met oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole, oxalate
3- [(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-4-fluorop enol, oxalate
2-{[2-fluoro-5-(2-fluoroet oxy)p enyl](1-met ylpiperidin-4-yloxy)met yl}-1 H- benzimidazole, oxalate
2-[(2-fluoro-5-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole, oxalate
4- {3-[(1-met ylpiperidin-4-yloxy)(5,6,7-trifluoro-1 H-benzimidazol-2- yl)methyl]phenylsulfanyl}butylamine, oxalate
4-{3-[(5,6-difluoro-1 H-benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}butylamine, oxalate
6-(3-{[1 -(2-ethoxyethyl)-1 H-benzimidazol-2-yl](1 -met ylpiperidin-4- yloxy)methyl}phenyl)hex-5-ynylamine, dioxalate
6-(3-{[1 -(2-met oxyet yl)-1 H-benzimidazol-2-yl](1 -met ylpiperidin-4- yloxy)methyl}phenyl)hex-5-ynylamine, dioxalate
2-{[3-(3-fluoropropylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1 H- benzimidazole, dioxalate 5 luoro-2 (2 luoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]- 1 H-benzimidazole, oxalate
4,5,6-trifluoro-2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4- yloxy)met yl]-1 H-benzimidazole
- 5,6-difluoro-2-[(2-fluoro-5-trifluoromet oxyp enyl)(1 -methylpiperidin-4- yloxy)methyl]-1 H-benzimidazole
2-{[2-fluoro-5-(2,2,2-trifluoroet oxy)p enyl](1 -met ylpiperidin-4-yloxy)met yl}-1 H- benzimidazole
2-[(2,6-difluoro-4-methylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
2-[(2-chloro-5-trifluoromethoxyphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole, oxalate
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole, oxalate
- 2-[(4-c loro-2,6-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
7-fluoro-2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]- 1 H-benzimidazole, oxalate
2-[(2,6-difluoro-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole, oxalate
2-[(4-c loro-2,6-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole, oxalate
2-[(3-et oxy-2,6-difluorop enyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
- 2-[(2,6-difluoro-4-met ylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzoxazole, oxalate
2-[(1 -met ylpiperidin-4-yloxy)(4-trifluoromet ylphenyl)met yl]-1 H-benzimidazole 2-[(2-fluoro-4-trifluoromethylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
- 2-[(2,4-dimet ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 2-[(3-met oxyp enyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 2-[chroman-7-yl(1 -met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
2-[(2-fluoro-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]benzoxazole, oxalate
- 2-[(3,5-bis-trifluoromethylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole, oxalate 5- fluoro-2-[(2-fluoro-4-met ylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
2-[(2,3-difluoro-4-met ylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
2-[(3-c loro-4-met ylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole ethyl 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]benzimidazole-1 -carboxylate, oxalate
2-[(3-fluoro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole 2-[(5-bromo-2-fluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
6- {3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex- 5-ynylamine, oxalate
5-{4-fluoro-3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynylamine
ethyl (5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}pent-4-ynyl)carbamate
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-chlorophenol ethyl (5-{4-fluoro-3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynyl)carbamate
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- trifluoromethoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-fluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-methoxyphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-5-methylphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-bromophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-ethoxyphenol 2-[(1 H-indol-7-yl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4,6-difluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4,6-dichlorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-6-fluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-3-fluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4,5-difluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-5-fluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-5-chlorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-6-methylphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- methylsulfanylphenol 2- [(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-ethylsulfanylphenol
3- [(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl biphenyl-4-ol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-tert-butylphenol 2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-propylphenol 2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -6-methoxyphenol 2-[(1 H-benzimidazol-2-yl)(1 methy-piperidin-4-yloxy)methyl -3-fluoro-5- met ylphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -3-chlorophenol 2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -6-fluoro-4-ethylphenol 2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-benzylphenol 2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4- trifluoromet ylphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-chloro-6- fluorop enol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -5-fluoro-3- methylphenol
6-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -2-fluoro-3- methylphenol
6-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl indan-5-ol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-propoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-(1 -methyl-1 - phenylethyl)phenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-(2- fluoroethoxy)phenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-(3- fluoropropoxy)phenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-fluoro-6- methylphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -6-fluoro-4- methoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-phenoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-fluoro-6- methoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4,5-dimethylphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl -4-(3- fluoropropylsulfanyl)phenol 2-[(1 H-benzimidazol-2-yl) -methylpiperidin-4-yloxy)methyl]-4-fluoro-5- met ylphenol
2- [(1 H-benzimidazol-2-yl)( l -methylpiperidin-4-yloxy)methyl]-4-(2- fluoroethylsulfanyl)phenol
3- [(1 H-benzimidazol-2-yl)( -methylpiperidin-4-yloxy)methyl]-2-hydroxybiphenyl 2-[(1 H-benzimidazol-2-yl)( -methylpiperidin-4-yloxy)methyl]-6-ethylphenol 2-[(1 H-benzimidazol-2-yl)( -methylpiperidin-4-yloxy)methyl]-5- trifluoromet ylphenol
2-[(1 H-benzimidazol-2-yl) -methylpiperidin-4-yloxy)methyl]-4-hydroxyphenol 2-[(1 H-benzimidazol-2-yl) -methylpiperidin-4-yloxy)methyl]-5,6,7,8-tetrahydro-1 - naphthol
2-[(1 H-benzimidazol-2-yl) -methylpiperidin-4-yloxy)methyl]-6- trifluoromet oxyp enol
2-[(1 H-benzimidazol-2-yl) l -methylpiperidin-4-yloxy)methyl]-5- trifluoromethoxyphenol
6-[(1 H-benzimidazol-2-yl) -methylpiperidin-4-yloxy)methyl]-2-fluoro-3,4- dimethylphenol
6-[(1 H-benzimidazol-2-yl) l -methylpiperidin-4-yloxy)methyl]-3-fluoro-2- methylphenol
6-[(1 H-benzimidazol-2-yl) l -methylpiperidin-4-yloxy)methyl]-2,4-difluoro-3- methylphenol
6-[(1 H-benzimidazol-2-yl) methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol (1 -{3-[benzothiazol-2-yl(1 methylpiperidin-4-yloxy)methyl]phenyl}-azetidin-3- yl)dimethylamine, oxalate
1 -{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3 ol, oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}-1 H- benzimidazole, dioxalate
2-[(5-chloro-2-fluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, oxalate
2-[(2-fluoro-5-trifluoromethylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, oxalate
6-{3-[(1 -ethyl-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}hex 5-ynylamine,oxalate
2-[(2-fluoro-5-methoxyphenyl)(1 -methylpyrrolidin-3-ylmethoxy)methyl]-1 H- benzimidazole, oxalate 2-[(1-met ylpiperidin-4-yloxy)(3-trifluoromet ylsulfanylphenyl)met yl]-1 H- benzimidazole, oxalate
2-[(4-fluoro-3-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole, oxalate
2-[(2-fluoro-5-propoxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole, oxalate
4- [(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenol
2-{[3-(3,3-difluoropyrrolidin-1 -yl)phenyl](1 -met ylpiperidin-4-yloxy)met yl}-1 H- benzimidazole, dioxalate
2-{[3-(5-fluorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1-methylpiperidin-4- yloxy)methyl}benzothiazole, dioxalate
6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}hexylamine, oxalate
5- {3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenylsulfanylmet yl}oxazolidin-2-one
N-(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenylsulfanyl}hexyl)guanidine, di ydroc loride
4-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}but- 2-enylamine
4-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}but-
2- enylamine, oxalate
N-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine
3- {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}allylamine cis-2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenylsulfanylmet yl}cyclopropylmet ylamine
N-(3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}allyl)guanidine, trihydrochloride
2-[(azetidin-3-ylmethoxy)(3-bromophenyl)methyl]-1 H-benzimidazole
2-[(3-bromop enyl)(1-met ylazetidin-3-ylmet oxy)met yl]-1 H-benzimidazole 2-[(2,6-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 2-[(2-fluoro-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 2-[(5-et ylsulfanyl-2-fluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
2-[(azetidin-3-ylmet oxy)(2-fluoro-5-trifluoromet oxyp enyl)met yl]-1 H- benzimidazole, oxalate 2-[(2Tluoro-5-trifluoromethoxyphenyl)(1 -methylazetidin-3-ylmethoxy)methyl]-1 H- benzimidazole, oxalate
2-[(3-ethylsulfanyl-2,6-difluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
- 2-[(2,2-difluorobenzo[1 ,3]dioxol-5-yl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
2-[(piperidin-4-yloxy)thiophen-3-ylmethyl]-1 H-benzimidazole
2-[(1 -methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1 H-benzimidazole
2-[(piperidin-4-yloxy)thiophen-2-ylmethyl]-1 H-benzimidazole
- 2-[(1 -methylpiperidin-4-yloxy)thiophen-2-ylmethyl]-1 H-benzimidazole as well as their enantiomers, diastereomers, mixtures thereof and pharmaceutically acceptable salts, free forms, tautomers, hydrates and solvates. The compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
The compounds of the invention may also comprise tautomeric forms which are all encompassed by the present invention. In parti in formula (I), the group:
Figure imgf000038_0001
may have tautomeric forms such as when HetAr is a phenyl and X is N, leading to 1 H- benzimidazole which is a tautomer of 3/-/-benzimidazole. A representative example is illustrated below:
Figure imgf000038_0002
The compounds of formula (I) can be provided in the form of a free base or in the form of addition salts with acids, which also form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but salts with other acids, useful for example for the purification or for the isolation of the compounds of formula (I), also form part of the invention.
As used herein, the term "patient" refers to a warm-blooded animal such as a mammal, preferably a human or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and conditions described herein.
As used herein, a "therapeutically effective amount" refers to an amount of a compound of the present invention which is effective in reducing, eliminating, treating or controlling the symptoms of the herein-described diseases and conditions. The term "controlling" is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment and chronic use.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propanoic, succinic, tartaric, citric, methanesulfonic, benzenesulfonic, glucuronic, glutamic, benzoic, salicylic, toluenesulfonic, oxalic, fumaric, maleic, and the like. Further addition salts include ammonium salts such as tromethamine, meglumine, epolamine, etc., metal salts such as sodium, potassium, calcium, zinc or magnesium. Hydrochloride and oxalate salts are preferred.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference. The compounds of the general formula (I) having geometrical and stereomers are also a part of the invention.
According to a further object, the present invention is also concerned with the process of preparation of the compounds of formula (I).
The compounds and process of the present invention may be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by application or adaptation of the methods described below, or variations thereon as appreciated by the skilled artisan. The appropriate modifications and substitutions will be readily apparent and well known or readily obtainable from the scientific literature to those skilled in the art.
In particular, such methods can be found in R.C. Larock, Comprehensive Organic Transformations, VCH publishers, 1989.
It will be appreciated that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare and isolate such optically active forms. For example, mixtures of stereomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.
Compounds of the present invention may be prepared by a variety of synthetic routes. The reagents and starting materials are commercially available, or readily synthesized by well-known techniques by one of ordinary skill in the arts. All substituents, unless otherwise indicated, are as previously defined.
In the reactions described hereinafter, it may be necessary to protect reactive functional groups, for example hydroxy, keto, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P. G. M. Wuts in Protective Groups in Organic Chemistry,
John Wiley and Sons, 1991 ; J. F. W. McOmie in Protective Groups in Organic Chemistry,
Plenum Press, 1973.
Some reactions may be carried out in the presence of a base. There is no particular restriction on the nature of the base to be used in this reaction, and any base conventionally used in reactions of this type may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: sodium hydroxide, potassium carbonate, triethylamine, alkali metal hydrides, such as sodium hydride and potassium hydride; alkyllithium compounds, such as methyllithium and butyllithium; and alkali metal alkoxides, such as sodium methoxide and sodium ethoxide.
Usually, reactions are carried out in a suitable solvent. A variety of solvents may be used, provided that it has no adverse effect on the reaction or on the reagents involved. Examples of suitable solvents include: hydrocarbons, which may be aromatic, aliphatic or cycloaliphatic hydrocarbons, such as hexane, cyclohexane, methylcyclohexane, toluene and xylene; amides, such as A/,A/-dimethylformamide; alcohols such as ethanol and methanol and ethers, such as diethyl ether, methyl fert-butyl ether, methyl cyclopentyl ether and tetrahydrofuran.
The reactions can take place over a wide range of temperatures. In general, we find it convenient to carry out the reaction at a temperature of from 0°C to ~\ 50°C (more preferably from about room temperature to l OCO). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 3 hours to 20 hours will usually suffice. The compound thus prepared may be recovered from the reaction mixture by conventional means. For example, the compounds may be recovered by distilling off the solvent from the reaction mixture or, if necessary, after distilling off the solvent from the reaction mixture, pouring the residue into water followed by extraction with a water-immiscible organic solvent and distilling off the solvent from the extract. Additionally, the product can, if desired, be further purified by various well-known techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
The process of preparation of a compound of formula (I) of the invention is another object of the present invention.
Compounds of formula (I) where A = O can be prepared by etherification of compound of formula (II):
Figure imgf000042_0001
(II)
in which X, HetAr and Ar are as defined in general formula (I)
with a compound of formula (II
Figure imgf000042_0002
in which R, HET and B are as defined in general formula (I)
This etherification reaction can be performed in acidic medium (toluenesulfonic acid, methanesulfonic acid) in an inert solvent (toluene, dichlorobenzene, dichloroethane) at a temperature between room temperature and about 160^. Compounds of formula (II) can be prepared by condensing a benzothiazole or a benzimidazole derivative with an aldehyde ArCHO, by condensing an organometallic derivative ArMetal with an optionally substituted benzimidazole-2-carboxaldehyde or an optionally substituted benzothiazole-2-carboxaldehyde, or by condensing a hydroxy acid ArCHOHCOOH with an optionally substituted orho-phenylenediamine or an optionally substituted 2-aminothiophenol or 2-aminophenol
Compounds of formula (I) wherein A = NH can be prepared by reduction of compound of formula (IV):
Figure imgf000042_0003
in which R, HET, B, X, HetAr and Ar are as defined in general formula (I)
This reduction can be performed by hydrogenation with dihydrogen or transfer hydrogenation (formic acid, formic acid / triethylamine, ammonium formate) in the presence of a catalyst (palladium on charcoal) in an inert solvent (methanol, ethanol, ethyl acetate) at a temperature comprised between room temperature and about 150°C. Compounds of formula (IV) in which R, HET, B, X, HetAr and Ar are as defined in general formula (I) can be prepared by condensing compound of formula (V):
Figure imgf000043_0001
(V)
in which X, He as defined in general formula (I) with an amine
Figure imgf000043_0002
This condensation can be performed in the presence of an acid (titanium tetraisopropoxide) in an inert solvent (tetrahydrofurane) at a temperature comprised between room temperature and reflux of the medium.
Compounds of formula (V) in which X, HetAr and Ar are as defined in general formula (I) can be prepared by oxidizing compound of formula (II) in which X, HetAr and Ar are as defined in general formula (I).
This oxidation can be performed with an oxidizing agent (potassium permanganate, barium permanganate, manganese dioxide) in an inert solvent (dioxane, acetonitrile) at a temperature comprised between room temperature and reflux of the medium.
Compounds of formula (I) where A = NH can be prepared by condensation of compound of formula (II):
Figure imgf000043_0003
(")
in which X, He as defined in general formula (I) with an amine
Figure imgf000043_0004
This condensation can be performed in the presence of a transition metal catalyst such as dichloro(pentamethylcyclopentadienyl)iridium(lll) dimer, in the presence of a base such as sodium hydrogenocarbonate in an inert solvent such as toluene at a temperature comprised between about 80 and 150°C.
Alternatively, compounds of formula (I) in which A and X are NH can be prepared by condensing an organometallic re ompound of formula (VI):
Figure imgf000044_0001
in which R, HET, B, HetAr and Ar are as defined in general formula (I)
This addition can be performed by adding a Grignard reagent onto an imine in an inert solvent (tetrahydrofurane) at a temperature comprised between room temperature and reflux of the medium.
Compounds of formula (VI) in which R, HET, B, HetAr and Ar are as defined in general formula (I) can be prepared by condensing an optionally substituted benzimi zole-2-carboxaldehyde or heteroaryl fused imidazole-2-carboxaldehyde with an
amine
Figure imgf000044_0002
This condensation can be performed in the presence of molecular sieves or other dehydrating agent in an inert solvent (ethanol) at a temperature comprised between 40 °C and the refluxing temperature. A Dean Stark apparatus can also be used. Alternatively, compounds of formula (I) in which A=0 can be prepared by alkylation of compound of formula (VII):
Figure imgf000044_0003
in which HET, B, X, HetAr and Ar are as defined in general formula (I)
This alkylation can be performed by reductive method using a carbonylated compound and a reducing agent such as a borohydride, a cyanoborohydride, a triacetoxyborohydride, hypophosphonous acid, formic acid, formic acid / triethylamine or hydrogen, a catalyst such as palladium can be added for this transformation when hydrogen or hydrogen donnors are used.
Compounds of formula (VII) can be prepared by deprotection of compound of formula (VIII):
Figure imgf000045_0001
in which HET, B, X, HetAr and Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom.
When Prot is a ferf-butoxycarbonyl group, the transformation is usually performed in acidic medium such a trifluoroacetic diluted with dichloromethane or in a solvent (ethyl acetate, ethanol, isopropanol) containing HCI. Preferably, this deprotection is performed at a temperature between O'C and the refluxing temperature of the medium.
Compounds of formula (VIII) in which HET, B, X, HetAr and Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom can be prepared using the general methods described above.
Alternatively, compounds of formula (VIII) in which A= O and HET, B, X, HetAr and
Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom can be prepared by condensing an acid of formula (IX):
Figure imgf000045_0002
in which HET, B and Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom,
with an optionally substituted ortho-phenylenediamine or an optionally substituted 2-aminothiophenol.
This condensation can be performed by reacting the two compounds in acidic medium, or by first forming the amide bond with usual bond forming reagents, then dehydrating in acidic medium (acetic acid, hydrochloric acid) at a temperature comprised between room temperature and reflux. Acids of formula (IX) in which HET, B and Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom can be prepared by hydrolysis of their esters. This hydrolysis can be performed in basic medium or in acidic medium at a temperature comprised between 0 °C and reflux of the medium.
Figure imgf000046_0001
Esters of the acid of formula (IX) in which HET, B, X and Ar are as defined in general formula (I) and Prot is a protecting group of the nitrogen atom can be prepared by condensing an ester of the acid (X)
with an alcohol
Figure imgf000046_0002
This condensation can be performed in the presence of a metal catalyst such as rhodium acetate dimer in an inert solvent such a dichloromethane or dichloroethane, at a temperature comprised between 0 °C and reflux of the medium.
Esters of the acid of formula (X) can be prepared from esters of an acid ArCH2COOH with a diazo transfer reagent such as tosylazide in the presence of a base such as 1 ,8-diazabicyclo[5.4.0]undec-7-ene in an inert solvent such as acetonitrile at a temperature comprised between -20 °C and 40 °C.
Furthermore, compounds of formula (I) can be prepared from compounds of formula (I) by group interconversion or group transformation. Such reaction include, but are not limited to, reaction on aromatic or heteroaromatic groups such as halogen exchange reaction, Sonogashira reaction, Heck reaction, Suzuki reaction, sulfide condensation, triflate displacement with grignard reagents, copper catalysed ether formation, metal catalysed amine aromatic substitution, aromatic carbonylation reaction; reaction on reactive groups such as acylation, alcoxycarbonylation of nitrogen containing groups such as amines, amidines, guanidines; substitution of hydroxy with nucleophile (Mitsunobu reaction or activation and nucleophilic substitution); hydrogenation of unsaturation (alkenyl to alkyl, alkynyl to alkenyl, alkynyl to alkyl); Staudinger reduction of azido group. The process of the invention may comprise the additional step of isolating the desired compound of formula (I).
The starting products and/or reagents may be commercially available, or may be readily prepared by the skilled person by applying or adapting the procedures disclosed in the experimental part below.
According to a still further object, the present invention is also concerned with pharmaceutical compositions comprising a compound of formula (I) as defined above with a pharmaceutically acceptable excipient. The compounds of the invenion are antagonists and/or inverse agonists of H4 R.
The pharmaceutical compositions and compounds of the invention may thus be useful for use in the treatment and/or prevention of a disease associated with H4 dysfunction, such as inflammatory disorders.
Said disease includes adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, conjunctivitis, nasal congestion, allergic congestion; disorders of the genito-urinary tract such as female and male sexual dysfunction, overactive bladder conditions, urinary incontinence, bladder overactivity, benign prostate hyperplasia and lower urinary tract symptoms; dermatological diseases such as dermatitis and psoriasis and treatment of itchy skin; diseases of the cardiovascular system including thromboembolic diseases, atherosclerosis, myocardial infarction, angina pectoris, myocardial ischaemia and arrhythmia, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses, hypotension, pulmonary hypertension, malignant hypertension, cardiac insufficiency, heart or kidney failure, stroke and renal dysfunction; diseases of the gastrointestinal tract including inflammatory bowel disease, Crohn's disease, ulcerative colitis; autoimmune diseases including rheumatoid arthritis, multiple sclerosis; cancer; pain; lymphatic diseases. According to a further object, the present invention also concerns a combination of a compound of the invention with one or more therapeutic agent(s) selected from:
• Histamine H2 or H3 receptor antagonists,
• Leukotriene antagonists,
· 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists
• CX and a2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use
• Xanthines, such as theophylline and aminophylline
· Non-steroidal antiinflammatories, such as sodium cromoglycate and nedocromil sodium
• Ketotifen
• COX-1 inhibitors (NSAIDs) and COX-2 selective inhibito
• Immunosuppressants
· mucolytics or anti-tussive agents
More particularly, the present invention also concerns combinations comprising a compound of formula (I) of the invention with a H1 R antagonist, such as cetirizine, desloratadine, bepotastine or doxepin. According to a still further object, the present invention is also concerned with a compound of formula (I) for the above conditions to be administered to a patient in the need thereof.
According to a still further object, the present invention also concerns the methods of treatment comprising administering an effective amount of a compound of the invention for treating and/or preventing the above conditions or disorders.
The identification of those subjects who are in need of treatment of herein- described diseases and conditions is well within the ability and knowledge of one skilled in the art. A clinician skilled in the art can readily identify, by the use of clinical tests, physical examination and medical/family history, those subjects who are in need of such treatment.
A therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of subject; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
The amount of a compound of formula (I), which is required to achieve the desired biological effect, will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g. hydrophobicity) of the compounds employed, the potency of the compounds, the type of disease, the diseased state of the patient, and the route of administration.
In general terms, the compounds of this invention may be provided in an aqueous physiological buffer solution containing 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from 1 μg kg to 0.1 g/kg of body weight per day; a preferred dose range is from 0.01 mg/kg to 10 mg/kg of body weight per day. A preferred daily dose for adult humans includes 1 , 5, 50, 100 and 200 mg, and an equivalent dose in a human child. The preferred dosage of drug to be administered is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
The compounds of the present invention are capable of being administered in unit dose forms, wherein the term "unit dose" means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition, as described hereinafter. As such, typical daily dose ranges are from 0.01 to 10 mg/kg of body weight. By way of general guidance, unit doses for humans range from 0.1 mg to 1000 mg per day. Preferably, the unit dose range is from 1 to 500 mg administered one to four times a day, and even more preferably from 1 mg to 300 mg, once a day. Compounds provided herein can be formulated into pharmaceutical compositions by admixture with one or more pharmaceutically acceptable excipients. Such compositions may be prepared for use in oral administration, particularly in the form of tablets or capsules; or parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, for example, topically or via trans-dermal patches or ocular administration, or intravaginal or intra-uterine administration, particularly in the form of pessaries or by rectal administration. The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro, A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000. Pharmaceutically compatible binding agents and/or adjuvant materials can be included as part of the composition. Oral compositions will generally include an inert diluent carrier or an edible carrier.
The tablets, pills, powders, capsules, troches and the like can contain one or more of any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, or methyl salicylate. Capsules can be in the form of a hard capsule or soft capsule, which are generally made from gelatin blends optionally blended with plasticizers, as well as a starch capsule. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents. Other oral dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes, colorings, and flavorings. In addition, the active compounds may be incorporated into fast dissolve, modified-release or sustained-release preparations and formulations, and wherein such sustained-release formulations are preferably bi-modal.
Preferred formulations include pharmaceutical compositions in which a compound of the present invention is formulated for oral or parenteral administration, or more preferably those in which a compound of the present invention is formulated as a tablet. Preferred tablets contain lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc in any combination. It is also an aspect of the present disclosure that a compound of the present invention may be incorporated into a food product or a liquid.
Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. The liquid compositions may also include binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring agents, and the like. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, acrylate copolymers, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include mixtures of alcohols and water, hydrogels, buffered media, and saline. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds. Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
Alternative modes of administration include formulations for inhalation, which include such means as dry powder, aerosol, or drops. They may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for buccal administration include, for example, lozenges or pastilles and may also include a flavored base, such as sucrose or acacia, and other excipients such as glycocholate. Formulations suitable for rectal administration are preferably presented as unit-dose suppositories, with a solid based carrier, such as cocoa butter, and may include a salicylate. Formulations for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include petroleum jelly, lanolin, polyethylene glycols, alcohols, or their combinations. Formulations suitable for transdermal administration can be presented as discrete patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
Alternative administrations include also solutions, ointments or other formulations acceptable for ocular administration.
Other features of the invention will become apparent in the course of the following description of exemplary embodiments that are given for illustration of the invention and not intended to be limiting thereof.
Examples
Melting points are determinated on Buchi capillary melting point apparatus.
Proton NMR spectra are recorded on a Bruker 250 MHz NMR instrument. Deuterochloroform is used as solvent unless otherwise stated. The chemicals shifts δ are expressed in ppm. The following abbreviations are used to denote signal patterns: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, ms = massif. The coupling contents are expressed in Hz. The spectra recorded are consistent with the proposed structures.
TLC are performed on 0.25 mm silica gel F254 plates. Example 1 2-[(1 -methylpiperidin-4-yloxy)phenylmethyl]benzothiazole 1A
A mixture of benzothiazol-2-ylphenylmethanol (0.36g), 4-hydroxy-1 - methylpiperidine (0.17g) and para-toluenesulfonic acid (0.57g) in toluene (22mL) is heated overnight in a Dean-Stark apparatus. The mixture is cooled back to room temperature and poored into water, alcalinised with 1 N sodium hydroxyde and extracted twice with ethyl acetate. Pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 98/2 to 90/10) to give 2-[(1 -methylpiperidin-4- yloxy)phenylmethyl]benzothiazole melting at 1 ~\ 5°C.
1 B
A solution of benzothiazole (1 .35g) in tetrahydrofurane (10ml_) in a dried round bottom baloon is cooled at -70°C. A solution of butyl lithium (4.1 mL) is added and the mixture stirred for 15 minutes. Benzaldehyde (1 .03ml_) diluted with tetrahydrofurane (10ml_) is then added. The mixture is stirred at -70 °C for 1 h, allowed to warm to -20 °C and quenched with saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate. Organic extracts are pooled, dried over magnesium sulfate and concentrated under reduced pressure. Trituration of the residue with diisopropyl oxyde affords benzothiazol-2-ylphenylmethanol.
TLC (heptane/ethyl acetate 1/1 ) Rf = 0.57
Further examples can be prepared according to the described general methods:
General Melting
Example Product
methods point
2-[(1 -methylpyrrolidin-3-yloxy)phenylmethyl]-
2 1A, 1 B 120°C benzothiazole, oxalate
2-[(4-fluorophenyl)(1 -methylpiperidin-4-
3 1A, 1 B 192°C yloxy)methyl]benzothiazole, oxalate
2-[(4-chlorophenyl)(1 -methylpiperidin-4- 147-
4 1A, 1 B
yloxy)methyl]benzothiazole, oxalate 148°C
2-[(3-fluorophenyl)(1 -methylpiperidin-4- 167-
5 1A, 1 B
yloxymethyl]benzothiazole, oxalate 170°C
2-[(2-fluorophenyl)(1 -methylpiperidin-4- 178-
6 1A, 1 B
yloxy)methyl]benzothiazole, oxalate 179°C General Melting
Example Product
methods point
2-[(1 -methylpiperidin-4-yloxy)-p-
7 1A, 1 B 177°C tolylmethyl]benzothiazole, oxalate
2-[(1 -methylpiperidin-4-yloxy)(m-
8 1A, 1 B 177°C tolyl)methyl]benzothiazole, oxalate
2-[(2,3-dihydrobenzo[1 ,4]dioxin-6-yl)(1 -
10 methylpiperidin-4-yloxy)methyl]benzothiazole, 1A, 1 B 71 °C hydrochloride
2-[(3-methoxyphenyl)(1 -methylpiperidin-4-
1 1 1A, 1 B 182°C yloxy)methyl]benzothiazole, hydrochloride
2-[(2,4-difluorophenyl)(1 -methylpiperidin-4-
12 1A, 1 B 182°C yloxy)methyl]benzothiazole, dioxalate
2-[(4-methoxyphenyl)(1 -methylpiperidin-4-
14 1A, 1 B 72 <Ό yloxy)methyl]benzothiazole, dihydrochloride
2-[(3,5-difluorophenyl)(1 -methylpiperidin-4-
15 1A, 1 B 165°C yloxy)methyl]benzothiazole, oxalate
Following compounds are prepared using general methods described in Example 1 :
Figure imgf000053_0001
Example 16
16 A
A mixture of (benzothiazol-2-yl)(thien-3-yl)methanol (0.247g), 4-hydroxy-1 - methylpiperidine (0.1 15g) and para-toluenesulfonic acid (0.27g) in dichloroethane (20ml_) is heated for 4H in a Dean-Stark apparatus. The mixture is concentrated under reduced pressure and the residue taken up in ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 95/5). Salification with oxalic acid in acetone gives -[(1 -methylpiperidin-4-yloxy)thiophen-3- ylmethyl]benzothiazole oxalate melting at 174qC.
16B (benzothiazol-2-yl)(thien-3-yl)methanol is prepared according to general method 1 B.
Example 21
21 A
A solution of [(benzothiazol-2-yl)(m-tolyl)methylene](1 -methylpiperidin-4-yl)amine (0.45g) in methanol (30ml_) containing 10% palladium on charcoal (0.1 g) is stirred under dihydrogene (1 atm) at room temperature for 3h. The suspension is filtered over clarcel and concentrated under reduced pressure. The residue is dissolved in acetone (2ml_) and mixed with a solution of oxalic acid (76mg) in acetone (2ml_). A precipitate forms which is filtered, rinsed with acetonitrile and diethyl ether and dried under vacuum to afford [(benzothiazol-2-yl)(m-tolyl)methyl](1 -methylpiperidin-4-yl)amine dioxalate melting at 127Ό.
21 B
To a solution of (benzothiazol-2-yl)(m-tolyl)methanone (1 .06g) and 4-amino-1 - methylpiperidine (0.456g) in tetrahydrofurane (4ml_) is added titanium tetraisopropoxyde (1 .42g). The mixture is stirred at room temperature for 1 h, then polymethyl hydrosiloxane (1 .2ml_) is added. The mixture is stirred for one day at room temperature, diluted with ethyl acetate (50ml_), hydolysed with 3N sodium hydroxyde (30ml_). The organic phase is separated by decantation, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is cristallised by trituration in diisopropyl oxyde. A second crop can be obtained form the mother liquor by chromatography over silica gel (gradiant dichloromethane / methanol from 98 / 2 to 95 / 5) to give [(benzothiazol-2-yl)(m- tolyl)methylene](1 -methylpiperidin-4-yl)amine meting at ~\ 25°C.
21 C
To a solution of (benzothiazol-2-yl)(m-tolyl)methanol (2.41 g) in dioxane (30ml_) is added manganese dioxyde (1 .2 molar equivalent). The mixture is stirred overnight at room temperature, then filtered over a clarcel pad. The filtrate is concentrated under reduced pressure. The residue is triturated in heptane and diisopropyl oxyde to give (benzothiazol- 2-yl)(m-tolyl)methanone
21 D (benzothiazol-2-yl)(m-tolyl)methanol can be obtained as described in Example
Further examples can be prepared according to the described general methods:
General Melting
Example Product
methods point
2-[(1 -methylpiperidin-4-yloxy)naphthalen-1 -
17 1A, 1 B 106,5°C ylmethyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)naphthalen-2-
18 1A, 1 B 198 <Ό ylmethyl]benzothiazole, dihydrochloride
2-[(1 -methylpiperidin-4-yloxy)(5-methylthiophen-2-
19 16A, 1 B 174Ό yl)methyl]benzothiazole, oxalate
2-[benzo[1 ,3]dioxol-5-yl(1 -methylpiperidin-4-
20 1A, 1 B 1 10 Ό yloxy)methyl]benzothiazole, dihydrochloride
2-[(1 -methylpiperidin-4-yloxy)(4-
24 1A, 1 B 155Ό trifluoromethoxyphenyl)methyl]benzothiazole, oxalate
[benzothiazol-2-yl(3-methoxyphenyl)methyl](1 - 21 A, 21 B,
25 160 <Ό methylpiperidin-4-yl)amine, dioxalate 21 C, 1 B
2-[(3-bromo-phenyl)(1 -methylpiperidin-4-
27 1A, 1 B 99 °C yloxy)methyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)(3-phenoxy-
28 1A, 1 B 92 °C phenyl)methyl]benzothiazole, oxalate
5-methyl-2-[(1 -methylpiperidin-4-
29 1A, 1 B 175Ό yloxy)phenylmethyl]benzothiazole, oxalate
2-[(1 -methylpiperidin-4-yloxy)phenylmethyl]-1 H-
30 1A, 1 B 1 10 Ό benzimidazole
2-[(1 -methylpiperidin-4-yloxy)(3-
31 trifluoromethylphenyl)methyl]benzothiazole, 1A, 1 B 61 °C hydrochloride
2-[(4-fluoro-3-methylphenyl)(1 -methylpiperidin-4-
34 1A, 1 B 120 <Ό yloxy)methyl]benzothiazole, oxalate
[benzothiazol-2-yl(4-fluoro-3-methyl-phenyl)methyl](1 -
35 1A, 1 B 160 Ό methylpiperidin-4-yl)amine, dioxalate General Melting
Example Product
methods point
(benzothiazol-2-yl-p-tolylmethyl)(1 -methylpiperidin-4-
36 1A, 1 B 1 10 Ό yl)amine, oxalate
2-[(3-fluoro-5-methylphenyl)(1 -methylpiperidin-4-
38 1A, 1 B 170 Ό yloxy)methyl]benzothiazole, oxalate
Example 26
To a solution of 2-[(3-allyloxyphenyl)(1 -methylpiperidin-4-yloxy)methyl] benzothiazole example 22 (250mg) in ethanol (10ml_) is added 10% palladium on charcoal (25mg). The mixture is stirred overnight under dihydrogene (1 atm) at room temperature, then filtrated over a clarcel pad. The filtrate is concentrated under reduced pressure to give the crude base which is converted to 2-[(1 -methylpiperidin-4-yloxy)(3- propoxy-phenyl)methyl]benzothiazole, dihydrochloride melting at 59 °C. Following compounds are prepared using general methods described in example
1 :
Figure imgf000056_0001
Example 37
37A
Reduction of [(benzofuran-2-yl)(benzothiazol-2-yl)methylene](1 -methylpiperidin-4- yl)amine as described in example 21A affords [(benzofuran-2-yl)(benzothiazol-2- yl)methyl](1 -methylpiperidin-4-yl)amine oxalate melting at 125°C. 37B
To a solution of (benzofuran-2-yl)(benzothiazol-2-yl)methanone (1 .4g) and 4- amino-1 -methylpiperidine (0.57g) in tetrahydrofurane (8ml_) is added dropwise titanium tetraisopropoxyde (1 .78g). The suspension is stirred for 24h at room temperature, diluted with ethyl acetate and 1 N sodium hydroxyde. The precipitate is filtered over a clarcel pad and rinsed with ethyl acetate. The pooled filtrates are washed with saturated sodium chloride solution, dried and concentrated under reduced pressure. The residue is purified over silica gel (gradiant dichloromethane / methanol from 100 / 0 to 90 / 10) to afford [(benzofuran-2-yl)(benzothiazol-2-yl)methylene](1 -methylpiperidin-4-yl)amine.
37C (benzofuran-2-yl)(benzothiazol-2-yl)methanone can be prepared as described in example 21 C.
37D (benzofuran-2-yl)(benzothiazol-2-yl)methanone can be prepared as described in example 1 B.
Further examples can be prepared according to the described general methods:
Figure imgf000057_0001
Example 42
[benzothiazol-2-yl(3-propoxyphenyl)methyl](1 -methylpiperidin-4-yl)amine
42A
Hydrogenation of [benzothiazol-2-yl(3-propoxyphenyl)methylene](1 -methyl- piperidin-4-yl)amine as described in example 21 A gives [benzothiazol-2-yl(3- propoxyphenyl)methyl](1 -methylpiperidin-4-yl)amine melting at 90 °C.
42 B
Condensation of benzothiazol-2-yl(3-propoxyphenyl)methanone with 4-amino-1 - methylpiperidine as described in example 37B gives [benzothiazol-2-yl(3- propoxyphenyl)methylene](1 -methylpiperidin-4-yl)amine.
42C
A mixture benzothiazol-2-yl(3-propoxyphenyl)methanol (1 g) and barium permanganate (0.95g) in acetonitrile 15mL) is refluxed for 30 minutes. The mixture is filtered over a clarcel pad, concentrated under reduced pressure and purified by column chromatography over silica gel (eluant heptane / ethyl acetate : 4 / 1 ) to give benzothiazol- 2-yl(3-propoxyphenyl)methanone as a white cristalline solid.
42 D
Benzothiazol-2-yl(3-propoxyphenyl)methanol can be prepared as described in example 1 B.
Further examples can be prepared according to the described general methods:
Figure imgf000058_0001
53
A mixture of 2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole (200mg), phenylboronic acid (70mg), palladium acetate (4.8mg) and 1 ,1 - bis(diphenylphosphino)ferrocene is placed in a round-bottom flask and purged with argon. A 1 M aqueous degased solution of potassium carbonate (1 .51 ml.) and degased tetrahydrofuran (2ml_) are introduced. The mixture is heated at 95°C for 30min, cooled back to room temperature and filtered over a celite pad. The cake is rinsed with ethyl acetate and water. The pooled phases are decanted. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (gradient dichloromethane / methanol from 98 / 2 to 90 / 10) to give the crude base which is then converted to the oxalate in acetone to give 2-[biphenyl-3-yl{1 -methylpiperidin-4- yloxy)methyl]benzothiazole, oxalate as a beige amorphous solid.
1 H NMR (DMSO-d6): 8.05 (d, 1 H), 7.91 (d, 1 H), 7.77 (s, 1 H), 7.68-7.58 (m, 3H), 7.55-7.30 (m, 7H), 6.20 (s, 1 H), 3.90-3.78 (m, 1 H), 3.32-2.90 (m, 4H), 2.67 (s, 3H), 2.20- 1 .70 (m, 4H)
Following compounds are prepared analogously:
Example Product
{3'-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxymethyl]biphenyl-3-
54
yljmethanol, oxalate
1 H NMR (DMSO-d6): 8.02 (d, 1 H), 7.87 (d, 1 H), 7.72 (s, 1 H), 7.62-7.35 (m, 8H), 7.27 (d, 1 H), 6.13 (s, 1 H), 4.51 (s, 2H), 3.92-3.80 (m, 1 H), 3.40-2.90 (m, 4H), 2.70 (s, 3H), 2.25- 1 .70 (m, 4H)
2-[(1 -methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]benzothiazole,
63
oxalate
1 H NMR (DMSO-d6): 8.86 (d, 1 H), 8.57 (dd, 1 H), 8.09-8.00 (m, 2H), 7.92 (d, 1 H), 7.84 (s, 1 H), 7.73-7.63 (m, 1 H), 7.58-7.37 (m, 5H), 6.21 (s, 1 H), 3.92-3.78 (m, 1 H), 3.40-2.95 (m, 4H), 2.70 (s, 3H), 2.25-1 .75 (m, 4H)
3'-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine,
79
oxalate
1 H NMR (DMSO-d6): 8.07 (d, 1 H), 7.91 (d, 1 H), 7.66 (s, 1 H), 7.53-7.37 (m, 5H), 7.07 (t, 1 H), 6.78 (s, 1 H), 6.71 (d, 1 H), 6.54 (d, 1 H), 6.18 (s, 1 H), 4.20-3.70 (m, 5H), 3.42-2.95 (m, 4H), 2.70 (s, 3H), 2.25-1 .75 (m, 4H)
81 2-[biphenyl-3-yl(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
1 H NMR : 12.38 (si, 1 H), 7.78 (s, 1 H), 7.65-7.40 (m, 10H), 7.15-7.05 (m, 2H), 5.91 (s, 1 H), 3.50-3.35 (m, 1 H), 2.68-2.50 (m, 2H), 2.10 (s, 3H), 2.05-1 .84 (m, 4H), 1 .70-1 .50 (m, 2H)
{3'-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]biphenyl-3-
86
yljmethanol 1H NMR (DMSO-d6): 12.37 (si, 1H), 7.77 (s, 1H), 7.62-7.35 (m, 8H), 7.28 (d, 1H), 7.15- 7.02 (m, 2H), 5.92 (s, 1H), 5.22 (t, 1H), 4.53 (d, 2H), 3.48-3.32 (m, 1H), 2.68-2.50 (m, 2H), 2.08 (s, 3H), 2.00-1.78 (m, 4H), 1.69-1.48 (m, 2H)
87 3'-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]bip enyl-3-ylamine
1H NM =t: 9.57 (si, 1H), 7.82-8.68 (m, 1H), 7.67 (s, 1H), 7.55-7.35 (m, 4H), 7.30-7.15 (m, 3H), 6.' 94 (d, 1 H), 6.85 (s, 1 H), 6.67 (d, 1 H), 5.92 (s, 1 H), 3.85-3.50 (m, 3H), 2.80-2.75 (m, 2H), 2.; 11 (s, 3H), 2.25-1.65 (m, 6H)
89 2-[(1-met ylpiperidin-4-yloxy)(3-pyridin-3-ylp enyl)met yl]-1 /-/-benzimidazole
1H NMR: 9.62 (si, 1H), 8.80 (d, 1H), 8.58 (dd, 1H), 7.83 (d, 1H), 7.80-7.65 (m, 2H), 7.55- 7.20 (m, 7H), 5.96 (s, 1H), 3.70-3.55 (m, 1H), 2.85-2.70 (m, 2H), 2.30 (s, 3H), 2.25-1.65 (m, 6H)
96 2-[(2'-met oxybip enyl-3-yl)(1-rTiet ylpiperidin-4-yloxy)met yl]benzot iazole
1H NM =t: 8.02 (d, 1H), 7.88 (d, 1H), 7.74 (s, 1H), 7.55-7.25 (m, 7H), 7.08-6.95 (m, 2H), 5.99 (s , 1H), 3.77 (s, 3H), 3.75-3.65 (m, 1H), 2.82-2.68 (m, 2H), 2.29 (s, 3H), 2.29-2.15
(m, 2H) , 2.10-1.80 (m, 4H)
97 2-[(1-met ylpiperidin-4-yloxy)(3'-nitrobip enyl-3-yl)met yl]benzot iazole
1H NM =t: 8.45 (d, 1H), 8.22 (d, 1H), 7.99 (d, 1H), 7.95-7.85 (m, 2H), 7.80 (s, 1H), 7.65- 7.35 (rr l, 6H), 6.00 (s, 1H), 3.80-3.65 (m, 1H), 2.88-2.70 (m, 2H), 2.42-2.25 (m, 2H), 2.34 (s, 3H) 2.10-1.70 (m, 4H)
99 2-[(3,-met oxybip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
1H NMR: 7.98 (d, 1H), 7.86 (d, 1H), 7.74 (s, 1H), 7.68-7.30 (m, 6H), 7.17 (d, 1H), 7.10 (d, 1H), 6.92 (d, 1H), 5.96 (s, 1H), 3.92-3.78 (m, 1H), 3.86 (s, 3H), 3.05-2.85 (m, 2H), 2.85- 2.55 (m, 2H), 2.50 (s, 3H), 2.35-2.12 (m, 2H), 2.12-1.85 (m, 2H)
2-[(4,-met oxybip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole,
100
oxalate
1H NMR: 8.06 (d, 1H), 7.91 (d, 1H), 7.71 (s, 1H), 7.50-7.30 (m, 7H), 7.02 (d, 2H), 6.18 (s, 1H), 3.92-3.78 (m, 1H), 3.77 (s, 3H), 3.45-2.90 (m, 4H), 2.70 (s, 3H), 2.12-1.72(m, 4H)
2-[(1-met ylpiperidin-4-yloxy)(3'-met ylsulfanylbip enyl-3-
128
yl)methyl]benzothiazole, oxalate
1H NMR (DMSO d6): 8.07 (d, 1H), 7.92 (d, 1H), 7.78 (s, 1H), 7.62 (si, 1H), 7.55-7.32 (m, 7H), 7.27 (si, 1 H), 6.20 (s, 1 H), 3.45-3.30 (m, 1 H), 3.30-2.82 (m, 4H), 2.67 (s, 3H), 2.47 (s, 3H), 2.25-1.75 (m, 4H) 133 2-[(3\4'-dichlorobiphenyl-3-yl)(1 -methylpiperidin-4-yloxy)metriyl]benzotriiazole
1 H NMR: 7.98 (d, 1 H), 7.88 (d, 1 H), 7.70 (s, 1 H), 7.66 (d, 1 H), 7.52-7.35 (m, 7H), 5.97 (s, 1 H), 3.82-3.68 (m, 1 H), 2.95-2.78 (m, 2H), 2.55-2.40 (m, 2H), 2.40 (s, 3H), 2.20-1 .80 (m, 4H)
136 I 2-[(4'-fluorobiphenyl-3-yl)(1 -metriylpiperidin-4-yloxy)metriyl]benzotriiazole ~ 1 H NMR: 7.98 (d, 1 H), 7.86 (d, 1 H), 7.71 (s, 1 H), 7.68-7.30 (m, 7H), 7.15 (d, 1 H), 7.10 (d, 1 H), 5.98 (s, 1 H), 3.80-3.63 (m, 1 H), 2.88-2.72 (m, 2H), 2.42-2.25 (m, 2H), 2.34 (s, 3H),
.75 (m, 4H)
137 2-[(2'-fluorobiphenyl-3-yl)(1 -metriylpiperidin-4-yloxy)metriyl]benzotriiazole
1 H NMR: 7.99 (d, 1 H), 7.88 (d, 1 H), 7.75 (s, 1 H), 7.50-7.10 (m, 9H), 5.98 (s, 1 H), 3.82- 3.75 (m, 1 H), 2.88-2.70 (m, 2H), 2.33 (s 3H), 2.40-2.20 (m, 2H), 2.12-1 .85 (m, 4H)
72 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole 72A
A mixture of 1 H-benzimidazol-2-yl(3-bromophenyl)methanol (12.9g), 4-hydroxy-1 - methylpiperidine (4.86g) and para-toluenesulfonic acid (24g) in chlorobenzene (60ml_) and A/-methylpyrrolidone (6m L) is heated under reflux for 120h in a Dean Stark apparatus. Solvent is removed by evaporation. To the residue is added water which is made alcaline by addition of sodium hydroxyde solution, then extracted with ethyl acetate. The pooled organic extracts are washed with water, treated with activated charcoal, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated in diethyl ether to give 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 - - benzimidazole. 72B
A mixture of (3-bromophenyl)hydroxyacetic acid (20g) and ortho- phenylenediamine (9.36g) in 5N aqueous hydrochloric solution (100ml_) is heated under reflux for 4h and cooled back to room temperature. The precipitate is separated by filtration, rinsed with acetonitrile and dried under vacuum with phosphorus pentoxyde et give 1 H-benzimidazol-2-yl(3-bromophenyl)methanol as a white crystalline solid used without further purification.
72C
To a solution of 3-bromobenzaldehyde (18.5g) in tetrahydrofuran (400ml_) is added trimethylsilylcyanide (10.9g). Two drops of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to the reaction mixture (a small exotherm is observed). After one hour at room temperature, solvent and volatiles are removed under reduced pressure. To the residual oil is added 6N aqueous hydrochloric acid (100ml_). The round-bottom flask is equipped with a Dean-Stark apparatus and the reaction mixture is heated to reflux for 3 hours while removing silanols.
The reaction mixture is cooled to 0°C and a 10N sodium hydroxide solution is added dropwise to reach pH 1 . The aqueous phase is extracted with ethyl acetate. The pooled organic phases are washed with brine; dried on magnesium sulphate and concentrated to dryness under reduced pressure. The residual solid is re-crystallized from hot toluene to give (3-bromophenyl)hydroxyacetic acid.
1 H NMR (DMSO-d6): 7.57 (t, 1 H), (d, 1 H), 7.45 (dt, 1 H), 7.38 (s, 1 H), 7.28 (t, 1 H), 5.03 (s, 1 H).
Following compounds are prepared using general methods 21 A and 21 B:
Figure imgf000062_0001
Example 56 : [benzothiazol-2-yl(3-propoxyphenyl)methyl](1 -methylpiperidin-4- yl)amine enantiomer A
A solution of racemic [benzothiazol-2-yl(3-propoxyphenyl)methyl](1 - methylpiperidin-4-yl)amine (10mg/ml_) in a mixture of heptane / isopropanol (80 / 20) containing diethylamine (0.1 %) is injected (20x100μΙ_) onto an analytical Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (80 / 20) containing diethylamine (0.1 %) at a flow of 1 mL/min. Products are detected at 220nm.
The first enantiomer has a retention time of 6.7min.
Collection affords [benzothiazol-2-yl(3-propoxyphenyl)methyl](1 -methylpiperidin-4- yl)amine enantiomer A with a chromatographic enantiomeric purity of 92.6%.
Example 57 : [benzothiazol-2-yl(3-propoxyphenyl)methyl](1 -methylpiperidin-4- yl)amine enantiomer B
The second enantiomer has a retention time of 8.2min. Collection affords [benzothiazol-2-yl(3-propoxyphenyl)methyl](1 -methylpiperidin-4- yl)amine enantiomer B with a chromatographic enantiomeric purity of 98.8%.
Example 59 : [(1 H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1 - methylpiperidin-4-yl)amine
59A
To a solution of (1 --benzimidazol-2-ylmethylene)(1 -methylpiperidin-4-yl)amine (70mg) in tetrahydrofurane (3ml_) is added a 1 .5M solution of 3-trifluoro- methylphenylmagnesium bromide in tetrahydrofurane (0.77ml_) at room temperature. The mixture is then stirred at 40°C for 1 h, hydrolyzed with water and extracted with ethyl acetate. The pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0.5 to 90 / 10 / 0.5) to give [(1 - -benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1 -methylpiperidin- 4-yl)amine as a yellow solid melting at 90 °C.
59 B
1 /-/-Benzimidazole-2-carboxaldehyde (781 mg, can be prepared according to Fegy, K. Angewandte Chemie Int Ed, 1998, vol. 37, 1270-1273), 4-amino-1 -methylpiperidine (781 mg) and 4A molecular sieves (15g) in ethanol (1 OOmL) are heated under reflux for 4h. The mixture is then filtered and the filtrate concentrated under reduced pressure to yield (1 - -benzimidazol-2-ylmethylene)(1 -methylpiperidin-4-yl)amine as a beige solid.
62
To a solution of 2-[(3-allyloxyphenyl)(1 -methylpiperidin-4-yloxy)methyl] benzothiazole (example 22) (2.35g) in tetrahydrofurane (40ml_) is added tetrakistriphenylphosphinepalladium (0.344g). The mixture is stirred for 5 min at room temperature, then sodium borohydride (0.576g) is added. The mixture is stirred for 20h at room temperature, filtered over a clarcel pad. The pad is rinsed with ethyl acetate. Pooled organic phases are washed with aqueous ammonium chloride solution, then sodium hydrogenocarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by three column chromatographies over silica gel (twice gradiant heptane / ethyl acetate from 95 / 5 to 80 / 20, third eluant heptane / dichloromethane 5 / 1 ). Pooled fractions are concentrated under reduced pressure. The residue is dissolved in methanol, refluxed for 5h and concentrated under reduced pressure. The residue is purified by column chromatography (gradiant dichloromethane / methanol / ammonia from 100 / 0 to 90 / 10 / 1 ) to give 3-[benzothiazol-2-yl(1 - methylpiperidin-4-yloxy)methyl]phenol as a beige solid melting at 201 °C.
* in the case of ketone-containing substituents, it is judicious to protect the carbonyl function (as an acetal for example) prior to the Grignard preparation
Example 91
91 A
A mixture of 4-amino-1 -methylpiperidine (0.23g), benzothiazol-2-yl(3- butoxyphenyl)methanol (0.63g), sodium hydrogenocarbonate (2mg) and dichloro(pentamethylcyclopentadienyl)iridium(lll) dimer (8mg) in toluene (3ml_) is heated in an autoclave at 1 10-120°C for 66 hours. The mixture is purified by chromatography over silica gel (eluant dichloromethane / methanol : 98 / 2) to give the crude base, which is transformed to the oxalate in acetone to give [benzothiazol-2-yl(3-butoxyphenyl)methyl](1 - methylpiperidin-4-yl)amine oxalate melting at M6°C.
91 B
Benzothiazol-2-yl(3-butoxyphenyl)methanol can be obtained as described in example 1 B.
Example 168
168A
2-[(1 -methylpiperidin-4-yloxy)(3-pent-4-enyloxy-phenyl)methyl]benzothiazole, oxalate can be prepared as described in example 1A starting from benzothiazol-2-yl(3- pent-4-enyloxy-phenyl)methanol to get an orange solid melting at 75°C.
168B
Benzothiazol-2-yl(3-pent-4-enyloxy-phenyl)methanol can be prepared as follows: to a 1 M solution of 3-pent-4-enyloxy-phenylmagnesium bromide in tetrahydrofurane (2.2ml_) diluted with the same solvent (6ml_) cooled at -50°C is added benzothiazole-2- carboxaldehyde (326mg). After stirring at -50°C for 1 h, the mixture is allowed to warm at room temperature, then hydrolyzed with aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient heptane / ethyl acetate from 4 / 1 to 2 / 1 ) to give benzothiazol- 2-yl(3-pent-4-enyloxy-phenyl)methanol as a yellow oil. 272
2-[(1 -methylpyrrolidin-3-yloxy)phenyl-methyl]-1 H-benzimidazole
272A A mixture of (1 - -benzimidazol-2-yl)phenylmethanol (61 1 mg) and 1 -methyl-3- pyrrolidinol (263mg) in methanesulfonic acid (1 .3ml_) is heated for 4 hours in a sealed tube at a temperature close to 140°C. The mixture is cooled back to room temperature, poored into water which is then made alkaline with concentrated sodium hydroxyde solution. The aqueous phase is extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate, concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to give 2-[(1 -methylpyrrolidin-3-yloxy)phenyl-methyl]-1 H-benzimidazole melting at 53 °C.
For the other examples prepared according this general procedure, it can be a good idea to rise the temperature progressively after having mixed the different reagents and to observe when etherification occurs. Once the right temperature has been found, reaction is continued up to adequate conversion.
272B
To a solution of 1 -pyrrolidin-1 -ylmethyl-1 H-benzimidazole (5g) in tetrahydrofurane (20ml_) cooled at a temperature close to -80 °C, is added a 2.5M solution of butyl lithium in hexanes (10ml_). The mixture is stirred for 15 minutes. A solution of benzaldehyde (2.64g) in tetrahydrofurane (20ml_) is added. The mixture is stirred at a temperature close to -80 °C for 1 hour, then at a temperature close to -20 °C for 2 hours. The reaction is quenched by addition of saturated ammonium chloride. The mixture is extracted with ethyl acetate. Pooled extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to give (1 H- benzimidazol-2-yl)phenylmethanol used without further purification.
1 -Pyrrolidin-1 -ylmethyl-1 H-benzimidazole can be prepared as described by Katritzky, Alan R.; Asian, Diana C; Leeming, Peter; Steel, Peter J. Tetrahedron: Asymmetry, 1997, 8, p. 1491 - 1500.
Example 370
370A
A mixture of 2-[3-(2-chloroethoxy)phenyl](1 -methylpiperidin-4-yloxy)methyl]- benzothiazole (625mg), potassium iodide (332mg), glycine ferf-butyl ester, hydrochloride (503mg) in triethylamine (630μΙ_) and A/,A/-dimethylformamide (20ml_) is heated overnight in a sealed tube at 70 °C, then for 16h at 90-100 °C. The mixture is cooled back to room temperature, poured into crushed ice and concentrated sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. The pooled organic phases are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 90 / 10 / 1 ). The crude base is converted into its salt in acetone to give (2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)acetic acid ferf-butyl ester, dioxalate melting at 136°C.
370B
2- [3-(2-chloroethoxy)phenyl](1 -methylpiperidin-4-yloxy)methyl]benzothiazole can be obtained as described in example 272A. 370C
benzothiazol-2-yl[3-(2-chloroethoxy)phenyl]methanol can be obtained as described in example 1 B.
Example 371
371 A
A mixture of 2-[[3-(5-azidopentyloxy)phenyl](1 -methyl-piperidin-4-yloxy)methyl] benzothiazole (0.13g) and triphenylphosphine (0.1 1 g) in a mixture of tetrahydrofurane (3ml_) and water (2 drops) is heated at 70°C overnight. Solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and 0.5N hydrochloric solution. The aqueous phase is washed with ethyl acetate, made alkaline with concentrated sodium hydroxide solution and extracted with ethyl acetate. The pooled extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 to 90 / 10 1 ) and salified with oxalic acid to give 5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenoxy} pentylamine, oxalate melting at 141 °C.
371 B
A mixture of 2-[[3-(5-chloropentyloxy)phenyl](1 -methyl-piperidin-4-yloxy)- methyl]benzothiazole (200mg) and sodium azide (85mg) in dimethylsulfoxyde (3ml_) is heated overnight at 70 °C, then cooled back to room temperature. Water is added and the product is extracted with ethyl acetate. Pooled extracts are washed with water, then brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2-[[3-(5- azidopentyloxy)phenyl](1 -methyl-piperidin-4-yloxy)methyl]benzothiazole used without further purification.
371 C
2-[[3-(5-chloropentyloxy)phenyl](1 -methyl-piperidin-4-yloxy)methyl]benzothiazole can be prepared according to the procedures described in examples 272A and 1 B.
Further examples can be prepared according to the described general methods:
General Melting
Example Product
methods point
2-[(3-isopropoxyphenyl)(1 -methylpiperidin-4-
55 1 A, 1 B 68 °C yloxy)methyl]benzothiazole, oxalate
[benzothiazol-2-yl(1 H-pyrrol-2-yl)methyl](1 - 21 A, 21 B,
58 125 <Ό methylpiperidin-4-yl)amine 42C, 1 B
[(1 H-benzimidazol-2-yl)(3-trifluoromethoxyphenyl)-
60 59A, 59 B 82 °C methyl](1 -methylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3-ethylphenyl)methyl](1 -
61 59A, 59 B 76 °C methylpiperidin-4-yl)amine
[(1 /-/-benzimidazol-2-yl)(3-benzyloxyphenyl)-
65 59A, 59 B 78 °C methyl](1 -methylpiperidin-4-yl)amine
[(1 /-/-benzimidazol-2-yl)(3-isopropylphenyl)-
66 59A, 59 B 82 °C methyl](1 -methylpiperidin-4-yl)amine
[(1 /-/-benzimidazol-2-yl)(3-isobutoxyphenyl)-
67 59A, 59 B 99 °C methyl](1 -methylpiperidin-4-yl)amine
{(1 H-benzimidazol-2-yl)[3-(3-methylbutoxy)-
68 59A, 59 B 70 °C phenyl]methyl}(1 -methylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3-butoxyphenyl)methyl](1 -
69 59A, 59 B 137Ό methylpiperidin-4-yl)amine, oxalate
[(1 /- -benzimidazol-2-yl)(3-methoxyphenyl)-
70 59A, 59 B 182 <Ό methyl](1 -methylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3-cyclohexylmethoxy-
73 59A, 59 B 88 °C phenyl)methyl](1 -methylpiperidin-4-yl)amine [(1 --benzimidazol-2-yl)(3-fluorop enyl)met yl](1 -
59A, 59 B 155Ό methylpiperidin-4-yl)amine, oxalate
[(1 H-benzimidazol-2-yl)(3-met ylsulfanylphenyl)-
59A, 59 B 166Ό met yl](1-met ylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3- exylp enyl)met yl](1 -
59A, 59 B 115Ό methylpiperidin-4-yl)amine, oxalate
[(1H-benzimidazol-2-yl)(3-isopropoxyphenyl)-
59A, 59 B 75 °C met yl](1-met ylpiperidin-4-yl)amine
[(1 --benzimidazol-2-yl)(3-et oxyp enyl)met yl](1 -
59A, 59 B 74 °C met ylpiperidin-4-yl)amine
[(1 --benzimidazol-2-yl)(m-tolyl)methyl](1 -
59A, 59 B 132^0 methylpiperidin-4-yl)amine, oxalate
[(1 --benzimidazol-2-yl)(3-p enoxyp enyl)-
59A, 59 B 1 4Ό methyl](1 -methylpiperidin-4-yl)amine, oxalate
21 A, 21 B,
[benzothiazol-2-yl(3-isopropoxyphenyl)methyl](1- 21C, 1B 96 °C methylpiperidin-4-yl)amine, oxalate
168B
1 -{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- 59A, 59 B ylamino)met yl]phenyl}et anone * 198 <Ό
2-[(3-butoxyphenyl)(1-methylpiperidin-4-
1A, 1B 135 <Ό yloxy)methyl]benzothiazole, oxalate
21A, 37B,
[benzot iazol-2-yl(3-cyclo exylmet oxyp enyl)- 42C, 1 B 98 °C methyl](1 -methylpiperidin-4-yl)amine, oxalate
168B
[(1 H-benzimidazol-2-yl)bip enyl-3-ylmet yl](1 -
59A, 59 B 98 °C met ylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-pentyloxyphenyl)-
59A, 59 B 128Ό methyl](1 -methylpiperidin-4-yl)amine, oxalate
21A, 37B,
(benzot iazol-2-ylbip enyl-3-ylmet yl)(1- 21C, 1B
methylpiperidin-4-yl)amine, oxalate
168B
{(1 --benzimidazol-2-yl)[3-(4-fluorobenzyloxy)- phenyl]met yl}(1-met ylpiperidin-4-yl)amine, 59A, 59 B 140Ό oxalate [(1 /-/-benzimidazol-2-yl)(3-benzylsulfanylphenyl)-
104 59A, 59 B 127 <Ό methyl](1 -methylpiperidin-4-yl)amine, oxalate
{(1 H-benzimidazol-2-yl)[3-(3-
105 fluorobenzyloxy)phenyl]methyl}(1 -methylpiperidin-4- 59A, 59 B 1 16Ό yl)amine, oxalate
{(1 /-/-benzimidazol-2-yl)[3-(2-phenoxyethoxy)-
106 phenyl]met yl}(1 -met ylpiperidin-4-yl)amine, 59A, 59 B 140 <Ό oxalate
[benzothiazol-2-yl(3-benzylsulfanylphenyl)- 91A
107 50 °C methyl](1 -methylpiperidin-4-yl)amine, oxalate 168B
1 -{3'-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-
108 53 1 15Ό yloxy)methyl]biphenyl-4-yl}ethanone, dioxalate
2-[(3'-fluoro-biphenyl-3-yl)(1 -methylpiperidin-4-
109 53 120 Ό yloxy)methyl]-1 - -benzimidazole, dioxalate
1 -{3'-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-
1 10 53 140 Ό yloxy)methyl]biphenyl-3-yl}ethanone, dioxalate
[benzothiazol-2-yl(3-methylsulfanylphenyl)- 91A
1 1 1 85 °C methyl](1 -methylpiperidin-4-yl)amine, oxalate 168B
[(3-allyloxyp enyl)(1 /-/-benzimidazol-2-yl)met yl](1 -
1 12 59A, 59 B 125^0 methylpiperidin-4-yl)amine, oxalate
{(1 /-/-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)-
1 13 phenyl]methyl}(1 -methylpiperidin-4-yl)amine, 59A, 59 B 1 18Ό oxalate
2-[(1 -methylpiperidin-4-yloxy)(2'-methylsulfanyl-
1 14 53 163 ^0 bip enyl-3-yl)met yl]-1 /-/-benzimidazole
2-[(4'-fluorobiphenyl-3-yl)(1 -methylpiperidin-4-
1 15 53 100 Ό yloxy)methyl]-1 /-/-benzimidazole, oxalate
2-[(1 -methylpiperidin-4-yloxy)(3'-methylsulfanyl-
1 16 53 80 °C biphenyl-3-yl)methyl]-1 /-/-benzimidazole, dioxalate
2-[(1 -methylpiperidin-4-yloxy)(4'-trifluoromethyl-
1 19 53 95 °C bip enyl-3-yl)met yl]-1 /-/-benzimidazole
{(1 H-benzimidazol-2-yl)[3-(tetrahydropyran-2-
120 59A, 59 B 97 °C yloxy)p enyl]met yl}(1 -met ylpiperidin-4-yl)amine
2-[(2'-Chlorobiphenyl-3-yl)(1 -methylpiperidin-4-
121 53 130 Ό yloxy)methyl]-1 /-/-benzimidazole, oxalate 2-[(3',4'-dichlorobiphenyl-3-yl)(1 -methylpiperidin-4-
122 53 150 <Ό yloxy)methyl]-1 /-/-benzimidazole, oxalate
{3'-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-
123 53 107<Ό yloxy)met yl]bip enyl-2-yl}met anol
{( y--benzimidazol-2-yl)[3-(4-met oxybenzyloxy)-
124 59A, 59 B 84 °C phenyl]met yl}(1-met ylpiperidin-4-yl)amine
{(1 /-/-benzimidazol-2-yl)[3-(3-methoxybenzyloxy)-
125 phenyl]met yl}(1-met ylpiperidin-4-yl)amine, 59A, 59 B 135 <Ό oxalate
{3'-[benzot iazol-2-yl(1-met ylpiperidin-4- 206-
127 53
yloxy)methyl]biphenyl-2-yl}methanol, oxalate 207 <Ό
{(1 /-/-benzimidazol-2-yl)[3-(2-methylbenzyloxy)-
129 phenyl]met yl}(1-met ylpiperidin-4-yl)amine, 59A, 59 B 121 °C oxalate
{(1 /-/-benzimidazol-2-yl)[3-(4-methylbenzyloxy)-
130 59A, 59 B 87 °C phenyl]met yl}(1-met ylpiperidin-4-yl)amine
[(3-azidophenyl)(1 --benzimidazol-2-yl)methyl](1 - 131, 231A,
132 202 <Ό met ylpiperidin-4-yl)amine 231 B
{3'-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-
138 yloxy)methyl]biphenyl-4-yl}carbamic acid ferf-butyl 53 135 <Ό ester
2-[(2'-fluorobip enyl-3-yl)(1 -met ylpiperidin-4-
142 53 90 °C yloxy)met yl]-1 --benzimidazole
[(1/-/-benzimidazol-2-yl)(3-furan-2-
144 59A, 59 B 108 <Ό ylphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1/-/-benzimidazol-2-yl)(3-but-3-enyloxyphenyl)-
145 59A, 59 B 71 °C methyl](1-methylpiperidin-4-yl)amine
{(1 H-benzimidazol-2-yl)[3-(4-methylpentyloxy)-
146 59A, 59 B 73 °C phenyl]methyl}(1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(2,5-difluoro-
149 benzyloxy)phenyl]methyl}(1-methylpiperidin-4- 59A, 59 B 159 <Ό yl)amine, oxalate
2-[(2-chlorophenyl)(1-methylpiperidin-4-
151 72A, 72 B 212<Ό yloxy)met yl]-1 /-/-benzimidazole 2-[(3-ethylphenyl)(1-methylpiperidin-4-
1A, 168B 123 <Ό yloxy)methyl]benzothiazole, oxalate
2-[(3-fluorophenyl)(1-methylpiperidin-4- 72A, 72B,
93 °C yloxy)met yl]-1 /-/-benzimidazole 72C
2-[[3-(2,3-difluorobenzyloxy)phenyl](1- met ylpiperidin-4-yloxy)met yl]benzot iazole, 1A, 168B 98 °C oxalate
{(1H-benzimidazol-2-yl)[3-(2,3-difluoro- benzyloxy)phenyl]methyl}(1-methylpiperidin-4- 59A, 59 B 151Ό yl)amine
2-[[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-
1A, 168B 147Ό yloxy)methyl]benzothiazole, oxalate
2-[(1 -met ylpiperidin-4-yloxy)(m-tolyl)met yl]-1 H- 72A, 72B,
119Ό benzimidazole 72C
5-fluoro-2-[(1-methylpiperidin-4-
165 134Ό yloxy)p enylmet yl]-1 --benzimidazole
2-[(2-fluorophenyl)(1-methylpiperidin-4- 72A, 72B,
181 °C yloxy)met yl]-1 /-/-benzimidazole 72C
2-{(1-methylpiperidin-4-yloxy)[3-(4,4,4-trifluoro-
1A, 168B 115Ό butoxy)phenyl]methyl}benzothiazole, oxalate
5-bromo-2-[(1-methylpiperidin-4-
165 143^0 yloxy)p enylmet yl]-1 /-/-benzimidazole
2-[[3-(3-fluorobenzyloxy)phenyl](1-methylpiperidin-
1A, 168B 65 °C 4-yloxy)methyl]benzothiazole, oxalate
((1H-benzimidazol-2-yl)-{3-[3-(2-methyl-
59A, 59 B
[1 ,3]dioxolan-2-yl)-propoxy]phenyl}methyl)(1 - * 120 <Ό methylpiperidin-4-yl)amine, oxalate
{(1/-/-benzimidazol-2-yl)[3-(4,4,4-trifluoro-
59A, 59 B 94 °C butoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
2-[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-
1A, 1B 72 °C yloxy)methyl]benzothiazole, oxalate
2-[(1 -methylpiperidin-4-yloxy)-p-tolyl-methyl]-1 H- 72A, 72B,
102^0 benzimidazole 72C 2-[(4-fluorophenyl)(1-methylpiperidin-4- 72A, 72B,
131 °C yloxy)met yl]-1 --benzimidazole 72C
{(1/-/-benzimidazol-2-yl)[3-(2-fluoro- et oxy)p enyl]met yl}(1-met ylpiperidin-4-yl)amine, 59A, 59 B oxalate
((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl- bicyclo[3.1.1]hept-2-en-2-
59A, 59 B 123^ yl)ethoxy]phenyl}methyl)(1-methylpiperidin-4- yl)amine, oxalate
2-[(1-methylpiperidin-4-yloxy)(4'-trifluoro-
53 90 °C met oxybip enyl-3-yl)met yl]-1 /-/-benzimidazole
2-[(4'-methoxybiphenyl-3-yl)(1-methylpiperidin-4-
53 92 °C yloxy)met yl]-1 /-/-benzimidazole
2-[(3-benzo[1 ,3]dioxol-5-ylphenyl)(1 -methyl-
53 95 °C piperidin-4-yloxy)met yl]-1 /-/-benzimidazole
2-[[3-(3-methoxybenzyloxy)phenyl](1-methyl-
1A, 168B 77 °C piperidin-4-yloxy)methyl]benzothiazole, oxalate
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
1A, 168B, * 72 °C yloxy)methyl]phenoxy}pentan-2-one, oxalate
2-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl-
1A, 168B 80 °C benzyloxy)phenyl]methyl}benzothiazole, oxalate
3-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- 117-
189
yloxy)methyl]phenyl}prop-2-yn-1-ol 120^
4-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- 104-
189
yloxy)methyl]phenyl}but-3-yn-1-ol ΙΟδ'Ό
5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
189 85 °C yloxy)met yl]phenyl}pent-4-yn-1-ol
2-[(1 -met ylpiperidin-4-yloxy)-o-tolyl-met yl]-1 H- 72A, 72B, benzimidazole 72C
3-[benzothiazol-2-yl(1-methylpiperidin-4-
72A, 1 B 75 °C yloxy)methyl]benzonitrile, oxalate
2-[(4-bromophenyl)(1-methylpiperidin-4- 72A, 72B,
122^0 yloxy)met yl]-1 /-/-benzimidazole 72C 2-[(2-chloro-4-methylphenyl)(1 -methylpiperidin-4-
213 72A, 272B 96 °C yloxy)methyl]-1 H-benzimidazole, oxalate
5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
214 53 170 ^0 yloxy)met yl]phenyl}pyrimidin-2-ol
2-[(1 -met ylpiperidin-4-yloxy)(3-pyrimidin-5-yl-
216 53 85 °C phenyl)met yl]benzot iazole
2-[(1 -methylpiperidin-4-yloxy)(3-vinyl-
218 217 165Ό phenyl)met yl]benzot iazole
3-[benzothiazol-2-yl(1 -methylpiperidin-4-
220 219 60 °C yloxy)methyl]-A/-propylbenzamide
2-[(2,4-difluorophenyl)(1 -methylpiperidin-4-
221 72A, 272B 106 <Ό yloxy)methyl]-1 H-benzimidazole, oxalate
21A, 37B,
[(1 H-benzimidazol-2-yl)(4'-methoxy-biphenyl-3-
222 21 1 B, 42C, 1 10 Ό yl)met yl](1 -met ylpiperidin-4-yl)amine
272B
3-[benzothiazol-2-yl(1 -methylpiperidin-4-
223 yloxy)met yl]-A/-met yl-A/-phenylbenzamide, 219 125^0 oxalate
2-[(3-chlorophenyl)(1 -methylpiperidin-4-
225 72A, 272B 158Ό yloxy)methyl]-1 H-benzimidazole, oxalate
2-[(4-chlorophenyl)(1 -methylpiperidin-4-
226 72A, 272B 175Ό yloxy)methyl]-1 H-benzimidazole, oxalate
3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
235 150 80 °C yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1 -ol
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
242 yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1 -ol, 148 80 °C oxalate
2-[(1 -methylpiperidin-4-yloxy)(3-morpholin-4-yl-
243 234 1 1 1 °C phenyl)methyl]benzothiazole, oxalate
2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
244 234 45 °C yloxy)methyl]phenoxy}ethanol, oxalate
3-{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
246 150 97-99 °C yloxy)methyl]phenylsulfanyl}propan-1 -ol 1 -{3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4- 120-
150
yloxy)methyl]phenylsulfanyl}propan-2-ol 122 ^0
2-{(1 -methylpiperidin-4-yloxy)[3-(2-methylsulfanyl-
272A, 1 B 89 °C ethoxy)phenyl]methyl}benzothiazole, oxalate
2-[(1 -methylpiperidin-4-yloxy)(2-trifluoromethoxy-
72A, 272B 193 <Ό phenyl)met yl]-1 H-benzimidazole
2-[(3-bromo-4-methylphenyl)(1 -methylpiperidin-4-
72A, 272B 92 °C yloxy)met yl]-1 H-benzimidazole
2-[(2-bromophenyl)(1 -methylpiperidin-4-
72A, 272B 213 Ό yloxy)methyl]-1 H-benzimidazole
2-{(1 -methylpiperidin-4-yloxy)[3-(pyridin-4-
258 101 °C ylmethoxy)phenyl]methyl}benzothiazole, oxalate
4-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
258 63 °C yloxy)methyl]phenoxy}butan-1 -ol, oxalate
2-[[3-(furan-2-ylmethoxy)phenyl](1 - methylpiperidin-4-yloxy)methyl]benzothiazole, 258 85 °C oxalate
2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
249, 149A 80 °C yloxy)methyl]phenylsulfanyl}ethylamine, dioxalate
2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- 371 A, 371 B,
76 °C yloxy)met yl]phenoxy}et ylamine 272A, 1 B
[(1 H-benzimidazol-2-yl)-p-tolyl-methyl](1 -
59A, 59C 183 Ό met ylpiperidin-4-yl)amine
2-[(3-ethylsulfanyl-4-methylphenyl)(1 -
148, 272A, met ylpiperidin-4-yloxy)met yl]-1 H- ■\ 42°C
272B
benzimidazole, oxalate
2-[[3-(2-methoxyethoxy)phenyl](1 -methylpiperidin-
1A.1 B 80 °C 4-yloxy)methyl]benzothiazole, oxalate
(2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)met yl]phenoxy}et yl)met yl-amine, 258 125^0 dioxalate
2-[(1 -methylpiperidin-4-yloxy)(3-trifluoromethoxy-
272A, 272B 172 Ό phenyl)methyl]-1 H-benzimidazole, oxalate
2-[(2-Chlorophenyl)(1 -methylpiperidin-4- 272A, 1 B 163 ^0 yloxy)methyl]benzothiazole, oxalate
2-{(1 -met ylpiperidin-4-yloxy)[3-(pyridin-2-
283 272A, 1 B 158Ό ylmethoxy)phenyl]methyl}benzothiazole, oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(pyridin-3-
284 272A, 1 B 102 ^0 ylmethoxy)phenyl]methyl}benzothiazole, oxalate
2-[(3-Cyclohexylmethoxyphenyl)(1 -
285 met ylpiperidin-4-yloxy)met yl]benzot iazole, 1A, 1 B 101 °C oxalate
5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
289 293, 194 1 10 Ό yloxy)met yl]phenyl}pentylamine, dihydrochloride
2-{3-[benzothiazol-2-yl(1 -ethyl-piperidin-4- 371 A, 371 B,
290
yloxy)methyl]phenoxy}ethylamine, dioxalate 272A, 1 B
2-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4- 371 A, 371 B,
291 90 °C yloxy)methyl]phenoxy}ethylamine 272A, 272B
6-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
292 148 80 °C yloxy)methyl]phenylsulfanyl}hexan-1 -ol, oxalate
2-[(2,3-dihydrobenzo[1 ,4]dioxin-6-yl)(1 -
300 272A, 272B 203 °C methylpiperidin-4-yloxy)methyl]-1 - -benzimidazole
A/-(2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
278A, 249,
302 yloxy)methyl]phenylsulfanyl}ethyl)guanidine, 125^0
149A
hydrochloride
A/-ferf-butoxycarbonyl-/V-(2-{3-[(benzothiazol-2-
304 yl)(1 -methylpiperidin-4- 307A, 194A 1 10 Ό yloxy)methyl]phenylsulfanyl}ethyl)guanidine
2-[{3-[2-(1 -methyl-1 H-imidazol-4-yl)ethyl]-
306 phenyl}(1 -methylpiperidin-4-yloxy)methyl]- 293, 194 80 °C benzothiazole, oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(pyridin-2-
310 272A, 272B 77 °C ylmethoxy)phenyl]methyl}-1 /-/-benzimidazole
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- 371 A, 371 B,
31 1 120 <Ό yloxy)methyl]phenoxy}propylamine, oxalate 272A, 1 B
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
314 305A, 305B 99 °C yloxy)methyl]phenylsulfanyl}propylamine, oxalate
6-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
319 194, 189 135Ό yloxy)methyl]phenyl}hex-5-ynylamine, oxalate 2-{(1 -met ylpiperidin-4-yloxy)[3-(4-morpholin-4-yl- 370A, 272A,
322 61 °C butoxy)phenyl]methyl}benzothiazole, oxalate 1 B
(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
323 yloxy)met yl]phenyl}pyrrolidin-2-yl)met anol, 258 76 °C oxalate
(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
324 yloxy)met yl]phenyl}pyrrolidin-2-yl)met anol, 258 99 °C oxalate
6-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
325 293, 194 1 15Ό yloxy)methyl]phenyl}hexylamine, oxalate
4-{3-[(1 - -benzimidazol-2-yl)(1 -met ylpiperidin-4-
326 305A, 305B 146^0 yloxy)methyl]phenylsulfanyl}butylamine, oxalate
3-{3-[(1 - -benzimidazol-2-yl)(1 -met ylpiperidin-4- 371 A, 371 B,
327 97 °C yloxy)methyl]phenoxy}propylamine 272A, 272B
4-(2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
370A, 272A;
329 yloxy)methyl]phenoxy}ethyl)piperazine-1 - 90 °C
1 B
carboxylic acid ferf-butyl ester, oxalate
4-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- 371 A, 371 B,
331 1 15Ό yloxy)methyl]phenoxy}butylamine, oxalate 272A, 272B
2-{(1 -met ylpiperidin-4-yloxy)[3-(4-morpholin-4-yl- 370A, 272A,
332 85 °C butoxy)phenyl]methyl}-1 - -benzimidazole, oxalate 272 B
2-{(1 -methylpiperidin-4-yloxy)[3-(4-piperidin-1 -yl- 370A, 272A,
333 130 <Ό butoxy)phenyl]methyl}-1 /-/-benzimidazole, oxalate 272 B
2-[(2-fluoro-3-iodophenyl)(1 -methylpiperidin-4-
334 272A, 272B 125^0 yloxy)met yl]-1 /-/-benzimidazole
/V-fert-butoxycarbonyl-/V-(5-{3-[(benzothiazol-2-
339 yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent- 307A, 194A 125^0
5-ynyl)guanidine
V-(5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
340 yloxy)methyl]phenyl}pent-4-ynyl)guanidine, 180 <Ό hydrochloride
A/-ferf-butoxycarbonyl-/V-(6-{3-[(benzothiazol-2-
341 yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}hex-5- 307A, 194A 130 Ό ynyl)guanidine V-(6-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
342 yloxy)methyl]phenyl}hex-5-ynyl)guanidine,
hydrochloride
4-(4-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-
370A, 272A,
343 4-yloxy)methyl]phenoxy}butyl)piperazine-1 - 64 °C
272 B
carboxylic acid ferf-butyl ester
2-{(1 -methylpiperidin-4-yloxy)[3-(3-[1 ,2,4]triazol-1 - 315A, 272A,
348 60 °C yl-propoxy)phenyl]methyl}benzothiazole, oxalate 1 B
2-{(1 -methylpiperidin-4-yloxy)[3-(3-[1 ,2,3]triazol-2-
315A, 272A,
349 yl-propoxy)phenyl]methyl}benzothiazole, oxalate 74 °C
1 B
(contains 23% of 1 ,2,3-triazol-1 -yl compound)
2-{(1 -methylpiperidin-4-yloxy)[3-(3-morpholin-4-yl- 370A, 272A,
350 Ι Οδ'Ό propoxy)phenyl]methyl}benzothiazole, oxalate 1 B
2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 423A, 150A,
352 204^0 yloxy)methyl]-2-fluorophenylsulfanyl}ethylamine 272A, 272B
2-[[3-(2-Chloroethoxy)phenyl](1 -methylpiperidin-4-
354 272A, 1 B 70 °C yloxy)methyl]benzothiazole, oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(2-piperidin-1 -yl- 370A, 272A,
356 ■\ 60 °C ethoxy)phenyl]methyl}-1 - -benzimidazole, oxalate 272B
4-(3-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-
370A, 272A,
360 4-yloxy)methyl]phenoxy}propyl)piperazine-1 - 140 <Ό
272B
carboxylic acid ferf-butyl ester, oxalate
4-(5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
370A, 272A,
362 yloxy)methyl]phenoxy}pentyl)piperazine-1 - 131 °C
1 B
carboxylic acid ferf-butyl ester
A/-(6-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
278A, 249,
363 yloxy)methyl]phenyl}hexyl)guanidine, 90 °C
149A
hydrochloride
A/-ferf-butoxycarbonyl-/V-(6-{3-[(1 /-/-benzimidazol-
364 2-yl)(1 -methylpiperidin-4- 307A, 194A 90 °C yloxy)methyl]phenyl}hexyl)guanidine
A/-(5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
278A, 249,
365 yloxy)methyl]phenyl}pentyl)guanidine, 90 °C
149A
hydrochloride 4-{3-[benzot iazol-2-yl(1 -met ylpiperidin-4-
366 293, 194 100°C yloxy)methyl]phenyl}butylamine, dioxalate
21A, 37B,
[[3-(4-aminobutoxy)p enyl](1 /-/-benzimidazol-2-
367 371 B, 42C, 68 °C yl)met yl](1 -met ylpiperidin-4-yl)amine
272B
3-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- 278A, 249,
368 126°C yloxy)methyl]phenylsulfanyl}propylamine 149A
4-(2-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-
370A, 272A;
369 4-yloxy)methyl]phenoxy}ethyl)piperazine-1 - 92 ^0
1 B
carboxylic acid ferf-butyl ester, dioxalate
A/-(3-{3-[benzot iazol-2-yl(1 -met ylpiperidin-4-
278A, 249,
373 yloxy)methyl]phenyl}prop-2-ynyl)guanidine, 125°C
149A
trihydroc loride
A/-(4-{3-[benzot iazol-2-yl(1 -met ylpiperidin-4-
278A, 249,
374 yloxy)methyl]phenyl}butyl)guanidine, 120°C
149A
trihydrochloride
(5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
370A, 272A,
375 yloxy)methyl]phenoxy}pentylamino)acetic acid 99°C
1 B
ferf-butyl ester, oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(piperidin-4-
377 423A, 258 90 °C ylmethoxy)phenyl]methyl}benzothiazole, dioxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(piperidin-3-
378 423A, 258 55 °C ylmethoxy)phenyl]methyl}benzothiazole, dioxalate
2-[[3-(1 -methylpiperidin-3-ylmethoxy)phenyl](1 -
165C, 423A,
379 methylpiperidin-4-yloxy)methyl]benzothiazole, 76°C
258
dioxalate
2-[(1 -methylpiperidin-4-yloxy)(3-piperidin-3-
380 376A, 189 97 °C ylethynylphenyl)methyl]-1 - -benzimidazole
5-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4-
381 305A, 305B 140°C yloxy)methyl]phenylsulfanyl}pentylamine, oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(pyrrolidin-3-
382 258 50 °C yloxy)phenyl]methyl}benzothiazole, dioxalate
21A, 37B,
{[3-(4-aminobutoxy)phenyl]benzothiazol-2-yl-
387 371 B, 42C, 67 °C methyl}(1 -methylpiperidin-4-yl)amine
1 B 2-[(3-azetidin-3-ylethynylphenyl)(1 -
388 249, 293,189 131 °C methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole
5-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-
389 384A, 53 125°C yloxy)methyl]phenyl}pent-4-en-1 -ol, oxalate
4-(5-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-
370A, 72A,
391 4-yloxy)methyl]phenoxy}pentyl)piperazine-1 - 101 °C
272B
carboxylic acid ferf-butyl ester, dioxalate
2-[[3-(2-azetidin-3-ylethyl)phenyl](1 -
392 249, 189 146°C met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
2-{(1 -methylpiperidin-4-yloxy)[3-(2-piperidin-2-yl-
395 249, 149A 164°C ethylsulfanyl)phenyl]methyl}-1 /-/-benzimidazole
V-fert-butoxycarbonyl- V-(4-{3-[(benzothiazol-2-
399 yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}but-3- 307A, 194A 120°C ynyl)guanidine
5-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- 371 A, 371 B,
400 1 1 1 °C yloxy)methyl]phenoxy}pentylamine, dioxalate 72A, 272B
2-[[3-(azetidin-3-yloxy)phenyl](1 -methylpiperidin-
402 423A, 258 81 °C
4-yloxy)methyl]benzothiazole, dioxalate
(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
404 yloxy)methyl]phenyl}pyrrolidin-3-yl)methanol, 403 106°C oxalate
1 -{3-[benzot iazol-2-yl(1 -methylpiperidin-4-
405 423A, 403 137°C yloxy)methyl]phenyl}piperidin-4-ylamine, dioxalate
1 -{3-[benzot iazol-2-yl(1 -methylpiperidin-4-
406 403 103°C yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate
1 -{3-[benzot iazol-2-yl(1 -methylpiperidin-4-
407 403 106°C yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate
Λ/-(1 -{3-[benzot iazol-2-yl(1 -methylpiperidin-4-
408 yloxy)methyl]phenyl}pyrrolidin-3-yl)acetamide, 403 1 1 1 °C oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(5-pyrazol-1 -yl-
410 pent-1 -ynyl)phenyl]methyl}-1 /-/-benzimidazole, 416A, 189 1 15°C oxalate acetic acid 1 -{3-[benzothiazol-2-yl(1 -methyl-
413 piperidin-4-yloxy)methyl]phenyl}piperidin-4-yl 403 74 °C ester, oxalate
2-[(3-bromo-phenyl)(1 -methylpyrrolidin-3- 165C, 272A,
414 61 °C ylmethoxy)methyl]-1 - -benzimidazole 72B, 72C
2-{(1 -methylpiperidin-4-yloxy)[3-(piperidin-4-
415 423A, 258 76°C yloxy)phenyl]methyl}benzothiazole, dioxalate
Λ/1 -(5-{3-[(1 H-benzimidazol-2-yl)(1 -methyl-
423A, 370A,
419 piperidin-4-yloxy)methyl]phenoxy}pentyl)butane- 162°C
72A, 272B
1 ,4-diamine, dioxalate
{[3-(6-aminohex-1 -ynyl)phenyl]benzothiazol-2-yl-
420 386A, 275 80 °C methyl}(1 -methylpiperidin-4-yl)amine, oxalate
4-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
422 258 73 °C yloxy)methyl]phenoxy}but-2-en-1 -ol, oxalate
2-[(2,5-difluorophenyl)(1 -methylpiperidin-4-
424 272A, 272B 140°C yloxy)methyl]-1 /-/-benzimidazole
2-[(2-fluoro-5-iodo-phenyl)(1 -methylpiperidin-4-
425 272A, 272B 175°C yloxy)methyl]-1 /-/-benzimidazole, dioxalate
4-{3-[(5-fluoro-1 /-/-benzimidazol-2-yl)(1 -methyl-
427 150 85 °C piperidin-4-yloxy)methyl]phenylsulfanyl}butan-1 -ol
2-{3-[(5-fluoro-1 /-/-benzimidazol-2-yl)(1 -methyl-
428 piperidin-4-yloxy)methyl]phenylsulfanyl}- 249, 149A 85 °C ethylamine, dioxalate
1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
429 yloxy)methyl]phenyl}pyrrolidin-3-ylamine, 423A, 423B 137°C dioxalate
2-[[3-(3-fluoropyrrolidin-1 -yl)phenyl](1 -
430 methylpiperidin-4-yloxy)methyl]benzothiazole, 423 B 70 °C oxalate
4-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- 386A, 424A,
431 1 17°C yloxy)methyl]phenoxy}but-2-enylamine, dioxalate 258
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -
433 272A, 272B 95 °C methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole
* in the case of ketone-containing substituents, it is judicious to protect the carbonyl function (as an acetal for example) prior to the Grignard preparation Example 434
2-[(2-fluoro-5-trifluorometrioxyprienyl)(1 -metriylpiperidin-4-yloxy)metriyl]-1 H- benzimidazole enantiomer A
A solution of racemic 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 /-/-benzimidazole (1 mg/mL) in a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) is injected (10μΙ_) onto an analytical Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. Products are detected at 220nm.
The first enantiomer has a retention time of 6.9min.
Collection affords 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 /-/-benzimidazole enantiomer A with a chromatographic enantiomeric purity of 99.8%.
Example 435
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole enantiomer B
The second enantiomer has a retention time of 8.3min.
Collection affords 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 /-/-benzimidazole enantiomer B with a chromatographic enantiomeric purity of 96.8%.
Following compounds are prepared using general methods described in example
1 :
Figure imgf000081_0001
80
2-[(3-butylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
80A To a mixture of trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1 - methylpiperidin-4-yloxy)methyl]phenyl ester (1 10mg) and ferric acetylacetonate (4mg) in a mixture of tetrahydrofurane (4.5ml_) and /V-methylpyrrolidone (0.25ml_) cooled at 0°C is added a 2M solution of butylamgnesium chloride in tetrahydrofurane (150μΙ_). The mixture is stirred at room temperature for 25 min, then warmed at 30°C for 15min. A second addition of butylamgnesium chloride in tetrahydrofurane (150μΙ_) is performed. The mixture is then diluted with diethyl ether and quenched with 0.5N hydrochloric solution. The aqueous phase is extracted with diethyl ether, then ethyl acetate. Organic phases are pooled, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradiant heptane / ethyl acetate from 99 / 1 to 90 / 10). The product is then refluxed in methanol and concentrated to give 2-[(3- butylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole.
TLC (eluent: CH2CI2/MeOH 90/10): Rf= 0.30
80 B
To a solution of 3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenol
(318mg) in pyridine (74μΙ_) and dichloromethane (3ml_) cooled at -5°C is added trifluoromethanesulfonic anhydride (152μΙ_). The mixture is stirred for 1 h, then allowed to warm to room temperature. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purifed by chromatography (gradiant heptane / ethyl acetate from 95 / 5 to 50 / 50) to give trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl ester used without further purification.
Following compounds are prepared using general methods described in example 21A, 21 C and 1 B:
Figure imgf000082_0001
Example 1 17
2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole enantiomer A A solution of racemic 2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]- benzothiazole (10mg/ml_) in a mixture of heptane / isopropanol (80 / 20) containing diethylamine (0.1 %) is injected (20x100μΙ_) onto an analytical Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (80 / 20) containing diethylamine (0.1 %) at a flow of 1 mL/min. Products are detected at 220nm.
The first enantiomer has a retention time of 6.0min.
Collection affords 2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl] benzothiazole enantiomer A with a chromatographic enantiomeric purity of 97.3%. Example 1 18
2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole enantiomer B The second enantiomer has a retention time of 7.0min.
Collection affords 2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl] benzo- thiazole enantiomer B with a chromatographic enantiomeric purity of 99.7%.
Example 126
3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-ylamino)methyl]phenol
A solution of {(1 - -benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1 - methylpiperidin-4-yl)amine (example 120, 500mg) in ethanol (5mL) is treated with aqueous 37% hydrochloric acid at room temperature for one night. The mixture is then neutralized with an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradiant dichloromethane / methanol / ammonia from 90 / 10 / 0.5 to 80 / 20 / 0.5) to give 3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-ylamino)methyl]phenol as a white solid melting at 230 °C.
Example 131
[(1 H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1 -methylpiperidin-4-yl)amine.
131A
To a solution of [(1 H-benzimidazol-2-yl)(3-nitrophenyl)methylene](1 -methyl- piperidin-4-yl)amine (1 .1 g) in methanol (50ml_) at 0 °C is added sodium cyanoborohydride, then dropwise acetic acid (0.19ml_). The reaction mixture is allowed to reach room temperature and stirred at that temperature overnight.
Cold water (70ml_) is added as well as concentrated hydrochloric acid to reach pH 1 . Then a concentrated sodium hydroxide solution is added to reach pH 10. The aqueous phase is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol from 99 / 1 to 95 / 5) to afford [(1 -/- benzimidazol-2-yl)(3-nitrophenyl)methyl](1 -methylpiperidin-4-yl)amine melting at 254 °C.
131 B
[(1 H-benzimidazol-2-yl)(3-nitrophenyl)methylene](1 -methylpiperidin-4-yl)amine can be prepared according to the method described in example 37B. Further examples can be prepared according to the described general methods:
General
Example Product TLC methods
2-[(3-allyloxyphenyl)(1 -methylpiperidin-4-
22 1A, 1 B 0.41 (C) yloxy)methyl]benzothiazole, hydrochloride
2-[(2,3-dihydrobenzofuran-5-yl)(1 -methyl-
32 piperidin-4-yloxy)methyl]benzothiazole, 1A, 1 B 0.32(C) oxalate
trifluoromethanesulfonic acid 3-[benzothiazol-
71 2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl 1A, 1 B 0.50(D) ester
[benzothiazol-2-yl(3-benzyloxyphenyl)-
101 91 A, 1 B 0.17(C) methyl](1 -methylpiperidin-4-yl)amine, oxalate
{(1 H-benzimidazol-2-yl)[3-(2-ethoxyethoxy)-
134 59A, 59B 0.26(A) phenyl]methyl}(1 -methylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3-pent-4-
135 enyloxyphenyl)methyl](1 -methylpiperidin-4- 59A, 59B 0.16(A) yl)amine
2-{(1 -methylpiperidin-4-yloxy)[3-(3,3,3-
178 trifluoro-propoxy)phenyl]methyl}- 1A, 168B 0.67(D) benzothiazole, oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(3-nitro-
196 benzyloxy)phenyl]methyl}benzothiazole, 1A, 1 B 0.17(B) oxalate
1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
1A, 168B
270 yloxy)methyl]benzyloxy}propan-2-one, * 0.32(A) oxalate
2-[benzo[1 ,3]dioxol-5-yl(1 -methylpiperidin-4-
297 272A, 272B 0.22(D) yloxy)methyl]-1 H-benzimidazole
4-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- 371 A, 371 B,
301 0.08(B) yloxy)methyl]phenoxy}butylamine, oxalate 272A, 1 B
4-(2-{3-[benzothiazol-2-yl(1 -methylpiperidin-
370A, 272A,
328 4-yloxy)methyl]phenoxy}ethyl)piperazine-1 - 0.69(D)
1 B
carboxylic acid ferf-butyl ester 2-{(1 -methylpiperidin-4-yloxy)[3-(2-piperazin-
423A, 370A,
330 1 -yl-ethoxy)phenyl]methyl}benzothiazole, 0.26(D)
272A, 1 B
oxalate
(2-{3-[(1 H-benzimidazol-2-yl)(1 -methyl- piperidin-4-yloxy)methyl]phenoxy}- 370A, 272A,
361 0.51 (D)
ethylamino)acetic acid ferf-butyl ester, 1 B
oxalate
Eluent A: CH2CI2/MeOH/NH4OH 90/10/0.5
Eluent B: CH2CI2/MeOH/NH4OH 95/5/0.5
Eluent C: CH2CI2/MeOH 90/10
Eluent D: CH2CI2/MeOH/NH4OH 90/10/1
* in the case of ketone-containing substituents, it is judicious to protect the carbonyl function (as an acetal for example) prior to the Grignard preparation
Example 147
2-[(1 -methylpiperidin-4-yloxy)(3-pyrazol-1 -ylphenyl)methyl]benzothiazole, oxalate
To a solution of 2-[(3-Bromophenyl)(1 -methylpiperidin-4-yloxy)methyl] benzothiazole (208mg) in A/,A/-dimethylformamide (1 ml_) are added pyrazole (68mg), cesium carbonate (401 mg) and copper(l) iodide (19mg). The tube is evacuated, filled with argon and sealed. After stirring at 120 ^ for 48h, the mixture is diluted with water and ammonia solution then extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 95 / 5 / 0.5). The residue is added to a solution of oxalic acid (1 molar equivalent) and the residual precipitate is filtered and dried to afford 2-[(1 -methylpiperidin-4-yloxy)(3-pyrazol- 1 -ylphenyl)methyl]benzothiazole oxalate melting at 89 °C.
Example 148
2-[(3-benzylsulfanylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole.
A screw-cap tube is charged with 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (208mg), palladium bis(dibenzylideneacetone) (14mg), Xantphos (14mg), benzyl mercaptan (59μΙ_), diisopropylethylamine (174μΙ_) and 1 ,4- dioxane (2 ml_). The tube is evacuated, filled with argon and sealed. After stirring at 120 °C for 15h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 95 / 5 / 0.5). The residual yellowish oil is re-crystallized from hot acetonitrile to give 2-[(3- benzylsulfanylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole melting at 195°C.
Further examples can be prepared according to the above described general method:
Example Product
2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
158
yloxy)methyl]phenylsulfanyl}ethanol
1 H NMR: 7.98 (d, 1 H), 7.88 (d, 1 H), 7.57 (s, 1 H), 7.47-7.27 (m, 5H), 5.88 (s, 1 H), 3.75 (t, 2H), 3.65 (m, 1 H), 3.12 (t, 2H), 2.70-2.81 (m, 2H), 2.30 (s, 3H), 1 .7-2.4 (m, 7H)
159 2-[(3-ethylsulfanylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
1 H NMR: 7.98 (d, 1 H), 7.88 (d, 1 H), 7.50-7.30 (m, 3H), 7.30-7.10 (m, 3H), 5.83 (s, 1 H), 3.93 (m, 1 H), 3.25-3.00 (m, 4H), 2.95 (q, 2H), 2.67 (s, 3H), 2.50-2.30 (m, 2H), 2.20-2.00 (m, 2H), 1 .30(t, 3H)
{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic
160
acid methyl ester
1 H NMR: 7.98 (d, 1 H), 7.87 (d, 1 H), 7.62 (s, 1 H), 7.50-7.29 (m, 5H), 5.85 (s, 1 H), 4.02 (s, 1 H), 3.74-3.65 (m, 5H), 3.4-3.2 (m, 4H), 2.79 (s, 3H), 2.6-2.4 (m, 2H), 2.25-2.05 (m, 2H)
201 2-[(1 -methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]benzothiazole
1 H NMR: 7.97 (d, 1 H), 7.87 (d, 1 H), 7.50-7.10 (m, 6H), 5.89 (s, 1 H), 3.70-3.58 (m, 1 H), 2.62-2.78 (m, 2H),2.48 (s, 3H) 2.23 (s, 3H), 2.23-2.10 (m, 2H), 2.00-1 .7 (m, 4H)
2-{(1 -methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-
233
ethylsulfanyl)phenyl]methyl}benzothiazole
1 H NMR: E I.47 (m, 1 H), 8.40 (m, 1 H), 7.96 (d, 1 H), 7.85 (d, 1 H), 7.53 (s, 1 H), 7.45-7.27 (m, 6H), 5.88 (s, 1 H), 3.8-3.60 (m, 1 H), 3.34 (t, 2H), 3.09 (t, 2H), 2.82-2.75 (m, 2H), 2.34 (s, 3H), 2.50- 2.20 (m, 2H), 2.1 -1 .70 (m, 4H)
(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
239
yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)acetic acid methyl ester
1 H NMR: 7.97 (d, 1 H), 7.87 (d, 1 H), 7.53 (s, 1 H), 7.48-7.24 (m, 5H), 5.87 (s, 1 H), 3.7-3.5 (m, 4H), 3.08 (s, 2H), 2.80-2.65 (m, 2H), 2.46 (s, 2H), 2.30 (s, 3H), 2.32-2.2 (m, 2H), 2.10- 1 .75 (m, 4H), 0.50 (m, 4H)
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
254
yloxy)methyl]phenylsulfanyl}propan-1 -ol Example Product
1 H NMR: 7.96 (d, 1 H), 7.87 (d, 1 H), 7.57 (s, 1 H), 7.46-7.24 (m, 5H), 5.88 (s, 1 H), 3.8-3.65 (m, 3H), 3.28-3.15 (m, 1 H), 3.07-2.97 (m, 1 H), 2.87-2.70 (m, 2H), 2.34 (s, 3H), 2.45-2.25 (m, 2H), 2.20-1 .75 (m, 7H)
1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
255
yloxy)methyl]phenylsulfanyl}propan-2-ol
1 H NMR: £ 1.06 (d, 1 H), 7.91 (d, 1 H), 7.46-7.24 (m, 6H), 6.09 (s, 1 H), 5.5-4.0 (si, 1 H), 3.85- 3.70 (m, 2 H), 3.28-3.07 (m, 2H), 3.07-2.85 (m, 4H), 2.63 (s, 3H), 2.18-1 .70 (m, 4H), 1 .1 1 (d, 3H)
4-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)metriyl]phenylsulfanyl}butan-
256
1 -ol
1 H NMR: 7.97 (d, 1 H), 7.87 (d, 1 H), 7.50-7.24 (m, 6H), 5.88 (s, 1 H), 3.77-3.60 (m, 3H), 3.00-2.90 (m,2H), 2.85-2.70 (m, 2H), 2.33 (s, 3H), 2.41 -2.20 (m, 2H), 2.20-1 .60 (m, 9H)
Example 150
2-[(3-benzylsulfanylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
A screw-cap tube is charged with 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 H-benzimidazole (200mg), palladium bis(dibenzylideneacetone) (14mg), Xantphos (14mg), benzyl mercaptan (59μΙ_), Diisopropylethylamine (174μΙ_) and 1 ,4- dioxane (2ml_). The tube is evacuated, filled with argon and sealed. After stirring at 120°C for 24h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 95 / 5 / 0.5) to afford 2-[(3-benzylsulfanylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
1 H NMR: 12.38 (si, 1 H), 7.55 (d, 1 H), 7.50-7.40 (m, 2H), 7.30-7.00 (m, 10H), 5.84 (s, 1 H), 4.20 (s, 2H), 3.65-3.45 (m, 1 H), 3.20-3.00 (m, 2H), 2.90-2.60 (m, 2H), 2.57 (s, 3H), 2.00-1 .60 (m, 4H) Further examples can be prepared according to the above described general method: Example Product
153 2-[(3-et ylsulfanylphenyl)(1-met ylpiperidin-4-yloxy)metriyl]-1 H-benzimidazole
1H NMR: 7.54 (si, 1H), 7.40 (s, 1H), 7.27-7.17 (m, 6H), 5.82 (s, 1H), 3.65-3.50 (m, 1H), 2.87 (q, 2H), 2.80-2.60 (m, 2H), 2.23 (s, 3H), 2.20-1.65 (m, 6H), 1.23 (s, 3H)
{3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-
154
yloxy)methyl]phenylsulfanyl}acetic acid methyl ester
1H NMR: 9.66 (si, 1H), 7.90-7.20 (m, 8H), 5.84 (s, 1H), 3.71-3.50 (m, 6H), 2.80-2.60 (m, 2H), 2.28 (s, 3H), 2.27-1.65 (m, 6H)
2-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-
157
yloxy)methyl]phenylsulfanyl}ethanol
1H NMR: 9.76 (si, 1H), 7.72 (s, 1H),7.52 (s, 1H), 7.42 (s, 1H) 7.30-7.15 (m, 5H), 5.84 (s, 1H),3.74 (t, 2H), 3.57-3.51 (m, 1H), 3.10 (t, 2H), 2.75-2.55 (m, 2H), 2.24 (s, 3H), 2.10-1.60 (m, 7H)
2-[[3-(furan-2-ylmethylsulfanyl)phenyl](1-metriylpiperidin-4-yloxy)metriyl]-1 H-
173
benzimidazole
1H NMR: 1 2.36 (si, 1H), 7.54-7.44 (m, 4H), 7.26 (m, 3H), 7.18-7.10 (m, 2H), 6.22-6.15 (m, 2H), 5.83 (s, 1H), 4.20 (s, 2H), 3.35-3.50 (m, 1H), 3.0-2.8 (m, 2H), 2.36 (s, 3H), 2.0-1.8 (m, 2H), 18-1.6 (m, 2H), 1.25-1.05 (m, 2H)
2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)metriyl]-1 H-
202
benzimidazole
1H NMR: 7.65-7.52 (m, 2H), 7.36 (s, 1H), 7.30-7.10 (m, 5H), 5.85 (s, 1H), 3.97-3.85 (m, 1H), 3.47-3.30 (m, 2H), 3.20-2.90 (m, 2H), 2.69 (s, 3H), 2.43 (s, 3H), 2.38-2.0 (m, 4H)
2-[(3-ferf-butylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1 --
215
benzimidazole
1H NMR: 9.51 (si, 1H), 7.67(s, 1H), 7.55-7.40 (m, 4H), 7.38-7.20 (m, 3H), 5.88 (s, 1H), 3.70-3.55 (m, 1H), 2.85-2.70 (m, 2H), 2.29 (s, 3H), 2.28-2.10 (m, 2H), 2.05-1.70 (m, 4H), 1.25 (s, 9H)
2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}-
232
1 H-benzimidazole
1H NMR: 1 0.24 (si, 1 H), 8.48 (m, 1 H), 8.41 (m, 2H), 7.73 (si, 1 H),7.51 (s, 1 H), 7.33 (si, 1 H) 7.27-7.15 (m, 5H), 5.85 (s, 1H), 3.70-3.60 (m, 1H), 3.34 (t, 2H), 3.09 (t, 2H), 1.60-1.80 (m, 2H), 2.23 s, 3H), 2.23-1.60 (m, 6H)
4-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-
248
yloxy)methyl]phenylsulfanyl}butan-1-ol
Figure imgf000089_0001
Example 165
165A
5,6-dichloro-2-[(1 -methylpiperidin-4-yloxy)phenylmethyl]-1 H-benzimidazole
A round-bottom flask is charged with 4,5-dichlorobenzene-1 ,2-diamine (354mg) and toluene (2ml_); a solution of trimethylaluminum 2M in toluene (1 ml_) is added dropwise. The reaction mixture is heated at 60 °C for one hour. A solution of (1 -methyl- piperidin-4-yloxy)phenylacetic acid ethyl ester in toluene (1 ml_) is added dropwise and heating is pursued for one hour. The reaction mixture is cooled to room-temperature and a solution of sodium hydroxide is added dropwise to pH 10. The slurry is filtered on celite, cake washed with water (4x5ml_) and ethyl acetate (4x5ml_). After decantation, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is diluted with glacial acetic acid (3ml_) and the reaction mixture is heated at reflux for one hour. Acetic acid is removed on a rotary evaporator and the residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0 to 95 / 5 / 0.5 to give 5,6-dichloro-2-[(1 -methylpiperidin-4-yloxy)phenylmethyl]-1 H-benzimidazole melting at 221 °C.
165B (1 -Methylpiperidin-4-yloxy)phenylacetic acid ethyl ester.
To a solution of 4-(Ethoxycarbonyl-phenyl-methoxy)-piperidine-1 -carboxylic acid ferf-butyl ester (3.4g) in dichloromethane (25ml_) is added trifluoroacetic acid (18ml_). After 30 minutes at room temperature, the volatiles are removed under reduced pressure. Water (30m L) is added and the solution is basified by adding a solution of saturated sodium carbonate to pH 10. The aqueous phase is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure to give (1 -methylpiperidin-4-yloxy)phenylacetic acid ethyl ester used without further purification.
165C
(1 -Methylpiperidin-4-yloxy)phenylacetic acid ethyl ester obtained above is dissolved in 1 ,4-dioxane (40ml_) and 40% aqueous solution of formaldehyde (4ml_) as well as a 1 molar solution of sodium hypophosphorous acid (46ml_); The reaction mixture is heated to 80°C overnight. 1 ,4-dioxane is removed under reduced pressure and the residual solution is basified by adding a solution of saturated sodium carbonate to pH 10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 95 / 5 / 0.5) to afford (1 -methylpiperidin-4-yloxy)phenylacetic acid ethyl ester.
1 H NMR: 7.50-7.45 (m, 2H), 7.38-7.20 (m, 3H), 5.00 (s, 1 H), 4.18 (q, 2H), 3.55- 3.40 (m, 1 H), 2.83-2.65 (m, 2H), 2.28 (s, 3H), 2.25-2.08 (m, 2H), 2.05-1 .65 (m, 4H), 1 .22 (t, 3H)
165D 4-(Ethoxycarbonylphenylmethoxy)piperidine-1 -carboxylic acid ferf-butyl ester To a solution of diazophenylacetic acid ethyl ester (2.55g) in 1 ,2-dichloroethane is added 4-hydroxypiperidine-1 -carboxylic acid ferf-butyl ester (5.4g). The flask is evacuated and filled with argon. Rhodium(ll) acetate-dimer (60mg) is added to the reaction mixture. Evolution of nitrogen occurs until the end of the reaction (about 1 hour). The solvent is removed under reduced pressure. The residue is purified by chromatography (gradient heptane / ethyl acetate from 95 / 5 to 80 / 20) to give 4-(ethoxy- carbonylphenylmethoxy)piperidine-1 -carboxylic acid ferf-butyl ester.
1 H NMR: 7.52-7.28 (m, 5H), 5.01 (s, 1 H), 4.15 (q, 2H), 3.90-3.70 (m, 2H), 3.68- 3.55 (m, 1 H), 3.18-3.00 (m, 2H), 2.00-1 .50 (m, 4H), 1 .44 (s, 9H), 1 .26 (t, 3H)
165E Diazophenylacetic acid ethyl ester
To a solution of ethyl phenylacetate (3.28g) in acetonitrile (60ml_) is added para- toluenesulfonylazide (4.53g). The reaction mixture is cooled to 0 *Ό and 1 ,8- diazabicyclo[5.4.0]undec-7-ene (3.9ml_) is added dropwise. The reaction mixture is kept at 5°C overnight. Solvent is removed to dryness and the residue is purified by chromatography (gradient petroleum ether / dichloromethane from 90 / 10 to 80 / 20) to give diazophenylacetic acid ethyl ester;
1 H NMR: 7.48-7.58 (m, 2H), 7.45-7.30 (m, 2H), 7.22-7.10 (m, 1 H), 4.35 (q, 2H), 1 .30 (t, 3H)
Example 172
3- [(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]benzonitrile
To a solution of 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl] benzothiazole (200mg) in A/,A/-dimethylformamide (2.5ml_) and water (0.2ml_) are added copper(l) cyanide (180mg), bis(dibenzylidenacetone)palladium (14.3mg) and Xantphos (14.4mg). The tube is evacuated, filled with argon and sealed. After stirring at 120 ^ for 48h, the mixture is diluted with water then extracted with ethyl acetate. The pooled organic extracts are washed with water, brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 92.5 / 7.5 / 0.75) to afford 3- [(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]benzonitrile
1 H NMR: 9.75 (si, 1 H), 7.82 (s, 1 H), 7.80-7.62 (m, 2H), 7.57 (d, 1 H), 7.50-7.20 (m, 4H), 5.89 (s, 1 H), 3.60-3.40 (m, 1 H), 2.75-2.55 (m, 2H), 2.25 (s, 3H), 2.20-1 .60 (m, 6H) Example 188
4- [benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1 ,1 -dimethylpiperidinium
To a solution of 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl] benzothiazole (100mg) in acetonitrile is added iodomethane (1 molar equivalent) and the reaction mixture is refluxed for 1 hour. Solvent is removed under reduced pressure to dryness, the residue is triturated with diethylether, filtered, the cake is washed with diethylether and dried to give 4-[benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1 ,1 - dimethylpiperidinium melting at 95°C.
Example 189
2-(3-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2- ynyl)isoindole-1 ,3-dione
A screw-cap tube is charged with 2-[(3-iodophenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 /-/-benzimidazole (200 mg), dichloro-bis(triphenylphosphine) palladium(ll)
(9.2 mg), copper(l) iodide (16.4 mg), N-propargylphthalimide (400 mg), diethylamine (310μΙ_) and A/,A/-dimethylformamide (2 ml_). The tube is evacuated, filled with argon and sealed. After stirring at room-temperature for 24h, the mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 95 / 5 / 0.5 to give2-(3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1 ,3-dione.
1 H NMR: 9.52 (si, 1 H), 7.91 -7.15 (m, 12H), 5.81 (s, 1 H), 4.66 (s, 2H), 3.65-3.55 (m, 1 H), 2.85-2.65 (m, 2H), 2.28 (s, 3H), 2.30-2.05 (m, 2H), 2.05-1 .60 (m, 4H)
Following compounds are prepared analogously:
Figure imgf000092_0001
Example 194
3-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2- ynylamine
194A
A solution of 2-(3-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]- phenyl}prop-2-ynyl)isoindole-1 ,3-dione (70mg) and hydrazine hydrate (70μΙ_) in ethanol (0.7ml_) is stirred a room temperature for 3 hours. Ethanol is removed under reduced pressure and 1 N hydrochloric acid in water is added to the organic residue and stirred for 5 minutes. The mixture is filtered, cake washed with ethyl acetate. The filtrate is extracted by dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure The residue purified by chromatography (dichloromethane / methanol / ammonia from 90 / 1 0 / 1 ) to afford 3-{3-[(1 - -benzimidazol- 2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine melting at 101 °C
194B
2-(3-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2- ynyl)isoindole-1 ,3-dione is prepared according to general procedure 1 89.
Following compounds are prepared analogously:
Figure imgf000093_0001
Example 195
2-[(3-ethynylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
195A
To a solution of 2-[(3-trimethylsilylethynylphenyl)(1 -methylpiperidin-4-yloxy)- methyl]-1 H-benzimidazole (205mg) in methanol (2ml_) is added potassium carbonate (81 mg). The reaction mixture is stirred at room temperature for 4 hours, then methanol is removed under reduced pressure. The residue is dissolved in water and extracted with ethyl acetate. The organic phase is dried on magnesium sulphate and solvent is removed under reduced pressure to give 2-[(3-ethynylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/- benzimidazole
1 H NMR: 9.42 (si, 1 H), 7.80-7.70 (m, 1 H), 7.62 (s, 1 H), 7.48-7.36 (m, 3H) 7.34-7.20 (m, 3H), 5.86 (s, 1 H), 3.65-3.48 (m, 1 H), 3.07 (s, 1 H), 2.78-2.65 (m, 2H), 2.25 (s, 3H), 2.20-1 .60 (m, 6H)
195B
2-[(3-trimethylsilylethynylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole can be obtained using general method described in example189.
Example 198
2- {(1 -methylpiperidin-4-yloxy)[3-(1 H-[1 ,2,3]triazol-4-yl)phenyl]methyl}-1 H- benzimidazole
To a solution of 2-[(3-(ethynylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/- benzimidazole (1 10mg) in methanol (2ml_) and A/JV-dimethylformamide (0.7ml_) in a screw-cap tube is added L). The reaction mixture copper(l) iodide (3.2mg) and azidotrimethylsilane (56 is heated at 100°c overnight, then solvents are removed under reduced pressure. The residue is dissolved in water and ammonia solution is added to pH10 ; the aqueous phase is extracted with dichloromethane. The organic phase is dried on magnesium sulphate and solvent is removed under reduced pressure to give 2-{(1 - methylpiperidin-4-yloxy)[3-(1 H-[1 ,2,3]triazol-4-yl)phenyl]methyl}-1 - -benzimidazole.
1 H NMR: 7.98 (s, 1 H), 7.86 (s, 1 H), 7.80-7.50 (m, 3H), 7.48-7.30 (m, 2H), 7.29- 7.15 (m, 2H), 5.95 (s, 1 H), 3.68-3.50 (m, 1 H), 2.96-2.89 (m, 1 H), 2.85-2.65 (m, 2H), 2.26 (s, 3H), 2.20-1 .70 (m, 6H)
Example 199
3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]benzoic acid methyl ester, oxalate
A solution of 3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]benzonitrile (109 mg, example 197) in methanol (5ml_) is treated with a flow of hydrogen chloride while refluxing for 4h. After stirring at room temperature for one night, the mixture is concentrated under reduced pressure and the residue purified over silica gel (dichloromethane / methanol / ammonia 95 / 5 / 0.5) to afford 3-[benzothiazol-2-yl(1 - methylpiperidin-4-yloxy)methyl]benzoic acid methyl ester which is then converted into its oxalate salt in acetone to give 3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]benzoic acid methyl ester, oxalate melting at 93 °C. Example 200
2-[(1 -metriylpiperidin-4-yloxy)prienyl-metriyl]-3 - -benzimidazol-4-ylamine
To a solution of DMF (44mg) in L). As soon as l ,2-dichloroethane (2.5ml_) is added dropwise oxalylchloride (51 the gas evolution ceased, the volatiles are removed under reduced pressure. To the residue are added 1 ,2-dichloroethane (2.5ml_) and (1 - methylpiperidin-4-yloxy)phenylacetic acid (125mg). The reaction mixture is stirred at room temperature for 1 hour, then 1 ,2-diamino-3-nitrobenzene is added and the mixture is stirred overnight. Water is added and the solution is basified by adding a solution of saturated sodium carbonate to pH 10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 95 / 5 / 0.5).
To the residual solid in ethanol (4.5ml_) is added tin(ll)dichloride. The reaction mixture is refluxed for 2 hours. The solution is basified by adding a solution of 10N sodium hydroxide to pH 6. The aqueous phase is extracted with chloroform. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in acetic acid and the reaction mixture is refluxed for 3 hours. Acetic acid is removed, methanol (1 ml_) and 12N hydrochloric acid are added to the residue. The reaction mixture is heated to 60 °C for 1 hour.
The solution is basified by adding a solution of saturated sodium carbonate to pH
10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ) to afford 2-[(1 -methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol- 4-ylamine melting at 96,7°C.
Example 203
2-[(3-methanesulfonylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole To a solution of 2-[(1 -methylpiperidin-4-yloxy)(3-methylsulfanylphenyl) methyl]- benzothiazole (100mg) in methanol (2ml_) and water (1 ml_) at 0°C is added portionwise Oxone® (400mg) over 1 hour.
The mixture is diluted with water. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol from 98 / 2 to 90 / 10) to afford 2- [(3-methanesulfonylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole. 1 H NMR: 8.17 (s, 1 H), 7.97 (d, 1 H), 7.90-7.83 (m, 3H), 7.60-7.39 (m, 3H), 6.00 (s, 1 H), 3.72-3.60 (m, 1 H), 3.06 (s, 3H), 2.82-2.75 (m, 2H), 2.28 (s, 3H), 2.28-2.10 (m, 2H), 2.05-1 .70 (m, 4H) Example 206
3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]benzoic acid ethyl ester, oxalate
3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]benzoic acid ethyl ester, oxalate melting at 104°C can be prepared as described in example 199.
Example 207
{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}methanol, oxalate A solution of 3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]benzoic acid ethyl ester (0.55g, example 206) in tetrahydrofurane (10ml_) is treated with lithium aluminum hydride (76mg) at room temperature for 1 h. Two other additions of lithium aluminum hydride (76mg each) allow a complete conversion. The mixture is then hydrolyzed with water (178μΙ_), 5% sodium hydroxide (178μΙ_) and water (535μΙ_), filtered through a pad of clarcel and concentrated under reduced pressure. The residue is purified over silica gel (dichloromethane / methanol / ammonia 95 / 5 / 0.5) to afford {3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}methanol which is then converted into its oxalate salt in acetone to give {3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]phenyl}methanol, oxalate.
1 H NMR (DMSO-d6): 8.06 (d, 1 H), 7,90 (d, 1 H), 7;50-7.20 (m, 6H), 6.09 (s, 1 H), 4.47 (s, 2H), 3.75 (m,1 H), 3,16 (m,2H), 2,98 (m, 2H), 2,64 (s, 3H), 2,10-1 ,75 (m, 4H).
Example 208
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}propionic acid tert- butyl ester
A screw-cap tube is charged with 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (208mg), palladium(ll) acetate (3mg), RuPhos ® (12mg), potassium 3-trifluoroboratopropionate ferf-butyl ester (1 18mg), potassium carbonate (207 mg), water (2.5 mL) and toluene (2.5 ml_). The tube is evacuated, filled with argon and sealed. After stirring at 120°C overnight, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol from 100 / 0 to 95 / 5) to afford 3-{3 benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}propionic acid tert- butyl ester.
1 H NMR : 7.97 (d, 1 H), 7.86 (s, 1 H), 7.45-7.22 (m, 5H), 7.12 (d, 1 H), 5.89 (s, 1 H), 3.72-3.58 (m, 1 H), 2.87 (t, 2H), 2.78-2.65 (m, 2H), 2.53 (t, 2H), 2.29 (s, 3H), 2.28-2.10 (m, 2H), 2.08-1 .72 (m, 4H), 1 .39 (s, 9H)
Example 210
2-[(1 -methylpiperidin-4-yloxy)phenylmethyl]-3H-benzimidazol-4-ol
To a solution of (1 -methylpiperidin-4-yloxy)phenylacetic acid (250mg) in acetonitrile (5m L) are added 2,3-diaminophenol (125mg), 2-chloro-1 -methylpyridinium iodide (255mg) and dropwise diisopropylethylamine (0.44ml_). The reaction mixture is stirred at room temperature for 3 hours. Solvent is removed under reduced pressure. Water is added to the residue and the solution is basified by adding a solution of saturated sodium carbonate to pH 10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ).
The residue is dissolved in acetic acid (2ml_) and the reaction mixture is refluxed for 24 hours. Acetic acid is removed under reduced pressure. Water is added to the residue and the solution is basified by adding a solution of saturated sodium carbonate to pH 10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ). The residual solid is re-crystallized from hot toluene to give 2-[(1 - methylpiperidin-4-yloxy)phenylmethyl]-3H-benzimidazol-4-ol melting at M0.5°C.
Example 21 1
[benzothiazol-2-yl(4'-methoxybiphenyl-3-yl)methyl](1 -methylpiperidin-4-yl)amine, dioxalate
21 1A
[benzothiazol-2-yl(4'-methoxybiphenyl-3-yl)methyl](1 -methylpiperidin-4-yl)amine, dioxalate melting at 130°C can be prepared according to general procedure 91 A from benzothiazol-2-yl(4'-methoxybiphenyl-3-yl)methanol. 21 1 B
A mixture of benzothiazol-2-yl(3-bromophenyl)methanol (200mg), 4-methoxy- phenylboronic acid (142mg), tetrakis(triphenylphosphine)palladium (50mg), potassium carbonate (259mg), water (4ml_), ethanol (1 mL) and toluene (9ml_) is purged with argon and refluxed for one night. After cooling at room temperature, the mixture is diluted with water and diethylether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (heptane / ethyl acetate 2 / 1 ) to afford benzothiazol-2-yl(4'-methoxybiphenyl-3- yl)methanol as a beige solid.
Example 217
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}acrylonitrile To a solution of 2-[(3-lodophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzimidazole (230mg) in tetrahydrofuran (2.5ml_) in a screw-capped tube are added acrylonitrile (0.15ml_), triethylamine (2.5ml_) and tetrakis(triphenylphosphine)palladium. The tube is evacuated, filled with argon, sealed and heated at 70 °C for 18h. Solvent and volatiles are removed under reduced pressure and the residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 95 / 5 / 0.5 to give 3-{3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}acrylonitrile.
1 H NMR: 7.98 (d, 1 H), 7.88 (d, 1 H), 7.65-7.55 (m, 2H), 7.55-7.35 (m, 5H), 5.92 (d,
1 H), 5.88 (s, 1 H), 4.00-3.90 (m, 1 H), 3.25-2.95 (m, 4H), 2.65 (s, 3H), 2.50-2.35 (m, 2H), 2.25-2.00 (m, 2H)
Following compounds are prepared analogously:
Example Product
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}acrylic acid
205
ferf-butyl ester
1 H NMR: 7.9 3 (d, 1 H), 7.87 (s, 1 H), 7.68 (s, 1 H), 7.60-7.36 (m, 6H), 6.37 (d, 1 H), 5.93 (s, 1 H), 3.72-3.59 (m, 1 H), 2.80-2.65 (m, 2H), 2.29 (s, 3H), 2.28-2.10 (m, 2H), 2.05-1 .60 (m, 4H), 1 .74 (s, 9H).
2-[[3-(2-benzenesulfonylvinyl)phenyl](1 -methylpiperidin-4-
209
yloxy)methyl]benzothiazole
1 H NMR: 8.02-7.92 (m, 3H), 7.98 (d, 1 H), 7.75-7.35 (m, 9H), 7.30-7.15 (m, 1 H), 6.90 (d, 1 H), 5.88 (s, 1 H), 4.10-3.95 (m, 1 H), 3.45-3.25 (m, 4H), 2.76 (s, 3H), 2.70-2.45 (m, 2H), 2.35-2.10 (m, 2H) Example Product
2-[[3-(2-methanesulfonylvinyl)phenyl](1 -methylpiperidin-4-
212
yloxy)methyl]benzothiazole
1 H NMR: 7.99 (d, 1 H), 7.88 (s, 1 H), 7.78-7.59 (m, 3H), 7.55-7.38 (m, 4H), 6.92 (d, 1 H), 5.94 (s, 1 H), 3.78-3.62 (m, 1 H), 3.03 (s, 3H), 2.87-2.70 (m, 2H), 2.32 (s, 3H), 2.40-2.13 (m, 2H), 2.10-1 .75 (m, 4H)
Example 219
3-[benzothiazol-2-yl(1 -metriylpiperidin-4-yloxy)metriyl]-A/-benzyl-A/- methylbenzamide
A screw-capped tube is charged with 2-[(3-bromo-phenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (example 27, 400 mg), A/-benzylmethylamine (178 μΙ_), 1 ,8- diazabicyclo(5.4.0)undec-7-ene (100 μΙ_), trans-di^-acetatobis[2-(di-o-tolyl- phosphino)benzyl]dipalladium(ll) (22 mg), tri-ferf-butylphosphonium tetrafluoroborate (17mg), molybdenum hexacarbonyl (127mg) and tetrahydrofurane (3mL). The tube is sealed and heated at 125^ for l Omin.The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue is purified over silica gel (gradiant dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 95 / 5 / 0.5) to afford 3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]-A/-benzyl-A/-methyl- benzamide which is then converted into its oxalate salt in acetone to give 3-[benzothiazol- 2-yl(1 -methylpiperidin-4-yloxy)methyl]-A/-benzyl-A/-methylbenzamide, oxalate melting at 103 Ό.
Example 224
3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylamine
224A
To a solution of 2-[(1 -methylpiperidin-4-yloxy)(3-nitrophenyl)methyl]-1 H- benzimidazole (1 10mg) in ethanol is added tin(ll)dichloride (340mg). The reaction mixture is refluxed for 2 hours. The solution is basified by adding a solution of 10N sodium hydroxide to pH 10. The aqueous phase is extracted with chloroform. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ) to give 3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylamine melting at 100 *Ό. 224 B
2- [(1 -Methylpiperidin-4-yloxy)(3-nitrophenyl)methyl]-1 H-benzimidazole can be prepared according to the method described in example 165. Example 228
3- {3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenoxymethyl}- phenylamine, oxalate
A suspension of 2-{(1 -methylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)phenyl]- methyljbenzothiazole (example 196, 55mg) and tin(ll) chloride dihydrate (250mg) in ethanol (2ml_) is refluxed for 1 h. The cooled mixture is diltued with dichloromethane and aqueous 1 N sodium hydroxide. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure to afford 3-{3-[benzothiazol-2-yl(1 -methylpiperidin- 4-yloxy)methyl]phenoxymethyl}-phenylamine which is then converted into its oxalate salt in acetone to give 3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl] phenoxymethylj-phenylamine, oxalate as an orange solid. TLC of the base (eluent: CH2CI2/MeOH/NH4OH 95/5/0.5): Rf= 0.14.
Example 229
2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol enantiomer A
A solution of racemic 2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethanol (10mg/ml_) in a mixture of heptane / isopropanol (75 / 25) containing diethylamine (0.1 %) is injected (20x100μΙ_) onto an analytical Chiralcel OD- H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (80 / 20) containing diethylamine (0.1 %) at a flow of 1 mL/min. Products are detected at 220nm.
The first enantiomer has a retention time of 7.0min.
Collection affords 2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl] phenylsulfanyljethanol enantiomer A with a chromatographic enantiomeric purity of 100.0%.
Example 230
2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol enantiomer B
The second enantiomer has a retention time of 9.4min. Collection affords 2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl] phenylsulfanyljethanol enantiomer B with a chromatographic enantiomeric purity of 97.8%. Example 231
2-[(3-azidophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
231A
To a solution of 3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]- phenylamine (57mg) in methanol (3ml_) are added at 0 °C copper(ll) sulphate and a solution of trifluoromethanesulfonylazide (freshly prepared from sodium azide (220mg) and trifluoromethanesulfonic anhydride (200mg)) in dichloromethane.
The reaction mixture is stirred overnight at 4°C. Volatiles are removed under reduced pressure. Water is added to the residue and the solution is basified by adding a solution of saturated sodium carbonate to pH 10. The aqueous phase is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ) to give 2- [(3-azidophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole melting at 53 °C. 231 B
To a solution of 2-[(1 -Methyl-piperidin-4-yloxy)-(3-nitro-phenyl)-methyl]- 1 Hbenzimidazole (1 10mg) in ethanol (5ml_) is added Tin(ll)dichloride-dihydrate (340mg). The reaction mixture is heated at reflux for 2 hours. Water is added to the mixture as well as sodium hydroxide 1 N solution to pH 10. The solution is extracted with chloroform. The pooled organic phases are dried with magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ) to give 3-[(1 H-benzimidazol-2-yl)(1 - methylpiperidin-4-yloxy)methyl]phenylamine that is used without further purification. Example 234
{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine, dioxalate
A screw-capped tube is charged with 2-[(3-iodophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (example 41 , 190mg), copper(l) iodide (4mg), ethylene glycol (45μΙ_), potassium carbonate (173mg), benzylamine (54μΙ_), and propan-2-ol (1 ml_). The tube is evacuated, filled with argon and sealed. After stirring at 80 °C for 15h, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 95 / 5 / 0.5). The base is converted into its dioxalate salt in acetone to give {3-[benzothiazol-2-yl(1 -methylpiperidin- 4-yloxy)methyl]phenyl}benzyl-amine, dioxalate melting at 75°C.
Example 258
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenoxy}propan-1 -ol, oxalate.
A screw-capped tube is charged with 2-[(3-iodophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (example 41 , 150mg), copper(l) iodide (6.5mg), 3,4,7,8- tetramethyl-1 ,10-phenanthroline (16.3mg), cesium carbonate (223mg), propan-1 ,3-diol (74mg), ground 4 A molecular sieves (80mg) and toluene (4ml_). The tube is evacuated, filled with argon and sealed. After stirring at 90 °C for 24h, the mixture is diluted with dichloromethane, water and ammonia. After filtration and decantation, the aqueous phase is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 95 / 5 / 0.5). The base is converted into its oxalate salt in acetone to give 3-{3-[benzothiazol-2- yl(1 -methylpiperidin-4-yloxy)methyl]phenoxy}propan-1 -ol, oxalate melting at 79 °C.
Example 240
2-{(1 -methylpiperidin-4-yloxy)[3-(2-[1 ,2,3]triazol-2-yl-ethylsulfanyl)phenyl]- methyljbenzothiazole
240A
To a solution of 1 ,2,3-triazole (36.5mg) in A/,A/-dimethylformamide (1 ml_) is added a dispersion of sodium hydride 60% in mineral oil (1 molar equivalent). The reaction mixture is stirred at room temperature for 15 minutes, then a solution of methanesulfonic acid 2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl ester (85mg) in A/,A/-dimethylformamide (1 ml_) is added. The reaction mixture is stirred at 60°C overnight. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane / methanol / ammonia 100 / 0 / 0 to 90 / 10 / 1 ) to afford 2-{(1 -methylpiperidin-4-yloxy)[3-(2- [1 ,2,3]triazol-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole. 1 H NMR: 7.97 (d, 1 H), 7.87 (d, 1 H), 7.65-7.25 (m, 8H), 5.90 (s, 1 H), 4.62 (t, 2H), 3.75-3.60 (m, 1 H), 3.44 (t, 2H), 2.82-2.65 (m, 2H), 2.29 (s, 3H), 2.45-2.15 (m, 2H), 2.10- 1 .70 (m, 4H)
and
2-{(1 -methylpiperidin-4-yloxy)[3-(2-[1 ,2,3]triazol-1 -yl-ethylsulfanyl)phenyl]methyl}- benzothiazole
1 H NMR: 7.95 (d, 1 H), 7.87 (d, 1 H), 7.86 (s, 1 H), 7.61 (s, 1 H), 7.56(s, 1 H), 7.51 - 7.25 (m, 5H), 5.90 (s, 1 H), 4.52 (t, 2H), 3.75-3.60 (m, 1 H), 3.39 (t, 2H), 2.82-2.65 (m, 2H), 2.31 (s, 3H), 2.35-2.15 (m, 2H), 2.08-1 .70 (m, 4H).
240B
Methanesulfonic acid 2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl] phenylsulfanyljethyl ester
To a solution of 2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)- methyl]phenylsulfanyl}ethanol (400mg) in dichloromethane (5m L) is added methanesulfonylchloride (1 .25 molar equivalent) in dichloromethane (1 .5ml_) and triethylamine (1 .5 molar equivalent). The reaction mixture is stirred overnight at room temperature. Volatiles are removed under reduced pressure to dryness. Water is added and the aqueous phase is extracted by diethylether. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (dichloromethane / methanol from 98 / 2) to afford methanesulfonic acid 2-{3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl ester that will be used without further purification. Example 245
2-[(1 -methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]-1 H-benzimidazole
In a screw-cap tube are placed 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzimidazole (200mg), potassium vinyltrifluoroborate (72mg), 1 ,1 - bis(diphenylphosphino)ferrocene-dichloro-palladium (7.5mg) and n-propanol (3ml_). The reaction mixture is degassed and purged with argon. The mixture is heated at reflux for 48h. Water and ammonia solution are added and the aqueous phase is extracted by ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (gradient dichloromethane / methanol from 95 / 5 to 90 / 10 then dichloromethane / methanol / ammonia 90 / 10 / 0.1 ) to give 2-[(1 - methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]-1 H-benzimidazole. 1 H NMR: 7.68-7.55 (m, 2H), 7.48 (s, 1 H), 7.45-7.33 (m, 3H), 7.33-7.20 (m, 2H), 6.65 (dd, 1 H), 5.83 (s, 1 H), 5.75 (d, 1 H), 5.26 (d, 1 H), 3.88-3.75 (m, 1 H), 3.28-3.10 (m, 2H), 3.05-2.75 (m, 2H), 2.63 (s, 3H), 2.30-1 .95 (m, 4H) Example 249
2-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)metriyl]phenylsulfanyl}- ethylamine
249A
To a solution of A/-fert-butoxycarbonyl-2-{3-[(1 H-benzimidazol-2-yl)(1 - methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine in dichloromethane (2ml_) is added trifluoroacetic acid (0.5ml) at room temperature. The mixture is stirred at room temperature for 24h. Water is added and the mixture is basified by adding a solution of sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated. The residue is triturated in diisopropylether to give 2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethylamine.
1 H NMR: 7.80-7.65 (m, 1 H), 7.51 (s, 1 H), 7.48-7.15 (m, 7H), 5.85 (s, 1 H), 3.65- 3.53 (m, 1 H), 3.08-2.95 (m, 2H), 2.95-2.80 (m, 2H), 2.80-2.60 (m, 2H), 2.25 (s, 3H), 2.18- 1 .62 (m, 6H)
249B
A/-ferf-butoxycarbonyl-2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethylamine could be prepared using method described in example 150A.
Example 252
2-[(1 -methylpiperidin-4-yloxy)-p-tolylmethyl]-1 H-benzimidazole enantiomer A
A solution of 2-[(1 -methylpiperidin-4-yloxy)-p-tolylmethyl]-1 H-benzimidazole
(10mg/ml_) in methanol containing diethylamine (0.1 %) is injected (17χ100μΙ_) onto an analytical Ceramospher chiral RU-1 , 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (80 / 20) containing diethylamine (0.1 %) at a flow of
1 mL/min. Products are detected at 220nm.
The first enantiomer has a retention time of 10.4min.
Collection affords 2-[(1 -methylpiperidin-4-yloxy)-p-tolylmethyl]-1 H-benzimidazole enantiomer A with a chromatographic enantiomeric purity of 90%. Example 253
2-[(1 -methylpiperidin-4-yloxy)-p-tolylmethyl]-1 H-benzimidazole enantiomer B The second enantiomer has a retention time of 13.7min.
Collection affords 2-[(1 -methylpiperidin-4-yloxy)-p-tolylmethyl]-1 H-benzimidazole enantiomer B with a chromatographic enantiomeric purity of 90%.
Example 259
2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-/V- methylacetamide
259A
To a solution of methylamine hydrochloride (76mg) in toluene (2ml_) is added a 2N solution of trimethylaluminum in toluene. The reaction mixture is heated at 60 °C for 1 hour. Then a solution of {3-[(benzothiazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenylsulfanyl}acetic acid methyl ester (50mg) in toluene (1 ml_) is added. The reaction mixture is heated at 60 °C for 24 hours. Water is added to the reaction mixture, pH is adjusted to 10 with a solution of sodium hydroxide, and the mixture is filtered on celite. The filtrate is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (toluene / acetone / triethylamine 80 / 20 / 0.2) to give 2-{3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-A/-methylacetamide.
1 H NMR (DMSO-d6): 8.12-7.97 (m, 2H), 7.89 (d, 1 H), 7.52-7.22 (m, 6H), 5.90 (s, 1 H), 3.60 (s, 2H), 3.59-3.45 (m, 1 H), 2.62-2.40 (m, 5H), 2.03 (s, 3H), 2.03-1 .82 (m, 4H), 1 .82-1 .45 (m, 4H) 259B
{3-[(benzothiazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid methyl ester can be obtained using method described in example 150.
Example 260
2-{(1 -methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole 260A
A solution of 2-((1 -Methyl-piperidin-4-yloxy)-{3-[2-(2-trimethylsilanyl-ethoxymethyl)- 2H-pyrazol-3-yl]-phenyl}-methyl)-benzothiazole (500mg) in 5N hydrochloric acid (4ml_) is stirred overnight at room temperature. 30% sodium hydroxide solution is added to reach pH 10, and the reaction is diluted with water. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol from 100 / 0 to 90 / 10) to afford 2-{(1 -methylpiperidin-4- yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole melting at 90 °C. 260B
2-((1 -Methyl-piperidin-4-yloxy)-{3-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol- 3-yl]-phenyl}-methyl)-benzothiazole can be prepared according to the method described in example 53. Example 264
{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid hydrazide
To a solution of {3-[(benzothiazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl] phenylsulfanyljacetic acid methyl ester (30mg) in absolute ethanol (1 ml_) is added hydrazine hydrate (0.1 mL). The reaction mixture is heated at 80 °C for 18 hours. Solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol from 95 / 5 to 80 / 20) to give {3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid hydrazide.
1 H NMR (DMSO-d6): 10.30 and 10.15 (two singlets, 1 H), 8.05 (d, 1 H), 7.89 (d, 1 H), 7.50-7.20 (m, 6H), 5.99 (s, 1 H), 3.89 (d, 2H), 3.58-3.45 (m, 1 H), 2.75-2.50 (m, 2H), 2.09 (s, 3H), 2.08-1 .95 (m, 2H), 1 .90-1 .50 (m, 6H)
Example 268
2-(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}- cyclopropyl)ethanol
268A
To a solution of 1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl] phenylsulfanylmethyljcyclopropanecarboxylic acid methyl ester (56mg) in tetrahydrofuran (5ml_) is added lithium aluminumhydride (25mg) at 0 °C. The reaction mixture is allowed to reach room temperature and ethyl acetate (2ml_) is added. After stirring for 5 minutes, a half-saturated aqueous solution of sodium carbonate (6ml_) is added. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 95 / 5 / 0.5) to afford 2-(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl- sulfanylmethyl}cyclopropyl)ethanol. 1 H NMR: 7.97 (d, 1 H), 7.87 (d, 1 H), 7.56 (s, 1 H), 7.52-7.22 (m, 5H), 5.86 (s, 1 H), 3.72 (t, 2H), 3.72-3.58 (m, 1 H), 2.98 (dd, 2H), 2.82-2.78 (m, 2H), 2.27 (s, 3H), 2.27-2.10 (m, 3H), 2.10-1 .75 (m, 4H), 1 .78 (t, 2H), 0.44 (m, 4H)
268B
1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}- cyclopropanecarboxylic acid methyl ester can be obtained according to the method described in example 150.
Further examples can be prepared according to the above described general method:
Figure imgf000107_0001
Example 275
1 -(3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)- propan-2-one, oxalate
A screw-capped tube is charged with 2-[(3-iodophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (example 41 , 300mg), copper(l) iodide (10mg), tetrakis palladium (36mg), triethylamine (0.33ml_), 1 -methyl-2-pyrrolidinone (1 .3ml_), and 1 -prop-2- ynyloxypropan-2-one (109mg). The tube is evacuated, filled with argon and sealed. After stirring at 80 °C for one night, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 95 / 5 / 0.5). The base is converted into its oxalate salt in acetone to give 1 -(3-{3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-one, oxalate. TLC of the base (eluent: CH2CI2/MeOH/NH4OH 95/5/0.5): Rf= 0.18.
Example 276
1 -(3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)- propan-2-ol, oxalate A solution of 1 -(3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl} prop-2-ynyloxy)-propan-2-one (example 275, 140mg) in methanol (20mL) is treated with sodium borohydride (30mg) at 0°C, stirred 1 h at 0°C and 2h at room temperature. The mixture is then diluted with water and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 95 / 5 / 0.5) affords the pure base that is then converted into its oxalate salt in acetone to give 1 -(3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-ol, oxalate. TLC of the base (eluent: CH2CI2/MeOH/NH4OH 95/5/0.5): Rf= 0.12.
Example 278 Λ/-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
278A
To a solution of 2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenylsulfanyl}ethylamine (130mg) in acetonitrile (2ml_) is added N,N'-bis-Boc- guanylpyrazole (1 12mg) and diisopropylethylamine (0.066ml_) at room temperature. The mixture is heated at 50 °C for 5h. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0 to 90 / 10 / 0 then 90 / 10 / 1 ).
The residue is then dissolved in 6N aqueous hydrochloric acid (1 .5ml_) and the solution is stirred overnight at room temperature. The reaction mixture is neutralized to pH7 by adding dropwise 30% sodium hydroxide solution. The solvent is removed under reduced pressure and the residue is triturated with a (dichloromethane / methanol)(95 / 5) and filtered. The filtrate is evaporated under reduced pressure to give Λ/-(2-{3-[(1 Η- benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine as the dihydrochloride salt.
m/z : [M+H]+ = 439.0
278B
2-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- ethylamine can be prepared as described in example 249.
Following compounds are prepared analogously:
Example Product
394 4-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- Example Product
yloxy)methyl]phenyl}piperidine-1 -carboxamidine hydrochloride
1 H NMR (D MSO-d6): 7.48-7.38 (m, 2H), 7.34 (s, 1 H), 7.32-7.20 (m, 2H), 7.17-7.00 (m, 3H), 5.78 (s , 1 H), 3.98 (si, 1 H), 3.92 (si, 1 H), 2.88-2.50 (m, 4H), 2.07 (s, 3H), 2.00-1 .75 (m, 4H), 1 .75-1 .45 (m, 6H)
Example 293
4-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}butylamine, dichlorhydrate
293A
To a solution of 4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenyl}but-3-ynylamine (50mg) in methanol (2.5ml_) is added platinum oxide (8mg). The flask is purged with argon then put under one atmosphere of hydrogen. The reaction mixture is stirred overnight at room temperature then filtered on celite, cake washed with methanol. The solvent is removed under reduced pressure to give 4-{3-[(1 H- benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}butylamine.
m/z : [M+H]+ = 393.1 ; [M+Na]+ = 415.2
293B
4-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}but-3- ynylamine can be prepared according to general method in example 194.
Following compounds are prepared analogously:
Figure imgf000109_0001
Following compounds are prepared according to the general methods: General
Example Product m/z methods
{3'-[benzothiazol-2-yl(1 -metriylpiperidin-4- [M+H]+ =
98 53
yloxy)methyl]biphenyl-3-yl}acetonitrile, oxalate 454.2
2-[(3'-fluorobiphenyl-3-yl)(1 -methylpiperidin-4- [M+H] + =
139 53
yloxy)methyl]benzothiazole 433.1
2-[(1 -methylpiperidin-4-yloxy)(4'- [M+H] + =
140 53
trifluoromethylbiphenyl-3-yl)methyl]benzothiazole 483.2
2- [(1 -met ylpiperidin-4-yloxy)(2',3',4'-trifluorobip enyl- [M+H] + =
141 53
3- yl)methyl]benzothiazole 468.6
{3'-[benzothiazol-2-yl(1 -metriylpiperidin-4-yloxy)- [M+H]+ =
143 53
methyl]biphenyl-4-yl}carbamic acid ferf-butyl ester 530.2
Λ/-(3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 278A, [M+H]+ =
320
yloxy)methyl]phenyl}propyl)guanidine, trihydrochloride 249, 149A 421 .0
[M+H]+ =
Λ/-(3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 278A, 421 .2
321
yloxy)methyl]phenyl}propyl)guanidine, trihydrochloride 249, 149A [M+Na]+ =
443.2
6-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- [M+H]+ =
344 293, 194
yloxy)methyl]phenyl}hexylamine 421 .2
Λ/-(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
278A, [M+H]+ =
346 yloxy)methyl]phenyl}hex-5-ynyl)guanidine,
249, 149A 459.2 hydrochloride
[M+H]+ =
Λ/-(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 278A, 463.2
355
yloxy)methyl]phenyl}hexyl)guanidine, trihydrochloride 249, 149A [M+Na]+ =
485.3
[M+H]+ =
Λ/-(5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
278A, 445.2
358 yloxy)methyl]phenyl}pent-4-ynyl)guanidine,
249, 149A [M+Na]+ = hydrochloride
467.3
A/-(4-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
278A, [M+H]+ =
372 yloxy)methyl]phenyl}but-3-ynyl)guanidine,
249, 149A 448.1 dihydrochloride
393 Λ/-(4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 278A, [M+H]+ = General
Example Product m/z methods
yloxy)methyl]phenyl}but-3-ynyl)guanidine, 249, 149A 431 .1 hydrochloride
[M+H]+ =
Λ/-(5-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- 278A, 449.2
397
yloxy)methyl]phenyl}pentyl)guanidine, hydrochloride 249, 149A [M+Na]+ =
471 .2
Λ/-(3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
278A, [M+H]+ =
418 yloxy)methyl]phenyl}prop-2-ynyl)guanidine,
249, 149A 417.1 hydrochloride
[M+H]+ =
3-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- 278A, 443.1
426
yloxy)methyl]phenylethynyl}azetidine-1 -carboxamidine 249, 149A [M+Na]+ =
465.4
Example 298
(2-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- ethyl)urea
298A
To a solution of 2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenylsulfanyl}ethylamine
(50mg) in ethanol (0.5ml_) in a screw-cap tube is added potassium cyanate (15mg). The reaction mixture is heated at 80°C for 24 hours. The mixture is diluted water, basified to pH 9 by adding of an aqueous saturated solution of sodium carbonate and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0.5 to 90 / 10 / 1 ) to afford (2-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl- sulfanyl}ethyl)urea melting at 136 °C.
298B
2-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- ethylamine can be prepared according to the method described in example 249.
Following compounds are prepared analogously: Example Product
(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl-
299
sulfanyl}ethyl)(4,5-dihydrothiazol-2-yl)amine
1 H NMR (D MSO-d6): 12.37 (si, 1 H), 7.53-7.38 (m, 3H), 7.27-6.95 (m, 5H), 5.80 (s, 1 H), 3.80 (t, 2H) 3.45-3.00 (m, 7H), 2.65-2.50 (m, 2H), 2.07 (s, 3H), 2.00-1 .75 (m, 4H), 1 .65- 1 .45 (m, 2H )
(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-
317
phenylsulfanyl}ethyl)(4,5-dihydro-1 /-/-imidazol-2-yl)amine
1 H NMR (DMSO-d6): 12.90 (si, 1 H), 10.80 and 10.40 (si, 1 H), 8.58-8.42 (m, 1 H), 7.53-7.38 (m, 3H), 7.27-6.95 (m, 5H), 5.93 (s, 1 H), 3.80 (t, 2H), 3.45-3.00 (m, 7H), 2.65-2.50 (m, 2H), 2.07 (s, 3H), 2.00-1 .75 (m, 4H), 1 .65-1 .45 (m, 2H)
1 -(2-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-
347
yloxy)methyl]phenylsulfanyl}ethyl)-3-isopropylthiourea
1 H NMR: 10.43 (si, 1 H), 7.72-7.50 (m, 3H), 7.35-7.20 (m, 5H), 6.45-6.15 (m, 2H), 5.83 (s, 1 H), 4.05-3.50 (m, 4H), 3.45-3.05 (m, 2H), 3.00-2.75 (m, 2H), 2.39 (s, 3H), 2.20-1 .75 (m, 4H), 1 .22 (m, 1 H), 1 .02 (d, 3H), 0.91 (d, 3H)
Example 305
5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- pentylamine, oxalate
305A
2-(5-{3-[(1 - -Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- pentyl)isoindole-1 ,3-dione (200mg) is dissolved in ethanol (1 ml_) and hydrazine hydrate (0.1 mL) is added. The reaction mixture is stirred at room temperature overnight. The mixture is evaporated to dryness and the residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ). The residue is added to oxalic acid (1 equivalent) in acetone (0.5ml), and the precipitate is filtered and dry to give 5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- pentylamine, oxalate melting at 201 °C. 305B
2-(5-{3-[(1 - -Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- pentyl)isoindole-1 ,3-dione
A screw-cap tube is charged with 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (200mg), palladium bis(dibenzylideneacetone) (14mg), Xantphos (14mg), thioacetic acid 5-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)-pentyl ester (209mg), diisopropylethylamine (170μΙ_), potassium phosphate (105mg), water (0.05ml_) and 1 ,4-dioxane (2mL). The tube is evacuated, filled with argon and sealed. After stirring at 120 ^ for 48h, solvents are removed under reduced pressure. The residual solution is basified by adding a solution of saturated sodium carbonate to pH 10 and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 95 / 5 / 0.5) to give 2-(5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl] phenylsulfanylpentyl)isoindole-1 ,3-dione that is used without further purification.
Example 307
A/-ferf-butoxycarbonyl-A/-(4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}but-3-ynyl)guanidine
307A
To a solution of 4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenyl}but-3-ynylamine (290mg) in acetonitrile (4.5ml_) is added N,N'-bis-Boc- guanylpyrazole (255mg) and diisopropylethylamine (0.15ml_) at room temperature. The mixture is heated at 50 °C overnight. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0 to 90 / 10 / 0 then 90 / 10 / 1 ).
A part of the residue (100mg) is then dissolved in 1 ,2-dichloroethane (2ml_) ; phenol (149mg) and chlorotrimethylsilane (0.2ml_) are added and the solution is heated at 50 °C for 20h. Solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0 to 90 / 10 / 0 then 90 / 10 / 1 ) to give A/-fert-butoxycarbonyl-A/-(4-{3-[(1 H-benzimidazol- 2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine.
1 H NMR: 7.54 (si, 2H), 7.32 (s, 1 H), 7.27-7.19 (m, 6H), 5.67 (s, 1 H), 3.70-3.52 (m, 1 H), 3.52-3.32 (m, 2H), 2.85-2.65 (m, 2H), 2.61 (t, 2H), 2.24 (s, 3H), 2.20-2.02 (m, 2H), 1 .92-1 .50 (m, 4H), 1 .49 (t, 9H)
307B
4-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}but-3- ynylamine can be prepared as described in example 194A.
Example 315 2-{(1 -methylpiperidin-4-yloxy)[3-(4-[1 ,2,3]triazol-2-yl-butoxy)phenyl]methyl}- benzothiazole, oxalate
315A
60% in oil sodium hydride (20mg) is washed with pentane and diluted with anhydrous A/JV-dimethylformamide (5ml_). 1 H-1 ,2,3-triazole is then added. After stirring at rrom temperature for 15 min, the mixture is treated with 2-[[3-(4-chloro-butoxy)phenyl]-(1 - methyl-piperidin-4-yloxy)methyl]benzothiazole (223mg) and warmed at 60 °C for one night. The mixture is then poured into water and extracted with diethylether. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 90 / 10 / 0.5) affords the pure base that is then converted into its oxalate salt in acetone to give 2-{(1 -methylpiperidin-4-yloxy)[3-(4-[1 ,2,3]triazol-2-yl- butoxy)phenyl]methyl}benzothiazole, oxalate. TLC of the base (eluent: CH2CI2/MeOH/NH4OH 90/10/0.5): Rf= 0.30.
315B
2-[[3-(4-Chlorobutoxy)phenyl](1 -methylpiperidin-4-yloxy)methyl]benzothiazole can be prepared according to the described general methods 272A and 1 B. Example 316
2-{(1 -methylpiperidin-4-yloxy)[3-(4-[1 ,2,4]triazol-1 -yl-butoxy)phenyl]methyl}- benzothiazole, oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(4-[1 ,2,4]triazol-1 -yl-butoxy)phenyl]methyl}- benzothiazole, oxalate can be prepared according general procedure 315A. TLC of the base (eluent: CH2CI2/MeOH/NH4OH 90/10/0.5): Rf= 0.22.
Example 318
Λ/-(2-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- ethyl)-A/-cyanoguanidine
318A
To a solution of 2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenylsulfanyl}ethylamine (50mg) in isopropanol (1 mL) in a screw-cap tube is added diphenylcyanocarbonimidate (30mg). The reaction mixture is stirred at room temperature overnight. Solvent is removed under reduced pressure and the residual solid is dried. This solid is dissolved in ethanol (2mL) saturated with ammonia gas in a screw- cap tube. The tube is sealed and the reaction mixture is heated to 80 °C for 2 hours. The solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ) to afford Λ/-(2-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl] phenylsulfanyl}ethyl)-A/-cyanoguanidine melting at 65 °C.
318B
2-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- ethylamine can be prepared according to the method described in example 249.
Example 338
2-{(1 -methylpiperidin-4-yloxy)[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1 H- benzimidazole
338A
To a solution of 4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenyl}-3,6-dihydro-2H-pyridine-1 -carboxylic acid ferf-butyl ester (407mg) in dichloromethane (2mL) is added trifluoroacetic acid (1 ml_). After 2 hours at room temperature, volatiles are removed under reduced pressure. The mixture is diluted with water, basified to pH 10 by adding of an aqueous saturated solution of sodium carbonate and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 85 / 15 / 1 .5) to afford 2-{(1 -methylpiperidin-4-yloxy)[3-(1 ,2,3,6-tetrahydro-pyridin-4- yl)phenyl]methyl}-1 H-benzimidazole.
1 H NMR: 10.0 (si, 1 H), 7.60 (s, 1 H), 7.70-7.45 (m, 2H), 7.40-7.20 (m, 5H), 6.06 (s, 1 H), 5.87 (s, 1 H), 3.50 (t, 2H), 3.65-3.45 (m, 1 H), 3.08 (d, 2H), 2.80-2.75 (m, 2H), 2.60- 2.22 (m, 3H), 2.26 (s, 3H), 2.20-1 .65 (m, 6H)
338A
4-{3-[(1 - -Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro- 2 - -pyridine-1 -carboxylic acid ferf-butyl ester can be prepared according to the procedure described in example 53.
Example 359
4-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- butylamine, oxalate
359A (4-{3-[Benzothiazol-2-yl-(1 -methyl-piperidin-4-yloxy)-methyl]-ph
carbamic acid ferf-butyl ester (140mg) is dissolved in dichloromethane (1 ml_) and trifluoroacetic acid (0.4ml_) is added. The reaction mixture is stirred at room temperature for 1 hour. The mixture is evaporated to dryness. The residue is basified by adding a solution of saturated sodium carbonate to pH 10 and the aqueous phase is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 90 / 10 / 1 ). The residue is added to oxalic acid (1 equivalent) in acetone (0.5ml), and the precipitate is filtered and dry to give 4-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)- methyl]phenylsulfanyl}butylamine, oxalate melting at Ι Οδ'Ό.
359B
(4-{3-[(1 - -Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- butyl)carbamic acid ferf-butyl ester.
A screw-cap tube is charged with 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (200mg), palladium bis(dibenzylideneacetone) (14mg), Xantphos (14mg), thioacetic acid S-(4-ferf-butoxycarbonylaminobutyl) ester (180mg), potassium phosphate (200mg), water (0.01 mL) and 1 ,4-dioxane (2ml_). The tube is evacuated, filled with argon and sealed. After stirring at 120 ^ for 48h, solvents are removed under reduced pressure. The residue is basified by adding a solution of saturated sodium carbonate to pH 10 and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 95 / 5 / 0.5) to give (4-{3-[(1 H- benzimidazol-2-yl)-(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)carbamic acid ferf-butyl ester that is used without further purification.
Example 376
2-[(1 -methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1 H- benzimidazole
376A
To a solution of 4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenylethynyl}piperidine-1 -carboxylic acid ferf-butyl ester (160mg) in 1 ,2- dichloroethane (10ml_) are added phenol (940mg) and chlorotrimethylsilane (1 .26ml_).The reaction mixture is heated to 100°C for 30 minutes. Volatiles are removed under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 85 / 15 / 1 .5) to afford 2-[(1 -methylpiperidin-4- yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1 H-benzimidazole.
1 H NMR: 9.80 (si, 1 H), 7.50 (s, 1 H), 7.80-7.50 (m, 2H), 7.45-7.20 (m, 5H), , 5.84 (s, 1 H), 3.65-3.50 (m, 1 H), 3.25-3.10 (m, 2H), 2.90-2.35 (m, 7H), 2.25 (s, 3H), 2.20-1 .65 (m, 9H)
376B
4- {3-[(1 - -Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylethynyl}- piperidine-1 -carboxylic acid ierf-butyl ester can be prepared according to the procedure described in example 189.
Example 384
5- {3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1 -ol 384A
To a solution of Acetic acid 5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-enyl ester (150mg) in a mixture of water (1 ml_), 1 ,4-dioxane (1 ml_) and methanol (1 ml_) is added 1 N sodium hydroxide solution (0.6ml_). The reaction mixture is stirred at room temperature for 2 hours. After neutralization to pH 7 with addition of 1 N hydrochloric acid, the reaction mixture is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0.5 to 90 / 10 / 1 ) to afford 5-{3-[benzothiazol-2-yl(1 - methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1 -ol.
1 H NMR: 7.97 (d, 1 H), 7.86 (dd, 1 H), 7.53-7.24 (m, 6H), 6.32 (dd, 1 H), 6.27 (dd, 1 H) 5.30 (s, 1 H), 3.71 (t, 2H), 3.77-3.60 (m, 1 H), 3.00-2.90 (m, 2H), 2.80-2.68 (m, 2H), 2.30 (s, 3H), 2.37-2.15 (m, 4H), 2.20-1 .55 (m, 5H)
384B
Acetic acid 5-{3-[benzothiazol-2-yl-(1 -methyl-piperidin-4-yloxy)-methyl]-phenyl}- pent-4-enyl ester can be prepared according to the method described in example 53.
Following examples can be prepared analogously:
General
Example Product
methods General
Example Product
methods
2-[[3-(2,5-difluorobenzyloxy)phenyl](1 -methylpiperidin-4-56 1 A,168B yloxy)methyl]benzothiazole, oxalate
H NMR ol the base (CDCI3): 7.96 (d, 1 H), 7.85 (d, 1 H), 6.90-7.50 (m, 9H), 5.86 (s, 1 H), .10 (s, 2H ), 3.83 (m, 1 H), 2.97 (m, 2H), 2.83 (m, 2H), 2.61 (s, 3H), 2.20 (m, 2H), 1 .93 (m, H).
2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-63 259A, 150 yloxy)methyl]phenylsulfanyl}acetamide
H NMR (DMSO-d6): 8.03 (s, 1 H), 7.86 (d, 1 H), 7.61 (si, 1 H), 7.48-7.18 (m, 6H), 7.1 1 (si, H), 5.95 (s, 1 H), 3.57 (s, 2H), 3.57-3.45 (m, 1 H), 2.62-2.40 (m, 2H), 2.07 (s, 3H), 2.07- .72 (m, 4H), 1 .70-1 .35 (m, 2H)
A/-ferf-butoxycarbonyl-A/-(4-{3-[(1 /-/-benzimidazol-2-yl)(1 -09 307A, 194A methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine
H NMR: 7.65-7.55 (m, 2H), 7.38 (s, 1 H), 7.30-7.15 (m, 4H), 7.01 (d, 1 H), 5.79 (s, 1 H), .70-3.55 (m, 1 H), 3.18-2.95 (m, 4H), 2.55-2.30 (m, 4H), 2.44 (s, 3H), 2.15-1 .95 (m, 2H), .95-1 .70 (m, 2H), 1 .65-1 .50 (m, 4H), 1 .49 (s, 9H)
A/-ferf-butoxycarbonyl-A/-(3-{3-[(1 H-benzimidazol-2-yl)(1 - 13 307A, 194A methylpiperidin-4-yloxy)methyl]phenyl}propyl)amine
H NMR: 7.68-7.58 (m, 2H), 7.52 (s, 1 H), 7.30-7.15 (m, 4H), 7.01 (d, 1 H), 5.79 (s, 1 H), .85-3.70 (m, 1 H), 3.45-3.18 (m, 4H), 2.78-2.50 (m, 4H), 2.62 (s, 3H), 2.20-1 .60 (m, 6H), .46 (s, 9H)
A/-ferf-butoxycarbonyl-A/-(-{3-[(1 /-/-benzimidazol-2-yl)(1 -35 methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine, 307A, 194A hydrochloride
H NMR: S .95 (si, 1 H), 7.68-7.58 (m, 2H), 7.41 (s, 1 H), 7.32-7.15 (m, 4H), 7.01 (d, 1 H), .78 (s, 1 H ), 3.92-3.82 (m, 1 H), 3.70-3.25 (m, 4H), 3.20-2.70 (m, 4H), 2.81 (s, 3H), 2.52 (t, H), 2.30-1 .85 (m, 4H), 1 .70-1 .50 (m, 2H), 1 .49 (s, 9H), 1 .35-1 .20 (m, 2H)
A/-fert-butoxycarbonyl-A/-(3-{3-[(1 H-benzimidazol-2-yl)(1 -36 307A, 194A methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine
H NMR: 7.68-7.58 (m, 2H), 7.41 (s, 1 H), 7.32-7.15 (m, 4H), 7.01 (d, 1 H), 5.78 (s, 1 H), .27 (s, 2H), 3.92-3.82 (m, 1 H), 3.10-2.80 (m, 2H), 2.37 (s, 3H), 2.65-2.30 (m, 2H), 2.15- .90 (m, 2H), 1 .90-1 .65 (m, 2H),1 .46 (s, 9H)
A/-fert-butoxycarbonyl-A/-(6-{3-[(1 H-benzimidazol-2-yl)(1 -45 307A, 194A methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine General
Example Product
methods
1H NMR (DMSO-d6): 10.91 (si, 1H), 8.71 (si, 1H), 7.65-7.48 (m, 2H), 7.48-7.15 (m, 6H), 6.00(s, 1H), 3.80 (s, 1H), 3.00-2.82 (m, 2H), 2.75 (m, 2H), 3.63 (m, 2H), 2.43 (s, 3H), 2.15-2.05 (m, 2H), 1.98-1.75 (m, 2H), 1.75-1.55 (m, 6H),1.44 (s, 9H)
4-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
370A, 272A
351 yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic acid tert- and 1B butyl ester, oxalate
1H NMR of the base (CDCI3): 7.96 (d, 1H), 7.82 (d, 1H), 7.50-7.20 (m, 3H), 7.07 (m, 2H), 6.79 (d, 1 h X), 5.86 (s, 1H), 3.97 (t, 2H), 3.60 (m, 1H), 3.40 (m, 4H), 2.67 (m, 2H), 2.48 (t, 2H), 2.36 ( m, 4H), 2.23 (s, 3H), 2.13 (m, 2H), 2.00-1.70 (m, 6H), 1.44 (s, 9H)
4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
353 yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxamidine, 376A, 189 hydrochloride
1H NMR (DMSO-d6): 10.7 and 10.45 (si, 1H), 7.68-7.50 (m, 1H), 7.50-7.35 (m, 2H), 7.28- 7.10 (m, 5H), 6.20 (s, 1H), 5.95 (d, 1H), 4.06 (s, 2H), 3.79 (s, 1H), 3.58 (t, 2H), 3.05-2.80 (m, 2H), 2.74 (s, 2H), 2.65-2.50 (m, 2H), 2.48 (s, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 2H)
A/-fert-butoxycarbonyl-A/-(5-{3-[(1 H-benzimidazol-2-yl)(1 -
357 307A, 194A methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine
1H NMR (DMSO-d6): 12.55 (si, 1H), 8.67 (si, 1H), 7.68-7.40 (m, 2H), 7.40-7.25 (m, 3H), 7.20-7.05 (m, 3H), 5.86(s, 1H), 3.78-3.50 (m, 1H), 3.10-2.80 (m, 2H), 2.75-2.50 (m, 4H), 2.46 (s, 3H), 2.20-1.65 (m, 8H), 1.42 (s, 9H)
2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-
383 258
yloxy)phenyl]methyl}benzothiazole, dioxalate
1H NMR of the base (CDCI3): 7.98 (d, 1H), 7.87 (d, 1H), 7.46-7.20 (m, 3H), 7.09 (m, 2H), 6.80 (d, 1 h H), 5.89 (s, 1H), 4.83 (m, 1H), 3.63 (m, 2H), 3.17 (m, 1H), 3.00-2.85 (m, 2H), 2.68 (m, 2\ H), 2.28 (s, 3H), 2.20-1.70 (m, 8H)
5-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-
390 384A, 53 yloxy)methyl]phenyl}pent-4-en-1-ol
1H NMR: 7.97 (d, 1H), 7.86 (dd, 1H), 7.54 (s, 1H), 7.50-7.25 (m, 4H), 7.19 (d, 1H), 6.43 (dd, 1H), 6.27 (dd, 1H) 5.94 (s, 1H), 5.73 (dd, 1H), 3.77-3.60 (m, 3H), 2.87-2.70 (m, 2H), 2.55-2.20 (m, 2H), 2.33 (s, 3H), 2.20-1.65 (m, 7H) Example 385
3-amino-4-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl- sulfanyl}ethylamino)-cyclobut-3-ene-1 ,2-dione 385A
To a solution of 2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenylsulfanyl}ethylamine (150mg) in diethylether (10ml_) is added L). The reaction mixture is stirred at 3,4-diethoxy-3-cyclobutene-1 ,2-dione (56 room temperature for 1 hour. The mixture is filtered, washed with diethylether and dried. The residue is dissolved in ethanol (2ml_) saturated with ammonia gas in a screw-capped tube. The tube is sealed and the reaction mixture is heated to 80 °C for 2 hours. The solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ) to afford 3-amino-4-(2-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethylamino) -cyclobut-3-ene-1 ,2-dione melting at 161 °C.
385B
2-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- amine can be prepared according to the method described in example 249.
Example 386
[[3-(6-aminohex-1 -ynyl)phenyl](1 /-/-benzimidazol-2-yl)methyl](1 -methylpiperidin-4- yl)amine
386A
A solution of 2-(5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-ylamino)- methyl]phenyl}pent-4-ynyl)isoindole-1 ,3-dione (230mg) and hydrazine hydrate (120μΙ_) in ethanol (3ml_) is stirred a room temperature for one night. The mixture is then concentrated under reduced pressure and the residue purified by chromatography (dichloromethane / methanol / ammonia from 90 / 10 / 0.5) to afford [[3-(6-aminohex-1 - ynyl)phenyl](1 - -benzimidazol-2-yl)methyl](1 -methylpiperidin-4-yl)amine melting at 79 °C. 386B
2-(5-{3-[(1 - -Benzimidazol-2-yl)(1 -methylpiperidin-4-ylamino)methyl]phenyl}pent-4- ynyl)isoindole-1 ,3-dione can be prepared according to general procedure 275 starting from [(1 H-benzimidazol-2-yl)(3-iodo-phenyl)methyl](1 -methylpiperidin-4-yl)amine. Example 398
2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1 -methylpiperidin-4-yloxy)methyl]- 1 /-/-benzimidazole
398A
To a solution of 2-({1 -methylpiperidin-4-yloxy){3-[3-(1 -trityl-1 H-imidazol-4- yl)propylsulfanyl]phenyl}methyl)-1 H-benzimidazole (200mg) in 1 ,2-dichloroethane (7mL) are added phenol (270mg) and chlorotrimethylsilane (0.37mL). The reaction mixture is heated at reflux overnight. Volatiles are removed under reduced pressure and the residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ) to give 2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1 - methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole.
1 H NMR: 7.72-7.40 (m, 4H), 7.25-7.15 (m, 5H), 6.82 (s, 1 H), 5.84 (s, 1 H), 3.60- 3.45 (m, 1 H), 3.00-2.65 (m, 6H), 2.25 (s, 3H), 2.15-1 .60 (m, 8H) 398B
2-((1 -Methylpiperidin-4-yloxy){3-[3-(1 -trityl-1 H-imidazol-4-yl)propylsulfanyl]phenyl}- methyl)-1 H-benzimidazole can be prepared according to the method described in example 359A. Example 401
A/-acetyl-A/-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl- sulfanyl}ethyl)guanidine
401A
To a solution of Λ/-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenylsulfanyl}ethyl)guanidine.dihydrochloride (100mg) in dry acetonitrile (1 ml_) is added acetic anhydride (64mg) et 4-dimethylaminopyridine (51 mg). After 24 hours at room temperature, solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography (toluene / acetone / triethylamine 50 / 50 / 1 then gradient dichloromethane / methanol / ammonia from 95 / 5 / 0.5 to 90 / 10 / 1 ) to give N- acetyl-A/-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl] phenyl- sulfanyl}ethyl)guanidine.
1 H NMR (DMSO-d6): 12.40 (si, 1 H), 7.55-7.40 (m, 1 H), 7.40-7.20 (m, 3H), 7.20- 7.05 (m, 4H), 5.81 (s, 1 H), 3.50-3.05 (m, 3H), 2.65-2.55 (m, 2H), 2.46 (s, 3H), 2.07 (s, 3H), 2.02-1 .72 (m, 4H), 1 .68-1 .45 (m, 4H). 401 B
Λ/-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- ethyl)guanidine can be obtained according to the method described in example 278. Example 403
1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}azetidin-3-ol, oxalate
A screw-capped tube is charged with 2-[(3-iodophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (example 41 , 150mg), copper(l) iodide (15mg), deanol (1 mL), potassium carbonate (306mg), azetidin-3-ol, hydrochloride (88mg). The tube is evacuated, filled with argon and sealed. After stirring at 60°C for 100h, the mixture is diluted with dichloromethane, water and ammonia. After decantation, the aqueous phase is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0.5 to 90 / 10 / 0.5). The base is converted into its oxalate salt in acetone to give 1 -{3-[benzothiazol- 2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}azetidin-3-ol, oxalate melting at 1 17°C.
Example 41 1
1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol, oxalate
A solution of acetic acid 1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]phenyl}piperidin-4-yl ester (example 413, 100mg) and aqueous 1 N sodium hydroxide in methanol (1 ml_) is stirred at room temperature for 30min. The mixture is diluted water and extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0.5 to 90 / 10 / 0.5). The base is converted into its oxalate salt in acetone to give 1 -{3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol, oxalate melting at 1 10°C.
Example 412
2-[{3-[2-(1 /-/-imidazol-4-yl)ethyl]phenyl}(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole 412A
To a solution of 2-{(1 -methylpiperidin-4-yloxy)[3-(1 -trityl-1 H-imidazol-4- ylethynyl)phenyl]methyl}-1 H-benzimidazole (260mg) in 1 ,2-dichloroethane (7mL) are added phenol (374mg) and chlorotnmethylsilane (0.51 mL). The reaction mixture is heated at reflux overnight. Volatiles are removed under reduced pressure and the residue is purified by chromatography (gradient dichloromethane / methanol from 95 / 5 to 90 / 10 then dichloromethane / methanol / ammonia 90 / 10 / 1 ).
The residue is then dissolved in methanol (3ml_) and palladium on charcoal (8mg). is added. The flask is purged with argon then put under one atmosphere of hydrogen. The reaction mixture is stirred overnight at room temperature then filtered on celite, cake washed with methanol. The solvent is removed under reduced pressure to give 2-[{3-[2- (1 /-/-imidazol-4-yl)ethyl]phenyl}(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole.
1 H NMR(methanol-d4): 7.65-7.55 (m, 3H), 7.40-7.15 (m, 6H), 6.70 (s, 1 H), 5.85 (s, 1 H), 3.80-3.70 (m, 1 H), 3.28-3.10 (m, 2H), 3.05-2.75 (m, 6H), 2.64 (s, 3H), 2.15-1 .85 (m, 4H).
412B
2-{(1 -Methylpiperidin-4-yloxy)[3-(1 -trityl-1 H-imidazol-4-ylethynyl)phenyl]methyl}- 1 H-benzimidazole can be prepared according to the method described in example 189.
Example 416
2-{(1 -methylpiperidin-4-yloxy)[3-(5-[1 ,2,3]triazol-2-yl-pent-1 -ynyl)phenyl]methyl}- 1 H-benzimidazole
416A
To a solution of 1 ,2,3-triazole (66mg) in DMF (0.6ml_) is added sodium hydride
(25mg). After gas evolution ceased, 2-[[3-(5-chloropent-1 -ynyl)phenyl](1 -methylpiperidin- 4-yloxy)methyl]-1 H-benzimidazole (50mg) and a catalytic quantity of n- tetrabutylammonium iodide are added. After stirring overnight at room temperature, the solvent is removed under reduced pressure to dryness. The residue is purified by chromatography (dichloromethane / methanol / ammonia 90 / 10 / 1 ) to afford 2-{(1 - methylpiperidin-4-yloxy)[3-(5-[1 ,2,3]triazol-2-yl-pent-1 -ynyl)phenyl]methyl}-1 H- benzimidazole.
1 H NMR: 9.43 (si, 1 H), 7.83-7.68 (m, 1 H), 7.60 (s, 2H), 7.52 (s, 1 H), 7.50-7.20 (m, 6H), 5.84 (s, 1 H), 4.61 (t, 2H), 3.68-3.50 (m, 1 H), 2.88-2.70 (m, 2H), 2.46 (t, 2H), 2.30 (s, 3H), 2.38-2.10 (m, 4H), 2.10-1 .65 (m, 6H). 416B
2-[[3-(5-Chloropent-1 -ynyl)phenyl](1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole can be obtained according to the synthetic method described in example 189.
Following compounds are prepared analogously:
Figure imgf000124_0001
Example 421
5-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4- enylamine.
421A
To a solution of 5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)- methyl]phenyl}pent-4-ynylamine (200mg) in A/JV-dimethylformamide (1 .8ml_) are added water (0.05ml_), potassium hydroxide (42mg) and palladium(ll) acetate. The tube is evacuated, filled with argon and sealed. After stirring at 120 ^ for 24h, the mixture is filtered on celite, and the solvent removed under reduced pressure.diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 90 / 10 / 0 to 90 / 10 / 1 ) to give 5-{3-[(1 H-benzimidazol-2-yl)(1 - methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine.
1 H NMR: 7.75-7.58 (m, 2H), 7.42-7.10 (m, 6H), 6.45 (d, 1 H), 5.90 (s, 1 H), 5.72 (dt, 1 H), 3.68-3.50 (m, 1 H), 2.95-2.85 (m, 2H), 2.85-2.65 (m, 2H), 2.50-2.35 (m, 2H), 2.25 (s, 3H), 2.25-1 .65 (m, 8H), 421 B 5-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4- ynylamine can be synthesized according to the procedure described in example 194.
Example 423
1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3- ylamine, dioxalate
423AA solution of crude (1 -{3-[benzothiazol-2-yl-(1 -methylpiperidin-4- yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamic acid ferf-butyl ester (289mg) in dichloromethane (3ml_) and trifluoroacetic acid (2.5ml_) is stirred at room temperature for one night. The mixture is concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous 1 N sodium hydroxide, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0.5 to 80 / 20 / 0.5). The base is converted into its dioxalate salt in acetone to give 1 -{3-[benzothiazol-2-yl(1 - methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine, dioxalate melting at 145°C.
423B
A screw-capped tube is charged with 2-[(3-iodophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (example 41 , 200mg), copper(l) iodide (7mg), 2- isobutyrylcyclohexanone (25mg), cesium carbonate (280mg), 3-(Boc-amino)pyrrolidine (160mg) and anhydrous A/JV-dimethylformamide (1 ml_). The tube is evacuated, filled with argon and sealed. After stirring at 55°C for 4 days, the mixture is diluted with ethyl acetate, water and ammonia. After decantation, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 95 / 5 / 0.5). to afford (1 -{3- [benzothiazol-2-yl-(1 -methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamic acid ferf-butyl ester. Example 432
432A
2-(5-{3-[(1 - -Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- pentyl)isoindole-1 ,3-dione
To a solution of 5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}pentan-1 -ol (35mg) in tetrahydrofuran are added triphenylphosphine (31 mg) and phthalimide (18mg). The reaction mixture is cooled to 0 °C and diethyl azodicarboxylate (31 μΙ_) is added. The reaction mixture is stirred at 0 °C for 30 minute. The mixture is evaporated to dryness and the residue is purified by chromatography (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 95 / 5 / 0.5) to give 2-(5-{3-[(1 - -benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl] phenylsulfanyl}pentyl)isoindole-1 ,3-dione (example 305B).
432B
5-{3-[(1 - -Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}- pentan-1 -ol can be prepared according to the method described in example 150.
Preparation of starting materials
1 -Bromo-3-(2-fluoroethoxy)benzene is prepared from 3-bromophenol and 2- fluoroethanol using standard Mitsunobu protocol.
1 - Bromo-3-(3-fluoropropoxy)benzene is prepared from 3-bromophenol and 3- fluoropropanol using standard Mitsunobu protocol.
2- [2-(3-Bromophenoxy)ethyl]-6,6-dimethylbicyclo[3.1 .1 ]hept-2-ene is prepared from 3-bromophenol and 2-(6,6-dimethylbicyclo[3.1 .1 ]hept-2-en-2-yl)ethanol using standard Mitsunobu protocol.
Example 436 : N-(2-aminoethyl)-2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}acetamide ;
The compound is made from example 154 and ethylenediamine using method described in example 264. 1 H NMR: 7.68-7.48 (m, 2H), 7.35-6.95 (m, 8H), 5.89 (s, 1 H), 3.83-3.50 (m, 3H), 3.50-3.35 (m, 1 H), 3.25-3.10 (m, 1 H), 2.82-2.62 (m, 3H), 2.59-2.45 (m, 1 H), 2.26 (s, 3H), 2.24-1 .95 (m, 3H), 1 .92-1 .50 (m, 5H).
Example 437 : N-(2-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine.
437A
To a solution of 2-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethylamine (example 437B, 230mg) in acetonitrile (15ml_) is added is added Ν,Ν'-bis-Boc-guanylpyrazole (172mg) and diisopropylethylamine (1 equivalent) at room temperature. The mixture is stirred at room temperature for 3h. The solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography on silica gel (gradient dichloromethane / methanol from 100 / 0 to 95 / 5). The residue is then dissolved in 5N aqueous hydrochloric acid (8ml_) and the solution is stirred overnight at room temperature. The solvent and volatiles are removed under reduced pressure and the residue is triturated with diethyl ether and filtered to afford N-(2- {3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl) guanidine trihydrochlorhide as a white crystalline solid melting at 170 °C.
437B
2-{3-[(5-Fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]
phenylsulfanyljethylamine.
To a solution of (2-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)carbamic acid tert-butyl ester (example 437C, 386mg) in chloroform (10ml_) are added phenol (750mg) and chlorotrimethylsilane (814mg). The mixture is heated at reflux for 2h. The solvent and volatiles are removed under reduced pressure. The residue is basified by adding a solution of 1 N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (gradient dichloromethane / methanol / ammonia from 100 / 0 /0 to 90 / 10 / 1 ) to give 2-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethylamine.
1 H NMR: 8.5-9 (si, 1 H),7.53 (s, 1 H), 7.32-7.20 (m, 5H),.7.08-6.98 (m, 1 H), 5.84 (s,
1 H), 3.70-3.50 (m, 1 H), 3.08-3.04 (m, 2H), 3.00-2.88 (m, 2H), 2.87-2.70 (m, 2H), 2.33 (s, 3H), 2.30-1 .60 (m, 8H).
437C
(2-{3-[(5-Fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)carbamic acid tert-butyl ester.
A screw-capped tube is charged with 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]-5-fluoro-1 H-benzimidazole (example 437D, 418mg), palladium bis(dibenzylideneacetone) (30mg), Xantphos (30mg), (2-mercaptoethyl)carbamic acid tert- butyl ester (1 equivalent), diisopropylethylamine (180μΙ_) and 1 ,4-dioxane (6ml_). The tube is evacuated, filled with argon and sealed. After stirring at 120°C overnight, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol from 98 / 2 to 95 / 5) to afford (2-{3-[(5-fluoro-1 H- benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)carbamic acid tert-butyl ester. 1 H NMR: 1 1 .07 (si, 1 H), 7.69-7.59 (m, 1 H), 7.39-7.36 (m, 1 H), 7.30-7.15 (m, 2H), 7.04-6.91 (m, 2H), 5.83 (s, 1 H), 5.30 (si, 1 H), 4.20 (s, 2H), 3.65-3.40 (m, 3H), 3.30-3.05 (m, 2H), 2.80-2.65 (m, 2H), 2.27 (s, 3H), 2.25-1 .75 (m, 6H), 1 .55 (s, 9H). 437D
2-[(3-Bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5-fluoro-1 H-benzimidazole A mixture of (3-bromophenyl)(5-fluoro-1 H-benzimidazol-2-yl)methanol (example 437E, 3.30g) and 1 -methylpiperidin-4-ol (2.37g) in methanesulfonic acid (10ml_) is heated overnight in a sealed tube at a temperature close to ~\ 40 °C. The mixture is cooled back to room temperature, poured into water which is then made alkaline with concentrated sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate, concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol / ammonia from 100 / 0 /0 to 90 / 10 / 1 ) to afford 2-[(3- bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5-fluoro-1 H-benzimidazole. 1 H NMR: 9.92 (si, 1 H), 7.60 (s, 1 H), 7.55-6.85 (m, 6H), 5.80 (s, 1 H), 3.65-3.50 (m, 1 H), 2.80-2.65 (m, 2H), 2.34 (s, 3H), 2.15-1 .65 (m, 6H).
437E
(3-Bromophenyl)(5-fluoro-1 H-benzimidazol-2-yl)methanol could be synthesized using the method described in example 449B.
Example 438
438A 5-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynylamine oxalate.
A solution of 2-(5-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1 ,3-dione (example 438B, 170mg) and hydrazine hydrate (200μΙ_) in ethanol (2.5ml_) is stirred a room temperature overnight. Water is added and the aqueous phase is extracted by diethyl ether. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (dichloromethane / methanol / ammonia from 95 / 5 / 0.5 to 90 / 10 / 1 )) to afford the free base. One equivalent of oxalic acid in acetone is added to the free base to afford 5-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynylamine oxalate as a white crystalline solid melting at 150°C 438B 2-(5-{3-[(5-Fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1 ,3-dione.
A screw-capped tube is charged with 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]-5-fluoro-1 H-benzimidazole (example 437D, 418mg), PEPPSi-sono catalyst (19mg), copper (I) iodide (38mg), N-pentynylphthalimide (428mg), diethylamine (880μΙ_) and A/,A/-dimethylformamide (1 .5mL). The tube is evacuated, filled with argon and sealed. The reaction mixture is stirred at 80 °C overnight. As the reaction is not completed, PEPPSi-sono catalyst (10mg) and N-pentynylphthalimide (214mg) are added, and the reaction mixture is heated at 80 °C for 24h. The mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane / methanol from 98 / 2 / to 90 / 10) to give 2-(5-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1 ,3-dione. 1 H NMR: 9.65 (si, 1 H), 7.84-7.65 (m, 4H), 7.54 (s, 1 H), 7.48-6.95 (m, 4H), 5.84 (s, 1 H), 3.90 (t, 2H, J = 6.9Hz),3.65-3.50 (m, 1 H), 2.85-2.70 (m, 2H),2.52 (t, 2H, J = 7.0Hz), 2.32 (s, 3H), 2.28-1 .50 (m, 8H).
Figure imgf000129_0001
Example 443 :1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]- phenyl}pyrrolidin-3-one, oxalate
To a solution of oxalyl chloride (317μΙ_) in dichloromethane (8ml_) at -78 Ό is added DMSO (517 μΙ_). After 15min, a solution of 1 -{3-[benzothiazol-2-yl(1 - methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol (example 406, 958mg) in dichloromethane (18ml_) is slowly added at the same temperature. After 45min triethylamine (2m L) is added and the mixture allowed to warm to room temperature. After hydrolysis with aqueous saturated ammonium chloride, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by chromatography over silica gel(dichloromethane / methanol / ammonia 98 / 2 / 0.5) affords the pure base that is then converted into its oxalate salt in acetone to give 1 -{3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-one, oxalate melting at 105<Ό.
Figure imgf000130_0001
Example 448 : 2-{(1 -methylpiperidin-4-yloxy)[3-(pyridin-3- yloxy)phenyl]methyl}benzothiazole, oxalate
A screw-capped tube is charged with 2-[(3-iodophenyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole (example 41 , 500mg), copper(l) iodide (9mg), 2,2,6,6- tetramethylheptane-3,5-dione (37mg), cesium carbonate (701 mg), 3-hydroxypyridine (125mg), powdered 4A molecular sieves (200mg) and anhydrous A/JV-dimethylformamide (1 ml_). The tube is evacuated, filled with argon and sealed. After stirring at 95°C for 2 days, the mixture is diluted with ethyl acetate, water and ammonia. After decantation, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 95 / 5 / 0.5). to afford the pure base that is then converted into its oxalate salt in acetone to give 2-{(1 -methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl} benzothiazole, oxalate melting at 78°C.
Example 449 : 2-[(3-bromophenyl)(1 -methylpyrrolidin-3-ylmethoxy)methyl]-5- fluoro-1 H-benzimidazole, oxalate
449A
2-[(3-bromophenyl)(1 -methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1 H- benzimidazole is prepared from 3-bromophenyl(5-fluoro-1 H-benzimidazol-2-yl)methanol and pyrrolidin-3-ylmethanol according to general procedures 165C and 272A. Conversion into its oxalate salt in acetone gives 2-[(3-bromophenyl)(1 -methylpyrrolidin-3- ylmethoxy)methyl]-5-fluoro-1 H-benzimidazole, oxalate melting at 70 °C.
449 B
A mixture of (3-bromophenyl)hydroxyacetic acid (3.7g) and 4-fluoro-ortho- phenylenediamine (2g) in 5N aqueous hydrochloric solution (3.2ml_) is heated under reflux for 15h and cooled back to room temperature. The mixture is basified with concentrated sodium hydroxide and extracted with ethyl acetate. The organic phase is then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 90 / 10 / 0.5) to afford the pure 3-bromophenyl(5-fluoro-1 H-benzimidazol-2- yl)methanol.
Example 455 : 4-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]aniline. To a solution of 2-[(1 -methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1 H- benzimidazole (example 447, 200mg) in methanol (5ml_) and a solution of 5N hydrochloric acid in isopropanol (0.2ml_) is added 10% palladium on carbon (50mg). The flask is evacuated and filled with hydrogen (balloon) and stirred overnight at room temperature. The reaction mixture is filtered on celite and the solvents are evaporated under reduced pressure to dryness. The residual solid is triturated twice with diethyl ether and the solid is filtered and dry to afford 4-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl] aniline hydrochloride as a cream-colored solid melting at ~\ 85°C
The following example is made using the same method :
Figure imgf000132_0001
Example 460 : 1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]phenyl}-3-trifluoromethylpyrrolidin-3-ol, oxalate
A solution of 1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl] phenyl}pyrrolidin-3-one (example 443, 170mg) in tetrahydrofuran (3ml_) is treated with cesium fluoride (612mg) and trifluoromethyltrimethylsilane (595μΙ_). After stirring for 2h, the mixture is hydrolyzed with 1 N aqueous hydrochloric acid for one night. The reaction mixture is then concentrated under reduced pressure and the residue purified by chromatography over silica gel (dichloromethane / methanol / ammonia 98 / 2 / 0.5) to afford the pure base that is then converted into its oxalate salt in acetone to give 1 -{3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}-3-trifluoromethylpyrrolidin-3- ol, oxalate. 1 H NMR of the base (CDCI3): 7.96 (d, 1 H), 7.86 (d, 1 H), 7.45-7.20 (m, 3H), 6.91 (d, 1 H), 6.73 (s, 1 H), 6.51 (d, 1 H), 5.85 (s, 1 H), 3.77-3.30 (m, 5H), 2.69 (m, 2H), 2.36 (m, 1 H), 2.25 (s, 3H), 2.20-1 .70 (m, 7H).
Example 468 : 2-[[3-(4,5-dihydro-1 H-imidazol-2-ylmethylsulfanyl)phenyl](1 - methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole.
To a solution of triphenylphosphine oxide (2.2 mmoles) in 4ml_ CH2CI2 cooled at
0*Ό is added dropwise trifluoromethanesulfonyl anhydride (310 mg, 1 .1 mmoles). The reaction mixture is stirred at 0°C for 30 minutes, then a solution of N-(2-aminoethyl)-2-{3- [(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetam
(Example 436) (250 mg, 0.55 mmole) in 2ml_ CH2CI2 is added dropwise. The reaction mixture is allowed to reach room temperature and stirred for 1 .5h. The organic phase is washed with 1 N sodium hydroxide solution, then dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (gradient dichloromethane / methanol / ammonia from 100 / 0 /0 to 80 / 20 / 2). The residue is then dissolved in acetone and one equivalent of oxalic acid is added. Acetone is removed under reduced pressure to afford 2-[[3-(4,5-dihydro-1 H-imidazol-2- ylmethylsulfanyl)phenyl](1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole melting at 62 °C (dec.) ; MS, [M+H]+= 436.1 .
The following example is made using the same method
Figure imgf000133_0001
Example 469 : 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5,6-difluoro-
1 H-benzimidazole
469A
2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1 H- benzimidazole is prepared from 3-bromophenyl(5,6-difluoro-1 H-benzimidazol-2- yl)methanol according to general procedure 272A, solid melting at 70 °C.
469 B
A mixture of (3-bromophenyl)hydroxyacetic acid (809mg) and 4,5-difluoro-ortho- phenylenediamine (500mg) in 5N aqueous hydrochloric solution (2ml_) is heated under reflux for 15h and cooled back to room temperature. The mixture is basified with concentrated sodium hydroxide and extracted with ethyl acetate. The organic phase is then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by trituration in dichloromethane to afford the pure 3-bromophenyl(5,6- difluoro-1 H-benzimidazol-2-yl)methanol.
Example 472 : 2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 -methyl-1 H- benzimidazole, dioxalate A solution of 2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole (example 51 , 260mg) in anhydrous acetonitrile (10ml_) is treated with 60% sodium hydride (47mg) for 1 h at room temperature. The mixture is then cooled to 0 °C and iodomethane (36μΙ_) is introduced. After stirring for 15h, dilution with water and extraction with ethyl acetate, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 95 / 5 / 0.5 to 90 / 10 / 0.5) to afford the pure base that is then converted into its dioxalate salt in acetone to give 2-[(3- iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 -methyl-1 H-benzimidazole, dioxalate, melting at 76 °C.
Example 479 : 2-amino-5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanylmethyl}-1 ,5-dihydroimidazol-4-one
479A 2-amino-5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanylmethyl}-1 ,5-dihydroimidazol-4-one.
To a solution of 3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}-2-(N,N'-bis-tert-butoxycarbonyl)guanidinopropionic acid methyl ester (260mg) in dichloromethane (2.6ml_) is added dropwise trifluoroacetic acid (1 ml_). The reaction mixture is stirred at room temperature for 28h.
Solvents are removed under reduced pressure. The residue is basified by adding 1 N sodium hydroxide, and the solution is evaporated to dryness. The residue is purified by chromatography on silica gel (gradient dichloromethane / methanol / ammonia from 90 / 10 /0 to 90 / 10 / 1 ). The residual solid is triturated in hot ethyl acetate, cooled down to room temperature and filtered. The solid is washed with ethyl acetate; then dried to afford 2-amino-5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl- methyl}-1 ,5-dihydroimidazol-4-one.
MS, [M+H]+ = 465.1 ; [M+Na]+ = 487.1 .
479 B
3-{3-[(1 H-Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-2-
(N,N'-bis-tert-butoxycarbonyl)guanidinopropionic acid methyl ester.
The compound is synthesized from Example 479C using the method described at example 307A ; mixture of diastereomers. 1 H NMR: 1 1 .35 and 1 1 .13 (si, 1 H), 10.25 and 10.06 (si, 1 H), 9.04 and 8.90 (d, 1 H, J = 7.5Hz), 7.82-7.70 (m, 2H), 7.52-7.18 (m, 6H), 5.89 and 5.84 (s, 1 H), 5.58-5.30 (m, 1 H), 5.25-5.90 (m, 1 H), 4.65-4.40 (m, 1 H), 3.82-3.05 (m, 6H), 2.95-2.75 (m, 2H), 2.38 (si, 3H), 2.252-1 .60 (m, 6H), 1 .60-1 .30 (m, 18H). 479C
2-Amino-3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}propionic acid methyl ester.
The compound is synthesized from example 479D using the method described in example 437B ; mixture of diastereomers. 1 H NMR: 9.74 and 9.67 (si, 1 H), 7.80-7.55 (m, 2H), 7.48-7.15 (m, 7H), 5.84 (s, 1 H), 3.75-3.50 (m, 3H), 3.42-3.15 (m, 3H), 2.90-2.70 (m, 2H), 2.40-2.15 (m, 5H), 2.10-1 .70 (m, 6H).
479 D
3-{3-[(1 H-Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-2- tert-butoxycarbonylaminopropionic acid methyl ester.
The compound is synthesized from 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 H-benzimidazole (example 72A) and N-Boc-Cysteine methyl ester using the method described in example 150 ; mixture of diastereomers. 1 H NMR: 10.66 and 9.83 (si, 1 H), 7.90-7.70 (m, 2H), 7.50-7.35 (m, 2H), 7.35-7.18 (m, 5H), 5.87 and 5.85 (s, 1 H),
5.58-5.30 (m, 1 H), 4.65-4.40 (m, 1 H), 3.70-3.20 (m, 6H), 2.82-2.62 (m, 2H), 2.28 and 2.26
(s, 3H), 2.22-1 .65 (m, 6H), 1 .53 and 1 .45 (s, 9H).
Example 481 : 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5,6,7- trifluoro-1 H-benzimidazole
481 A
2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5,6,7-trifluoro-1 H- benzimidazole, solid melting at 140°C, is prepared according to general procedure 165C from 2-[(3-bromophenyl)(piperidin-4-yloxy)methyl]-5,6,7-trifluoro-1 H-benzimidazole.
481 B
To a solution of 4-[(3-bromophenyl)carboxymethoxy]piperidine-1 -carboxylic acid tert-butyl ester (general procedure 165D + saponification^ g) in acetonitrile (10ml_) are added 3,4,5-trifluorobenzene-1 ,2-diamine (470mg), 2-chloro-1 -methylpyridinium iodide (802mg) and dropwise diisopropylethylamine (1 .1 mL). The reaction mixture is stirred at room temperature for 2 hours. Solvent is removed under reduced pressure and the residue diluted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ) to get 4-[(6-amino-2,3,4-trifluorophenylcarbamoyl)(3- bromophenyl)methoxy]piperidine-1 -carboxylic acid tert-butyl ester. This intermediate is dissolved in acetic acid (15ml_) and the reaction mixture is refluxed for 3 hours. Acetic acid is removed under reduced pressure. Water is added to the residue and the solution is basified by adding a solution of saturated sodium hydrogencarbonate to pH 10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.2 to 90 / 10 / 1 ) to yield 2-[(3-bromophenyl)(piperidin-4-yloxy)methyl]-5,6,7-trifluoro- 1 H-benzimidazole.
Example 497 : 1 -(2-ethoxyethyl)-2-[(3-iodophenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 H-benzimidazole, dioxalate
A solution of 2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole (example 51 , 260mg) in anhydrous acetonitrile (10ml_) is treated with 60% sodium hydride (47mg) for 30 min at room temperature. 1 -Bromo-2-ethoxyethane (84μΙ_) is then introduced. After warming at 60 °C for 8h, dilution with water and extraction with diethylether, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 98 / 2 / 0.5 to 95 / 5 / 0.5) to afford the pure base that is then converted into its dioxalate salt in acetone to give 1 -(2-ethoxyethyl)-2-[(3- iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, dioxalate, melting at 88 °C.
Example 505
505A : 5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]benzylidene}-
2-iminoimidazolidin-4-one.
To a solution of 3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]- benzaldehyde (example 505C, 200mg) in a mixture of ethanol-water (8 : 2) (3ml_) is added thiohydantoin (70mg) and piperidine (57μΙ_). The reaction mixture is heated at 55 °C for 5h. Ethanol is removed under reduced pressure. Water is added and the reaction mixture is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (gradient dichloromethane / methanol from 95 / 5 to 90 / 10). The residue is dissolved in methanol (6ml_) and 30% solution of aqueous ammonia (1 .1 mL) and tert- butylhydroperoxide (90μΙ_) are added. The reaction mixture is stirred at room temperature for two days. The reaction mixture is evaporated to dryness. The residue is purified by chromatography on silica gel (gradient dichloromethane / methanol / ammonia from 90 / 10 / 0.1 to 70 / 30 /0.1 ) to give 5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]benzylidene}-2-iminoimidazolidin-4-one. MS, [M+H]+ = 431 .1 ; [M+Na]+ = 453.1
505B
3-[(1 H-Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]benzaldehyde.
To a solution of 3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]- benzonitrile (example 172, 740mg) in 80% aqueous formic acid (3ml_) is added platinum(IV) oxide (48mg). The reaction mixture is heated at 60 °C for 7h, then at room temperature for 2 days. As the reaction is not complete, 80% aqueous formic acid (3ml_) and platinum (IV) oxide (48mg) are added and the reaction mixture is heated at 60 °C overnight. Water is added and the reaction mixture is filtered on celite. The phase is basified by adding a solution of 1 N sodium hydroxide and extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated to give 3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]benzaldehyde. 1 H NMR: 9.99 (s, 1 H), 9.67 (si, 1 H), 8.01 (s, 1 H), 7.85-7.65 (m, 2H), 7.60-7.40 (m, 2H), 7.32- 7.15 (m, 3H), 5.95 (s, 1 H), 3.65-3.50 (m, 1 H), 2.82-2.65 (m, 2H), 2.26 (s, 3H), 2.20-1 .65 (m, 6H).
Example 507 : 4-{3-[(1 H-benzimidazol-2-yl)(1 -methylazetidin-3-ylmethoxy)methyl]- phenylsulfanyljbutylamine, oxalate. Compound made from example 506 using methods described in examples 150, 432. 1 H NMR (methanol-d4)(base) : 7.65-7.40 (m, 3H), 7.40- 7.10 (m, 5H), 5.69 (s, 1 H), 3.785-3.40 (m, 4H), 3.40-3.10 (m, 5H), 2.44 (s, 3H), 1 .80-1 .45 (m, 3H), 1 .35-1 .10 (m, 2H), 1 .00-1 .75 (m, 1 H).
Example 525 : 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]benzoxazole, oxalate 525A
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]benzoxazole, oxalate (solid melting at 103°C) is prepared according to general procedure 272A. 525B
A mixture of (2-fluoro-5-trifluoromethoxyphenyl)hydroxyacetic acid (prepared according to 72C) (2.4g), ortho-aminophenol (1 .03g) in xylene (25ml_) is refluxed for 4h with a Dean-Stark apparatus and concentrated under reduced pressure. Purification by chromatography on silica gel (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 98 / 2 / 0.5) to afford the pure benzoxazol-2-yl(2-fluoro-5- trifluoromethoxyphenyl)methanol.
Example 528
528A
2-[(1 -methylpiperidin-4-yloxy)(3-methylsulfanylmethylphenyl)methyl]-1 H- benzimidazole.
To a solution of {3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}methanol (example 528B, 320mg) in dichloromethane (3ml_) is added triethylamine (0.16ml_). The reaction mixture is cooled to 0°C, and methanesulfonyl chloride (84μΙ_) is added dropwise. The reaction mixture is stirred at room temperature for 3h, then cooled to 0°C and sodium thiomethoxide (191 mg) is added. After one night at room temperature, methanol (2ml_) is added to help solubilizing the suspension. The reaction mixture is stirred at room temperature overnight. Water is added and the aqueous phase is extracted by dichloromethane. The organic phase is washed by water, then dried over magnesium sulfate and concentrated. . The residue is purified by chromatography on silica gel (gradient dichloromethane / methanol / ammonia from 90 / 10 / 0 to 90 / 10 / 0.1 then 80 / 20 / 0.1 ), followed by a purification by preparative thin-layer chromatography (dichloromethane / methanol / ammonia from 90 / 10 / 0.1 ) to give 2-[(1 -methylpiperidin-4- yloxy)(3-methylsulfanylmethylphenyl)methyl]-1 H-benzimidazole. MS, [M+H]+ = 382.1 ;
528B
{3-[(1 H-Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}methanol. To a solution of 3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]benzaldehyde (example 505B, 310mg) in methanol (4ml_) is added portionwise sodium borohydride (50mg). The reaction mixture is stirred at room temperature for 15 minutes then heated at reflux for 3h. Methanol is removed under reduced pressure. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated to give {3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]- phenyljmethanol. 1 H NMR: 9.85 (si, 1 H), 7.78-7.65 (m, 1 H), 7.50-7.12 (m, 7H), 5.87 (s, 1 H), 4.64 (s, 2H), 3.62-3.45 (m, 1 H), 2.78-2.58 (m, 2H), 2.22 (s, 3H), 2.15-1 .50 (m, 6H).
Example 530
530A 2-[(3-bromophenyl)(1 -methyl-1 ,2,3,6-tetrahydropyridin-4- ylsulfanyl)methyl]-1 H-benzimidazole.
To a solution of 1 ,2-phenylenediamine (213mg) in toluene (2ml_) is added dropwise a solution of 2M trimethylaluminium in toluene (1 ml). The reaction mixture is heated at 75 °C for 2 hours then a solution of (3-bromophenyl)(1 -methyl-1 ,2,3,6- tetrahydropyridin-4-ylsulfanyl)acetic acid methyl ester (example 530B, 358mg) in toluene (2ml_) is added, and the heating is continued at 75 °C for 3 hours. Water is added and the reaction mixture is made alkaline by adding 1 N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated. The residue is the dissolved in acetic acid (5ml_) and the reaction mixture is refluxed for 3 hours. The solvent is removed under reduced pressure. Water is added and the reaction mixture is made alkaline by adding 2N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated. The residual solid is triturated with acetonitrile, filtered and the solid is washed with diethyl ether to give 2-[(3-bromophenyl)(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-ylsulfanyl)methyl]- 1 H-benzimidazole melting at 189°C.
530 B
(3-Bromophenyl)(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-ylsulfanyl)acetic acid methyl ester
To a solution of 4-[(3-bromophenyl)methoxycarbonylmethylsulfanyl]-1 - methylpyridinium iodide (example 530C, 480mg) in methanol (5ml_) is added portionwise sodium borohydride (2 equivalents). The mixture is refluxed for one hour then concentrated to dryness. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated to give (3-Bromophenyl)(1 -methyl-1 ,2,3, 6-tetrahydropyridin-4- ylsulfanyl)acetic acid methyl ester. 1 H NMR: 7.62 (s, 1 H), 7.50-7.35 (m, 2H), 7.30-7.15 (m, 1 H), 5.75 (si, 1 H), 4.77 (s, 1 H), 3.76 (s, 3H), 3.10-2.98 (m, 2H), 2.68-2.55 (m, 2H), 2.45- 2.25 (m, 5H). 530C
4-[(3-Bromophenyl)methoxycarbonylmethylsulfanyl]-1 -methylpyridinium iodide.
To a solution of (3-bromophenyl)(pyridin-4-ylsulfanyl)acetic acid methyl ester (example 530D, 2.2g) in acetonitrile (50ml_) is added iodomethane (1 .2 equivalent) and the mixture is stirred over-the-weekend at room temperature. The solid is filtered and washed with diethyl ether to give 4-[(3-Bromophenyl)methoxycarbonylmethylsulfanyl]-1 - methylpyridinium iodide. 1 H NMR (dmso-d6): 8.75-8.65 (m, 2H), 7.98-7.88 (m, 2H), 7.78 (s, 1 H), 7.63-7.51 (m, 2H), 7.42-7.30 (m, 1 H), 6.20 (s, 1 H), 4.13 (s, 3H), 3.70 (s, 3H). 530D
(3-Bromophenyl)(pyridin-4-ylsulfanyl)acetic acid methyl ester
To a solution of dimethylsulfoxonium ylide and 3-bromophenylacetic acid methyl ester (example 530E, 3g) in dichloroethane (50ml_) are added 4-mercaptopyridine (2 equivalents) and [lr(COD)CI]2 (20mg). The reaction mixture is refluxed overnight then concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel (heptane / ethyl acetate 1 /1 ) to give (3- Bromophenyl)(pyridin-4-ylsulfanyl)acetic acid methyl ester. 1 H NMR: 8.50-8.35 (m, 2H), 7.68 (s, 1 H), 7.55-7.45 (m, 2H), 7.35-7.20 (m, 1 H), 7.20-7.05 (m, 2H), 5.08 (s, 1 H), 3.77 (s, 3H).
530 E
Dimethylsulfoxonium ylide of 3-Bromophenylacetic acid methyl ester
To a solution of (3-bromophenyl)diazoacetic acid methyl ester (synthesized according to the method described in example 165E, 7.5g) in dimethylsulfoxide (35ml_) is added copper(ll)cyanide (150mg), and the mixture is heated at 60°C for 1 h, with evolution of nitrogen. The solvent is removed under reduced pressure. Water is added and the reaction mixture is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated. The residual solid is triturated with diisopropyl ether, filtered and dried to give the dimethylsulfoxonium ylide of 3- bromophenylacetic acid methyl ester. 1 H NMR: 7.47 (s, 1 H), 7.45-7.35 (m, 1 H), 7.30-7.12 (m, 2H), 3.63 (s, 3H), 3.45 (s, 6H)
Example 533 2-[(2-fluoro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, enantiomer B
A solution of racemic 2-[(2-fluoro-4-methylphenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 H-benzimidazole (10mg/ml_) in a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) is injected (30x100μΙ_) onto an analytical Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. Products are detected at 210nm. The enantiomer B has a retention time of 13.2min. Collection affords 2-[(2-fluoro-4- methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole enantiomer B with a chromatographic enantiomeric purity of 97.4%.
Example 534 : 2-[(2,6-difluoro-3-methoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 H-benzimidazole
534A
2-[(2,6-Difluoro-3-methoxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole (solid melting at Ι δδ'Ό) is prepared according to general procedure 172A from (1 H-benzimidazol-2-yl)(2,6-difluoro-3-methoxyphenyl)methanol. 534B
A solution of (2,6-difluoro-3-methoxyphenyl)[1 -(2-trimethylsilylethoxymethyl)-1 H- benzimidazol-2-yl]methanol (1 .4g) in tetrahydrofuran (20ml_) is refluxed for 15h with tetrabutylammonium fluoride (10ml_ of a 1 M solution in tetrahydrofuran). The mixture is then concentrated under reduced pressure and purified by chromatography over silica gel (gradient dichloromethane / methanol from 100 / 0 to 95 / 5) to afford the pure (1 H- benzimidazol-2-yl)-(2,6-difluoro-3-methoxyphenyl)methanol.
534C
To a solution of 2,4-difluoro-1 -methoxybenzene (156mg) in tetrahydrofuran (5ml_) at -78^ is added a 2M solution of lithium diisopropylamide in THF (540μΙ_). After stirring for 45min a solution of 1 -(2-trimethylsilylethoxymethyl)-1 H-benzimidazole-2-carbaldehyde (which can be prepared according to US2003/220341 or US6476041 for example) (300mg) in tetrahydrofuran (5m L) is added at -78 °C and the reaction mixture allowed to warm to room temperature. After hydrolysis with aqueous saturated ammonium chloride and extraction with ethyl acetate, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol from 100 / 0 to 95 / 5) to afford (2,6- difluoro-3-methoxyphenyl)[1 -(2-trimethylsilylethoxymethyl)-1 H-benzimidazol-2- yl]methanol. Example 549 : ethyl (6-{3-[(1 -methyl-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}hex-5-ynyl)carbamate, oxalate
To a cooled solution of 6-{3-[(1 -methyl-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}hex-5-ynylamine (example 480, 22mg) in dichloromethane is added ethyl chloroformate (1 eq). After stirring at room temperature, the organic phase is washed with aqueous sodium hydroxide, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol from 100 / 0 to 90 / 10) to afford the pure base that is then converted into its oxalate salt in acetone to give ethyl (6-{3-[(1 -methyl-1 H-benzimidazol-2- yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate, oxalate melting at 90 °C.
Example 550 : 2-[(1 H-indol-6-yl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, oxalate
550 A
2-[(1 -Benzenesulfonyl-1 H-indol-6-yl)(1 -methyl-piperidin-4-yloxy)methyl]-1 H- benzimidazole (150mg) and sodium hydroxide (excess) in methanol are refluxed for 3h. The reaction mixture is then concentrated under reduced pressure, diluted with water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 80 / 20 / 2) to afford the pure base that is then converted into its oxalate salt in acetone to give 2-[(1 H- indol-6-yl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, oxalate, melting at 170°C.
550 B
2-[(1 -Benzenesulfonyl-1 H-indol-6-yl)(1 -methyl-piperidin-4-yloxy)methyl]-1 H- benzimidazole is prepared according to general procedures 172A and 172B from 1 benzenesulfonyl-1 H-indole-6-carbaldehyde.
Example 556 : 2-[benzo[b]thiophen-6-yl(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, oxalate
556A
2-[Benzo[b]thiophen-6-yl(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, oxalate melting at 160°C is prepared according to general procedures 272A and 534B from benzo[b]thiophen-6-yl[1 -{2-trimet ylsilylet oxymet yl)-1 H-benzimidazol-2- yl]methanol.
556B
To a suspension of magnesium (86mg) in tetrahydrofuran is added a solution of 6- bromobenzo[b]thiophene (which can be prepared according to WO2006/107784) (500mg) in tetrahydrofuran. After reflux for 3h, a solution of 1 -(2-trimethylsilylethoxymethyl)-1 H- benzimidazole-2-carbaldehyde (which can be prepared according to US2003/220341 or US6476041 for example) (635mg) in tetrahydrofuran is added to the Grignard reagent at room temperature. After stirring for 12h, the reaction mixture is treated with diluted hydrochloric acid and the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol from 100 / 0 to 90 / 10) to afford benzo[b]thiophen-6-yl[1 -(2-trimethylsilylethoxymethyl)-1 H-benzimidazol-2-yl]methanol.
Example 559 : 2-[(2,6-difluoro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-
1 H-benzimidazole, enantiomer B
A solution of racemic 2-[(2,6-difluoro-4-methylphenyl)(1 -methylpiperidin-4- yloxy)methyl]-1 H-benzimidazole (example 523) (10mg/ml_) in a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) is injected (30x100μΙ_) onto an analytical Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min.
Products are detected at 210nm. The enantiomer B has a retention time of 13.9min.
Collection affords 2-[(2,6-difluoro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, enantiomer B with a chromatographic enantiomeric purity of 99.3%
Example 561 : 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol 561 A
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol (solid melting at Ι ΐ δ-^Ο 'Ό) is prepared from 2-[(1 H-benzimidazol-2-yl)hydroxymethyl]phenol according to general procedure 1A.
561 B
To a solution of 1 -pyrrolidin-1 -ylmethyl-1 H-benzimidazole (6g) in tetrahydrofuran (40ml_) at -78 Ό, is added a 2.3M solution of butyllithium in hexanes (13ml_). The mixture is stirred for 25 minutes. Salicaldehyde (1 .82g) is then dropwise introduced at -78 °C. After 1 h at the same temperature, the mixture is allowed to warm to room temperature and hydrolyzed with aqueous saturated ammonium chloride. After 1 h, the mixture is extracted with ethyl acetate. Pooled extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by titruration in dichloromethane to afford 2-[(1 H-benzimidazol-2-yl)hydroxymethyl]phenol.
Example 562 : 2-[(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]- 4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol
A mixture of 6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}hex-5-ynylamine, oxalate (example 557, 70mg), 2-hydroxybenzophenone (30mg) in ethanol (4ml_) is refluxed for 4h. The mixture is then cooled, diluted with water and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0 to 90 / 10 / 0.5) to afford 2-[(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol. TLC (Eluent: CHgClg/MeOH/NI-UOH 95/5/0.5) Rf=0.15.
Example 563 : 5-(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]- 4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1 -enol
A mixture of 6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}hex-5-ynylamine, oxalate (example 557, 50mg), 3-methyl-1 ,2- cyclopentanedione (1 1 .8mg) in ethanol (2ml_) is refluxed for 2h. The mixture is then cooled, diluted with water and 1 N sodium hydroxide and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0.5 to 95 / 5 / 0.5) to afford 5-(6-{3- [(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5- ynylimino)-2-methylcyclopent-1 -enol. TLC (Eluent: CH2CI2/MeOH/NH4OH 95/5/0.5) Rf=0.30.
Example 564 : 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, enantiomer B
Resolution of racemic 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole (example 78)with (1 R)-(-)-10-camphorsulfonic acid (0.45eq) in ethyl acetate affords after several recristallizations enantiopure 2-[(3-bromophenyl)(1 - methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, enantiomer B (solid melting at δδ'Ό). HPLC analysis: analytical Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. The enantiomer B has a retention time of 10.4min.
Example 565 : 5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynylamine, enantiomer A
5-{3-[(1 H-Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4- ynylamine, enantiomer A (melting at 84 °C) is prepared according to general procedures 194 and 189 from 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, enantiomer A (prepared according example 564 with (1 S)-(+)- camphorsulfonic acid).
Example 566 : 5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynylamine, enantiomer B
5-{3-[(1 H-Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4- ynylamine, enantiomer B (melting at 82 °C) is prepared according to general procedures 194 and 189 from 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, enantiomer B (example 564).
Example 567 : 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5-fluoro-1 H- benzimidazole, enantiomer A
Resolution of racemic 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5- fluoro-1 H-benzimidazole with (1 S)-(+)-10-camphorsulfonic acid (0.5eq) in ethyl acetate affords after several recristallizations 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]-5-fluoro-1 H-benzimidazole, enantiomer A (solid melting at 89°C). HPLC analysis: analytical Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. The enantiomer A has a retention time of 8.2min. e.e.=93.5%
Example 568 : 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5-fluoro-1 H- benzimidazole, enantiomer B
Resolution of racemic 2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5- fluoro-1 H-benzimidazole with (1 R)-(-)-10-camphorsulfonic acid (0.5eq) in ethyl acetate affords after several recristallizations 2-[(3-bromophenyl)(1 -methylpiperidin-4- yloxy)methyl]-5-fluoro-1 H-benzimidazole, enantiomer B (solid melting at 89°C). HPLC analysis: analytical Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. The enantiomer B has a retention time of 10.3min. e.e.=95.5% Example 578 : 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- methylphenol
A mixture of 2-[(1 H-benzimidazol-2-yl)hydroxymethyl]-4-methylphenol (prepared according to procedure 561 B) (360mg), methanesulfonic acid (500μΙ_) and 1 -methyl-4- piperidinol (500mg) in 1 ,2-dichloroethane (20ml_) and N-methylpyrrolidinone (2ml_) is warmed at 90 °C for 2h. After cooling at 0°C, the mixture is diluted with water and dichloromethane and concentrated sodium hydroxide slowly added up to pH 9. Organic phase is then dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane / methanol / ammonia from 100 / 0 / 0.5 to 80 / 20 / 0.5) to afford 2-[(1 H-benzimidazol-2- yl)(1 -methylpiperidin-4-yloxy)methyl]-4-methylphenol, melting at 151 °C.
For the other examples prepared according this general procedure, it can be advantageous to rise the temperature progressively after having mixed the different reagents and to observe when etherification occurs. Once the right temperature has been found, reaction may be continued up to adequate conversion. Use of N- methylpyrrolidinone can be optional depending of the solubility of the mixture. Additional equivalents of methanesulfonic acid can be used for a better conversion if necessary.
Example 626: 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol enantiomer A
2-[(1 H-Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol enantiomer A is prepared by separation on Chiralpak AD-H from racemic 2-[(1 H-benzimidazol-2-yl)(1 - methylpiperidin-4-yloxy)methyl]phenol (example 561 ). HPLC analysis: Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. The enantiomer A has a retention time of 18.8min. e.e.=100%
Example 627 : 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol enantiomer B
2-[(1 H-Benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol enantiomer B is prepared by separation on Chiralpak AD-H from racemic 2-[(1 H-benzimidazol-2-yl)(1 - methylpiperidin-4-yloxy)methyl]phenol (example 561 ). HPLC analysis: Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. The enantiomer B has a retention time of 34.3min. e.e.=100% Example 628 : 6-[(1 Hbenzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-2-fluoro-
3-methylphenol enantiomer A
By analogy with example 626 from racemic 6-[(1 H-benzimidazol-2-yl)(1 - methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol (example 601 ). HPLC analysis: Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. The enantiomer A has a retention time of 15.8min.
Example 629 : 6-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-2- fluoro-3-methylphenol enantiomer B
By analogy with example 627 from racemic 6-[(1 H-benzimidazol-2-yl)(1 - methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol (example 601 ). HPLC analysis: Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. The enantiomer B has a retention time of 19.9min.
Example 630 : 6-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-2,3- difluorophenol enantiomer A
By analogy with example 626 from racemic 6-[(1 H-benzimidazol-2-yl)(1 - methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol (example 625). HPLC analysis: Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. The enantiomer A has a retention time of 13.4min.
Example 631 : 6-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-2,3- difluorophenol enantiomer B
By analogy with example 627 from racemic 6-[(1 H-benzimidazol-2-yl)(1 - methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol (example 625). HPLC analysis: Chiralpak AD-H, 250x4.6 mm column. Elution is performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1 %) at a flow of 1 mL/min. The enantiomer B has a retention time of 15.3min.
Further examples can be prepared according to the described general methods: General
Example Product Melting point methods
5-{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
442 yloxy)met yl]-4-fluorop enyl}pent-4-ynylamine, 194, 189, 425 139°C
dioxalate
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- 194, 432A,
453 91 °C
yloxy)methyl]phenoxy}cyclopentylamine, oxalate 258
2-{[3-(3-fluoropyrrolidin-1 -yl)phenyl](1 -
454 met ylpiperidin-4-yloxy)met yl}benzot iazole, 423B 103°C
oxalate
5-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -
462 methylpyrrolidin-3-ylmethoxy)methyl]phenyl}pent-4- 194, 189, 449 200 °C
ynylamine, oxalate
2-[(3-bromop enyl)(1 -metriylpyrrolidin-3-
464 ylmethoxy)methyl]benzothiazole, oxalate (one 165C,1 A,1 B 68 °C
epimer)
2-[(3-bromophenyl)(1 -methylpyrrolidin-3-
465 ylmethoxy)methyl]benzothiazole, oxalate (50/50 165C,1 A,1 B 68°C
mixture of two epimers)
2-{(1 -methylpiperidin-4-yloxy)[3-
466 (octahydrocyclopenta[c]pyrrol-5- 249, 258 70 °C
yloxy)phenyl]methyl}benzothiazole, dioxalate
(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
467 yloxy)met yl]phenyl}pyrrolidin-3-yl)met ylamine, 249, 423B 216°C
dioxalate
4-{3-[(5,6-difluoro-1 H-benzimidazol-2-yl)(1 -
470 met ylpiperidin-4- 150, 469 60 °C
yloxy)methyl]phenylsulfanyl}butan-1 -ol
2-{3-[benzot iazol-2-yl(1 -met ylpiperidin-4-
194, 432A,
471 yloxy)methyl]phenyl}octahydrocyclopenta[c]pyrrol- 126°C
423B
5-ylamine, dioxalate
2-{[3-(3-fluoropropoxy)phenyl](1 -methylpiperidin-4-
475 272A, 272B 106°C
yloxy)methyl}-1 H-benzimidazole, oxalate 2-{[3-(2-fluoroethoxy)phenyl](1 -methylpiperidin-4-
476 272A, 272B 136°C yloxy)methyl}-1 H-benzimidazole,oxalate
4-{3-[benzothiazol-2-yl(1 -methylpiperidin-4- 194, 432A,
477 95 °C yloxy)methyl]phenoxy}cyclohexylamine, oxalate 258
6-{3-[(1 -methyl-1 H-benzimidazol-2-yl)(1 -
480 methylpiperidin-4-yloxy)methyl]phenyl}hex-5- 194, 189, 472 1 13°C ynylamine, dioxalate
1 -{3-[benzot iazol-2-yl(1 -methylpiperidin-4-
194, 432A,
482 yloxy)met yl]phenyl}pyrrolidin-2-ylmet ylamine, 145°C
423B
oxalate
(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
483 yloxy)methyl]phenyl}pyrrolidin-3-yl)(methyl)amine, 249, 423B 1 15°C oxalate
(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
484 yloxy)met yl]phenyl}pyrrolidin-3-yl)(dimet yl)amine, 423B 106°C oxalate
2-{[3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-
485 yl)phenyl](1 -methylpiperidin-4- 423B 131 °C yloxy)methyl}benzothiazole, dioxalate
2-[(2-fluoro-5-methoxyphenyl)(1 -methylpiperidin-4-
486 272A, 272B 105°C yloxy)methyl]-1 H-benzimidazole, oxalate
3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
487 272A, 272B 135°C yloxy)methyl]-4-fluorophenol, oxalate
2-{[2-fluoro-5-(2-fluoroethoxy)phenyl](1 -
489 methylpiperidin-4-yloxy)methyl}-1 H-benzimidazole, 272A, 272B 109°C oxalate
2-[(2-fluoro-5-methylphenyl)(1 -methylpiperidin-4-
490 272A, 272B 132°C yloxy)methyl]-1 H-benzimidazole, oxalate
4-{3-[(1 -methylpiperidin-4-yloxy)(5,6,7-trifluoro-1 H-
305A, 305B,
493 benzimidazol-2- 1 10°C
481
yl)methyl]phenylsulfanyl}butylamine, oxalate
4-{3-[(5,6-difluoro-1 H-benzimidazol-2-yl)(1 -
305A, 305B,
495 methylpiperidin-4- 180°C
469
yloxy)methyl]phenylsulfanyl}butylamine, oxalate 6-(3-{[1 -(2-ethoxyethyl)-1 H-benzimidazol-2-yl](1 -
500 methylpiperidin-4-yloxy)methyl}phenyl)hex-5- 194, 189, 497 103°C ynylamine, dioxalate
6-(3-{[1 -(2-methoxyethyl)-1 H-benzimidazol-2-yl](1 -
501 methylpiperidin-4-yloxy)methyl}phenyl)hex-5- 194, 189, 497 109°C ynylamine, dioxalate
2-{[3-(3-fluoropropylsulfanyl)phenyl](1 -
508 met ylpiperidin-4-yloxy)met yl}-1 H-benzimidazole, 150 85 °C dioxalate
5-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -
509 methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, 272A, 272B 70 °C oxalate
4,5,6-trifluoro-2-[(2-fluoro-5-
510 trifluoromethoxyphenyl)(1 -methylpiperidin-4- 272A, 272B 75°C yloxy)methyl]-1 H-benzimidazole
5,6-difluoro-2-[(2-fluoro-5-
51 1 trifluoromethoxyphenyl)(1 -methylpiperidin-4- 272A, 272B 79 °C yloxy)met yl]-1 H-benzimidazole
2-{[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl](1 -
522 272A, 272B 204 °C met ylpiperidin-4-yloxy)met yl}-1 H-benzimidazole
2-[(2,6-difluoro-4-methylphenyl)(1 -methylpiperidin-
523 272A, 272B 21 1 °C
4-yloxy)methyl]-1 H-benzimidazole
2-[(2-chloro-5-trifluoromethoxyphenyl)(1 -
524 met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole, 272A, 272B 107°C oxalate
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -
526 met ylpiperidin-4-yloxy)met yl]benzot iazole, 272A,1 B 95 °C oxalate
2-[(4-chloro-2,6-difluorophenyl)(1 -methylpiperidin-4-
527 272A, 272B 195°C yloxy)methyl]-1 H-benzimidazole
7-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -
529 met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole, 165C, 165A 135°C oxalate
2-[(2,6-difluoro-4-methylphenyl)(1 -methylpiperidin-
531 272A, 168B 125°C
4-yloxy)methyl]benzothiazole, oxalate 2-[(4-chloro-2,6-difluorophenyl)(1 -methylpiperidin-4-
532 272A, 1 B 158°C yloxy)methyl]benzothiazole, oxalate
2-[(3-ethoxy-2,6-difluorophenyl)(1 -methylpiperidin-
535 534 130°C
4-yloxy)met yl]-1 H-benzimidazole
2-[(2,6-difluoro-4-methylphenyl)(1 -methylpiperidin-
536 525 1 14°C
4-yloxy)methyl]benzoxazole, oxalate
2-[(1 -methylpiperidin-4-yloxy)(4-
537 272A, 272B 86 °C trifluoromethylphenyl)methyl]-1 H-benzimidazole
2-[(2-fluoro-4-trifluoromethylphenyl)(1 -
540 272A, 272B 91 °C met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
2-[(2,4-dimethylphenyl)(1 -methylpiperidin-4-
541 272A, 272B 120°C yloxy)met yl]-1 H-benzimidazole
2-[(3-methoxyphenyl)(1 -methylpiperidin-4-
542 272A, 272B 83 °C yloxy)met yl]-1 H-benzimidazole
2-[chroman-7-yl(1 -methylpiperidin-4-yloxy)methyl]-
543 272A, 272B 128°C
1 H-benzimidazole
2-[(2-fluoro-4-methylphenyl)(1 -methylpiperidin-4-
545 525 1 10°C yloxy)methyl]benzoxazole, oxalate
2-[(3,5-bis-trifluoromethylphenyl)(1 -methylpiperidin-
547 272A, 272B 130°C
4-yloxy)met yl]-1 H-benzimidazole, oxalate
5-fluoro-2-[(2-fluoro-4-methylphenyl)(1 -
548 272A, 272B 90 °C met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
2-[(2,3-difluoro-4-methylphenyl)(1 -methylpiperidin-
551 272A, 272B 80 °C
4-yloxy)methyl]-1 H-benzimidazole
2-[(3-chloro-4-methylphenyl)(1 -methylpiperidin-4-
552 272A, 272B 86°C yloxy)met yl]-1 H-benzimidazole
ethyl 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -
553 methylpiperidin-4-yloxy)methyl]benzimidazole-1 - 549 1 18°C carboxylate, oxalate
2-[(3-fluoro-4-methylphenyl)(1 -methylpiperidin-4-
554 272A, 272B 92 ^0 yloxy)methyl]-1 H-benzimidazole
2-[(5-bromo-2-fluorophenyl)(1 -methylpiperidin-4-
555 272A, 272B 232 °C yloxy)methyl]-1 H-benzimidazole 6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
557 yloxy)met yl]-4-fluorop enyl}hex-5-ynylamine, 194, 189, 555 195°C oxalate
5-{4-fluoro-3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -
194, 189,
558 methylpiperidin-4-yloxy)methyl]phenyl}pent-4- 90 °C
272A, 272B ynylamine
ethyl (5-{3-[(1 H-benzimidazol-2-yl)(1 -
560 methylpiperidin-4-yloxy)methyl]-4- 549, 442 87 °C fluorophenyl}pent-4-ynyl)carbamate
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
569 272A, 561 B 185°C yloxy)methyl]-4-chlorophenol
ethyl (5-{4-fluoro-3-[(5-fluoro-1 H-benzimidazol-2-
189, 272A,
570 yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4- 95 °C
272B
ynyl)carbamate
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
571 272A, 561 B 132°C yloxy)methyl]-4-trifluoromethoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
572 272A, 561 B 142°C yloxy)methyl]-4-fluorophenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
573 1A, 561 B 146°C yloxy)methyl]-4-methoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
574 1A, 561 B 145°C yloxy)methyl]-5-methylphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
575 272A, 561 B 145°C yloxy)methyl]-4-bromophenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
576 272A, 561 B 213°C yloxy)methyl]-4-ethoxyphenol
2-[(1 H-indol-7-yl)(1 -methylpiperidin-4-yloxy)methyl]- 550A, 1 A,
577 1 10°C
1 H-benzimidazole 272B
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
579 272A, 561 B 142°C yloxy)methyl]-4,6-difluorophenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
580 272A, 561 B 161 °C yloxy)methyl]-4,6-dichlorophenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
581 578 145°C yloxy)methyl]-6-fluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
582 578 129°C yloxy)met yl]-3-fluorop enol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
583 272A, 561 B 198°C yloxy)met yl]-4,5-difluorop enol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
584 578 140°C yloxy)met yl]-5-fluorop enol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
585 578 142°C yloxy)met yl]-5-c lorop enol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
586 578 111°C yloxy)met yl]-6-met ylphenol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
587 578 138°C yloxy)met yl]-4-met ylsulfanylphenol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
588 578 116°C yloxy)met yl]-4-et ylsulfanylphenol
3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
589 578 140°C yloxy)met yl]bip enyl-4-ol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
590 272A, 561 B 139°C yloxy)methyl]-4-tert-butylphenol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
591 578 120°C yloxy)methyl]-4-propylphenol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
592 578 112°C yloxy)met yl]-6-met oxyp enol
2-[(1 H-benzimidazol-2-yl)(1 -met y-piperidin-4-
593 578 136°C yloxy)met yl]-3-fluoro-5-met ylphenol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
594 272A, 561 B 145°C yloxy)met yl]-3-c lorop enol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
595 272A, 561 B 144°C yloxy)met yl]-6-fluoro-4-met ylphenol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
596 272A, 561 B 120°C yloxy)met yl]-4-benzylphenol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
598 578 135°C yloxy)met yl]-4-trifluoromet ylphenol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
599 272A, 561 B 146°C yloxy)met yl]-4-c loro-6-fluorop enol 2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
600 272A, 561 B 146°C yloxy)met yl]-5-fluoro-3-met ylphenol
6-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
601 272A, 561 B 148°C yloxy)met yl]-2-fluoro-3-met ylphenol
6-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
602 578 152°C yloxy)met yl]indan-5-ol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
603 578 120°C yloxy)methyl]-4-propoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-
604 272A, 561 B 130°C yloxy)met yl]-4-(1 -methyl-1 -phenylethyl)phenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
605 578 222 °C yloxy)methyl]-4-(2-fluoroethoxy)phenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
606 578 1 14°C yloxy)methyl]-4-(3-fluoropropoxy)phenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
607 272A, 561 B 1 1 1 °C yloxy)methyl]-4-fluoro-6-methylphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
608 272A, 561 B 132°C yloxy)methyl]-6-fluoro-4-methoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
609 578 140°C yloxy)methyl]-4-phenoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
610 578 108°C yloxy)methyl]-4-fluoro-6-methoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
61 1 578 139°C yloxy)methyl]-4,5-dimethylphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
612 578 128°C yloxy)methyl]-4-(3-fluoropropylsulfanyl)phenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
613 1A, 561 B 102°C yloxy)methyl]-4-fluoro-5-methylphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
614 578 127°C yloxy)methyl]-4-(2-fluoroethylsulfanyl)phenol
3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
615 578 129°C yloxy)methyl]-2-hydroxybiphenyl
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
616 578 105°C yloxy)methyl]-6-ethylphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
617 272A, 561 B 144°C yloxy)methyl]-5-trifluoromethylphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
618 1A, 561 B 189°C yloxy)methyl]-4-hydroxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
619 578 125°C yloxy)methyl]-5,6,7,8-tetrahydro-1 -naphthol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
620 578 126°C yloxy)methyl]-6-trifluoromethoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
621 578 133°C yloxy)methyl]-5-trifluoromethoxyphenol
6-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
622 578 163°C yloxy)methyl]-2-fluoro-3,4-dimethylphenol
6-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
623 578 97 °C yloxy)methyl]-3-fluoro-2-methylphenol
6-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
624 578 146°C yloxy)methyl]-2,4-difluoro-3-methylphenol
6-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
625 578 184°C yloxy)methyl]-2,3-difluorophenol
Further examples can be prepared according to the described general methods:
General
Example Product TLC
methods
(1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-
165C, 249,
450 yloxy)methyl]phenyl}-azetidin-3- 0.22(A)
423B
yl)dimethylamine, oxalate
1 -{3-[(1 H-benzimidazol-2-yl)(1 -
452 methylpiperidin-4- 423B 0.18(D)
yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate
2-{(1 -methylpiperidin-4-yloxy)[3-(pyrrolidin-3-
272A, 272B,
461 yloxy)phenyl]methyl}-1 H-benzimidazole, 0.04(D)
258
dioxalate
2-[(5-chloro-2-fluorophenyl)(1 -
496 methylpiperidin-4-yloxy)methyl]-1 H- 272A, 272B 0.14(B)
benzimidazole, oxalate 2-[(2-fluoro-5-trifluoromethylphenyl)(1 -
498 methylpiperidin-4-yloxy)methyl]-1 H- 272A, 272B 0.25(A)
benzimidazole, oxalate
6-{3-[(1 -ethyl- 1 H-benzimidazol-2-yl)(1 -
194, 1 89,
503 methylpiperidin-4-yloxy)methyl]phenyl}hex-5- 0.08(E)
472
ynylamine, oxalate
2-[(2-fluoro-5-methoxyphenyl)(1 -
504 methylpyrrolidin-3-ylmethoxy)methyl]-1 H- 165C, 449A 0.33(E)
benzimidazole, oxalate
2-[(1 -methylpiperidin-4-yloxy)(3-
517 trifluoromethylsulfanylphenyl)methyl]-1 H- 272A, 272B 0.36(A)
benzimidazole, oxalate
2-[(4-fluoro-3-trifluoromethoxyphenyl)(1 -
518 methylpiperidin-4-yloxy)methyl]-1 H- 272A, 272B 0.32(A)
benzimidazole, oxalate
2-[(2-fluoro-5-propoxyphenyl)(1 -
519 methylpiperidin-4-yloxy)methyl]-1 H- 272A, 272B 0.33(A)
benzimidazole, oxalate
4-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-
597 578 0.20(A)
4-yloxy)methyl]phenol
Eluent A: CH2CI2/MeOH/NH4OH 90/1 0/0.5
Eluent B: CH2CI2/MeOH/NH4OH 95/5/0.5
Eluent C: CH2CI2/MeOH 90/10
Eluent D: CH2CI2/MeOH/NH4OH 90/10/1
Eluent E: CH2CI2/MeOH/NH4OH 80/20/0.5
Further examples can be prepared according to the described general methods:
General
Example Product
methods
2-{[3-(3,3-difluoropyrrolidin-1 -yl)phenyl](1 -methylpiperidin-4- 272A, 91
yloxy)methyl}-1 H-benzimidazole, dioxalate 272BH NMR o f the base (CDCI3): 9.90 (si, 1 H), 7.69 (si, 1 H), 7.18 (m, 3H), 6.86 (d , 1 H), 6.64s, 1 H), 6, 43 (d, 1 H), 5.80 (s, 1 H), 3.65-3.35 (m, 5H), 2.67 (m, 2H), 2.38 (m, 3 H), 2.22 (s, H), 2.20- 1 .60 (m, 5H) General
Example Product
methods
2-{[3-(5-fluorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1 -
492 423 B methylpiperidin-4-yloxy)methyl}benzothiazole, dioxalate
1 H NMR of the base (CDCI3): 7.96 (d, 1 H), 7.85 (d, 1 H), 7.15-7.50 (m, 3H), 6.90 (d, 1 H), 6.80 (s, 1 H), 6.57 (d, 1 H), 5.85 (s, 1 H), 5.25 (d, 1 H), 3.66 (m, 1 H), 3.33 (m, 2H), 3.17 (m, 2H), 3.00 (m, 2H), 2.73 (m, 2H), 2.30 (s, 3H), 2.40-1 .60 (m, 10H).
6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
451 432, 150 yloxy)methyl]phenylsulfanyl}hexylamine, oxalate
1 H NMR (base): 7.65-7.48 (m, 2H), 7.43 (s, 1 H), 7.30-7.15 (m, 5H), 5.85 (s, 1 H), 3.60-3.45 (m, 1 H), 2.86 (t, 2H, J = 7.1 Hz), 2.78-2.60 (m, 4H), 2.23 (s, 3H), 2.18-1 .50 (m, 10H), 1 .50- 1 .20 (m, 2H).
5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
457 359B yloxy)methyl]phenylsulfanylmethyl}oxazolidin-2-one
mp = 109Ό
N-(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 278,432,
458
yloxy)methyl]phenylsulfanyl}hexyl)guanidine, dihydrochloride 150
1 H NMR (dmso-d6): 7.65-7.48 (m, 2H), 7.43 (s, 1 H), 7.30-7.15 (m, 5H), 5.85 (s, 1 H), 3.60- 3.45 (m, 1 H), 2.86 (t, 2H, J = 7.1 Hz), 2.78-2.60 'm, 4H), 2.23 (m, 3H), 2.18-1 .50 (m, 10H), 1 .50-1 .20 (m, 2H).
4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 437B,
473
yloxy)methyl]phenylsulfanyl}but-2-enylamine 359B,
MS, [M=H]+ = 423.2
4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 437B,
474
yloxy)methyl]phenylsulfanyl}but-2-enylamine, oxalate 359B,
N-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
478 401
yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine
MS, [M+H]+ = 509.2 ; [M+Na]+ = 531 .1
3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-
488 437B, 53 yloxy)methyl]phenyl}allylamine
mp = 183°C ; MS, [M+H]+ = 377.3 ; [M+Na]+ = 399.1 cis-2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 437B,
494
yloxy)methyl]phenylsulfanylmethyl}cyclopropylmethylamine 359 B mp = 99°C ; MS, [M+H]+ = 437.1 ; [M+Na]+ = 459.2 N-(3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- 278 , 437B,
499
yloxy)methyl]phenyl}allyl)guanidine, trihydrochloride 359B
MS, [M+H]+ = 419.2 ; [M+Na]+ = 441 .3
2-[(azetidin-3-ylmet oxy)(3-bromop enyl)met yl]-1 H-
502 210, 165D, E benzimidazole
mp = 104<Ό
2-[(3-bromop enyl)(1 -met ylazetidin-3-ylmet oxy)met yl]-1 H- 165C, 437B,
506
benzimidazole 210, 165D, E
MS, 79Br [M+H]+ = 386.1 ; [M+Na]+ = 408.0 ; MS, 80Br [M+H]+ = 388.0 ; [M+Na]+ = 410.0
2-[(2,6-difluorop enyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H-
512 272A, 1 B
benzimidazole
mp = 210Ό
2-[(2-fluoro-4-met ylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H-
513 272A, 1 B
benzimidazole
mp = 85 °C
2-[(5-ethylsulfanyl-2-fluorophenyl)(1 -methylpiperidin-4-
514 150, 272A, 1 B yloxy)met yl]-1 H-benzimidazole
mp = 90 °C
2-[(azetidin-3-ylmethoxy)(2-fluoro-5-
515 165B, A, D, E trifluoromet oxyp enyl)met yl]-1 H-benzimidazole, oxalate
1 H NMR (base) : 7.57-7.62 (m, 2H), 7.38-7.52 (m, 1 H), 7.25-7.1 1 (m, 4H), 6.07 (s, 1 H), .99-3.90 (m, 2H), 3.80-3.74 (m, 2H), 3.64-3.51 (m, 2H), 2.88-3.00 (m, 1 H).
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylazetidin-3- 165C, B, A, D,
516
ylmethoxy)methyl]-1 H-benzimidazole, oxalate E
1 H NMR (base) :7.65-7.48 (m, 2H), 7.38-7.33 (m, 1 H), 7.25-7.10 (m, 4H), 6.04 (s, 1 H), .89-3.70 (m, 2H), 3.44-3.48 (m, 1 H), 3.32-3.38 (m, 3H), 2.52-2.76 (m, 1 H), 2.44 (m, 3H)
2-[(3-ethylsulfanyl-2,6-difluorophenyl)(1 -methylpiperidin-4-
520 150, 272A, 1 B yloxy)met yl]-1 H-benzimidazole
mp = 150<Ό
2-[(2,2-difluorobenzo[1 ,3]dioxol-5-yl)(1 -methylpiperidin-4-
521 272A, 1 B
yloxy)met yl]-1 H-benzimidazole
MS, [M+H]+ = 402.1
538 2-[(piperidin-4-yloxy)thiophen-3-ylmethyl]-1 H-benzimidazole 165B, A, D, E 1 H NMR:9.50 (si, 1 H), 7.75 (si, 1 H), 7.48 (si, 1 H), 7.38-7.22 (m, 5H), 7.12-7.05 (m, 1 H),
5.98 (s, 1 H), 3.75-3.60 (m, 1 H), 3.20-3.05 (m, 2H), 2.72-2.55 (m, 2H), 2.10-1 .85 (m, 2H),
1 .70-1 .45 (m, 2H)
2-[(1 -methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1 H-
539 165C, B, A, D, E benzimidazole
MS, [M+H]+ = 328.03
544 2-[(piperidin-4-yloxy)thiophen-2-ylmethyl]-1 H-benzimidazole 165B, A, D, E mp = 185<Ό
2-[(1 -methylpiperidin-4-yloxy)thiophen-2-ylmethyl]-1 H-
546 165C, B, A, D, E benzimidazole
mp = 85 °C
Preparation of starting materials Salicaldehydes can be prepared from the corresponding phenols according to following procedures (non exhaustive):
-with paraformaldehyde, magnesium chloride and triethylamine according J. Med. Chem., 2006, 49 (26), pp 7731 -7739.
-protection of phenol with a tetrahydropyranyl (THP) group followed by metalation and addition of dimethylformamide and final THP deprotection according to WO2009/089057
-with the Reimer-Tiemann procedure Org. React. 1982, 28, 2)
-with hexamethylenetetramine (Duff reaction, Organic Syntheses Coll. Vol. 10, p.96; Vol. 75, p.1 )
Biological data
In vitro evaluation of compounds
• Membrane preparation
SH-SY5Y cells stably expressing human H4 receptor are grown until sub- confluence and centrifuged at 300g 15 minutes at 4°C. Pellets are resuspended in buffer I Tris-HCI 50mM, MgCI2 10mM, NaCI 140mM, pH=7.4 supplemented by Leupeptin ^g/mL, Phenyl Methyl Sulphonyl Fluoride (PMSF) 0.1 mM, Aprotinin 2μg/mL and Pepstatin 2μΜ (or a 1 /50 dilution of a mix of protease inhibitors). The obtained suspension is stirred gently and submitted to a 25-26xg mechanic pressure exerted through a syringe. The cell lysate is then centrifuged at 300g 15 minutes at 4°C in order to eliminate nucleus and cell scraps. The obtained supernatant is then centrifuged at 48000 g for 30 minutes at 4°C. The final pellet is resuspended in buffer I with a potter homogenizer. Aliquots are frozen in liquid nitrogen and stored until use at -80 °C. Protein content is measured by the Bradford method.
GTPy [35S] binding
Defreezed membranes are diluted at a final concentration of 5μς/180μί/ννβΙΙ in buffer I supplemented by GDP 10μΜ and distributed in 96 well polystyrene microplate. GTPy [35S] labelled ligand (0.2-0.3 nM) is added for additional 30 minutes. After transfer in a Millipore GF/C HTS® microplate, the filtration of the reactional mix is followed by a three times 250 μΙ wash to stop the reaction.
The filter-bound radioactivity is measured in a liquid scintillation counter Microbeta TRILUX® with 50μΙ of scintillation fluid.
GTPy [35S] dependent binding activity is determined in vitro for Histamine, Imetit,
R(-)-alpha-methyl-histamine and all our compounds.
Compounds can also be tested against Histamine or Imetit to evaluate their antagonist potential. Results are expressed with IC50 and Ki values. · Membrane preparation
CHO cells stably expressing human H4 receptor were grown until sub-confluence and centrifuged at 300g 15 minutes at 4°C. Pellets were resuspended in buffer I Tris-HCI 50mM, MgCI2 10mM, NaCI 140mM, pH=7,4 supplemented by a 1 /50 dilution of a mix of protease inhibitors. The obtained suspension is stirred gently and submitted to a 25-26xg mechanic pressure exerted through a syringe. The cell lysate is then centrifuged at 300g 15 minutes at 4 °C in order to eliminate nucleus and cell scraps. The obtained supernatant was then centrifuged at 48000 g for 30 minutes at 4°C. The final pellet is resuspended in buffer I with a potter homogenizer. Aliquots were frozen in liquid nitrogen and stored until use at -80 °C. Protein content is measured by the Bradford method.
[3H]Histamine binding
Defreezed membranes were diluted at a final concentration of 20μg / 180μΙ_/ well in a binding buffer containing 50 mM Tris/HCI, 0.5 mM EDTA, pH=7.4 and distributed in 96 well polystyrene microplate. [3H] Histamine labelled ligand (10-15 nM) is added for 60 minutes with compounds at room temperature under continuous stirring. Non specific binding was estimated in the presence of 10 μΜ BP1 .2404 (JNJ 7777120). The reaction was terminated by filtration through GF/B filters pre-soaked 2 hours at 4 °C in 1 % polyethyleneimine. Filters were rinsed 3 times with 250 μΙ of ice cold incubation binding buffer.
The filter-bound radioactivity was measured in a liquid scintillation counter Microbeta TRILUX® with 50μΙ of scintillation fluid.
The hH4 binding investigated by use of [3H] Histamine give a Bmax ~1 pmole/mg prot and a Kd ~9 nM.
Racemates decribed hereabove have been evaluated in the GTPy [35S] assay or in the [3H] histamine binding assay and have been found active with a Ki or IC50 under 1000nM.
Example Activity Example Activity Example Activity
1 B 36 B 71 B
2 A 37 A 73 B
3 B 38 B 74 B
4 A 39 B 75 C
5 B 40 C 76 B
6 B 41 C 77 B
7 B 42 C 78 B
8 C 43 B 79 B
9 C 44 A 80 B
10 C 45 C 81 B
1 1 C 46 B 82 B
12 B 47 C 83 B
13 B 48 B 84 A
14 A 49 A 85 B
15 B 50 C 86 B
16 C 51 C 87 B
17 A 52 A 88 C
18 B 53 B 89 B
19 B 54 B 90 B
20 B 55 C 91 C
21 B 56 B 92 B
22 C 57 C 93 B
23 C 58 B 94 C
24 A 59 C 95 C
25 C 60 C 96 B
26 C 61 C 97 B
27 C 62 C 98 B
28 B 63 B 99 B
29 A 64 A 100 B
30 B 65 C 101 C
31 C 66 A 102 C
32 B 67 C 103 B
33 B 68 B 104 C
34 B 69 C 105 C
35 A 70 B 106 B Example Activity Example Activity Example Activity
107 C 160 C 213 B
108 B 161 C 214 B
109 B 162 C 215 B
1 10 B 163 C 216 B
1 1 1 C 164 B 217 B
1 12 A 165 B 218 C
1 13 C 166 C 219 A
1 14 B 167 C 220 C
1 15 B 168 B 221 B
1 16 B 169 A 222 B
1 17 C 170 B 223 B
1 18 C 171 C 224 B
1 19 B 172 B 225 B
120 A 173 B 226 B
121 B 174 B 227 C
122 B 175 B 228 C
123 A 176 C 229 C
124 C 177 B 231 B
125 C 178 B 232 A
126 B 179 B 233 B
127 B 180 C 234 B
128 B 181 C 235 A
129 C 182 C 236 B
130 B 183 B 237 B
131 B 184 B 238 A
132 B 185 C 239 A
133 B 186 A 240 B
134 B 187 C 241 B
135 B 188 C 242 A
136 B 189 B 243 B
137 B 190 B 244 B
138 B 191 B 245 B
139 C 192 B 246 B
140 B 193 B 247 B
141 B 194 B 248 B
142 B 195 B 249 B
143 B 196 C 250 B
144 C 197 C 251 A
145 B 198 C 252 A
146 B 199 B 253 C
147 B 200 B 254 C
148 B 201 C 255 C
149 C 202 C 256 C
150 B 203 A 257 A
151 B 204 B 258 B
152 C 205 A 259 B
153 C 206 B 260 C
154 B 207 A 261 B
155 B 208 B 262 B
156 C 209 B 263 A
157 B 210 A 264 B
158 C 21 1 B 265 B
159 C 212 A 266 B Example Activity Example Activity Example Activity
267 C 320 C 374 C
268 B 321 C 375 A
269 C 322 A 376 A
270 A 323 A 377 B
271 C 324 B 378 A
272 A 325 C 379 A
273 A 326 C 380 B
274 B 327 B 381 C
275 B 328 C 382 C
276 C 330 B 383 B
277 B 331 B 384 B
278 C 332 A 385 B
279 A 333 B 386 C
280 B 334 B 387 C
281 A 335 B 388 A
282 A 336 B 389 B
283 C 337 C 390 C
284 B 338 B 391 A
285 A 339 B 392 A
286 B 340 C 393 C
287 C 341 B 394 A
288 A 342 B 395 B
289 C 343 B 396 A
290 B 344 B 397 B
291 B 345 B 398 B
292 B 346 B 399 B
293 B 347 A 400 C
294 C 348 A 401 B
295 B 349 B 402 B
296 B 350 A 403 B
297 B 351 A 404 B
298 A 352 B 405 B
299 A 353 B 406 C
300 B 354 C 407 C
301 C 355 B 408 B
302 C 356 A 409 B
303 B 357 B 410 B
304 C 358 C 41 1 A
305 C 359 C 412 A
306 B 360 A 413 B
307 A 361 A 414 B
308 B 362 A 415 B
309 B 363 B 416 B
310 B 364 A 417 A
31 1 B 365 B 418 C
312 B 366 C 419 A
313 B 367 B 421 C
314 C 368 C 422 C
315 A 369 A 423 B
316 B 370 A 424 B
317 A 371 C 425 C
318 C 372 C 426 B
319 C 373 C 427 B Example Activity Example Activity Example Activity
428 B 483 B 536 C
429 B 484 C 537 A
430 C 485 A 538 A
431 C 486 C 539 B
433 C 487 C 540 B
435 C 488 A 541 C
436 C 489 C 542 C
437 C 490 B 543 C
438 C 491 A 544 A
439 C 492 A 545 B
440 C 493 C 546 B
441 C 494 C 547 A
442 C 495 C 548 C
443 C 496 B 549 A
444 B 497 A 550 C
445 B 498 B 551 B
446 B 499 C 552 B
447 A 500 B 553 A
448 B 501 B 554 B
449 C 502 A 555 C
450 A 503 B 556 C
451 B 504 C 557 C
452 B 505 A 558 C
453 C 506 B 559 C
454 C 507 C 560 B
455 C 508 C 561 C
456 A 509 C 562 C
457 C 510 B 563 B
458 B 51 1 B 564 C
459 C 512 C 565 B
460 A 513 C 566 C
461 B 514 C 567 B
462 B 515 A 568 C
463 A 516 B 569 C
464 C 517 C 570 B
465 C 518 A 571 C
466 C 519 C 572 C
467 C 520 B 573 B
468 B 521 A 574 C
469 A 522 C 575 C
470 B 523 C 576 C
471 B 524 B 577 B
472 B 525 B 578 C
473 C 526 C 579 A
474 C 527 C 580 A
475 B 528 B 581 C
476 C 529 B 582 C
477 A 530 A 583 B
478 B 531 C 584 C
479 C 532 B 585 C
480 B 533 C 586 C
481 A 534 B 587 C
482 C 535 B 588 C Example Activity Example Activity Example Activity
589 A 602 B 615 B
590 A 603 B 616 C
591 B 604 B 617 C
592 B 605 C 618 C
593 C 606 B 619 B
594 C 607 A 620 C
595 B 608 B 621 C
596 C 609 B 622 B
597 A 610 A 623 C
598 B 61 1 C 624 C
599 B 612 C 625 C
600 C 613 C 627 C
601 C 614 C
A: Ki or IC50 <1000nM
B: Ki or IC50 <300nM
C: Ki or IC50 <30nM

Claims

1 . A compound of formula (I):
Figure imgf000166_0001
wherein:
X represents NR', S or O;
HetAr represents a phenyl or heteroaryl, optionally substituted with one or more substituents chosen from halogen, OR" alkyl, cyano, NR"R"', -COR", -COOR", -CONR"R"', aryl, -alkylaryl;
R represents a lower alkyl or H
R' represents H, lower alkyl, alkoxyalkyl or alkoxycarbonyl;
R", R'" identical or different independently represent H or alkyl;
HET representing a non aromatic monocyclic heterocycle containing at least one nitrogen atom, which is linked to R;
B represents a single bond or an -alkyl- group;
A represents O, NH or S;
Ar is a mono or polycyclic aromatic or a mono or polycyclic heteroaromatic which can be optionally substituted with one or more of:
• halo; azido; cyano; hydroxy; nitro;
· alkyl; alkoxy; alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy; alkenylsulfanyl; alkynylsulfanyl; cycloalkoxy; cyloalkylalkyl;
whose alkyl, alkenyl, alkynyl or cycloalkyl part can be substituted with one or more of halo, hydroxy, polyhydroxy, alkoxy, hydroxyalkoxy, cyano, amino, aminoalkyl, alkylamino, dialkylamino, aminoalkylamino, aminoalkylaminocarbonyl, alkoxycarbonylamino, diarylmethylimino (where aryl is optionally substituted with one or more of hydroxy or halo), cycloalkenylimino (where cylalkenyl is optionally substituted with one or more of alkyl, OH), alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkyl, polycycloalkyl, cycloalkenyl, polycycloalkenyl, guanidino, alkylcarbonylguanidino, acylguanidino, cyanoguanidino, alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylalkylcycloalkyl, alkoxycarbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroaryl, heterocyclyl (heterocyclyl being optionally substituted with one or more of oxo, amino, imino), heteroaryloxy, heterocyclyloxy, heteroarylamino, heterocyclylamino, hydrazinocarbonyl, hydroxyalkylcycloalkyl, N-alkyl(thioureido), phtalimido, ureido, oxocycloalkenylamino substituted with amino, carbamimidoylheterocyclyl;
• amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfinyl; alkylsulfonyl; alkylsulfonyloxy
whose alkyl can be substituted with one or more of halo;
• aminocarbonyl which can be N-substituted with one or two of alkyl, aryl, arylalkyl;
• aryl; arylalkyl; aryloxy; arylalkoxy; arylalkylamino; arylalkylsulfanyl; heteroaryl;heteroaryloxy
whose aryl part can be substituted with one or more of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, nitro, cyanoalkyi, or fused with a non aromatic heterocycle;
• heterocyclyl; heterocyclyloxy; heterocyclylalkoxy
whose heterocycle can be substituted with one or more of halogenoalkyl, acylamino, acyloxy, amino, alkyl, alkylamino, dialkylamino, aminoalkyl, oxo, carbamimidoyl, halo, hydroxy, hydroxyalkyl, hydroxymethyl, alkoxcarbonyl;
or
• fused with a non aromatic heterocycle (optionally substituted with one or more of halogens) or carbocycle;
as well as their enantiomers, diastereomers, mixtures thereof and pharmaceutically acceptable salts, tautomers, hydrates and solvates.
2. The compound according to claim 1 wherein:
wherein:
X represents NR' or S;
HetAr represents a phenyl, optionally substituted with one or more substituents chosen from hydrogen, halogen, amino, alkyl;
R represents H or a lower alkyl;
R' represents H, alkyl, alkoxyalkyl, alkoxycarbonyl;
HET representing a non aromatic 5 or 6 membered heterocycle containing one nitrogen atom, which is linked to R;
B represents a single bond or a -CH2- group;
A represents O, NH or S; Ar is a thienyl, phenyl or naphtyl or 5 to 6 membered heteroaromatic where the phenyl can be optionally substituted with one or more of:
• halo; azido; cyano; hydroxy; nitro; alkyl;
• alkoxy; alkylsulfanyl; alkenyl; alkenylsulfanyl;alkynyl; alkenyloxy; alkenyloxy; cycloalkoxy; cyloalkylalkyl
whose alkyl, alkenyl, alkynyl or or cycloalkyl part can be substituted with one or more of halo, hydroxy, alkoxy, hydroxyalkoxy, cyano, amino, aminoalkyl, alkylamino, aminoalkylamino, dialkylamino, aminoalkylaminocarbonyl, alkoxycarbonylamino, diarylmethylimino (where aryl is optionally substituted with one or more of hydroxy or halo), cycloalkenylimino (where cylalkenyl is optionally substituted with one or more of alkyl, OH), alkylsulfanyl, alkylsulfonyl, cycloalkyl, (poly)cycloalkenyl, guanidino, alkylcarbonylguanidino, acylguanidino, alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxy- carbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl, heterocyclyl (heterocyclyl being optionally substituted with one or more of oxo, amino, imino), heterocyclylamino, hydrazinocarbonyl, N-alkyl(thioureido), phtalimido, ureido, oxocycloalkenylamino substituted with amino, carbamimidoylheterocyclyl;
• amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfonyl; alkylsulfonyloxy
whose alkyl can be substituted with one or more of halo;
• aminocarbonyl which can be N-substituted with one or two of alkyl, aryl, arylalkyl;
• aryl; arylalkyl; aryloxy; arylalkoxy; arylalkylsulfanyl; heteroaryl; heteroaryloxy whose aryl part can be substituted with one or more of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, nitro, cyanoalkyl, or is fused with a non aromatic heterocycle;
• heterocyclyloxy; heterocyclylalkoxy; heterocyclyl
whose heterocycle can be substituted with one or more of halo, halogenoalkyl, acylamino, acyloxy, amino, alkyl, alkylamino, dialkylamino, aminoalkyl, oxo, carbamimidoyl, hydroxy, hydroxyalkyl;
or
• fused with a non aromatic heterocycle (optionally substituted with one or more of halogens) or carbocycle;
as well as their enantiomers, diastereomers, mixtures thereof and pharmaceutically acceptable salts, tautomers, hydrates and solvates.
3. The compound of formula (I) according to claim 1 or 2, where X represents NH or S.
4. The compound according to anyone of the preceding claims, wherein HetAr is phenyl.
5. The compound according to anyone of the preceding claims, wherein R represents methyl.
6. The compound according to anyone of the preceding claims, wherein B represents a single bond.
7. The compound according to anyone of the preceding claims, wherein Ar is a phenyl which can be optionally substituted with one or more of:
halo; azido; cyano; hydroxy; nitro; alkyl;
alkoxy; alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy;
whose alkyl; alkenyl or alkynyl part can be substituted with one or more of halo, hydroxy, alkoxy, hydroxyalkoxy, cyano, amino, alkylamino, aminoalkylamino, alkylsulfanyl, alkylsulfonyl, cycloalkyl, (poly)cycloalkenyl, guanidino, acylguanidino, alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl, heterocyclyl, heterocyclylamino, hydrazinocarbonyl, N-alkyl(thioureido), phtalimido, ureido, oxocycloalkenylamino substituted with amino, carbamimidoylheterocyclyl;
amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfonyl; alkylsulfonyloxy
whose alkyl can be substituted with one or more of halo;
aminocarbonyl which can be N-substituted with one or two of alkyl, aryl, arylalkyl; aryl; aryloxy; arylalkoxy; arylalkylsulfanyl; heteroaryl
whose aryl part can be substituted with one or more of amino, halo, alkyl,
(poly)haloalkyl, hydroxyalkyl, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, nitro, cyanoalkyl, or is fused with a non aromatic heterocycle;
heterocyclyloxy; heterocyclylalkoxy whose heterocycle can be substituted with one or more of acylamino, acyloxy, amino, alkyl, carbamimidoyl, hydroxy, hydroxyalkyl;
or
fused with a non aromatic heterocycle;
8. The compound according to anyone of the preceding claims which is chosen from the group consisting in:
2-[(1 -methylpiperidin-4-yloxy)phenylmethyl]benzothiazole
- 2-[(1 -methylpyrrolidin-3-yloxy)phenylmethyl]benzothiazole
2-[(4-fluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(4-chlorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(3-fluorophenyl)(1 -methylpiperidin-4-yloxymethyl]benzothiazole
2-[(2-fluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
- 2-[(1 -methylpiperidin-4-yloxy)-p-tolylmethyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)(m-tolyl)methyl]benzothiazole
(benzothiazol-2-yl-phenylmethyl)(1 -methylpiperidin-4-yl)amine
2-[(2,3-dihydrobenzo[1 ,4]dioxin-6-yl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole
- 2-[(3-methoxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(2,4-difluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)thiophen-2-ylmethyl]benzothiazole
2-[(4-methoxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(3,5-difluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
- 2-[(1 -methylpiperidin-4-yloxy)thiophen-3-ylmethyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)naphthalen-1 -ylmethyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)naphthalen-2-ylmethyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)(5-methylthiophen-2-yl)methyl]benzothiazole
2-[benzo[1 ,3]dioxol-5-yl(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
- [(benzothiazol-2-yl)(m-tolyl)methyl](1 -methylpiperidin-4-yl)amine
2-[(3-allyloxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)(3-trifluoromethoxyphenyl)methyl]benzothiazole 2-[(1 -methylpiperidin-4-yloxy)(4-trifluoromethoxyphenyl)methyl]benzothiazole
[benzothiazol-2-yl(3-methoxyphenyl)methyl](1 -methylpiperidin-4-yl)amine
- 2-[(1 -methylpiperidin-4-yloxy)(3-propoxy-phenyl)methyl]benzothiazole
2-[(3-bromo-phenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole 2-[(1-met ylpiperidin-4-yloxy)(3-p enoxy-p enyl)met yl]benzot iazole
5-met yl-2-[(1-met ylpiperidin-4-yloxy)p enylmet yl]benzot iazole
2-[(1 -met ylpiperidin-4-yloxy)p enylmet yl]-1 H-benzimidazole
2-[(1-met ylpiperidin-4-yloxy)(3-trifluoromet ylphenyl)met yl]benzot iazole
2-[(2,3-di ydrobenzofuran-5-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
5-fluoro-2-[(1-met ylpiperidin-4-yloxy)p enylmet yl]benzot iazole
2-[(4 luoro-3-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
[benzot iazol-2-yl(4 luoro-3-met yl-phenyl)met yl](1-met ylpiperidin-4-yl)amine
(benzot iazol-2-yl-p-tolylmet yl)(1-met ylpiperidin-4-yl)amine
[(benzofuran-2-yl)(benzot iazol-2-yl)met yl](1-met ylpiperidin-4-yl)amine
2-[(3 luoro-5-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
[(1 H-benzimidazol-2-yl)phenylmet yl](1-met ylpiperidin-4-yl)amine
2-[(3-fluoro-5-met oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(3-iodop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[benzot iazol-2-yl(3 luoro-5-met oxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
[benzot iazol-2-yl(3 luoro-5-met ylphenyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(3-benzyloxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[benzofuran-5-yl(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(3-et oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
[benzot iazol-2-yl(3-iodop enyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(1-met ylpiperidin-4-yloxy)(3-propoxyp enyl)met yl]-1 --benzimidazole
[(1 H-benzimidazol-2-yl)(3-propoxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(3-iodop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
(benzot iazol-2-ylpyridin-3-ylmet yl)(1-met ylpiperidin-4-yl)amine
2-[bip enyl-3-yl(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
{3'-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxymet yl]bip enyl-3-yl}rTiet anol
2-[(3-isopropoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[benzot iazol-2-yl(1 --pyrrol-2-yl)met yl](1-met ylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3-trifluoromet ylphenyl)met yl](1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-trifluoromet oxyp enyl)met yl](1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-et ylphenyl)met yl](1-met ylpiperidin-4-yl)amine 3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenol
2-[(1-met ylpiperidin-4-yloxy)(3-pyridin-3-ylp enyl)met yl]benzot iazole
[(1 H-benzimidazol-2-yl)(3-bromop enyl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-benzyloxyp enyl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-isopropylp enyl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-isobutoxyp enyl)met yl](1-met ylpiperidin-4-yl)amine {(1 H-benzimidazol-2-yl)[3-(3-met ylbutoxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-butoxyp enyl)met yl](1-met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-met oxyp enyl)met yl](1-met ylpiperidin-4-yl)amine trifluoromet anesulfonic acid 3-[benzot iazol-2-yl(1 -met ylpiperidin-4- yloxy)methyl]phenyl ester
trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1 -methylpiperidin-4- yloxy)methyl]phenyl ester
[(1 H-benzimidazol-2-yl)(3-cyclohexylmetrioxyprienyl)metriyl](1-metriylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3 luorophenyl)metriyl](1-metriylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-metriylsulfanylphenyl)metriyl](1-metriylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-riexylprienyl)metriyl](1-metriylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3-isopropoxyphenyl)metriyl](1-metriylpiperidin-4-yl)amine
2-[(3-bromophenyl)(1-metriylpiperidin-4-yloxy)metriyl]-1 H-benzimidazole
3'-[benzothiazol-2-yl(1-metriylpiperidin-4-yloxy)metriyl]biprienyl-3-ylamine
2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)metriyl]-1 H-benzimidazole
[benzothiazol-2-yl(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine
[(1 --benzimidazol-2-yl)(3-ethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1 --benzimidazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine
[(1 --benzimidazol-2-yl)(3-phenoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
{3'-[(1 --benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3- yljmethanol
3'-[(1 --benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine [benzothiazol-2-yl(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine 2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]-1 H-benzimidazole 1 -{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-ylamino)methyl]phenyl}ethanone [benzothiazol-2-yl(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amine 2-[(3-butoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
[benzot iazol-2-yl(3-cyclo exylmet oxyp enyl)met yl](1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)bip enyl-3-ylmet yl](1-met ylpiperidin-4-yl)amine
[(1 H-benzimidazol-2-yl)(3-pentyloxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
2-[(2'-met oxybip enyl-3-yl)(1-met ylpiperidiri-4-yloxy)rTiet yl]benzot iazole
2-[(1-met ylpiperidin-4-yloxy)(3'-nitrobip enyl-3-yl)met yl]benzot iazole
{S'^benzothiazol^-y I-methylpiperidin^-yloxyJmethy biphenyl-S-ylJacetonitrile
2-[(3'-met oxybip enyl-3-yl)(1-met ylpiperidiri-4-yloxy)rTiet yl]benzot iazole
2-[(4'-met oxybip enyl-3-yl)(1-met ylpiperidiri-4-yloxy)rTiet yl]benzot iazole
[benzot iazol-2-yl(3-benzyloxyp enyl)met yl](1-met ylpiperidin-4-yl)amine
(benzot iazol-2-ylbip enyl-3-ylmet yl)(1-met ylpiperidin-4-yl)amine
{(1 H-benzimidazol-2-yl)[3-(4-fluorobenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[(1 H-benzimidazol-2-yl)(3-benzylsulfanylphenyl)met yl](1-met ylpiperidin-4- yl)amine
{(1 H-benzimidazol-2-yl)[3-(3-fluorobenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
{(1 H-benzimidazol-2-yl)[3-(2-phenoxyet oxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[benzot iazol-2-yl(3-benzylsulfanylphenyl)met yl](1-met ylpiperidin-4-yl)amine 1 -{3'-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]biphenyl-4- yljethanone
2-[(3'-fluoro-bip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 1 -{3'-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]biphenyl-3- yljethanone
[benzot iazol-2-yl(3-met ylsulfanylphenyl)met yl](1-met ylpiperidin-4-yl)amine [(3-allyloxyp enyl)(1 --benzimidazol-2-yl)met yl](1-met ylpiperidin-4-yl)amine {(1 H-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
2-[(1-met ylpiperidin-4-yloxy)(2'-met ylsulfanylbip enyl-3-yl)rTiet yl]-1 H- benzimidazole
2-[(4'-fluorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
2-[(1-met ylpiperidin-4-yloxy)(3'-met ylsulfanylbip enyl-3-yl)met yl]-1 -- benzimidazole
2-[(3-iodop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole 2-[(3-iodop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(1 -met ylpiperidin-4-yloxy)(4'-trifluoromethylbip enyl-3-yl)met yl]-1 H- benzimidazole
{(1 --benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1- met ylpiperidin-4-yl)amine
2-[(2'-c lorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 --benzimidazole
2- [(3',4,-dic lorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole {3'-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]bip enyl-2- yljmethanol
{(1 /-/-benzimidazol-2-yl)[3-(4-met oxybenzyloxy)p enyl]met yl}(1-met ylpiperidin- 4-yl)amine
{(1 /-/-benzimidazol-2-yl)[3-(3-met oxybenzyloxy)p enyl]met yl}(1-met ylpiperidin- 4-yl)amine
3- [(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-ylamino)met yl]phenol
{3'-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]bip enyl-2-yl}met anol 2-[(1-met ylpiperidin-4-yloxy)(3'-met ylsulfanylbip enyl-3-yl)met yl]benzot iazole {(1 /-/-benzimidazol-2-yl)[3-(2-met ylbenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
{(1/-/-benzimidazol-2-yl)[3-(4-met ylbenzyloxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[(1 /-/-benzimidazol-2-yl)(3-nitrop enyl)met yl](1-met ylpiperidin-4-yl)amine
[(3-azidop enyl)(1/-/-benzimidazol-2-yl)met yl](1-met ylpiperidin-4-yl)amine
2-[(3',4'-dic lorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
{(1/-/-benzimidazol-2-yl)[3-(2-et oxyet oxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
[(1 /-/-benzimidazol-2-yl)(3-pent-4-enyloxyp enyl)met yl](1-met ylpiperidin-4- yl)amine
2-[(4'-fluorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(2'-fluorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
{3'-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]bip enyl-4- yljcarbamic acid ferf-butyl ester
2-[(3'-fluorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(1-met ylpiperidin-4-yloxy)(4'-trifluoromet ylbip enyl-3-yl)met yl]benzot iazole 2-[(1-met ylpiperidin-4-yloxy)(2',3',4,-trifluorobip enyl-3-yl)met yl]benzot iazole 2-[(2'-fluorobip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole {3' benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamic acid ferf-butyl ester
[(1 H-benzimidazol-2-yl)(3 uran-2-ylphenyl)met yl](1 -met ylpiperidin-4-yl)amine [(1 H-benzimidazol-2-yl)(3-but-3-enyloxyp enyl)met yl](1 -metriylpiperidiri-4- yl)amine
{(1 H-benzimidazol-2-yl)[3-(4-met ylpentyloxy)p enyl]met yl}(1 -metriylpiperidin-4- yl)amine
2-[(1 -methylpiperidin-4-yloxy)(3-pyrazol-1 -ylphenyl)methyl]benzothiazole
2-[(3-benzylsulfanylphenyl)(1 -met ylpiperidin-4-yloxy)metriyl]benzotriiazole {(1 H-benzimidazol-2-yl)[3-(2,5-difluoro-benzyloxy)phenyl]methyl}(1 - met ylpiperidin-4-yl)amine
2-[(3-benzylsulfanylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 - -benzimidazole 2-[(2-chlorophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole
2-[(3-et ylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]benzot iazole
2-[(3-et ylsulfanylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}acetic acid methyl ester
2-[(3-fluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole
2-[[3-(2,5-difluorobenzyloxy)phenyl](1 -methylpiperidin-4- yloxy)methyl]benzothiazole
2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethanol
2-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol 2-[(3-ethylsulfanylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid methyl ester
2-[[3-(2,3-difluorobenzyloxy)phenyl](1 -methylpiperidin-4- yloxy)methyl]benzothiazole
{(1 /-/-benzimidazol-2-yl)[3-(2,3-difluoro-benzyloxy)phenyl]methyl}(1 - methylpiperidin-4-yl)amine
2-[[3-(2-fluoroethoxy)phenyl](1 -methylpiperidin-4-yloxy)methyl]benzothiazole 2-[(1 -methylpiperidin-4-yloxy)(m-tolyl)methyl]-1 /-/-benzimidazole
5,6-dichloro-2-[(1 -methylpiperidin-4-yloxy)phenyl-methyl]-1 /-/-benzimidazole 5-fluoro-2-[(1 -methylpiperidin-4-yloxy)phenyl-methyl]-1 /-/-benzimidazole
2-[(2-fluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole
2-[(1 -methylpiperidin-4-yloxy)(3-pent-4-enyloxy-phenyl)methyl]benzothiazole 2-{(1-methylpiperidin-4-yloxy)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}benzothiazole 5-bromo-2-[(1-met ylpiperidin-4-yloxy)p enyl-met yl]-1 --benzimidazole
2- [[3-(3-fluorobenzyloxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole
3- [(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]benzonitrile
2-[[3-(furan-2-ylmet ylsulfanyl)phenyl](1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
((1 H-benzimidazol-2-yl)-{3-[3-(2-methyl-[1 ,3]dioxolan-2-yl)- propoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine
{(1 H-benzimidazol-2-yl)[3-(4,4,4-trifluoro-butoxy)p enyl]met yl}(1-met ylpiperidin-
4- yl)amine
2-[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole 2-[(1-met ylpiperidin-4-yloxy)-p-tolyl-met yl]-1 /-/-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(3,3,3-trifluoro- propoxy)phenyl]methyl}benzothiazole
2-[(4-fluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
{(1 /-/-benzimidazol-2-yl)[3-(2-fluoro-et oxy)p enyl]met yl}(1-met ylpiperidin-4- yl)amine
((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2- yl)et oxy]p enyl}met yl)(1-met ylpiperidin-4-yl)amine
2-[(1-met ylpiperidin-4-yloxy)(4'-trifluoromet oxy-bip enyl-3-yl)met yl]-1 H- benzimidazole
2-[(4'-met oxybip enyl-3-yl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole 2-[(3-benzo[1 ,3]dioxol-5-ylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
2-[[3-(3-met oxybenzyloxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole
5- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentan-2-one 2-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl- benzyloxy)p enyl]met yl}benzot iazole
4-[benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1 ,1-dimet ylpiperidinium
2- (3-{3-[(1/-/-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2- ynyl)isoindole-1 ,3-dione
3- {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}prop-2-yn-1 - ol
4- {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}but-3-yn-1 -ol
5- {3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1 - ol 2- [(1 -met ylpiperidin-4-yloxy)-o-tolyl-met yl]-1 - -benzimidazole
3- {3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}prop-2- ynylamine
2-[(3-et ynylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
2- {(1 -met ylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)p enyl]met yl}benzot iazole
3- [benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]benzonitrile
2- {(1 -methylpiperidin-4-yloxy)[3-(1 H-[1 ,2,3]triazol-4-yl)phenyl]methyl}-1 H- benzimidazole
3- [benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]benzoic acid methyl ester 2-[(1 -methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ylamine
2-[(1 -methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]benzothiazole 2-[(1 -methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]-1 /-/-benzimidazole 2-[(3-methanesulfonylphenyl)(1 -methylpiperidin-4-yloxy)methyl]benzothiazole
2- [(4-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole
3- {3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}acrylic acid tert- butyl ester
3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]benzoic acid ethyl ester {3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}methanol
3-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}propionic acid tert- butyl ester
2-[[3-(2-benzenesulfonylvinyl)phenyl](1 -methylpiperidin-4- yloxy)methyl]benzothiazole
2-[(1 -methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ol
[benzothiazol-2-yl(4'-methoxy-biphenyl-3-yl)methyl](1 -methylpiperidin-4-yl)amine 2-[[3-(2-methanesulfonylvinyl)phenyl](1 -methylpiperidin-4- yloxy)methyl]benzothiazole
2-[(2-chloro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole 5-{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}pyrimidin-2-ol 2-[(3-ferf-butylsulfanylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole
2- [(1 -methylpiperidin-4-yloxy)(3-pyrimidin-5-yl-phenyl)methyl]benzothiazole
3- {3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}acrylonitrile
2- [(1 -methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]benzothiazole
3- [benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]-/V-benzyl-/V- methylbenzamide
3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]-/V-propylbenzamide
2-[(2,4-difluorophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 /-/-benzimidazole [(1 H-benzimidazol-2-yl)(4'-met oxy-bip enyl-3-yl)met yl](1-met ylpiperidin-4- yl)amine
3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]-A/-met yl-A/- phenylbenzamide
3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenylamine
2-[(3-c lorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
2- [(4-c lorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol 3-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxymet yl}- p enylamine
2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}et anol 2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}et anol 2-[(3-azidop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
2-{(1-met ylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-et ylsulfanyl)phenyl]met yl}-1H- benzimidazole
2- {(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl- ethylsulfanyl)phenyl]methyl}benzothiazole
{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}benzyl-amine
3- {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}-3- methyl-butan-1-ol
4- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}but-3-yn-1-ol
5- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4-yn-1-ol 4-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}butan-1-ol (1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanylmet yl}- cyclopropyl)acetic acid methyl ester
2-{(1 -methylpiperidin-4-yloxy)[3-(2-[1 ,2,3]triazol-2-yl- ethylsulfanyl)phenyl]methyl}benzothiazole
2- {(1 -methylpiperidin-4-yloxy)[3-(2-[1 ,2,3]triazol-1 -yl- ethylsulfanyl)phenyl]methyl}benzothiazole
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-3-methyl- butan-1-ol
2-[(1-methylpiperidin-4-yloxy)(3-morpholin-4-yl-phenyl)methyl]benzothiazole 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethanol
2- [(1-methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]-1 H-benzimidazole
3- {3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}propan-1-ol 1 -{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}propan-2-ol
4-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}butan-1-ol
2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanyl}et ylamine
2-{(1-methylpiperidin-4-yloxy)[3-(2-methylsulfanyl- ethoxy)phenyl]methyl}benzothiazole
2-[(1-met ylpiperidin-4-yloxy)(2-trifluoromet oxy-p enyl)met yl]-1 --benzimidazole 2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1 /-/-benzimidazole
2- [(1-met ylpiperidin-4-yloxy)-p-tolyl-met yl]-1 /-/-benzimidazole
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1- ol
1- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2- ol
4- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}butan-1-ol
2- (1 -{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propan-1-ol 2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}-/V- methylacetamide
2-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole 2-[(3-bromo-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole 2-[(2-bromop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid hydrazide
2-{(1-met ylpiperidin-4-yloxy)[3-(pyridin-4-ylmet oxy)p enyl]met yl}benzot iazole
4- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}butan-1-ol 2-[[3-(furan-2-ylmet oxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole 2-(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanylmet yl}- cyclopropyl)ethanol
2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}et ylamine
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]benzyloxy}propan-2-one
2- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}et ylamine 2-[(1-met ylpyrrolidin-3-yloxy)p enyl-met yl]-1 /-/-benzimidazole [(1 H-benzimidazol-2-yl)-p-tolyl-met yl](1-met ylpiperidin-4-yl)amine
2-[(3-et ylsulfanyl-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)- propan-2-one
1- (3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)- propan-2-ol
2- [[3-(2-met oxyet oxy)p enyl](1-met ylpiperidin-4-yloxy)met yl]benzot iazole Λ/-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
(2-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}et yl)met yl- amine
2-[(1-met ylpiperidin-4-yloxy)(3-trifluoromet oxy-p enyl)met yl]-1 --benzimidazole 2-[(2-c lorop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
4-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}but-3-ynyl amine 2-{(1-met ylpiperidin-4-yloxy)[3-(pyridin-2-ylmet oxy)p enyl]met yl}benzot iazole 2-{(1-met ylpiperidin-4-yloxy)[3-(pyridin-3-ylmet oxy)p enyl]met yl}benzot iazole
2- [(3-Cyclo exylmet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole
4- {3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}but-3- ynylamine
5- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4-ynylamine
3- {3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}propane-1 ,2-diol
5- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pentylamine 2-{3-[benzot iazol-2-yl(1-et yl-piperidin-4-yloxy)met yl]phenoxy}et ylamine
2- {3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenoxy}et ylamine
6- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}hexan-1-ol
4- {3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}butylamine
5- {3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4- ynylamine
6- {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanyl}hexan-1-ol
3- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}prop-2-ynylamine 2-[benzo[1 ,3]dioxol-5-yl(1 -met ylpiperidin-4-yloxy)met yl]-1 /-/-benzimidazole (2-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-urea (2-{3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-thiazol-2-yl)amine
2- [(2,3-di ydrobenzo[1 ,4]dioxin-6-yl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
4- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}butylamine A/-(2-{3-[benzot iazol-2-yl(1-met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
3- {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}propylamine A/-ferf-butoxycarbonyl-/V-(2-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
5- {3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}pentylamine
2-[{3-[2-(1 -met yl-1 --imidazol4-yl)et yl]phenyl}(1 -met ylpiperidin-4- yloxy)met yl]benzot iazole
A/-ferf-butoxycarbonyl-N'-(4-{3-[(1 --benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenyl}but-3-ynyl)guanidine
Λ/-(4-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}butyl)guanidine
A/-ferf-butoxycarbonyl-N'-(4-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenyl}butyl)guanidine
2- {(1-met ylpiperidin-4-yloxy)[3-(pyridin-2-ylmet oxy)p enyl]met yl}-1 H- benzimidazole
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine 5-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}pentylamine A/-ferf-butoxycarbonyl-N'-(3-{3-[(1 --benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenyl}propyl)guanidine
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}propylamine
2-{(1 -methylpiperidin-4-yloxy)[3-(4-[1 ,2,3]triazol-2-yl- butoxy)phenyl]methyl}benzothiazole
2-{(1 -methylpiperidin-4-yloxy)[3-(4-[1 ,2,4]triazol-1 -yl- butoxy)phenyl]methyl}benzothiazole
(2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanyl}et yl)(4,5-di ydro-1 --imidazol-2-yl)amine
Λ/-(2-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-N'-cyanoguanidine 6-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}hex-5-ynyl amine
Λ/-(3-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}propyl)guanidine
Λ/-(3-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}propyl)guanidine
2- {(1-met ylpiperidin-4-yloxy)[3-(4-morpholin-4-yl- butoxy)phenyl]methyl}benzothiazole
(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-2- yl)methanol
(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-2- yl)methanol
6-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}hexylamine 4-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanyl}butylamine
3- {3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}propylamine
4- (2-{3-[benzothiazol-2-yl(1-met ylpiperidin-4- yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid ferf-butyl ester
4-(2-{3-[benzothiazol-2-yl(1-met ylpiperidin-4- yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid ferf-butyl ester
2-{(1 -methylpiperidin-4-yloxy)[3-(2-piperazin-1 -yl- ethoxy)phenyl]methyl}benzothiazole
4-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenoxy}butylamine
2-{(1-met ylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)p enyl]metriyl}-1 -- benzimidazole
2-{(1 -met ylpiperidin-4-yloxy)[3-(4-piperidin-1 -yl-butoxy)p enyl]met yl}-1 H- benzimidazole
2-[(2-fluoro-3-iodop enyl)(1-metriylpiperidin-4-yloxy)metriyl]-1 --benzimidazole A/-ferf-butoxycarbonyl-V-(-{3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenyl}pentyl)guanidine
A/-ferf-butoxycarbonyl-V-(3-{3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenyl}prop-2-ynyl)guanidine
6-{3-[(1 /-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}hex-5- ynylamine
2-{(1 -methylpiperidin-4-yloxy)[3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1 H- benzimidazole A/-feA-butoxycarbonyl-/V-(5-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4- yloxy)methyl]phenyl}pent-5-ynyl)guanidine
A/-(5-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4- ynyl)guanidine
A/-ferf-butoxycarbonyl-/V-(6-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4- yloxy)met yl]phenyl}hex-5-ynyl)guanidine
A/-(6-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}hex-5- ynyl)guanidine
4-(4-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}butyl)piperazine-1-carboxylic acid ferf-butyl ester
6-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}hexylamine
A/-feA-butoxycarbonyl-A/,-(6-{3-[(1H-benzimidazol-2-yl)(1-metriylpiperidin-4- yloxy)met yl]phenyl}hex-5-ynyl)guanidine
A/-(6-{3 (1H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)metriyl]phenyl}hex-5- ynyl)guanidine
1 -(2-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-3-isopropyl-thiourea
2-{(1 -methylpiperidin-4-yloxy)[3-(3-[1 ,2,4]triazol-1 -yl- propoxy)phenyl]methyl}benzothiazole
2-{(1 -methylpiperidin-4-yloxy)[3-(3-[1 ,2,3]triazol-2-yl- propoxy)phenyl]methyl}benzothiazole
2-{(1-met ylpiperidin-4-yloxy)[3-(3-morpholin-4-yl- propoxy)phenyl]methyl}benzothiazole
4-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic acid ferf-butyl ester
2-{3-[(1 H-benzimidazol-2-yl)(1-metriylpiperidin-4-yloxy)metriyl]-2-fluoro- phenylsulfanyl}et ylamine
4-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)metriyl]phenyl}-3,6-diriydro- 2H-pyridine-1 -carboxamidine
2-[[3-(2-c loroet oxy)p enyl](1-met ylpiperidin-4-yloxy)metriyl]berizotriiazole Λ/-(6-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenyl}hexyl)guanidine
2-{(1 -met ylpiperidin-4-yloxy)[3-(2-piperidin-1 -yl-et oxy)p enyl]metriyl}-1 H- benzimidazole
A/-ferf-butoxycarbonyl-/V-(5-{3-[(1 --benzimidazol-2-yl)(1-metriylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynyl)guanidine Λ/-(5-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4- ynyl)guanidine
4-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}butylamine 4-(3-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic acid ferf-butyl ester
(2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}ethylamino)acetic acid ferf-butyl ester
4-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic acid ferf-butyl ester
A/-(6-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)metriyl]phenyl}hexyl)guanidine A/-ferf-butoxycarbonyl-/V-(6-{3-[(1 --benzimidazol-2-yl)(1-metriylpiperidin-4- yloxy)met yl]phenyl}hexyl)guanidine
A/-(5-{3-[benzot iazol-2-yl(1-met ylpiperidin-4- yloxy)methyl]phenyl}pentyl)guanidine
4-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)metriyl]phenyl}butylamine
[[3-(4-aminobutoxy)p enyl](1 H-benzimidazol-2-yl)met yl](1-met ylpiperidin-4- yl)amine
3- {3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}propylamine
4- (2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid ferf-butyl ester
(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenoxy}ethylamino)acetic acid ferf-butyl ester
5- {3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}pentylamine A-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3- ynyl)guanidine
A/-(3-{3 benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2- ynyl)guanidine
A/-(4-{3 benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)metriyl]phenyl}butyl)guanidine
(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenoxy}pentylamino)acetic acid ferf-butyl ester
2-[(1 -met ylpiperidin-4-yloxy)(3-piperidin-4-ylet ynyl-phenyl)met yl]-1 H- benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4- ylmet oxy)prienyl]metriyl}benzotriiazole 2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-3- ylmet oxy)p enyl]met yl}benzot iazole
2-[[3-(1-met ylpiperidin-3-ylmet oxy)p enyl](1-met ylpiperidin-4- yloxy)met yl]benzot iazole
2-[(1-met ylpiperidin-4-yloxy)(3-piperidin-3-ylet ynyl-phenyl)met yl]-1 H- benzimidazole
5-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}pentylamine
2-{(1-met ylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)p enyl]met yl}benzot iazole
2- {(1-met ylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)p enyl]met yl}benzot iazole 5-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4-en-1-ol
3- amino-4-(2-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione
[[3-(6-amino ex-1 -ynyl)phenyl](1 --benzimidazol-2-yl)met yl](1 -met ylpiperidin-4- yl)amine
{[3-(4-aminobutoxy)p enyl]benzot iazol-2-yl-met yl}(1-met ylpiperidin-4-yl)amine 2-[(3-azetidin-3-ylet ynylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
5-{3-[(1 /-/-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}pent-4-en-1 - ol
5-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4-en-1-ol
4- (5-{3-[(1 --benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic acid ferf-butyl ester
2-[[3-(2-azetidin-3-ylethyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1 -- benzimidazole
Λ/-(4-{3-[(1 H-benzimidazol-2-yl)(1-metriylpiperidin-4-yloxy)metriyl]phenyl}but-3- ynyl)guanidine
4-{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)metriyl]phenyl}piperidine-1 - carboxamidine
2-{(1-met ylpiperidin-4-yloxy)[3-(2-piperidin-2-yl-et ylsulfanyl)phenyl]metriyl}-1 H- benzimidazole
2-{{1 -methylpiperidin-4-yloxy)[3-(2-piperidin-4-yl-et yl)phenyl]met yl}-1 H- benzimidazole
Λ/-(5-{3-[(1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pentyl)guanidine 2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1-methylp^
1 --benzimidazole
A/-ferf-butoxycarbonyl-/V-(4-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4- yloxy)methyl]phenyl}but-3-ynyl)guanidine
5-{3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenoxy}pentylamine
N-acetyl-N'-(2-{3-[(1/-/-benzimidazol-2-yl)(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
2-[[3-(azetidin-3-yloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole 1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}azetidin-3-ol (1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)methanol
1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}piperidin-4-ylamine 1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3-ol
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3-ol /V-(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)acetamide
2- [[3-(5-imidazol-1 -ylpent-1 -ynyl)phenyl](1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
2-{(1 -methylpiperidin-4-yloxy)[3-(5-pyrazol-1 -yl-pent-1 -ynyl)phenyl]methyl}-1 H- benzimidazole
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}piperidin-4-ol
2- [{3-[2-(1 H-imidazol-4-yl)et yl]phenyl}(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
acetic acid 1 -{3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]- phenyl}piperidin-4-yl ester
2-[(3-bromo-prienyl)(1-metriyl-pyrrolidin-3-ylmetrioxy)metriyl]-1 /-/-benzimidazole 2-{(1-met ylpiperidin-4-yloxy)[3-(piperidin-4-yloxy)p enyl]met yl}benzot iazole 2-{(1 -methylpiperidin-4-yloxy)[3-(5-[1 ,2,3]triazol-2-yl-pent-1 -ynyl)phenyl]methyl}- 1 /-/-benzimidazole
2-{(1 -methylpiperidin-4-yloxy)[3-(5-[1 ,2,3]triazol-1 -yl-pent-1 -ynyl)phenyl]methyl}- 1 /-/-benzimidazole
A/-(3-{3-[(1/-/-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}prop-2- ynyl)guanidine
Λ/1 -(5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenoxy}pentyl)butane-1,4-diamine {[3-(6-amino ex-1-ynyl)phenyl]benzot iazol-2-yl-met yl}(1-met ylpiperidin-4- yl)amine
5- {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}pent-4- enylamine
4-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}but-2-en-1-ol
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- ylamine
2- [(2,5-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 --benzimidazole
2- [(2-fluoro-5-iodo-p enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 --benzimidazole
3- {3-[(1 /-/-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenylet ynyl}azetidine-1-carboxamidine
4- {3-[(5-fluoro-1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}butan-1-ol
2-{3-[(5-fluoro-1 --benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenylsulfanyl}et ylamine
1- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- ylamine
2- [[3-(3-fluoropyrrolidin-1 -yl)phenyl](1 -methylpiperidin-4- yloxy)met yl]benzot iazole
4- {3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}but-2-enylamine 2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 -- benzimidazole
2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 -- benzimidazole (enantiomer A)
2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 -- benzimidazole (enantiomer B)
N-(2-aminoet yl)-2-{3-[(1 H-benzimidazol-2-yl)(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}acetamide
N-(2-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine
2-(5-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione
6- {3-[(5-fluoro-1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}hex-
5- ynylamine oxalate
4-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}butylamine oxalate N-(3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}propyl)guanidine, dihydrochloride
1 - {3 benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3-one, oxalate
N-(4-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}butyl)guanidine, dihydrochloride
5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}pentan-1 -ol
N-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-N-(2,2-dimethylpropionyl)guanidine
2- [(1 -methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1 H-benzimidazole
2-{(1 -methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl}benzothiazole, oxalate
2-[(3-bromophenyl)(1 -methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1 H- benzimidazole, oxalate
4-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]aniline
4-[(1 H-benzimidazol-2-yl)(piperidin-4-yloxy)methyl]aniline, hydrochloride
N-(2-amino-ethyl)-2-{3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}acetamide
1 - {3-[benzothiazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}-3- trifluoromethylpyrrolidin-3-ol, oxalate
2- [[3-(4,5-dihydro-1 H-imidazol-2-ylmethylsulfanyl)phenyl](1 -methylpiperidin-4- yloxy)methyl]-1 H-benzimidazole
2-[[3-(4,5-dihydro-1 H-imidazol-2-ylmethylsulfanyl)phenyl](1 -methylpiperidin-4- yloxy)methyl]-5-fluoro-1 H-benzimidazole
2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1 H- benzimidazole
2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 -methyl-1 H-benzimidazole, dioxalate
2-amino-5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanylmethyl}-1 ,5-dihydroimidazol-4-one
2- [(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5,6,7-trifluoro-1 H- benzimidazole
1 -(2-ethoxyethyl)-2-[(3-iodophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, dioxalate
3- [(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]benzaldehyde 4- {3-[(1 H-benzimidazol-2-yl)(1 -methylazetidin-3- ylmethoxy)methyl]phenylsulfanyl}butylamine, oxalate
2-[(2-fluoro-5-trifluoromet oxyp enyl)(1 -met ylpiperidin-4- yloxy)methyl]benzoxazole, oxalate
{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}met anol. dimet ylsulfoxonium ylide of 3-bromophenylacetic acid methyl ester
2-[(2-fluoro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)metriyl]-1 H-benzimidazole, enantiomer B
2-[(2,6-difluoro-3-methoxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
ethyl (6-{3-[(1 -methyl-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}hex-5-ynyl)carbamate, oxalate
2-[(1 H-indol-6-yl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, oxalate 2-[benzo[b]thiophen-6-yl(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, oxalate
2-[(2,6-difluoro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, enantiomer B
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol
2-[(1 H-benzimidazol-2-yl)hydroxymethyl]phenol
2-[(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol
5- (6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1 -enol
2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, enantiomer B
5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4- ynylamine, enantiomer A
5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}pent-4- ynylamine, enantiomer B
2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5-fluoro-1 H-benzimidazole, enantiomer A
2-[(3-bromophenyl)(1 -methylpiperidin-4-yloxy)methyl]-5-fluoro-1 H-benzimidazole, enantiomer B
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-methylphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol enantiomer A 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenol enantiomer B 6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2-fluoro-3- met ylphenol enantiomer A
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2-fluoro-3- met ylphenol enantiomer B
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2,3-difluorop enol enantiomer A
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2,3-difluorop enol enantiomer B
5-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-4- fluorophenyl}pent-4-ynylamine, dioxalate
3- {3-[benzothiazol-2-yl(1-methylpiperidin-4- yloxy)methyl]phenoxy}cyclopentylamine, oxalate
2-{[3-(3-fluoropyrrolidin-1 -yl)phenyl](1 -methylpiperidin-4- yloxy)methyl}benzothiazole, oxalate
5- {3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -met ylpyrrolidin-3- ylmethoxy)methyl]phenyl}pent-4-ynylamine, oxalate
2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole, oxalate (one epimer)
2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole, oxalate (50/50 mixture of two epimers)
2-{(1-methylpiperidin-4-yloxy)[3-(octahydrocyclopenta[c]pyrrol-5- yloxy)phenyl]methyl}benzothiazole, dioxalate
(1-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)methylamine, dioxalate
4- {3-[(5,6-difluoro-1 H-benzimidazol-2-yl)(1-met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}butan-1-ol
2-{3-[benzothiazol-2-yl(1-met ylpiperidin-4- yloxy)methyl]phenyl}octahydrocyclopenta[c]pyrrol-5-ylamine, dioxalate
2-{[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H- benzimidazole, oxalate
2-{[3-(2-fluoroet oxy)p enyl](1-met ylpiperidin-4-yloxy)met yl}-1 H- benzimidazole, oxalate
4-{3-[benzot iazol-2-yl(1-met ylpiperidin-4-yloxy)met yl]phenoxy}cyclo exylamine, oxalate
6- {3-[(1 -methyl-1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenyl}hex-5-ynylamine, dioxalate 1 -{3-[benzot iazol-2-yl(1 -methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2- ylmethylamine, oxalate
(1 -{3-[benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)(methyl)amine, oxalate
(1 -{3-[benzot iazol-2-yl(1 -met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- yl)(dimethyl)amine, oxalate
2-{[3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)phenyl](1-methylpiperidin-4- yloxy)methyl}benzothiazole, dioxalate
2- [(2-fluoro-5-met oxyp enyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole, oxalate
3- [(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]-4-fluorop enol, oxalate
2-{[2-fluoro-5-(2-fluoroet oxy)p enyl](1 -met ylpiperidin-4-yloxy)met yl}-1 H- benzimidazole, oxalate
2-[(2-fluoro-5-met ylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole, oxalate
4- {3-[(1 -met ylpiperidin-4-yloxy)(5,6,7-trifluoro-1 H-benzimidazol-2- yl)methyl]phenylsulfanyl}butylamine, oxalate
4- {3-[(5,6-difluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}butylamine, oxalate
6-(3-{[1 -(2-et oxyet yl)-1 H-benzimidazol-2-yl](1 -methylpiperidin-4- yloxy)methyl}phenyl)hex-5-ynylamine, dioxalate
6-(3-{[1 -(2-methoxyethyl)-1 H-benzimidazol-2-yl](1 -met ylpiperidin-4- yloxy)methyl}phenyl)hex-5-ynylamine, dioxalate
2-{[3-(3-fluoropropylsulfanyl)phenyl](1 -methylpiperidin-4-yloxy)methyl}-1 H- benzimidazole, dioxalate
5- fluoro-2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]- 1 H-benzimidazole, oxalate
4,5,6-trifluoro-2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4- yloxy)met yl]-1 H-benzimidazole
5,6-difluoro-2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4- yloxy)met yl]-1 H-benzimidazole
2-{[2-fluoro-5-(2,2,2-trifluoroet oxy)p enyl](1 -methylpiperidin-4-yloxy)methyl}-1 H- benzimidazole
2-[(2,6-difluoro-4-met ylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole 2-[(2-chloro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, oxalate
2-[(2-fluoro-5-trifluoromet oxyp enyl)(1 -methylpiperidin-4- yloxy)methyl]benzothiazole, oxalate
- 2-[(4-c loro-2,6-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
7-fluoro-2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylpiperidin-4-yloxy)met yl]- 1 H-benzimidazole, oxalate
2-[(2,6-difluoro-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole, oxalate
2-[(4-c loro-2,6-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]benzot iazole, oxalate
2-[(3-et oxy-2,6-difluorop enyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
- 2-[(2,6-difluoro-4-methylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]benzoxazole, oxalate
2-[(1 -met ylpiperidin-4-yloxy)(4-trifluoromet ylphenyl)met yl]-1 H-benzimidazole 2-[(2-fluoro-4-trifluoromet ylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
- 2-[(2,4-dimet ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 2-[(3-met oxyp enyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 2-[chroman-7-yl(1 -met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole
2-[(2-fluoro-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]benzoxazole, oxalate
- 2-[(3,5-bis-trifluoromethylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole, oxalate
5-fluoro-2-[(2-fluoro-4-methylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
2-[(2,3-difluoro-4-methylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
2-[(3-chloro-4-methylphenyl)(1 -met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole ethyl 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1 -methylpiperidin-4- yloxy)methyl]benzimidazole-1 -carboxylate, oxalate
2-[(3-fluoro-4-methylphenyl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole - 2-[(5-bromo-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole 6-{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]-4-fluorop enyl}hex- 5-ynylamine, oxalate
5-{4-fluoro-3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenyl}pent-4-ynylamine
ethyl (5-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}pent-4-ynyl)carbamate
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-chlorophenol ethyl (5-{4-fluoro-3-[(5-fluoro-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}pent-4-ynyl)carbamate
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- trifluoromethoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-fluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-methoxyphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-5-methylphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-bromophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-ethoxyphenol 2-[(1 H-indol-7-yl)(1 -methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4,6-difluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4,6-dichlorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-6-fluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-3-fluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4,5-difluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-5-fluorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-5-chlorophenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-6-methylphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- methylsulfanylphenol
2- [(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-ethylsulfanylphenol
3- [(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]biphenyl-4-ol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-tert-butylphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-propylphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-6-methoxyphenol 2-[(1 H-benzimidazol-2-yl)(1 -methy-piperidin-4-yloxy)methyl]-3-fluoro-5- methylphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-3-chlorophenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-6-fluoro-4-ethylphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-benzylphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4- trifluoromethylphenol
2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-4-chloro-6- fluorophenol
2-[(1 H-benzimidazol-2-yl)(1 ■methylpiperidin-4-yloxy)methyl]-5-fluoro-3- methylphenol
6-[(1 H-benzimidazol-2-yl)(1 ■methylpiperidin-4-yloxy)methyl]-2-fluoro-3- methylphenol
6-[(1 H-benzimidazol-2-yl)(1 ■methylpiperidin-4-yloxy)methyl]indan-5-ol
2-[(1 H-benzimidazol-2-yl)(1■methylpiperidin-4-yloxy)methyl]-4-propoxyphenol
2-[(1 H-benzimidazol-2-yl)(1■methylpiperidin-4-yloxy)methyl]-4-( 1 -methyl- 1 - phenylethyl)phenol
2-[(1 H-benzimidazol-2-yl)(1 ■methylpiperidin-4-yloxy)methyl]-4-(2- fluoroethoxy)phenol
2-[(1 H-benzimidazol-2-yl)(1 ■methylpiperidin-4-yloxy)methyl]-4-(3- fluoropropoxy)phenol
2-[(1 H-benzimidazol-2-yl)(1 ■methylpiperidin-4-yloxy)methyl]-4-fluoro-6- methylphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-6-fluoro-4- methoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-4-phenoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-4-fluoro-6- methoxyphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-4,5-dimethylphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-4-(3- fluoropropylsulfanyl)phenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-4-fluoro-5- methylphenol
2- [(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-4-(2- fluoroethylsulfanyl)phenol
3- [(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-2-hydroxybiphenyl 2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-6-ethylphenol 2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-5- trifluoromethylphenol
2-[(1 H-benzimidazol-2-yl)(1 methylpiperidin-4-yloxy)methyl]-4-hydroxyphenol 2-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]-5,6,7,8-tetrahydro-1 - naphthol
2-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-6- trifluoromethoxyphenol
2-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-5- trifluoromet oxyp enol
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2-fluoro-3,4- dimet ylphenol
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-3-fluoro-2- met ylphenol
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2,4-difluoro-3- met ylphenol
6-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]-2,3-difluorop enol (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}-azetidin-3- yl)dimethylamine, oxalate
1 -{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4-yloxy)met yl]phenyl}pyrrolidin-3- ol, oxalate
2-{(1-met ylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)p enyl]met yl}-1 H- benzimidazole, dioxalate
2-[(5-c loro-2-fluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole, oxalate
2-[(2-fluoro-5-trifluoromet ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole, oxalate
6-{3-[(1 -ethyl-1 H-benzimidazol-2-yl)(1 -methylpiperidin-4-yloxy)methyl]phenyl}hex- 5-ynylamine,oxalate
2-[(2-fluoro-5-methoxyphenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-1 H- benzimidazole, oxalate
2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylsulfanylphenyl)methyl]-1 H- benzimidazole, oxalate
2-[(4-fluoro-3-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole, oxalate
2-[(2-fluoro-5-propoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole, oxalate
4-[(1 H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol
2-{[3-(3,3-difluoropyrrolidin-1 -yl)phenyl](1 -methylpiperidin-4-yloxy)methyl}-1 H- benzimidazole, dioxalate 2-{[3-(5 luorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1-methylpiperidin-4- yloxy)methyl}benzothiazole, dioxalate
6-{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)methyl]phenylsulfanyl}hexylamine, oxalate
5-{3-[(1 H-benzimidazol-2-yl)(1 -met ylpiperidin-4- yloxy)met yl]phenylsulfanylmet yl}oxazolidin-2-one
N-(6-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenylsulfanyl}hexyl)guanidine, di ydroc loride
4-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}but-
2-enylamine
4-{3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenylsulfanyl}but-
2- enylamine, oxalate
N-(2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine
3- {3-[(1 H-benzimidazol-2-yl)(1-met ylpiperidin-4-yloxy)met yl]phenyl}allylamine cis-2-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)met yl]phenylsulfanylmet yl}cyclopropylmet ylamine
N-(3-{3-[(1 H-benzimidazol-2-yl)(1 -methylpiperidin-4- yloxy)methyl]phenyl}allyl)guanidine, trihydrochloride
2-[(azetidin-3-ylmet oxy)(3-bromop enyl)met yl]-1 H-benzimidazole
2-[(3-bromop enyl)(1-met ylazetidin-3-ylmet oxy)met yl]-1 H-benzimidazole 2-[(2,6-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 2-[(2-fluoro-4-met ylphenyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H-benzimidazole 2-[(5-et ylsulfanyl-2-fluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
2-[(azetidin-3-ylmet oxy)(2-fluoro-5-trifluoromet oxyp enyl)met yl]-1 H- benzimidazole, oxalate
2-[(2-fluoro-5-trifluoromet oxyp enyl)(1-met ylazetidin-3-ylmet oxy)met yl]-1 H- benzimidazole, oxalate
2-[(3-et ylsulfanyl-2,6-difluorop enyl)(1-met ylpiperidin-4-yloxy)met yl]-1 H- benzimidazole
2-[(2,2-difluorobenzo[1 ,3]dioxol-5-yl)(1 -methylpiperidin-4-yloxy)methyl]-1 H- benzimidazole
2-[(piperidin-4-yloxy)t iop en-3-ylmet yl]-1 H-benzimidazole
2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1 H-benzimidazole
2-[(piperidin-4-yloxy)t iop en-2-ylmet yl]-1 H-benzimidazole 2-[(1 -met ylpiperidin-4-yloxy)thiop en-2-ylmet yl]-1 H-benzimidazole as well as their enantiomers, diastereomers, mixtures thereof and pharmaceutically acceptable salts, free forms, tautomers, hydrates and solvates.
9. Process of preparation of a compound of formula (I) according to anyone of claims 1 to 8 where A = O comprising the ste etherification of compound of formula (II)
Figure imgf000197_0001
in which X, HetAr and Ar are as defined in anyone of claims 1 to 8
with a compound of formula (III)
Figure imgf000197_0002
in which R, HET and B are as defined in in anyone of claims 1 to 8.
10. Process of preparation of a compound of formula (I) according to anyone of claims 1 to 8 wherein A = NH comprising the step of reduction of a compound of formula (IV)
Figure imgf000197_0003
in which R, HET, B, X, HetAr and Ar are as defined in anyone of claims 1 to 8.
1 1 . Process of preparation of a compound of formula (I) according to anyone of claims 1 to 8 where A = NH comprising the step of condensation of compound of formula (II)
Figure imgf000197_0004
(N) in which X, Het as defined in anyone of claims 1 to 8 with an amine
Figure imgf000198_0001
12. Process of preparation of a compound of formula (I) according to anyone of claims 1 to 8 in which A and X are NH comprising the step of condensing an organometallic reagent ArM onto a la (VI):
Figure imgf000198_0002
in which R, HET, B, HetAr and Ar are as defined in anyone of claims 1 to 8.
13. Process of preparation of a compound of formula (I) according to anyone of claims 1 to 8 in which A=0 comprising the step of alkylation of compound of formula (VII)
Figure imgf000198_0003
in which HET, B, X, HetAr and Ar are as defined in anyone of claims 1 to 8.
8.
14. The process according to anyone of claims 9 to 13 further comprising the additional step of isolating the desired compound.
15. A pharmaceutical composition comprising a compound of formula (I) according tio anyone of claims 1 to 8 with a pharmaceutically acceptable excipient.
16. The compound according to any of claims 1 to 8 for use to treat and/or prevent a disease associated with H4 dysfunction.
17. The compound for use according to claim 17 for the treatment or prevention of respiratory diseases such as respiratory inflammatory diseases, adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy induced airway responses, allergic rhinitis, viral rhinitis, non- allergic rhinitis, perennial and seasonal rhinitis, conjunctivitis, nasal congestion, allergic congestion; disorders of the genito-urinary tract such as female and male sexual dysfunction, overactive bladder conditions, urinary incontinence, bladder overactivity, benign prostate hyperplasia and lower urinary tract symptoms; dermatological diseases such as dermatitis and psoriasis and treatment of itchy skin; diseases of the cardiovascular system including thromboembolic diseases, atherosclerosis, myocardial infarction, angina pectoris, myocardial ischaemia and arrhythmia, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses, hypotension, pulmonary hypertension, malignant hypertension, cardiac insufficiency, heart or kidney failure, stroke and renal dysfunction; diseases of the gastrointestinal tract including inflammatory bowel disease, Crohn's disease, ulcerative colitis, food allergy; autoimmune and inflammatory diseases including rheumatoid arthritis, multiple sclerosis; cancer; pain; chronic hypereosinophilias; chronic diseases associated with mast-cell multiplication; lymphatic system diseases.
18. A combination of a compound according to any one of claims 1 to 8 with one or more therapeutic agent(s) selected from:
· Histamine H2 or H3 receptor antagonists,
• Leukotriene antagonists,
• 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists
• CX and a2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use
• Xanthines, such as theophylline and aminophylline
• Steroidal and non-steroidal antiinflammatories, such as sodium cromoglycate and nedocromil sodium
• Ketotifen
· COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors
• Immunosuppressants
• mucolytics or anti-tussive agents
19. The combination according to claim 18, wherein the H1 R antagonist is chosen from cetirizine, desloratadine, bepotastine or doxepin.
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