# Patent

## Title
Benzazole derivatives as histamine H4 receptor ligands

## Abstract

The present patent application concerns new ligands of the H4-receptor, their process of preparation and their therapeutic use.

## Background
This application is a divisional of application Ser. No. 13/825,989, filed May 21, 2013 (which is hereby incorporated by reference).


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. It 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 H1R 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 H1R 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):




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), phthalimido, 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, cyanoalkyl, 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, —CCl3, —CF2Cl, —CH2Cl, —CH2CF2—CF3.
“Perhaloalkoxy” represents a perhaloalkyl linked via an oxygen atom, for example, —O—CF3, —O—CHF2, —O—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 or saturated on unsaturated non aromatic mono- or multicyclic hydrocarbon ring system of 3 to 10 carbon atoms, preferably of 4 to 10 carbon atoms.
“Cycloalkyl” 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 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Exemplary multicyclic cycloalkyl 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, tetrahydrofuranyl, 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:




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 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, alkoxycarbonylheterocyclyl, 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), phthalimido, 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, 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.

    
    


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 0 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, cycloalkyl, (poly)cycloalkenyl, guanidino, acylguanidino, alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl, heterocyclyl, heterocyclylamino, hydrazinocarbonyl, N-alkyl(thioureido), phthalimido, 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;
    
    


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 (I′) below:




and (I′′) below:




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, perhalogenoalkyl, alkoxy; and/or
Z is chosen from halo, hydroxy, alkyl, alkoxy.
More particularly, in formula (I′) and (I′′):
i is 1, 2 or 3 and Y is chosen from halo, hydroxy, alkyl, perhalogenoalkyl, 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-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-methylpiperidin-4-yloxy)(3-phenoxy-phenyl)methyl]benzothiazole
    5-methyl-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole
    2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazole
    2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylphenyl)methyl]benzothiazole
    2-[(2,3-dihydrobenzofuran-5-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole
    2-[(4-fluoro-3-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    [benzothiazol-2-yl(4-fluoro-3-methyl-phenyl)methyl](1-methylpiperidin-4-yl)amine
    (benzothiazol-2-yl-p-tolylmethyl)(1-methylpiperidin-4-yl)amine
    [(benzofuran-2-yl)(benzothiazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
    2-[(3-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    [(1H-benzimidazol-2-yl)phenylmethyl](1-methylpiperidin-4-yl)amine
    2-[(3-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    [benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    [benzothiazol-2-yl(3-fluoro-5-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    [benzothiazol-2-yl(3-fluoro-5-methylphenyl)methyl](1-methylpiperidin-4-yl)amine
    2-[(3-benzyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[benzofuran-5-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(3-ethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    [benzothiazol-2-yl(3-iodophenyl)methyl](1-methylpiperidin-4-yl)amine
    2-[(1-methylpiperidin-4-yloxy)(3-propoxyphenyl)methyl]-1H-benzimidazole
    [(1H-benzimidazol-2-yl)(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    (benzothiazol-2-ylpyridin-3-ylmethyl)(1-methylpiperidin-4-yl)amine
    2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    {3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxymethyl]biphenyl-3-yl}methanol
    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
    [benzothiazol-2-yl(1H-pyrrol-2-yl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-trifluoromethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-ethylphenyl)methyl](1-methylpiperidin-4-yl)amine
    3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol
    2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]benzothiazole
    [(1H-benzimidazol-2-yl)(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-isopropylphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-isobutoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    {(1H-benzimidazol-2-yl)[3-(3-methylbutoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester
    trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester
    [(1H-benzimidazol-2-yl)(3-cyclohexyl methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-fluorophenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-hexylphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine
    2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    [benzothiazol-2-yl(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-ethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-phenoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    {3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}methanol
    3′-[(1H-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]-1H-benzimidazole
    1-{3-[(1H-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
    [benzothiazol-2-yl(3-cyclohexylmethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)biphenyl-3-ylmethyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-pentyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    2-[(2′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(1-methylpiperidin-4-yloxy)(3′-nitrobiphenyl-3-yl)methyl]benzothiazole
    {3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}acetonitrile
    2-[(3′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    [benzothiazol-2-yl(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    (benzothiazol-2-ylbiphenyl-3-ylmethyl)(1-methylpiperidin-4-yl)amine
    {(1H-benzimidazol-2-yl)[3-(4-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine
    {(1H-benzimidazol-2-yl)[3-(3-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    {(1H-benzimidazol-2-yl)[3-(2-phenoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    [benzothiazol-2-yl(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine
    1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}ethanone
    2-[(3′-fluoro-biphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}ethanone
    [benzothiazol-2-yl(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(3-allyloxyphenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
    {(1H-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    2-[(1-methylpiperidin-4-yloxy)(2′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole
    2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole
    2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]-1H-benzimidazole
    {(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    2-[(2′-chlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    {3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol
    {(1H-benzimidazol-2-yl)[3-(4-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    {(1H-benzimidazol-2-yl)[3-(3-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol
    {3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol
    2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]benzothiazole
    {(1H-benzimidazol-2-yl)[3-(2-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    {(1H-benzimidazol-2-yl)[3-(4-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1-methylpiperidin-4-yl)amine
    [(3-azidophenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
    2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    {(1H-benzimidazol-2-yl)[3-(2-ethoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-pent-4-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    {3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamic acid tert-butyl ester
    2-[(3′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]benzothiazole
    2-[(1-methylpiperidin-4-yloxy)(2′,3′,4′-trifluorobiphenyl-3-yl)methyl]benzothiazole
    2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    {3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamic acid tert-butyl ester
    [(1H-benzimidazol-2-yl)(3-furan-2-ylphenyl)methyl](1-methylpiperidin-4-yl)amine
    [(1H-benzimidazol-2-yl)(3-but-3-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
    {(1H-benzimidazol-2-yl)[3-(4-methylpentyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    2-[(1-methylpiperidin-4-yloxy)(3-pyrazol-1-ylphenyl)methyl]benzothiazole
    2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    {(1H-benzimidazol-2-yl)[3-(2,5-difluoro-benzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(3-ethylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    {3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid methyl ester
    2-[(3-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[[3-(2,5-difluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-{3-[(1H-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-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]-1H-benzimidazole
    5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole
    5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole
    2-[(2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole
    2-[[3-(3-fluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile
    2-[[3-(furan-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    ((1H-benzimidazol-2-yl)-{3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine
    {(1H-benzimidazol-2-yl)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    2-[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(3,3,3-trifluoro-propoxy)phenyl]methyl}benzothiazole
    2-[(4-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    {(1H-benzimidazol-2-yl)[3-(2-fluoro-ethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
    ((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)ethoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine
    2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethoxy-biphenyl-3-yl)methyl]-1H-benzimidazole
    2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(3-benzo[1,3]dioxol-5-ylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[[3-(3-methoxybenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentan-2-one
    2-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl-benzyloxy)phenyl]methyl}benzothiazole
    4-[benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1,1-dimethylpiperidinium
    2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol
    2-[(1-methylpiperidin-4-yloxy)-o-tolyl-methyl]-1H-benzimidazole
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine
    2-[(3-ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)phenyl]methyl}benzothiazole
    3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzonitrile
    2-{(1-methylpiperidin-4-yloxy)[3-(1H-[1,2,3]triazol-4-yl)phenyl]methyl}-1H-benzimidazole
    3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]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]-1H-benzimidazole
    2-[(3-methanesulfonylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(4-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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]-1H-benzimidazole
    5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrimidin-2-ol
    2-[(3-tert-butylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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]-N-benzyl-N-methylbenzamide
    3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-propylbenzamide
    2-[(2,4-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    [(1H-benzimidazol-2-yl)(4′-methoxy-biphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine
    3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-methyl-N-phenylbenzamide
    3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine
    2-[(3-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(4-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol
    3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine
    2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol
    2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol
    2-[(3-azidophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole
    {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol
    5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butan-1-ol
    (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-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]-1H-benzimidazole
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1-ol
    1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2-ol
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol
    2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine
    2-{(1-methylpiperidin-4-yloxy)[3-(2-methylsulfanyl-ethoxy)phenyl]methyl}benzothiazole
    2-[(1-methylpiperidin-4-yloxy)(2-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole
    2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole
    2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-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-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol
    2-(1-{3-[(1H-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-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-N-methylacetamide
    2-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole
    2-[(3-bromo-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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-methylpiperidin-4-yloxy)[3-(pyridin-4-ylmethoxy)phenyl]methyl}benzothiazole
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butan-1-ol
    2-[[3-(furan-2-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol
    2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine
    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzyloxy}propan-2-one
    2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine
    2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole
    [(1H-benzimidazol-2-yl)-p-tolyl-methyl](1-methylpiperidin-4-yl)amine
    2-[(3-ethylsulfanyl-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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-methoxyethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine
    (2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)methyl-amine
    2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole
    2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine
    2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}benzothiazole
    2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-ylmethoxy)phenyl]methyl}benzothiazole
    2-[(3-Cyclohexylmethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine
    5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propane-1,2-diol
    5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamine
    2-{3-[benzothiazol-2-yl(1-ethyl-piperidin-4-yloxy)methyl]phenoxy}ethylamine
    2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine
    6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine
    6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol
    3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine
    2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    (2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-urea
    (2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-thiazol-2-yl)amine
    2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamine
    N-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propylamine
    N-tert-butoxycarbonyl-N′-(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-methyl-1H-imidazol4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]benzothiazole
    N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine
    N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine
    N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine
    2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}-1H-benzimidazole
    3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamine
    N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-1H-imidazol-2-yl)amine
    N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N′-cyanoguanidine
    6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine
    N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine
    N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine
    2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}benzothiazole
    (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol
    (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol
    6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamine
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine
    4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid tert-butyl ester
    4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid tert-butyl ester
    2-{(1-methylpiperidin-4-yloxy)[3-(2-piperazin-1-yl-ethoxy)phenyl]methyl}benzothiazole
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamine
    2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(4-piperidin-1-yl-butoxy)phenyl]methyl}-1H-benzimidazole
    2-[(2-fluoro-3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine
    N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methyl piperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine
    6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine
    2-{(1-methylpiperidin-4-yloxy)[3-(1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1H-benzimidazole
    N-tert-butoxycarbonyl-N′-(5-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-5-ynyl)guanidine
    N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine
    N-tert-butoxycarbonyl-N′-(6-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine
    N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine
    4-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butyl)piperazine-1-carboxylic acid tert-butyl ester
    6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamine
    N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine
    N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine
    1-(2-{3-[(1H-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-methylpiperidin-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 tert-butyl ester
    2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-phenylsulfanyl}ethylamine
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxamidine
    2-[[3-(2-chloroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine
    2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-1-yl-ethoxy)phenyl]methyl}-1H-benzimidazole
    N-tert-butoxycarbonyl-N′-(5-{3-[(1H-benzimidazol-2-yl)(1-methyl piperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine
    N-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine
    4-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic acid tert-butyl ester
    (2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)acetic acid tert-butyl ester
    4-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic acid tert-butyl ester
    N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine
    N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine
    N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine
    [[3-(4-aminobutoxy)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propylamine
    4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid tert-butyl ester
    (2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)acetic acid tert-butyl ester
    5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamine
    N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine
    N-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine
    N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine
    (5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamino)acetic acid tert-butyl ester
    2-[(1-methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-ylmethoxy)phenyl]methyl}benzothiazole
    2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-3-ylmethoxy)phenyl]methyl}benzothiazole
    2-[[3-(1-methylpiperidin-3-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    2-[(1-methylpiperidin-4-yloxy)(3-piperidin-3-ylethynyl-phenyl)methyl]-1H-benzimidazole
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine
    2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole
    2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole
    5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol
    3-amino-4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione
    [[3-(6-aminohex-1-ynyl)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
    {[3-(4-aminobutoxy)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine
    2-[(3-azetidin-3-ylethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol
    5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol
    4-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic acid tert-butyl ester
    2-[[3-(2-azetidin-3-ylethyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidine-1-carboxamidine
    2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-4-yl-ethyl)phenyl]methyl}-1H-benzimidazole
    N-(5-{3-[(1H-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]-1H-benzimidazole
    N-tert-butoxycarbonyl-N′-(4-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamine
    N-acetyl-N′-(2-{3-[(1H-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-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}azetidin-3-ol
    (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methanol
    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ylamine
    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol
    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol
    N-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)acetamide
    2-[[3-(5-imidazol-1-ylpent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(5-pyrazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole
    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol
    2-[{3-[2-(1H-imidazol-4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    acetic acid 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-yl ester
    2-[(3-bromo-phenyl)(1-methyl-pyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-yloxy)phenyl]methyl}benzothiazole
    2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-2-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole
    N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine
    N1-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)butane-1,4-diamine
    {[3-(6-aminohex-1-ynyl)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-en-1-ol
    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine
    2-[(2,5-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2-fluoro-5-iodo-phenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylethynyl}azetidine-1-carboxamidine
    4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol
    2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine
    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine
    2-[[3-(3-fluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-enylamine
    2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (enantiomer A)
    2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (enantiomer B)
    N-(2-aminoethyl)-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide
    N-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine
    2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione
    6-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine oxalate
    4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine oxalate
    N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propyl)guanidine, dihydrochloride
    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-one, oxalate
    N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)guanidine, dihydrochloride
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-ol
    N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-(2,2-dimethylpropionyl)guanidine
    2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-benzimidazole
    2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl}benzothiazole, oxalate
    2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1H-benzimidazole, oxalate
    4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline
    4-[(1H-benzimidazol-2-yl)(piperidin-4-yloxy)methyl]aniline, hydrochloride
    N-(2-amino-ethyl)-2-{3-[(5-fluoro-1H-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-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole
    2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1H-benzimidazole
    2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole, dioxalate
    2-amino-5-{3-[(1H-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-1H-benzimidazole
    1-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, dioxalate
    3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde
    4-{3-[(1H-benzimidazol-2-yl)(1-methylazetidin-3-ylmethoxy)methyl]phenylsulfanyl}butylamine, oxalate
    2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole, oxalate
    {3-[(1H-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]-1H-benzimidazole, enantiomer B
    2-[(2,6-difluoro-3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    ethyl (6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate, oxalate
    2-[(1H-indol-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    2-[benzo[b]thiophen-6-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, enantiomer B
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol
    2-[(1H-benzimidazol-2-yl)hydroxymethyl]phenol
    2-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol
    5-(6-{3-[(1H-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]-1H-benzimidazole, enantiomer B
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine, enantiomer A
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine, enantiomer B
    2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole, enantiomer A
    2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole, enantiomer B
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer A
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B
    6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol enantiomer A
    6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol enantiomer B
    6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol enantiomer A
    6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol enantiomer B
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-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-1H-benzimidazol-2-yl)(1-methylpyrrolidin-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-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methylamine, dioxalate
    4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-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-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, oxalate
    4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}cyclohexylamine, oxalate
    6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine, dioxalate
    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-ylmethylamine, oxalate
    (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)(methyl)amine, oxalate
    (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]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-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol, oxalate
    2-{[2-fluoro-5-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, oxalate
    2-[(2-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    4-{3-[(1-methylpiperidin-4-yloxy)(5,6,7-trifluoro-1H-benzimidazol-2-yl)methyl]phenylsulfanyl}butylamine, oxalate
    4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine, oxalate
    6-(3-{[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine, dioxalate
    6-(3-{[1-(2-methoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine, dioxalate
    2-{[3-(3-fluoropropylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, dioxalate
    5-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    4,5,6-trifluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    5,6-difluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-{[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole
    2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2-chloro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate
    2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    7-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate
    2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate
    2-[(3-ethoxy-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole, oxalate
    2-[(1-methylpiperidin-4-yloxy)(4-trifluoromethylphenyl)methyl]-1H-benzimidazole
    2-[(2-fluoro-4-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2,4-dimethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[chroman-7-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole, oxalate
    2-[(3,5-bis-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    5-fluoro-2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2,3-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(3-chloro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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]-1H-benzimidazole
    2-[(5-bromo-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate
    5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine
    ethyl (5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}pent-4-ynyl)carbamate
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chlorophenol
    ethyl (5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)carbamate
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethoxyphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methoxyphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-methylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-bromophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethoxyphenol
    2-[(1H-indol-7-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-difluorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-dichlorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-difluorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-chlorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylsulfanylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethylsulfanylphenol
    3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-ol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-tert-butyl phenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methoxyphenol
    2-[(1H-benzimidazol-2-yl)(1-methy-piperidin-4-yloxy)methyl]-3-fluoro-5-methylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-chlorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-ethylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-benzylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chloro-6-fluorophenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-3-methylphenol
    6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol
    6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]indan-5-ol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propoxyphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(1-methyl-1-phenylethyl)phenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethoxy)phenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropoxy)phenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-methoxyphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-phenoxyphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methoxyphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-dimethylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropylsulfanyl)phenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-5-methylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethylsulfanyl)phenol
    3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-hydroxybiphenyl
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-ethylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethylphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-hydroxyphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7,8-tetrahydro-1-naphthol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-trifluoromethoxyphenol
    2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethoxyphenol
    6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3,4-dimethylphenol
    6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluoro-2-methylphenol
    6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,4-difluoro-3-methylphenol
    6-[(1H-benzimidazol-2-yl)(1-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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate
    2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}-1H-benzimidazole, dioxalate
    2-[(5-chloro-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    2-[(2-fluoro-5-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    6-{3-[(1-ethyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine, oxalate
    2-[(2-fluoro-5-methoxyphenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole, oxalate
    2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylsulfanylphenyl)methyl]-1H-benzimidazole, oxalate
    2-[(4-fluoro-3-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    2-[(2-fluoro-5-propoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
    4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol
    2-{[3-(3,3-difluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, dioxalate
    2-{[3-(5-fluorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole, dioxalate
    6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexylamine, oxalate
    5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}oxazolidin-2-one
    N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexyl)guanidine, dihydrochloride
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine
    4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine, oxalate
    N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine
    3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allylamine
    cis-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropylmethylamine
    N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allyl)guanidine, trihydrochloride
    2-[(azetidin-3-ylmethoxy)(3-bromophenyl)methyl]-1H-benzimidazole
    2-[(3-bromophenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole
    2-[(2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(5-ethylsulfanyl-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(azetidin-3-ylmethoxy)(2-fluoro-5-trifluoromethoxyphenyl)methyl]-1H-benzimidazole, oxalate
    2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole, oxalate
    2-[(3-ethylsulfanyl-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(2,2-difluorobenzo[1,3]dioxol-5-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
    2-[(piperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole
    2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole
    2-[(piperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole
    2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]-1H-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 particular, in formula (I), the group:




may have tautomeric forms such as when HetAr is a phenyl and X is N, leading to 1H-benzimidazole which is a tautomer of 3H-benzimidazole. A representative example is illustrated below:





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 N,N-dimethylformamide; alcohols such as ethanol and methanol and ethers, such as diethyl ether, methyl tert-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 150° C. (more preferably from about room temperature to 100° C.). 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):




in which X, HetAr and Ar are as defined in general formula (I)
with a compound of formula (III):




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° C.
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 ortho-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):




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):




in which X, HetAr and Ar are as defined in general formula (I)
with an amine




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):




in which X, HetAr and Ar are as defined in general formula (I)
with an amine




This condensation can be performed in the presence of a transition metal catalyst such as dichloro(pentamethylcyclopentadienyl)iridium(III) 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 reagent ArM onto a compound of formula (VI):




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 benzimidazole-2-carboxaldehyde or heteroaryl fused imidazole-2-carboxaldehyde with an amine




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=O can be prepared by alkylation of compound of formula (VII):




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):




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 tert-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 HCl. Preferably, this deprotection is performed at a temperature between 0° 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):




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.




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




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 invention 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 H1, H2 or H3 receptor antagonists,
        Leukotriene antagonists,
        5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists
        CX1- and α2-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 H1R 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 Büchi 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 (0.36 g), 4-hydroxy-1-methylpiperidine (0.17 g) and para-toluenesulfonic acid (0.57 g) in toluene (22 mL) is heated overnight in a Dean-Stark apparatus. The mixture is cooled back to room temperature and poured into water, alcalinised with 1N sodium hydroxide 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 115° C.
1B
A solution of benzothiazole (1.35 g) in tetrahydrofurane (10 mL) in a dried round bottom balloon is cooled at −70° C. A solution of butyl lithium (4.1 mL) is added and the mixture stirred for 15 minutes. Benzaldehyde (1.03 mL) diluted with tetrahydrofurane (10 mL) 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 oxide affords benzothiazol-2-ylphenylmethanol.
TLC (heptane/ethyl acetate 1/1) Rf=0.57
Further examples can be prepared according to the described general methods:













Example
Product
General methods
Melting point



















2
2-[(1-methylpyrrolidin-3-yloxy)phenylmethyl]-
1A, 1B
120°
C.



benzothiazole, oxalate


3
2-[(4-fluorophenyl)(1-methylpiperidin-4-
1A, 1B
192°
C.



yloxy)methyl]benzothiazole, oxalate


4
2-[(4-chlorophenyl)(1-methylpiperidin-4-
1A, 1B
147-148°
C.



yloxy)methyl]benzothiazole, oxalate


5
2-[(3-fluorophenyl)(1-methylpiperidin-4-
1A, 1B
167-170°
C.



yloxymethyl]benzothiazole, oxalate


6
2-[(2-fluorophenyl)(1-methylpiperidin-4-
1A, 1B
178-179°
C.



yloxy)methyl]benzothiazole, oxalate


7
2-[(1-methylpiperidin-4-yloxy)-p-
1A, 1B
177°
C.



tolylmethyl]benzothiazole, oxalate


8
2-[(1-methylpiperidin-4-yloxy)(m-
1A, 1B
177°
C.



tolyl)methyl]benzothiazole, oxalate


10
2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-
1A, 1B
71°
C.



methylpiperidin-4-yloxy)methyl]benzothiazole,



hydrochloride


11
2-[(3-methoxyphenyl)(1-methylpiperidin-4-
1A, 1B
182°
C.



yloxy)methyl]benzothiazole, hydrochloride


12
2-[(2,4-difluorophenyl)(1-methylpiperidin-4-
1A, 1B
182°
C.



yloxy)methyl]benzothiazole, dioxalate


14
2-[(4-methoxyphenyl)(1-methylpiperidin-4-
1A, 1B
72°
C.



yloxy)methyl]benzothiazole, dihydrochloride


15
2-[(3,5-difluorophenyl)(1-methylpiperidin-4-
1A, 1B
165°
C.



yloxy)methyl]benzothiazole, oxalate









Following compounds are prepared using general methods described in Example 1:











Example
Product







 9
(benzothiazol-2-yl-phenylmethyl)(1-methylpiperidin-4-



yl)amine







1H NMR: 8.00 (d, 1H), 7.90 (d, 1H), 7.55-7.35 (m, 2H), 7.32 (d, 1H),


7.10 (d, 1H), 6.98 (d, 1H), 6.17 (s, 1H), 3.80-3.65 (m, 1H), 2.80-


2.65 (m, 2H), 2.29 (s, 3H),), 2.28-2.15 (m, 2H), 2.10-1.80 (m, 4H)








13
2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]benzothiazole







1H NMR: 7.95 (d, 1H), 7.84 (d, 1H), 7.52 (m, 2H), 7.50-7.25 (m, 5H),


5.44 (s, 1H), 3.88-3.75 (m, 2H), 3.65-3.50 (m, 1H), 2.24 (s, 3H),), 2.15-


1.85 (m, 4H), 1.65-1.35 (m, 2H)








23
2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxy-



phenyl)methyl]benzothiazole, oxalate







1H NMR (DMSO-d6): 7.99 (d, 1H), 7.87 (d, 1H), 7.55-7.35 (m, 5H),


7.27-7.15 (m, 1H), 6.11 (s, 1H), 3.95-3.80 (m, 1H), 3.50-3.00 (m, 6H),


2.79 (s, 3H),), 2.20-1.70 (m, 4H),









Example 16
16A
A mixture of (benzothiazol-2-yl)(thien-3-yl)methanol (0.247 g), 4-hydroxy-1-methylpiperidine (0.115 g) and para-toluenesulfonic acid (0.27 g) in dichloroethane (20 mL) 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 174° C.
16B
(benzothiazol-2-yl)(thien-3-yl)methanol is prepared according to general method 1B.
Example 21
21A
A solution of [(benzothiazol-2-yl)(m-tolyl)methylene](1-methylpiperidin-4-yl)amine (0.45 g) in methanol (30 mL) containing 10% palladium on charcoal (0.1 g) is stirred under dihydrogene (1 atm) at room temperature for 3 h. The suspension is filtered over clarcel and concentrated under reduced pressure. The residue is dissolved in acetone (2 mL) and mixed with a solution of oxalic acid (76 mg) in acetone (2 mL). 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 127° C.
21B
To a solution of (benzothiazol-2-yl)(m-tolyl)methanone (1.06 g) and 4-amino-1-methylpiperidine (0.456 g) in tetrahydrofurane (4 mL) is added titanium tetraisopropoxide (1.42 g). The mixture is stirred at room temperature for 1 h, then polymethyl hydrosiloxane (1.2 mL) is added. The mixture is stirred for one day at room temperature, diluted with ethyl acetate (50 mL), hydolysed with 3N sodium hydroxide (30 mL). The organic phase is separated by decantation, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is crystallised by trituration in diisopropyl oxide. A second crop can be obtained form the mother liquor by chromatography over silica gel (gradient dichloromethane/methanol from 98/2 to 95/5) to give [(benzothiazol-2-yl)(m-tolyl)methylene](1-methylpiperidin-4-yl)amine meting at 125° C.
21C
To a solution of (benzothiazol-2-yl)(m-tolyl)methanol (2.41 g) in dioxane (30 mL) is added manganese dioxide (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 oxide to give (benzothiazol-2-yl)(m-tolyl)methanone
21D
(benzothiazol-2-yl)(m-tolyl)methanol can be obtained as described in Example 1B.
Further examples can be prepared according to the described general methods:















General
Melting


Example
Product
methods
point







17
2-[(1-methylpiperidin-4-yloxy)naphthalen-1-
1A, 1B
106.5° C.  



ylmethyl]benzothiazole


18
2-[(1-methylpiperidin-4-yloxy)naphthalen-2-
1A, 1B
198° C.



ylmethyl]benzothiazole, dihydrochloride


19
2-[(1-methylpiperidin-4-yloxy)(5-methylthiophen-2-
16A, 1B
174° C.



yl)methyl]benzothiazole, oxalate


20
2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-
1A, 1B
110° C.



yloxy)methyl]benzothiazole, dihydrochloride


24
2-[(1-methylpiperidin-4-yloxy)(4-
1A, 1B
155° C.



trifluoromethoxyphenyl)methyl]benzothiazole, oxalate


25
[benzothiazol-2-yl(3-methoxyphenyl)methyl](1-
21A, 21B,
160° C.



methylpiperidin-4-yl)amine, dioxalate
21C, 1B


27
2-[(3-bromo-phenyl)(1-methylpiperidin-4-
1A, 1B
 99° C.



yloxy)methyl]benzothiazole


28
2-[(1-methylpiperidin-4-yloxy)(3-phenoxy-
1A, 1B
 92° C.



phenyl)methyl]benzothiazole, oxalate


29
5-methyl-2-[(1-methylpiperidin-4-
1A, 1B
175° C.



yloxy)phenylmethyl]benzothiazole, oxalate


30
2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-
1A, 1B
110° C.



benzimidazole


31
2-[(1-methylpiperidin-4-yloxy)(3-
1A, 1B
 61° C.



trifluoromethylphenyl)methyl]benzothiazole,



hydrochloride


34
2-[(4-fluoro-3-methylphenyl)(1-methylpiperidin-4-
1A, 1B
120° C.



yloxy)methyl]benzothiazole, oxalate


35
[benzothiazol-2-yl(4-fluoro-3-methyl-phenyl)methyl](1-
1A, 1B
160° C.



methylpiperidin-4-yl)amine, dioxalate


36
(benzothiazol-2-yl-p-tolylmethyl)(1-methylpiperidin-4-
1A, 1B
110° C.



yl)amine, oxalate


38
2-[(3-fluoro-5-methylphenyl)(1-methylpiperidin-4-
1A, 1B
170° C.



yloxy)methyl]benzothiazole, oxalate









Example 26
To a solution of 2-[(3-allyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole example 22 (250 mg) in ethanol (10 mL) is added 10% palladium on charcoal (25 mg). 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:











Example
Product







33
5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzo-



thiazole







1H NMR: 7.80 (dd, 1H), 7.65 (dd, 1H), 7.58-7.68 (m, 2H), 7.45-7.28


(m, 3H), 7.14 (dt, 1H), 5.89 (s, 1H), 3.80-3.60 (m, 1H), 2.90-2.72


(m, 2H), 2.38 (s, 3H), 2.15-1.70 (m, 6H)









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 (1.4 g) and 4-amino-1-methylpiperidine (0.57 g) in tetrahydrofurane (8 mL) is added dropwise titanium tetraisopropoxide (1.78 g). The suspension is stirred for 24 h at room temperature, diluted with ethyl acetate and 1N sodium hydroxide. 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 (gradient 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 21C.
37D
(benzofuran-2-yl)(benzothiazol-2-yl)methanone can be prepared as described in example 1B.
Further examples can be prepared according to the described general methods:















General
Melting


Example
Product
methods
point



















39
[(1H-benzimidazol-2-yl)phenylmethyl](1-
21A, 37B,
133°
C.



methylpiperidin-4-yl)amine
21C, 1B


40
2-[(3-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-
1A, 1B
145°
C.



yloxy)methyl]benzothiazole, oxalate


41
2-[(3-iodophenyl)(1-methylpiperidin-4-
1A, 1B
165-170°
C.



yloxy)methyl]benzothiazole, oxalate









Example 42
[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
42A
Hydrogenation of [benzothiazol-2-yl(3-propoxyphenyl)methylene](1-methylpiperidin-4-yl)amine as described in example 21A gives [benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine melting at 90° C.
42B
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 (0.95 g) in acetonitrile 15 mL) 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 crystalline solid.
42D
Benzothiazol-2-yl(3-propoxyphenyl)methanol can be prepared as described in example 1B.
Further examples can be prepared according to the described general methods:















General
Melting


Example
Product
methods
point



















43
[benzothiazol-2-yl(3-fluoro-5-methoxyphenyl)methyl](1-
21A, 37B,
157°
C.



methylpiperidin-4-yl)amine, oxalate
21C, 1B


44
[benzothiazol-2-yl(3-fluoro-5-methylphenyl)methyl](1-
21A, 37B,
102°
C.



methylpiperidin-4-yl)amine
21C, 1B


45
2-[(3-benzyloxyphenyl)(1-methylpiperidin-4-
1A, 1B
52°
C.



yloxy)methyl]benzothiazole, oxalate


46
2-[benzofuran-5-yl(1-methylpiperidin-4-
1A, 1B
153°
C.



yloxy)methyl]benzothiazole, oxalate


47
2-[(3-ethoxyphenyl)(1-methylpiperidin-4-
1A, 1B
84°
C.



yloxy)methyl]benzothiazole, oxalate


48
[benzothiazol-2-yl(3-iodophenyl)methyl](1-
21A, 37B,
188-195°
C.



methylpiperidin-4-yl)amine, oxalate
21C, 1B


49
2-[(1-methylpiperidin-4-yloxy)(3-propoxyphenyl)methyl]-
1A, 1B
135°
C.



1H-benzimidazole


50
[(1H-benzimidazol-2-yl)(3-propoxyphenyl)methyl](1-
21A, 37B,
143°
C.



methylpiperidin-4-yl)amine
21C, 1B


51
2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-
1A, 1B
173.5°
C.



benzimidazole


52
(benzothiazol-2-ylpyridin-3-ylmethyl)(1-
21A, 37B,
109°
C.



methylpiperidin-4-yl)amine
42C, 1B









53
A mixture of 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (200 mg), phenylboronic acid (70 mg), palladium acetate (4.8 mg) and 1,1-bis(diphenylphosphino)ferrocene is placed in a round-bottom flask and purged with argon. A 1M aqueous degassed solution of potassium carbonate (1.51 mL) and degassed tetrahydrofuran (2 mL) are introduced. The mixture is heated at 95° C. for 30 min, 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.
1H NMR (DMSO-d6): 8.05 (d, 1H), 7.91 (d, 1H), 7.77 (s, 1H), 7.68-7.58 (m, 3H), 7.55-7.30 (m, 7H), 6.20 (s, 1H), 3.90-3.78 (m, 1H), 3.32-2.90 (m, 4H), 2.67 (s, 3H), 2.20-1.70 (m, 4H)
Following compounds are prepared analogously:











Example
Product







54
{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxymethyl]biphenyl-3-yl}methanol,



oxalate







1H NMR (DMSO-d6): 8.02 (d, 1H), 7.87 (d, 1H), 7.72 (s, 1H), 7.62-7.35 (m, 8H), 7.27 (d, 1H),


6.13 (s, 1H), 4.51 (s, 2H), 3.92-3.80 (m, 1H), 3.40-2.90 (m, 4H), 2.70 (s, 3H), 2.25-1.70 (m,


4H)








63
2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]benzothiazole,



oxalate







1H NMR (DMSO-d6): 8.86 (d, 1H), 8.57 (dd, 1H), 8.09-8.00 (m, 2H), 7.92 (d, 1H), 7.84 (s, 1H),


7.73-7.63 (m, 1H), 7.58-7.37 (m, 5H), 6.21 (s, 1H), 3.92-3.78 (m, 1H), 3.40-2.95 (m, 4H),


2.70 (s, 3H), 2.25-1.75 (m, 4H)








79
3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine,



oxalate







1H NMR (DMSO-d6): 8.07 (d, 1H), 7.91 (d, 1H), 7.66 (s, 1H), 7.53-7.37 (m, 5H), 7.07 (t, 1H),


6.78 (s, 1H), 6.71 (d, 1H), 6.54 (d, 1H), 6.18 (s, 1H), 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]-1H-benzimidazole







1H NMR: 12.38 (sl, 1H), 7.78 (s, 1H), 7.65-7.40 (m, 10H), 7.15-7.05 (m, 2H), 5.91 (s, 1H),


3.50-3.35 (m, 1H), 2.68-2.50 (m, 2H), 2.10 (s, 3H), 2.05-1.84 (m, 4H), 1.70-1.50 (m, 2H)








86
{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-



yl}methanol







1H NMR (DMSO-d6): 12.37 (sl, 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′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine







1H NMR: 9.57 (sl, 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, 1H), 6.85 (s, 1H), 6.67 (d, 1H), 5.92 (s, 1H), 3.85-3.50 (m, 3H), 2.80-2.75 (m, 2H),


2.27 (s, 3H), 2.25-1.65 (m, 6H)








89
2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]-1H-benzimidazole







1H NMR: 9.62 (sl, 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′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole







1H NMR: 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-methylpiperidin-4-yloxy)(3′-nitrobiphenyl-3-yl)methyl]benzothiazole







1H NMR: 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 (m, 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′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole







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)








100 
2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,



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)








128 
2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-



yl)methyl]benzothiazole, oxalate







1H NMR (DMSO d6): 8.07 (d, 1H), 7.92 (d, 1H), 7.78 (s, 1H), 7.62 (sl, 1H), 7.55-7.32 (m, 7H),


7.27 (sl, 1H), 6.20 (s, 1H), 3.45-3.30 (m, 1H), 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)methyl]benzothiazole







1H NMR: 7.98 (d, 1H), 7.88 (d, 1H), 7.70 (s, 1H), 7.66 (d, 1H), 7.52-7.35 (m, 7H), 5.97 (s, 1H),


3.82-3.68 (m, 1H), 2.95-2.78 (m, 2H), 2.55-2.40 (m, 2H), 2.40 (s, 3H), 2.20-1.80 (m, 4H)








136 
2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole







1H NMR: 7.98 (d, 1H), 7.86 (d, 1H), 7.71 (s, 1H), 7.68-7.30 (m, 7H), 7.15 (d, 1H), 7.10 (d, 1H),


5.98 (s, 1H), 3.80-3.63 (m, 1H), 2.88-2.72 (m, 2H), 2.42-2.25 (m, 2H), 2.34 (s, 3H),


2.15-1.75 (m, 4H)








137 
2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole







1H NMR: 7.99 (d, 1H), 7.88 (d, 1H), 7.75 (s, 1H), 7.50-7.10 (m, 9H), 5.98 (s, 1H),


3.82-3.75 (m, 1H), 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]-1H-benzimidazole
72A
A mixture of 1H-benzimidazol-2-yl(3-bromophenyl)methanol (12.9 g), 4-hydroxy-1-methylpiperidine (4.86 g) and para-toluenesulfonic acid (24 g) in chlorobenzene (60 mL) and N-methylpyrrolidone (6 mL) is heated under reflux for 120 h in a Dean Stark apparatus. Solvent is removed by evaporation. To the residue is added water which is made alcaline by addition of sodium hydroxide 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]-1H-benzimidazole.
72B
A mixture of (3-bromophenyl)hydroxyacetic acid (20 g) and ortho-phenylenediamine (9.36 g) in 5N aqueous hydrochloric solution (100 mL) is heated under reflux for 4 h and cooled back to room temperature. The precipitate is separated by filtration, rinsed with acetonitrile and dried under vacuum with phosphorus pentoxide et give 1H-benzimidazol-2-yl(3-bromophenyl)methanol as a white crystalline solid used without further purification.
72C
To a solution of 3-bromobenzaldehyde (18.5 g) in tetrahydrofuran (400 mL) is added trimethylsilylcyanide (10.9 g). Two drops of a 1M 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 (100 mL). 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.
1H NMR (DMSO-d6): 7.57 (t, 1H), (d, 1H), 7.45 (dt, 1H), 7.38 (s, 1H), 7.28 (t, 1H), 5.03 (s, 1H).
Following compounds are prepared using general methods 21A and 21B:











Example
Product







64
[(1H-benzimidazol-2-yl)(3-bromophenyl)methyl](1-methyl-



piperidin-4-yl)amine







1H NMR: 9.60 (sl, 1H), 7.75 (sl, 1H), 7.65 (s, 1H), 7.50-7.32 (m, 3H),


7.30-7.15 (m, 3H), 5.84 (s, 1H), 3.62-3.58 (m, 1H), 2.85-2.68 (m, 2H),


2.28 (s, 3H), 2.25-1.65 (m, 7H)









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 (10 mg/mL) in a mixture of heptane/isopropanol (80/20) containing diethylamine (0.1%) is injected (20×100 μL) onto an analytical Chiralpak AD-H, 250×4.6 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 220 nm.
The first enantiomer has a retention time of 6.7 min.
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 8.2 min.
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
[(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine
59A
To a solution of (1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine (70 mg) in tetrahydrofurane (3 mL) is added a 1.5M solution of 3-trifluoromethylphenylmagnesium bromide in tetrahydrofurane (0.77 mL) 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 [(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine as a yellow solid melting at 90° C.
59B
1H-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 4 Å molecular sieves (15 g) in ethanol (100 mL) are heated under reflux for 4 h. The mixture is then filtered and the filtrate concentrated under reduced pressure to yield (1H-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) (2.35 g) in tetrahydrofurane (40 mL) is added tetrakistriphenylphosphinepalladium (0.344 g). The mixture is stirred for 5 min at room temperature, then sodium borohydride (0.576 g) is added. The mixture is stirred for 20 h 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 gradient 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 5 h and concentrated under reduced pressure. The residue is purified by column chromatography (gradient 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
91A
A mixture of 4-amino-1-methylpiperidine (0.23 g), benzothiazol-2-yl(3-butoxyphenyl)methanol (0.63 g), sodium hydrogenocarbonate (2 mg) and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (8 mg) in toluene (3 mL) is heated in an autoclave at 110-120° 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 176° C.
91B
Benzothiazol-2-yl(3-butoxyphenyl)methanol can be obtained as described in example 1B.
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 1M solution of 3-pent-4-enyloxy-phenylmagnesium bromide in tetrahydrofurane (2.2 mL) diluted with the same solvent (6 mL) cooled at −50° C. is added benzothiazole-2-carboxaldehyde (326 mg). 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]-1H-benzimidazole
272A
A mixture of (1H-benzimidazol-2-yl)phenylmethanol (611 mg) and 1-methyl-3-pyrrolidinol (263 mg) in methanesulfonic acid (1.3 mL) is heated for 4 hours in a sealed tube at a temperature close to 140° 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 from 100/0 to 90/10) to give 2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-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-1H-benzimidazole (5 g) in tetrahydrofurane (20 mL) cooled at a temperature close to −80° C., is added a 2.5M solution of butyl lithium in hexanes (10 mL). The mixture is stirred for 15 minutes. A solution of benzaldehyde (2.64 g) in tetrahydrofurane (20 mL) 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 (1H-benzimidazol-2-yl)phenylmethanol used without further purification.
1-Pyrrolidin-1-ylmethyl-1H-benzimidazole can be prepared as described by Katritzky, Alan R.; Aslan, 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 (625 mg), potassium iodide (332 mg), glycine tert-butyl ester, hydrochloride (503 mg) in triethylamine (630 μL) and N,N-dimethylformamide (20 mL) is heated overnight in a sealed tube at 70° C., then for 16 h 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 tert-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 1B.
Example 371
371A
A mixture of 2-[[3-(5-azidopentyloxy)phenyl](1-methyl-piperidin-4-yloxy)methyl]benzothiazole (0.13 g) and triphenylphosphine (0.11 g) in a mixture of tetrahydrofurane (3 mL) 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.
371B
A mixture of 2-[[3-(5-chloropentyloxy)phenyl](1-methyl-piperidin-4-yloxy)-methyl]benzothiazole (200 mg) and sodium azide (85 mg) in dimethylsulfoxide (3 mL) 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.
371C
2-[[3-(5-chloropentyloxy)phenyl](1-methyl-piperidin-4-yloxy)methyl]benzothiazole can be prepared according to the procedures described in examples 272A and 1B.
Further examples can be prepared according to the described general methods:















General
Melting


Example
Product
methods
point



















55
2-[(3-isopropoxyphenyl)(1-methylpiperidin-4-
1A, 1B
68°
C.



yloxy)methyl]benzothiazole, oxalate


58
[benzothiazol-2-yl(1H-pyrrol-2-yl)methyl](1-
21A, 21B,
125°
C.



methylpiperidin-4-yl)amine
42C, 1B


60
[(1H-benzimidazol-2-yl)(3-trifluoromethoxyphenyl)-
59A, 59B
82°
C.



methyl](1-methylpiperidin-4-yl)amine


61
[(1H-benzimidazol-2-yl)(3-ethylphenyl)methyl](1-
59A, 59B
76°
C.



methylpiperidin-4-yl)amine


65
[(1H-benzimidazol-2-yl)(3-benzyloxyphenyl)-
59A, 59B
78°
C.



methyl](1-methylpiperidin-4-yl)amine


66
[(1H-benzimidazol-2-yl)(3-isopropylphenyl)-
59A, 59B
82°
C.



methyl](1-methylpiperidin-4-yl)amine


67
[(1H-benzimidazol-2-yl)(3-isobutoxyphenyl)-
59A, 59B
99°
C.



methyl](1-methylpiperidin-4-yl)amine


68
{(1H-benzimidazol-2-yl)[3-(3-methylbutoxy)-
59A, 59B
70°
C.



phenyl]methyl}(1-methylpiperidin-4-yl)amine


69
[(1H-benzimidazol-2-yl)(3-butoxyphenyl)methyl](1-
59A, 59B
137°
C.



methylpiperidin-4-yl)amine, oxalate


70
[(1H-benzimidazol-2-yl)(3-methoxyphenyl)-
59A, 59B
182°
C.



methyl](1-methylpiperidin-4-yl)amine


73
[(1H-benzimidazol-2-yl)(3-cyclohexylmethoxy-
59A, 59B
88°
C.



phenyl)methyl](1-methylpiperidin-4-yl)amine


74
[(1H-benzimidazol-2-yl)(3-fluorophenyl)methyl](1-
59A, 59B
155°
C.



methylpiperidin-4-yl)amine, oxalate


75
[(1H-benzimidazol-2-yl)(3-methylsulfanylphenyl)-
59A, 59B
166°
C.



methyl](1-methylpiperidin-4-yl)amine


76
[(1H-benzimidazol-2-yl)(3-hexylphenyl)methyl](1-
59A, 59B
115°
C.



methylpiperidin-4-yl)amine, oxalate


77
[(1H-benzimidazol-2-yl)(3-isopropoxyphenyl)-
59A, 59B
75°
C.



methyl](1-methylpiperidin-4-yl)amine


83
[(1H-benzimidazol-2-yl)(3-ethoxyphenyl)methyl](1-
59A, 59B
74°
C.



methylpiperidin-4-yl)amine


84
[(1H-benzimidazol-2-yl)(m-tolyl)methyl](1-
59A, 59B
132°
C.



methylpiperidin-4-yl)amine, oxalate


85
[(1H-benzimidazol-2-yl)(3-phenoxyphenyl)-
59A, 59B
144°
C.



methyl](1-methylpiperidin-4-yl)amine, oxalate


88
[benzothiazol-2-yl(3-isopropoxyphenyl)methyl](1-
21A, 21B,
96°
C.



methylpiperidin-4-yl)amine, oxalate
21C, 1B




168B


90
1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
59A, 59B*
198°
C.



ylamino)methyl]phenyl}ethanone


92
2-[(3-butoxyphenyl)(1-methylpiperidin-4-
1A, 1B
135°
C.



yloxy)methyl]benzothiazole, oxalate


93
[benzothiazol-2-yl(3-cyclohexylmethoxyphenyl)-
21A, 37B,
98°
C.



methyl](1-methylpiperidin-4-yl)amine, oxalate
42C, 1B




168B


94
[(1H-benzimidazol-2-yl)biphenyl-3-ylmethyl](1-
59A, 59B
98°
C.



methylpiperidin-4-yl)amine


95
[(1H-benzimidazol-2-yl)(3-pentyloxyphenyl)-
59A, 59B
128°
C.



methyl](1-methylpiperidin-4-yl)amine, oxalate


102
(benzothiazol-2-ylbiphenyl-3-ylmethyl)(1-
21A, 37B,
112°
C.



methylpiperidin-4-yl)amine, oxalate
21C, 1B




168B


103
{(1H-benzimidazol-2-yl)[3-(4-fluorobenzyloxy)-
59A, 59B
140°
C.



phenyl]methyl}(1-methylpiperidin-4-yl)amine,



oxalate


104
[(1H-benzimidazol-2-yl)(3-benzylsulfanylphenyl)-
59A, 59B
127°
C.



methyl](1-methylpiperidin-4-yl)amine, oxalate


105
{(1H-benzimidazol-2-yl)[3-(3-
59A, 59B
116°
C.



fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-



yl)amine, oxalate


106
{(1H-benzimidazol-2-yl)[3-(2-phenoxyethoxy)-
59A, 59B
140°
C.



phenyl]methyl}(1-methylpiperidin-4-yl)amine,



oxalate


107
[benzothiazol-2-yl(3-benzylsulfanylphenyl)-
91A
50°
C.



methyl](1-methylpiperidin-4-yl)amine, oxalate
168B


108
1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
53
115°
C.



yloxy)methyl]biphenyl-4-yl}ethanone, dioxalate


109
2-[(3′-fluoro-biphenyl-3-yl)(1-methylpiperidin-4-
53
120°
C.



yloxy)methyl]-1H-benzimidazole, dioxalate


110
1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
53
140°
C.



yloxy)methyl]biphenyl-3-yl}ethanone, dioxalate


111
[benzothiazol-2-yl(3-methylsulfanylphenyl)-
91A
85°
C.



methyl](1-methylpiperidin-4-yl)amine, oxalate
168B


112
[(3-allyloxyphenyl)(1H-benzimidazol-2-yl)methyl](1-
59A, 59B
125°
C.



methylpiperidin-4-yl)amine, oxalate


113
{(1H-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)-
59A, 59B
118°
C.



phenyl]methyl}(1-methylpiperidin-4-yl)amine,



oxalate


114
2-[(1-methylpiperidin-4-yloxy)(2′-methylsulfanyl-
53
163°
C.



biphenyl-3-yl)methyl]-1H-benzimidazole


115
2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-
53
100°
C.



yloxy)methyl]-1H-benzimidazole, oxalate


116
2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanyl-
53
80°
C.



biphenyl-3-yl)methyl]-1H-benzimidazole, dioxalate


119
2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethyl-
53
95°
C.



biphenyl-3-yl)methyl]-1H-benzimidazole


120
{(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2-
59A, 59B
97°
C.



yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine


121
2-[(2′-Chlorobiphenyl-3-yl)(1-methylpiperidin-4-
53
130°
C.



yloxy)methyl]-1H-benzimidazole, oxalate


122
2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-
53
150°
C.



yloxy)methyl]-1H-benzimidazole, oxalate


123
{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
53
107°
C.



yloxy)methyl]biphenyl-2-yl}methanol


124
{(1H-benzimidazol-2-yl)[3-(4-methoxybenzyloxy)-
59A, 59B
84°
C.



phenyl]methyl}(1-methylpiperidin-4-yl)amine


125
{(1H-benzimidazol-2-yl)[3-(3-methoxybenzyloxy)-
59A, 59B
135°
C.



phenyl]methyl}(1-methylpiperidin-4-yl)amine,



oxalate


127
{3′-[benzothiazol-2-yl(1-methylpiperidin-4-
53
206-207°
C.



yloxy)methyl]biphenyl-2-yl}methanol, oxalate


129
{(1H-benzimidazol-2-yl)[3-(2-methylbenzyloxy)-
59A, 59B
121°
C.



phenyl]methyl}(1-methylpiperidin-4-yl)amine,



oxalate


130
{(1H-benzimidazol-2-yl)[3-(4-methylbenzyloxy)-
59A, 59B
87°
C.



phenyl]methyl}(1-methylpiperidin-4-yl)amine


132
[(3-azidophenyl)(1H-benzimidazol-2-yl)methyl](1-
131, 231A,
202°
C.



methylpiperidin-4-yl)amine
231B


138
{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
53
135°
C.



yloxy)methyl]biphenyl-4-yl}carbamic acid tert-butyl



ester


142
2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-
53
90°
C.



yloxy)methyl]-1H-benzimidazole


144
[(1H-benzimidazol-2-yl)(3-furan-2-
59A, 59B
108°
C.



ylphenyl)methyl](1-methylpiperidin-4-yl)amine


145
[(1H-benzimidazol-2-yl)(3-but-3-enyloxyphenyl)-
59A, 59B
71°
C.



methyl](1-methylpiperidin-4-yl)amine


146
{(1H-benzimidazol-2-yl)[3-(4-methylpentyloxy)-
59A, 59B
73°
C.



phenyl]methyl}(1-methylpiperidin-4-yl)amine


149
{(1H-benzimidazol-2-yl)[3-(2,5-difluoro-
59A, 59B
159°
C.



benzyloxy)phenyl]methyl}(1-methylpiperidin-4-



yl)amine, oxalate


151
2-[(2-chlorophenyl)(1-methylpiperidin-4-
72A, 72B
212°
C.



yloxy)methyl]-1H-benzimidazole


152
2-[(3-ethylphenyl)(1-methylpiperidin-4-
1A, 168B
123°
C.



yloxy)methyl]benzothiazole, oxalate


155
2-[(3-fluorophenyl)(1-methylpiperidin-4-
72A, 72B,
93°
C.



yloxy)methyl]-1H-benzimidazole
72C


161
2-[[3-(2,3-difluorobenzyloxy)phenyl](1-
1A, 168B
98°
C.



methylpiperidin-4-yloxy)methyl]benzothiazole,



oxalate


162
{(1H-benzimidazol-2-yl)[3-(2,3-difluoro-
59A, 59B
151°
C.



benzyloxy)phenyl]methyl}(1-methylpiperidin-4-



yl)amine


163
2-[[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-
1A, 168B
147°
C.



yloxy)methyl]benzothiazole, oxalate


164
2-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]-1H-
72A, 72B,
119°
C.



benzimidazole
72C


166
5-fluoro-2-[(1-methylpiperidin-4-
165
134°
C.



yloxy)phenylmethyl]-1H-benzimidazole


167
2-[(2-fluorophenyl)(1-methylpiperidin-4-
72A, 72B,
181°
C.



yloxy)methyl]-1H-benzimidazole
72C


169
2-{(1-methylpiperidin-4-yloxy)[3-(4,4,4-trifluoro-
1A, 168B
115°
C.



butoxy)phenyl]methyl}benzothiazole, oxalate


170
5-bromo-2-[(1-methylpiperidin-4-
165
143°
C.



yloxy)phenylmethyl]-1H-benzimidazole


171
2-[[3-(3-fluorobenzyloxy)phenyl](1-methylpiperidin-
1A, 168B
65°
C.



4-yloxy)methyl]benzothiazole, oxalate


174
((1H-benzimidazol-2-yl)-{3-[3-(2-methyl-
59A, 59B*
120°
C.



[1,3]dioxolan-2-yl)-propoxy]phenyl}methyl)(1-



methylpiperidin-4-yl)amine, oxalate


175
{(1H-benzimidazol-2-yl)[3-(4,4,4-trifluoro-
59A, 59B
94°
C.



butoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine


176
2-[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-
1A, 1B
72°
C.



yloxy)methyl]benzothiazole, oxalate


177
2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-
72A, 72B,
102°
C.



benzimidazole
72C


179
2-[(4-fluorophenyl)(1-methylpiperidin-4-
72A, 72B,
131°
C.



yloxy)methyl]-1H-benzimidazole
72C


180
{(1H-benzimidazol-2-yl)[3-(2-fluoro-
59A, 59B
155°
C.



ethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine,



oxalate


181
((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl-
59A, 59B
123°
C.



bicyclo[3.1.1]hept-2-en-2-



yl)ethoxy]phenyl}methyl)(1-methylpiperidin-4-



yl)amine, oxalate


182
2-[(1-methylpiperidin-4-yloxy)(4′-trifluoro-
53
90°
C.



methoxybiphenyl-3-yl)methyl]-1H-benzimidazole


183
2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-
53
92°
C.



yloxy)methyl]-1H-benzimidazole


184
2-[(3-benzo[1,3]dioxol-5-ylphenyl)(1-methyl-
53
95°
C.



piperidin-4-yloxy)methyl]-1H-benzimidazole


185
2-[[3-(3-methoxybenzyloxy)phenyl](1-methyl-
1A, 168B
77°
C.



piperidin-4-yloxy)methyl]benzothiazole, oxalate


186
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
1A, 168B, *
72°
C.



yloxy)methyl]phenoxy}pentan-2-one, oxalate


187
2-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl-
1A, 168B
80°
C.



benzyloxy)phenyl]methyl}benzothiazole, oxalate


190
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
189
117-120°
C.



yloxy)methyl]phenyl}prop-2-yn-1-ol


191
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
189
104-108°
C.



yloxy)methyl]phenyl}but-3-yn-1-ol


192
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
189
85°
C.



yloxy)methyl]phenyl}pent-4-yn-1-ol


193
2-[(1-methylpiperidin-4-yloxy)-o-tolyl-methyl]-1H-
72A, 72B,
190°
C.



benzimidazole
72C


197
3-[benzothiazol-2-yl(1-methylpiperidin-4-
72A, 1B
75°
C.



yloxy)methyl]benzonitrile, oxalate


204
2-[(4-bromophenyl)(1-methylpiperidin-4-
72A, 72B,
122°
C.



yloxy)methyl]-1H-benzimidazole
72C


213
2-[(2-chloro-4-methylphenyl)(1-methylpiperidin-4-
72A, 272B
96°
C.



yloxy)methyl]-1H-benzimidazole, oxalate


214
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
53
170°
C.



yloxy)methyl]phenyl}pyrimidin-2-ol


216
2-[(1-methylpiperidin-4-yloxy)(3-pyrimidin-5-yl-
53
85°
C.



phenyl)methyl]benzothiazole


218
2-[(1-methylpiperidin-4-yloxy)(3-vinyl-
217
165°
C.



phenyl)methyl]benzothiazole


220
3-[benzothiazol-2-yl(1-methylpiperidin-4-
219
60°
C.



yloxy)methyl]-N-propylbenzamide


221
2-[(2,4-difluorophenyl)(1-methylpiperidin-4-
72A, 272B
106°
C.



yloxy)methyl]-1H-benzimidazole, oxalate


222
[(1H-benzimidazol-2-yl)(4′-methoxy-biphenyl-3-
21A, 37B,
110°
C.



yl)methyl](1-methylpiperidin-4-yl)amine
211B, 42C,




272B


223
3-[benzothiazol-2-yl(1-methylpiperidin-4-
219
125°
C.



yloxy)methyl]-N-methyl-N-phenylbenzamide,



oxalate


225
2-[(3-chlorophenyl)(1-methylpiperidin-4-
72A, 272B
158°
C.



yloxy)methyl]-1H-benzimidazole, oxalate


226
2-[(4-chlorophenyl)(1-methylpiperidin-4-
72A, 272B
175°
C.



yloxy)methyl]-1H-benzimidazole, oxalate


235
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
150
80°
C.



yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol


242
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
148
80°
C.



yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol,



oxalate


243
2-[(1-methylpiperidin-4-yloxy)(3-morpholin-4-yl-
234
111°
C.



phenyl)methyl]benzothiazole, oxalate


244
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
234
45°
C.



yloxy)methyl]phenoxy}ethanol, oxalate


246
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
150
97-99°
C.



yloxy)methyl]phenylsulfanyl}propan-1-ol


247
1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
150
120-122°
C.



yloxy)methyl]phenylsulfanyl}propan-2-ol


250
2-{(1-methylpiperidin-4-yloxy)[3-(2-methylsulfanyl-
272A, 1B
89°
C.



ethoxy)phenyl]methyl}benzothiazole, oxalate


251
2-[(1-methylpiperidin-4-yloxy)(2-trifluoromethoxy-
72A, 272B
193°
C.



phenyl)methyl]-1H-benzimidazole


261
2-[(3-bromo-4-methylphenyl)(1-methylpiperidin-4-
72A, 272B
92°
C.



yloxy)methyl]-1H-benzimidazole


262
2-[(2-bromophenyl)(1-methylpiperidin-4-
72A, 272B
213°
C.



yloxy)methyl]-1H-benzimidazole


265
2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-4-
258
101°
C.



ylmethoxy)phenyl]methyl}benzothiazole, oxalate


266
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
258
63°
C.



yloxy)methyl]phenoxy}butan-1-ol, oxalate


267
2-[[3-(furan-2-ylmethoxy)phenyl](1-
258
85°
C.



methylpiperidin-4-yloxy)methyl]benzothiazole,



oxalate


269
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
249, 149A
80°
C.



yloxy)methyl]phenylsulfanyl}ethylamine, dioxalate


271
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
371A, 371B,
76°
C.



yloxy)methyl]phenoxy}ethylamine
272A, 1B


273
[(1H-benzimidazol-2-yl)-p-tolyl-methyl](1-
59A, 59C
183°
C.



methylpiperidin-4-yl)amine


274
2-[(3-ethylsulfanyl-4-methylphenyl)(1-
148, 272A,
142°
C.



methylpiperidin-4-yloxy)methyl]-1H-
272B



benzimidazole, oxalate


277
2-[[3-(2-methoxyethoxy)phenyl](1-methylpiperidin-
1A, 1B
80°
C.



4-yloxy)methyl]benzothiazole, oxalate


279
(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
258
125°
C.



yloxy)methyl]phenoxy}ethyl)methyl-amine,



dioxalate


280
2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxy-
272A, 272B
172°
C.



phenyl)methyl]-1H-benzimidazole, oxalate


281
2-[(2-Chlorophenyl)(1-methylpiperidin-4-
272A, 1B
163°
C.



yloxy)methyl]benzothiazole, oxalate


283
2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-
272A, 1B
158°
C.



ylmethoxy)phenyl]methyl}benzothiazole, oxalate


284
2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-
272A, 1B
102°
C.



ylmethoxy)phenyl]methyl}benzothiazole, oxalate


285
2-[(3-Cyclohexylmethoxyphenyl)(1-
1A, 1B
101°
C.



methylpiperidin-4-yloxy)methyl]benzothiazole,



oxalate


289
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
293, 194
110°
C.



yloxy)methyl]phenyl}pentylamine, dihydrochloride


290
2-{3-[benzothiazol-2-yl(1-ethyl-piperidin-4-
371A, 371B,
112°
C.



yloxy)methyl]phenoxy}ethylamine, dioxalate
272A, 1B


291
2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
371A, 371B,
90°
C.



yloxy)methyl]phenoxy}ethylamine
272A, 272B


292
6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
148
80°
C.



yloxy)methyl]phenylsulfanyl}hexan-1-ol, oxalate


300
2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-
272A, 272B
203°
C.



methylpiperidin-4-yloxy)methyl]-1H-benzimidazole


302
N-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
278A, 249,
125°
C.



yloxy)methyl]phenylsulfanyl}ethyl)guanidine,
149A



hydrochloride


304
N-tert-butoxycarbonyl-N′-(2-{3-[(benzothiazol-2-
307A, 194A
110°
C.



yl)(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}ethyl)guanidine


306
2-[{3-[2-(1-methyl-1H-imidazol-4-yl)ethyl]-
293, 194
80°
C.



phenyl}(1-methylpiperidin-4-yloxy)methyl]-



benzothiazole, oxalate


310
2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-
272A, 272B
77°
C.



ylmethoxy)phenyl]methyl}-1H-benzimidazole


311
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
371A, 371B,
120°
C.



yloxy)methyl]phenoxy}propylamine, oxalate
272A, 1B


314
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
305A, 305B
99°
C.



yloxy)methyl]phenylsulfanyl}propylamine, oxalate


319
6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
194, 189
135°
C.



yloxy)methyl]phenyl}hex-5-ynylamine, oxalate


322
2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-
370A, 272A,
61°
C.



butoxy)phenyl]methyl}benzothiazole,oxalate
1B


323
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
258
76°
C.



yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol,



oxalate


324
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
258
99°
C.



yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol,



oxalate


325
6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
293, 194
115°
C.



yloxy)methyl]phenyl}hexylamine, oxalate


326
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
305A, 305B
146°
C.



yloxy)methyl]phenylsulfanyl}butylamine, oxalate


327
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
371A, 371B,
97°
C.



yloxy)methyl]phenoxy}propylamine
272A, 272B


329
4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
370A, 272A;
90°
C.



yloxy)methyl]phenoxy}ethyl)piperazine-1-
1B



carboxylic acid tert-butyl ester, oxalate


331
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
371A, 371B,
115°
C.



yloxy)methyl]phenoxy}butylamine, oxalate
272A, 272B


332
2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-
370A, 272A,
85°
C.



butoxy)phenyl]methyl}-1H-benzimidazole, oxalate
272B


333
2-{(1-methylpiperidin-4-yloxy)[3-(4-piperidin-1-yl-
370A, 272A,
130°
C.



butoxy)phenyl]methyl}-1H-benzimidazole, oxalate
272B


334
2-[(2-fluoro-3-iodophenyl)(1-methylpiperidin-4-
272A, 272B
125°
C.



yloxy)methyl]-1H-benzimidazole


339
N-tert-butoxycarbonyl-N′-(5-{3-[(benzothiazol-2-
307A, 194A
125°
C.



yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-



5-ynyl)guanidine


340
N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-

180°
C.



yloxy)methyl]phenyl}pent-4-ynyl)guanidine,



hydrochloride


341
N-tert-butoxycarbonyl-N′-(6-{3-[(benzothiazol-2-
307A, 194A
130°
C.



yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-



ynyl)guanidine


342
N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-

185°
C.



yloxy)methyl]phenyl}hex-5-ynyl)guanidine,



hydrochloride


343
4-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-
370A, 272A,
64°
C.



4-yloxy)methyl]phenoxy}butyl)piperazine-1-
272B



carboxylic acid tert-butyl ester


348
2-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,4]triazol-1-
315A, 272A,
60°
C.



yl-propoxy)phenyl]methyl}benzothiazole,oxalate
1B


349
2-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,3]triazol-2-
315A, 272A,
74°
C.



yl-propoxy)phenyl]methyl}benzothiazole, oxalate
1B



(contains 23% of 1,2,3-triazol-1-yl compound)


350
2-{(1-methylpiperidin-4-yloxy)[3-(3-morpholin-4-yl-
370A, 272A,
105°
C.



propoxy)phenyl]methyl}benzothiazole, oxalate
1B


352
2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
423A, 150A,
204°
C.



yloxy)methyl]-2-fluorophenylsulfanyl}ethylamine
272A, 272B


354
2-[[3-(2-Chloroethoxy)phenyl](1-methylpiperidin-4-
272A, 1B
70°
C.



yloxy)methyl]benzothiazole, oxalate


356
2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-1-yl-
370A, 272A,
160°
C.



ethoxy)phenyl]methyl}-1H-benzimidazole, oxalate
272B


360
4-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-
370A, 272A,
140°
C.



4-yloxy)methyl]phenoxy}propyl)piperazine-1-
272B



carboxylic acid tert-butyl ester, oxalate


362
4-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
370A, 272A,
131°
C.



yloxy)methyl]phenoxy}pentyl)piperazine-1-
1B



carboxylic acid tert-butyl ester


363
N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
278A, 249,
90°
C.



yloxy)methyl]phenyl}hexyl)guanidine,
149A



hydrochloride


364
N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-
307A, 194A
90°
C.



2-yl)(1-methylpiperidin-4-



yloxy)methyl]phenyl}hexyl)guanidine


365
N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
278A, 249,
90°
C.



yloxy)methyl]phenyl}pentyl)guanidine,
149A



hydrochloride


366
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
293, 194
100°
C.



yloxy)methyl]phenyl}butylamine, dioxalate


367
[[3-(4-aminobutoxy)phenyl](1H-benzimidazol-2-
21A, 37B,
68°
C.



yl)methyl](1-methylpiperidin-4-yl)amine
371B, 42C,




272B


368
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A, 249,
126°
C.



yloxy)methyl]phenylsulfanyl}propylamine
149A


369
4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-
370A, 272A;
92°
C.



4-yloxy)methyl]phenoxy}ethyl)piperazine-1-
1B



carboxylic acid tert-butyl ester, dioxalate


373
N-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
278A, 249,
125°
C.



yloxy)methyl]phenyl}prop-2-ynyl)guanidine,
149A



trihydrochloride


374
N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
278A, 249,
120°
C.



yloxy)methyl]phenyl}butyl)guanidine,
149A



trihydrochloride


375
(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
370A, 272A,
99°
C.



yloxy)methyl]phenoxy}pentylamino)acetic acid
1B



tert-butyl ester, oxalate


377
2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-
423A, 258
90°
C.



ylmethoxy)phenyl]methyl}benzothiazole, dioxalate


378
2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-3-
423A, 258
55°
C.



ylmethoxy)phenyl]methyl}benzothiazole, dioxalate


379
2-[[3-(1-methylpiperidin-3-ylmethoxy)phenyl](1-
165C, 423A,
76°
C.



methylpiperidin-4-yloxy)methyl]benzothiazole,
258



dioxalate


380
2-[(1-methylpiperidin-4-yloxy)(3-piperidin-3-
376A, 189
97°
C.



ylethynylphenyl)methyl]-1H-benzimidazole


381
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
305A, 305B
140°
C.



yloxy)methyl]phenylsulfanyl}pentylamine, oxalate


382
2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-
258
50°
C.



yloxy)phenyl]methyl}benzothiazole, dioxalate


387
{[3-(4-aminobutoxy)phenyl]benzothiazol-2-yl-
21A, 37B,
67°
C.



methyl}(1-methylpiperidin-4-yl)amine
371B, 42C,




1B


388
2-[(3-azetidin-3-ylethynylphenyl)(1-
249, 293, 189
131°
C.



methylpiperidin-4-yloxy)methyl]-1H-benzimidazole


389
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
384A, 53
125°
C.



yloxy)methyl]phenyl}pent-4-en-1-ol, oxalate


391
4-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-
370A, 72A,
101°
C.



4-yloxy)methyl]phenoxy}pentyl)piperazine-1-
272B



carboxylic acid tert-butyl ester, dioxalate


392
2-[[3-(2-azetidin-3-ylethyl)phenyl](1-
249, 189
146°
C.



methylpiperidin-4-yloxy)methyl]-1H-benzimidazole


395
2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-2-yl-
249, 149A
164°
C.



ethylsulfanyl)phenyl]methyl}-1H-benzimidazole


399
N-tert-butoxycarbonyl-N′-(4-{3-[(benzothiazol-2-
307A, 194A
120°
C.



yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-



ynyl)guanidine


400
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
371A, 371B,
111°
C.



yloxy)methyl]phenoxy}pentylamine, dioxalate
72A, 272B


402
2-[[3-(azetidin-3-yloxy)phenyl](1-methylpiperidin-
423A, 258
81°
C.



4-yloxy)methyl]benzothiazole, dioxalate


404
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
403
106°
C.



yloxy)methyl]phenyl}pyrrolidin-3-yl)methanol,



oxalate


405
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
423A, 403
137°
C.



yloxy)methyl]phenyl}piperidin-4-ylamine, dioxalate


406
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
403
103°
C.



yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate


407
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
403
106°
C.



yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate


408
N-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
403
111°
C.



yloxy)methyl]phenyl}pyrrolidin-3-yl)acetamide,



oxalate


410
2-{(1-methylpiperidin-4-yloxy)[3-(5-pyrazol-1-yl-
416A, 189
115°
C.



pent-1-ynyl)phenyl]methyl}-1H-benzimidazole,



oxalate


413
acetic acid 1-{3-[benzothiazol-2-yl(1-methyl-
403
74°
C.



piperidin-4-yloxy)methyl]phenyl}piperidin-4-yl



ester, oxalate


414
2-[(3-bromo-phenyl)(1-methylpyrrolidin-3-
165C, 272A,
61°
C.



ylmethoxy)methyl]-1H-benzimidazole
72B, 72C


415
2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-
423A, 258
76°
C.



yloxy)phenyl]methyl}benzothiazole, dioxalate


419
N1-(5-{3-[(1H-benzimidazol-2-yl)(1-methyl-
423A, 370A,
162°
C.



piperidin-4-yloxy)methyl]phenoxy}pentyl)butane-
72A, 272B



1,4-diamine, dioxalate


420
{[3-(6-aminohex-1-ynyl)phenyl]benzothiazol-2-yl-
386A, 275
80°
C.



methyl}(1-methylpiperidin-4-yl)amine, oxalate


422
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
258
73°
C.



yloxy)methyl]phenoxy}but-2-en-1-ol, oxalate


424
2-[(2,5-difluorophenyl)(1-methylpiperidin-4-
272A, 272B
140°
C.



yloxy)methyl]-1H-benzimidazole


425
2-[(2-fluoro-5-iodo-phenyl)(1-methylpiperidin-4-
272A, 272B
175°
C.



yloxy)methyl]-1H-benzimidazole, dioxalate


427
4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methyl-
150
85°
C.



piperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol


428
2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methyl-
249, 149A
85°
C.



piperidin-4-yloxy)methyl]phenylsulfanyl}-



ethylamine, dioxalate


429
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
423A, 423B
137°
C.



yloxy)methyl]phenyl}pyrrolidin-3-ylamine,



dioxalate


430
2-[[3-(3-fluoropyrrolidin-1-yl)phenyl](1-
423B
70°
C.



methylpiperidin-4-yloxy)methyl]benzothiazole,



oxalate


431
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
386A, 424A,
117°
C.



yloxy)methyl]phenoxy}but-2-enylamine, dioxalate
258


433
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-
272A, 272B
95°
C.



methylpiperidin-4-yloxy)methyl]-1H-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-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole enantiomer A
A solution of racemic 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (1 mg/mL) in a mixture of heptane/isopropanol (90/10) containing diethylamine (0.1%) is injected (10 μL) onto an analytical Chiralpak AD-H, 250×4.6 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 220 nm.
The first enantiomer has a retention time of 6.9 min.
Collection affords 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole enantiomer A with a chromatographic enantiomeric purity of 99.8%.
Example 435
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole enantiomer B
The second enantiomer has a retention time of 8.3 min.
Collection affords 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methyl piperidin-4-yloxy)methyl]-1H-benzimidazole enantiomer B with a chromatographic enantiomeric purity of 96.8%.
Following compounds are prepared using general methods described in example 1:











Example
Product







78
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-



benzimidazole







1H NMR: 9.62 (sl, 1H), 7.85-7.70 (m, 1H), 7.65 (s, 1H), 7.50-7.35


(m, 3H), 7.30-7.15 (m, 3H), 5.84 (s, 1H), 3.65-3.50 (m, 1H), 2.85-2.65


(m, 2H), 2.28 (s, 3H), 2.25-1.60 (m, 6H)









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 (110 mg) and ferric acetylacetonate (4 mg) in a mixture of tetrahydrofurane (4.5 mL) and N-methylpyrrolidone (0.25 mL) cooled at 0° C. is added a 2M solution of butylmagnesium chloride in tetrahydrofurane (150 μL). The mixture is stirred at room temperature for 25 min, then warmed at 30° C. for 15 min. A second addition of butylmagnesium chloride in tetrahydrofurane (150 μL) 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 (gradient 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: CH2Cl2/MeOH 90/10): Rf=0.30
80B
To a solution of 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol (318 mg) in pyridine (74 μL) and dichloromethane (3 mL) cooled at −5° C. is added trifluoromethanesulfonic anhydride (152 μL). 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 purified by chromatography (gradient 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, 21C and 1B:











Example
Product







82
[benzothiazol-2-yl(3-bromophenyl)methyl](1-methylpiperidin-



4-yl)amine







1H NMR (DMSO d6): 9.21 (sl, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.52-7.20


(m, 6H), 5.39 (s, 1H), 3.45-3.30 (m, 1H), 3.05-2.80 (m, 2H), 2.75-2.55


(m, 2H), 2.65 (s, 3H), 2.25-1.85 (m, 2H), 1.80-1.45 (m, 2H)









Example 117
2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole enantiomer A
A solution of racemic 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-benzothiazole (10 mg/mL) in a mixture of heptane/isopropanol (80/20) containing diethylamine (0.1%) is injected (20×100 μL) onto an analytical Chiralpak AD-H, 250×4.6 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 220 nm.
The first enantiomer has a retention time of 6.0 min.
Collection affords 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole enantiomer A with a chromatographic enantiomeric purity of 97.3%.
Example 118
2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole enantiomer B
The second enantiomer has a retention time of 7.0 min.
Collection affords 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole enantiomer B with a chromatographic enantiomeric purity of 99.7%.
Example 126
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol
A solution of {(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine (example 120, 500 mg) in ethanol (5 mL) 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 (gradient dichloromethane/methanol/ammonia from 90/10/0.5 to 80/20/0.5) to give 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol as a white solid melting at 230° C.
Example 131
[(1H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1-methylpiperidin-4-yl)amine
131A
To a solution of [(1H-benzimidazol-2-yl)(3-nitrophenyl)methylene](1-methylpiperidin-4-yl)amine (1.1 g) in methanol (50 mL) at 0° C. is added sodium cyanoborohydride, then dropwise acetic acid (0.19 mL). The reaction mixture is allowed to reach room temperature and stirred at that temperature overnight.
Cold water (70 mL) 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 [(1H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1-methylpiperidin-4-yl)amine melting at 254° C.
131B
[(1H-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:













Example
Product
General methods
TLC


















22
2-[(3-allyloxyphenyl)(1-methylpiperidin-4-
1A, 1B
0.41(C)



yloxy)methyl]benzothiazole, hydrochloride


32
2-[(2,3-dihydrobenzofuran-5-yl)(1-methyl-
1A, 1B
0.32(C)



piperidin-4-yloxy)methyl]benzothiazole,



oxalate


71
trifluoromethanesulfonic acid 3-[benzothiazol-
1A, 1B
0.50(D)



2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl



ester


101
[benzothiazol-2-yl(3-benzyloxyphenyl)-
91A, 1B
0.17(C)



methyl](1-methylpiperidin-4-yl)amine, oxalate


134
{(1H-benzimidazol-2-yl)[3-(2-ethoxyethoxy)-
59A, 59B
0.26(A)



phenyl]methyl}(1-methylpiperidin-4-yl)amine


135
[(1H-benzimidazol-2-yl)(3-pent-4-
59A, 59B
0.16(A)



enyloxyphenyl)methyl](1-methylpiperidin-4-



yl)amine


178
2-{(1-methylpiperidin-4-yloxy)[3-(3,3,3-
1A, 168B
0.67(D)



trifluoro-propoxy)phenyl]methyl}-



benzothiazole, oxalate


196
2-{(1-methylpiperidin-4-yloxy)[3-(3-nitro-
1A, 1B
0.17(B)



benzyloxy)phenyl]methyl}benzothiazole,



oxalate


270
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
1A, 168B*
0.32(A)



yloxy)methyl]benzyloxy}propan-2-one,



oxalate


297
2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-
272A, 272B
0.22(D)



yloxy)methyl]-1H-benzimidazole


301
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
371A, 371B,
0.08(B)



yloxy)methyl]phenoxy}butylamine, oxalate
272A, 1B


328
4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-
370A, 272A,
0.69(D)



4-yloxy)methyl]phenoxy}ethyl)piperazine-1-
1B



carboxylic acid tert-butyl ester


330
2-{(1-methylpiperidin-4-yloxy)[3-(2-piperazin-
423A, 370A,
0.26(D)



1-yl-ethoxy)phenyl]methyl}benzothiazole,
272A, 1B



oxalate


361
(2-{3-[(1H-benzimidazol-2-yl)(1-methyl-
370A, 272A,
0.51(D)



piperidin-4-yloxy)methyl]phenoxy}-
1B



ethylamino)acetic acid tert-butyl ester,



oxalate





Eluent A: CH2Cl2/MeOH/NH4OH 90/10/0.5


Eluent B: CH2Cl2/MeOH/NH4OH 95/5/0.5


Eluent C: CH2Cl2/MeOH 90/10


Eluent D: CH2Cl2/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 (208 mg) in N,N-dimethylformamide (1 mL) are added pyrazole (68 mg), cesium carbonate (401 mg) and copper(I) iodide (19 mg). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 48 h, 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 (208 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), benzyl mercaptan (59 μL), diisopropylethylamine (174 μL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 15 h, 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







158
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}ethanol







1H NMR: 7.98 (d, 1H), 7.88 (d, 1H), 7.57 (s, 1H), 7.47-7.27 (m, 5H), 5.88 (s, 1H), 3.75 (t,


2H), 3.65 (m, 1H), 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







1H NMR: 7.98 (d, 1H), 7.88 (d, 1H), 7.50-7.30 (m, 3H), 7.30-7.10 (m, 3H), 5.83 (s, 1H),


3.93 (m, 1H), 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)








160
{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic



acid methyl ester







1H NMR: 7.98 (d, 1H), 7.87 (d, 1H), 7.62 (s, 1H), 7.50-7.29 (m, 5H), 5.85 (s, 1H), 4.02 (s,


1H), 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







1H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.50-7.10 (m, 6H), 5.89 (s, 1H), 3.70-3.58 (m, 1H),


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)








233
2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-



ethylsulfanyl)phenyl]methyl}benzothiazole







1H NMR: 8.47 (m, 1H), 8.40 (m, 1H), 7.96 (d, 1H), 7.85 (d, 1H), 7.53 (s, 1H), 7.45-7.27 (m,


6H), 5.88 (s, 1H), 3.8-3.60 (m, 1H), 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)








239
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)acetic acid methyl ester







1H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.53 (s, 1H), 7.48-7.24 (m, 5H), 5.87 (s, 1H),


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)








254
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}propan-1-ol







1H NMR: 7.96 (d, 1H), 7.87 (d, 1H), 7.57 (s, 1H), 7.46-7.24 (m, 5H), 5.88 (s, 1H),


3.8-3.65 (m, 3H), 3.28-3.15 (m, 1H), 3.07-2.97 (m, 1H), 2.87-2.70 (m, 2H), 2.34 (s, 3H),


2.45-2.25 (m, 2H), 2.20-1.75 (m, 7H)








255
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}propan-2-ol







1H NMR: 8.06 (d, 1H), 7.91 (d, 1H), 7.46-7.24 (m, 6H), 6.09 (s, 1H), 5.5-4.0 (sl, 1H),


3.85-3.70 (m, 2H), 3.28-3.07 (m, 2H), 3.07-2.85 (m, 4H), 2.63 (s, 3H), 2.18-1.70 (m, 4H),


1.11 (d, 3H)








256
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-



1-ol







1H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.50-7.24 (m, 6H), 5.88 (s, 1H), 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]-1H-benzimidazole
A screw-cap tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (200 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), benzyl mercaptan (59 μL), Diisopropylethylamine (174 μL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 24 h, 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]-1H-benzimidazole
1H NMR: 12.38 (sl, 1H), 7.55 (d, 1H), 7.50-7.40 (m, 2H), 7.30-7.00 (m, 10H), 5.84 (s, 1H), 4.20 (s, 2H), 3.65-3.45 (m, 1H), 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-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole







1H NMR: 7.54 (sl, 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)








154
{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}acetic acid methyl ester







1H NMR: 9.66 (sl, 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)








157
2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}ethanol







1H NMR: 9.76 (sl, 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)








173
2-[[3-(furan-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-



benzimidazole







1H NMR: 12.36 (sl, 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), 1.8-1.6 (m, 2H), 1.25-1.05 (m, 2H)








202
2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]-1H-



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)








215
2-[(3-tert-butylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-



benzimidazole







1H NMR: 9.51 (sl, 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)








232
2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}-



1H-benzimidazole







1H NMR: 10.24 (sl, 1H), 8.48 (m, 1H), 8.41 (m, 2H), 7.73 (sl, 1H), 7.51 (s, 1H), 7.33 (sl, 1H)


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)








248
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}butan-1-ol







1H NMR: 10.04 (sl, 1H), 7.88-7.35 (m, 3H), 7.30-7.15 (m, 5H), 5.83 (s, 1H), 3.75-3.62 (m,


2H), 3.62-3.58 (m, 1H), 2.92 (t, 2H), 2.85-2.65 (m, 2H), 2.27 (s, 3H), 2.20-2.05 (m, 2H),


2.05-1.6 (m, 9H)








288
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}propane-1,2-diol







1H NMR: 12.38 (sl, 1H), 7.52 (d, 1H), 7.40-7.40 (m, 2H) 7.30-7.0.4 (m, 5H), 5.83 (s,


1H), 5.00-4.3 (m, 3H), 3.80-4.10 (m, 4H), 2.90-2.70 (m, 2H), 2.50-2.33 (m, 1H), 2.33 (s,


3H), 2.00-1.80 (m, 2H), 1.70-1.50 (m, 2H)








295
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}hexan-1-ol







1H NMR: 10.08 (sl, 1H), 7.85-7.60 (m, 1H), 7.43 (sl, 2H), 7.32-7.15 (m, 5H), 5.84 (s, 1H),


3.70-3.50 (m, 3H), 2.92-2.65 (m, 4H), 2.28 (s, 3H), 2.20-1.30 (m, 14H)









Example 165
165A
5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazole
A round-bottom flask is charged with 4,5-dichlorobenzene-1,2-diamine (354 mg) and toluene (2 mL); 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 (4×5 mL) and ethyl acetate (4×5 mL). 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 (3 mL) 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]-1H-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 tert-butyl ester (3.4 g) in dichloromethane (25 mL) is added trifluoroacetic acid (18 mL). After 30 minutes at room temperature, the volatiles are removed under reduced pressure. Water (30 mL) 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 (40 mL) and 40% aqueous solution of formaldehyde (4 mL) as well as a 1 molar solution of sodium hypophosphorous acid (46 mL); 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.
1H NMR: 7.50-7.45 (m, 2H), 7.38-7.20 (m, 3H), 5.00 (s, 1H), 4.18 (q, 2H), 3.55-3.40 (m, 1H), 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 tert-butyl ester
To a solution of diazophenylacetic acid ethyl ester (2.55 g) in 1,2-dichloroethane is added 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (5.4 g). The flask is evacuated and filled with argon. Rhodium(II) acetate-dimer (60 mg) 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 tert-butyl ester.
1H NMR: 7.52-7.28 (m, 5H), 5.01 (s, 1H), 4.15 (q, 2H), 3.90-3.70 (m, 2H), 3.68-3.55 (m, 1H), 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 (3.28 g) in acetonitrile (60 mL) is added para-toluenesulfonylazide (4.53 g). The reaction mixture is cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 mL) 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;
1H NMR: 7.48-7.58 (m, 2H), 7.45-7.30 (m, 2H), 7.22-7.10 (m, 1H), 4.35 (q, 2H), 1.30 (t, 3H)
Example 172
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile
To a solution of 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (200 mg) in N,N-dimethylformamide (2.5 mL) and water (0.2 mL) are added copper(I) cyanide (180 mg), bis(dibenzylidenacetone)palladium (14.3 mg) and Xantphos (14.4 mg). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 48 h, 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile
1H NMR: 9.75 (sl, 1H), 7.82 (s, 1H), 7.80-7.62 (m, 2H), 7.57 (d, 1H), 7.50-7.20 (m, 4H), 5.89 (s, 1H), 3.60-3.40 (m, 1H), 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 (100 mg) 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-[(1H-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]-1H-benzimidazole (200 mg), dichloro-bis(triphenylphosphine) palladium(II) (9.2 mg), copper(I) iodide (16.4 mg), N-propargylphthalimide (400 mg), diethylamine (310 μL) and N,N-dimethylformamide (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at room-temperature for 24 h, 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 give 2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione.
1H NMR: 9.52 (sl, 1H), 7.91-7.15 (m, 12H), 5.81 (s, 1H), 4.66 (s, 2H), 3.65-3.55 (m, 1H), 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:











Example
Product







227
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol







1H NMR: 7.96 (d, 1H), 7.85 (d, 1H), 7.51 (s, 1H), 7.55-7.23 (m, 5H), 5.89 (s, 1H), 4.46


(s, 2H), 3.70-3.55 (m, 1H), 2.78-2.62 (m, 2H), 2.27 (s, 3H), 2.27-2.08 (m, 2H), 2.05-1.70


(m, 4H)








236
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol







1H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.58 (s, 1H), 7.47-7.27 (m, 5H), 5.87 (s, 1H),


3.88-3.65 (m, 3H), 2.95-2.80 (m, 2H), 2.67 (t, 2H), 2.39 (s, 3H), 2.45-2.30 (m, 2H),


2.18 (s, 1H), 2.17-1.80 (m, 4H)








237
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol



hydrochloride







1H NMR (DMSO-d6): 9.79 (sl, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.50-7.30 (m, 5H), 6.12


(d, 1H), 3.92-3.70 (m, 1H), 3.50-2.95 (m, 6H), 2.76 and 2.67 (d, 3H), 2.48-2.35 (m, 2H),


2.30 1.60 (m, 6H)









Example 194
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine
194A
A solution of 2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-phenyl}prop-2-ynyl)isoindole-1,3-dione (70 mg) and hydrazine hydrate (70 μL) in ethanol (0.7 mL) is stirred a room temperature for 3 hours. Ethanol is removed under reduced pressure and 1N 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 90/10/1) to afford 3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine melting at 101° C.
194B
2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione is prepared according to general procedure 189.
Following compounds are prepared analogously:











Example
Product







282
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-



ynylamine







1H NMR: 7.98 (d, 1H), 7.88 (d, 1H), 7.58 (s, 1H), 7.52-7.25 (m, 5H), 5.86 (s, 1H),


3.82-3.68 (m, 1H), 2.95-2.70 (m, 2H), 2.68-2.50 (m, 4H), 2.47 (s, 3H), 2.40-1.75 (m, 6H)








286
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-



ynylamine







1H NMR: 9.50 (sl, 1H), 7.72 (sl, 1H), 7.55-7.20 (m, 7H), 5.84 (s, 1H), 3.65-3.55 (m, 1H),


2.91 (t, 2H), 2.80-2.65 (m, 2H), 2.54 (t, 2H), 2.26 (s, 3H), 2.18-1.60 (m, 6H)








287
e5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-



ynylamine







1H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.56 (s, 1H), 7.46-7.24 (m, 5H), 5.87 (s, 1H),


3.71-3.56 (m, 1H), 2.95-2.82 (m, 2H), 2.82-2.66 (m, 2H), 2.47 (t, 2H), 2.29 (s, 3H),


2.28-2.18 (m, 2H), 2.10-1.70 (m, 8H)








337
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-



ynylamine







1H NMR: 7.70-7.45 (m, 3H), 7.40-7.10 (m, 5H), 5.84 (s, 1H), 3.60-3.55 (m, 2H), 3.32-3.17


(m, 1H), 2.80-2.60 (m, 4H), 2.45-2.30 (m, 2H), 2.24 (s, 3H), 2.18-1.50 (m, 10H)









Example 195
2-[(3-ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
195A
To a solution of 2-[(3-trimethylsilylethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (205 mg) in methanol (2 mL) 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]-1H-benzimidazole
1H NMR: 9.42 (sl, 1H), 7.80-7.70 (m, 1H), 7.62 (s, 1H), 7.48-7.36 (m, 3H) 7.34-7.20 (m, 3H), 5.86 (s, 1H), 3.65-3.48 (m, 1H), 3.07 (s, 1H), 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]-1H-benzimidazole can be obtained using general method described in example 189.
Example 198
2-{(1-methylpiperidin-4-yloxy)[3-(1H-[1,2,3]triazol-4-yl)phenyl]methyl}-1H-benzimidazole
To a solution of 2-[(3-(ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (110 mg) in methanol (2 mL) and N,N-dimethylformamide (0.7 mL) in a screw-cap tube is added L). The reaction mixture□copper(I) iodide (3.2 mg) 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-(1H-[1,2,3]triazol-4-yl)phenyl]methyl}-1H-benzimidazole.
1H NMR: 7.98 (s, 1H), 7.86 (s, 1H), 7.80-7.50 (m, 3H), 7.48-7.30 (m, 2H), 7.29-7.15 (m, 2H), 5.95 (s, 1H), 3.68-3.50 (m, 1H), 2.96-2.89 (m, 1H), 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 (5 mL) is treated with a flow of hydrogen chloride while refluxing for 4 h. 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-methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ylamine
To a solution of DMF (44 mg) in L). As soon as □1,2-dichloroethane (2.5 mL) is added dropwise oxalylchloride (51 the gas evolution ceased, the volatiles are removed under reduced pressure. To the residue are added 1,2-dichloroethane (2.5 mL) and (1-methylpiperidin-4-yloxy)phenylacetic acid (125 mg). 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 (4.5 mL) is added tin(II)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 (100 mg) in methanol (2 mL) and water (1 mL) at 0° C. is added portionwise Oxone® (400 mg) 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.
1H NMR: 8.17 (s, 1H), 7.97 (d, 1H), 7.90-7.83 (m, 3H), 7.60-7.39 (m, 3H), 6.00 (s, 1H), 3.72-3.60 (m, 1H), 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 (0.55 g, example 206) in tetrahydrofurane (10 mL) is treated with lithium aluminum hydride (76 mg) at room temperature for 1 h. Two other additions of lithium aluminum hydride (76 mg each) allow a complete conversion. The mixture is then hydrolyzed with water (178 μL), 5% sodium hydroxide (178 μL) and water (535 μL), 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.
1H NMR (DMSO-d6): 8.06 (d, 1H), 7.90 (d, 1H), 7.50-7.20 (m, 6H), 6.09 (s, 1H), 4.47 (s, 2H), 3.75 (m, 1H), 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 (208 mg), palladium(II) acetate (3 mg), RuPhos® (12 mg), potassium 3-trifluoroboratopropionate tert-butyl ester (118 mg), 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.
1H NMR: 7.97 (d, 1H), 7.86 (s, 1H), 7.45-7.22 (m, 5H), 7.12 (d, 1H), 5.89 (s, 1H), 3.72-3.58 (m, 1H), 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 (250 mg) in acetonitrile (5 mL) are added 2,3-diaminophenol (125 mg), 2-chloro-1-methylpyridinium iodide (255 mg) and dropwise diisopropylethylamine (0.44 mL). 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 (2 mL) 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 170.5° C.
Example 211
[benzothiazol-2-yl(4′-methoxybiphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine, dioxalate
211A
[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 91A from benzothiazol-2-yl(4′-methoxybiphenyl-3-yl)methanol.
211B
A mixture of benzothiazol-2-yl(3-bromophenyl)methanol (200 mg), 4-methoxy-phenylboronic acid (142 mg), tetrakis(triphenylphosphine)palladium (50 mg), potassium carbonate (259 mg), water (4 mL), ethanol (1 mL) and toluene (9 mL) 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-Iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzimidazole (230 mg) in tetrahydrofuran (2.5 mL) in a screw-capped tube are added acrylonitrile (0.15 mL), triethylamine (2.5 mL) and tetrakis(triphenylphosphine)palladium. The tube is evacuated, filled with argon, sealed and heated at 70° C. for 18 h. 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.
1H NMR: 7.98 (d, 1H), 7.88 (d, 1H), 7.65-7.55 (m, 2H), 7.55-7.35 (m, 5H), 5.92 (d, 1H), 5.88 (s, 1H), 4.00-3.90 (m, 1H), 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







205
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylic acid



tert-butyl ester







1H NMR: 7.98 (d, 1H), 7.87 (s, 1H), 7.68 (s, 1H), 7.60-7.36 (m, 6H), 6.37 (d, 1H), 5.93


(s, 1H), 3.72-3.59 (m, 1H), 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).








209
2-[[3-(2-benzenesulfonylvinyl)phenyl](1-methylpiperidin-4-



yloxy)methyl]benzothiazole







1H NMR: 8.02-7.92 (m, 3H), 7.98 (d, 1H), 7.75-7.35 (m, 9H), 7.30-7.15 (m, 1H), 6.90


(d, 1H), 5.88 (s, 1H), 4.10-3.95 (m, 1H), 3.45-3.25 (m, 4H), 2.76 (s, 3H), 2.70-2.45


(m, 2H), 2.35-2.10 (m, 2H)








212
2-[[3-(2-methanesulfonylvinyl)phenyl](1-methylpiperidin-4-



yloxy)methyl]benzothiazole







1H NMR: 7.99 (d, 1H), 7.88 (s, 1H), 7.78-7.59 (m, 3H), 7.55-7.38 (m, 4H), 6.92 (d, 1H),


5.94 (s, 1H), 3.78-3.62 (m, 1H), 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-methylpiperidin-4-yloxy)methyl]-N-benzyl-N-methylbenzamide
A screw-capped tube is charged with 2-[(3-bromo-phenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 27, 400 mg), N-benzylmethylamine (178 μL), 1,8-diazabicyclo(5.4.0)undec-7-ene (100 μL), trans-di-μ-acetatobis[2-(di-o-tolyl-phosphino)benzyl]dipalladium(II) (22 mg), tri-tert-butylphosphonium tetrafluoroborate (17 mg), molybdenum hexacarbonyl (127 mg) and tetrahydrofurane (3 mL). The tube is sealed and heated at 125° C. for 10 min. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The residue is purified over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5) to afford 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-benzyl-N-methylbenzamide which is then converted into its oxalate salt in acetone to give 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-benzyl-N-methylbenzamide, oxalate melting at 103° C.
Example 224
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine
224A
To a solution of 2-[(1-methylpiperidin-4-yloxy)(3-nitrophenyl)methyl]-1H-benzimidazole (110 mg) in ethanol is added tin(II)dichloride (340 mg). 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine melting at 100° C.
224 B
2-[(1-Methylpiperidin-4-yloxy)(3-nitrophenyl)methyl]-1H-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]-methyl}benzothiazole (example 196, 55 mg) and tin(II) chloride dihydrate (250 mg) in ethanol (2 mL) is refluxed for 1 h. The cooled mixture is diluted with dichloromethane and aqueous 1N 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]phenoxymethyl}-phenylamine, oxalate as an orange solid. TLC of the base (eluent: CH2Cl2/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 (10 mg/mL) in a mixture of heptane/isopropanol (75/25) containing diethylamine (0.1%) is injected (20×100 μL) onto an analytical Chiralcel OD-H, 250×4.6 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 220 nm.
The first enantiomer has a retention time of 7.0 min.
Collection affords 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol 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 9.4 min.
Collection affords 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol enantiomer B with a chromatographic enantiomeric purity of 97.8%.
Example 231
2-[(3-azidophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
231A
To a solution of 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-phenylamine (57 mg) in methanol (3 mL) are added at 0° C. copper(II) sulphate and a solution of trifluoromethanesulfonylazide (freshly prepared from sodium azide (220 mg) and trifluoromethanesulfonic anhydride (200 mg)) 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]-1H-benzimidazole melting at 53° C.
231B
To a solution of 2-[(1-Methyl-piperidin-4-yloxy)-(3-nitro-phenyl)-methyl]-1Hbenzimidazole (110 mg) in ethanol (5 mL) is added Tin(II)dichloride-dihydrate (340 mg). The reaction mixture is heated at reflux for 2 hours. Water is added to the mixture as well as sodium hydroxide 1N 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-[(1H-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, 190 mg), copper(I) iodide (4 mg), ethylene glycol (45 μL), potassium carbonate (173 mg), benzylamine (54 μL), and propan-2-ol (1 mL). The tube is evacuated, filled with argon and sealed. After stirring at 80° C. for 15 h, 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, 150 mg), copper(I) iodide (6.5 mg), 3,4,7,8-tetramethyl-1,10-phenanthroline (16.3 mg), cesium carbonate (223 mg), propan-1,3-diol (74 mg), ground 4 Å molecular sieves (80 mg) and toluene (4 mL). The tube is evacuated, filled with argon and sealed. After stirring at 90° C. for 24 h, 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]-methyl}benzothiazole
240A
To a solution of 1,2,3-triazole (36.5 mg) in N,N-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 (85 mg) in N,N-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.
1H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.65-7.25 (m, 8H), 5.90 (s, 1H), 4.62 (t, 2H), 3.75-3.60 (m, 1H), 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
1H NMR: 7.95 (d, 1H), 7.87 (d, 1H), 7.86 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.51-7.25 (m, 5H), 5.90 (s, 1H), 4.52 (t, 2H), 3.75-3.60 (m, 1H), 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]phenylsulfanyl}ethyl ester
To a solution of 2-{3-[benzothiazol-2-yl(1-methyl piperidin-4-yloxy)-methyl]phenylsulfanyl}ethanol (400 mg) in dichloromethane (5 mL) is added methanesulfonylchloride (1.25 molar equivalent) in dichloromethane (1.5 mL) 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]-1H-benzimidazole
In a screw-cap tube are placed 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzimidazole (200 mg), potassium vinyltrifluoroborate (72 mg), 1,1-bis(diphenylphosphino)ferrocene-dichloro-palladium (7.5 mg) and n-propanol (3 mL). The reaction mixture is degassed and purged with argon. The mixture is heated at reflux for 48 h. 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]-1H-benzimidazole.
1H NMR: 7.68-7.55 (m, 2H), 7.48 (s, 1H), 7.45-7.33 (m, 3H), 7.33-7.20 (m, 2H), 6.65 (dd, 1H), 5.83 (s, 1H), 5.75 (d, 1H), 5.26 (d, 1H), 3.88-3.75 (m, 1H), 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethylamine
249A
To a solution of N-tert-butoxycarbonyl-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine in dichloromethane (2 mL) is added trifluoroacetic acid (0.5 ml) at room temperature. The mixture is stirred at room temperature for 24 h. 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine.
1H NMR: 7.80-7.65 (m, 1H), 7.51 (s, 1H), 7.48-7.15 (m, 7H), 5.85 (s, 1H), 3.65-3.53 (m, 1H), 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
N-tert-butoxycarbonyl-2-{3[(1H-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]-1H-benzimidazole enantiomer A
A solution of 2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole (10 mg/mL) in methanol containing diethylamine (0.1%) is injected (17×100 μL) onto an analytical Ceramospher chiral RU-1, 250×4.6 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 220 nm.
The first enantiomer has a retention time of 10.4 min.
Collection affords 2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole enantiomer A with a chromatographic enantiomeric purity of 90%.
Example 253
2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole enantiomer B
The second enantiomer has a retention time of 13.7 min.
Collection affords 2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole enantiomer B with a chromatographic enantiomeric purity of 90%.
Example 259
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-N-methylacetamide
259A
To a solution of methylamine hydrochloride (76 mg) in toluene (2 mL) 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 (50 mg) 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}-N-methylacetamide.
1H NMR (DMSO-d6): 8.12-7.97 (m, 2H), 7.89 (d, 1H), 7.52-7.22 (m, 6H), 5.90 (s, 1H), 3.60 (s, 2H), 3.59-3.45 (m, 1H), 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}-methylybenzothiazole (500 mg) in 5N hydrochloric acid (4 mL) 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]phenylsulfanyl}acetic acid methyl ester (30 mg) 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.
1H NMR (DMSO-d6): 10.30 and 10.15 (two singlets, 1H), 8.05 (d, 1H), 7.89 (d, 1H), 7.50-7.20 (m, 6H), 5.99 (s, 1H), 3.89 (d, 2H), 3.58-3.45 (m, 1H), 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]phenylsulfanylmethyl}cyclopropanecarboxylic acid methyl ester (56 mg) in tetrahydrofuran (5 mL) is added lithium aluminumhydride (25 mg) at 0° C. The reaction mixture is allowed to reach room temperature and ethyl acetate (2 mL) is added. After stirring for 5 minutes, a half-saturated aqueous solution of sodium carbonate (6 mL) 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]phenylsulfanylmethyl}cyclopropyl)ethanol.
1H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.56 (s, 1H), 7.52-7.22 (m, 5H), 5.86 (s, 1H), 3.72 (t, 2H), 3.72-3.58 (m, 1H), 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:











Example
Product







257
2-(1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl-



sulfanylmethyl}-cyclopropyl)ethanol







1H NMR: 10.0 (sl, 1H), 7.60 (s, 1H), 7.80-7.35 (m, 2H), 7.32-7.15 (m, 5H), 5.82


(s, 1H), 3.75 (t, 2H), 3.68-3.50 (m, 1H), 3.01 (dd, 2H), 2.90-2.70 (m, 2H), 2.30 (s, 3H),


2.27-2.10 (m, 2H), 2.10-1.75 (m, 5H), 1.67 (t, 2H), 0.45 (m, 4H)









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, 300 mg), copper(I) iodide (10 mg), tetrakis palladium (36 mg), triethylamine (0.33 mL), 1-methyl-2-pyrrolidinone (1.3 mL), and 1-prop-2-ynyloxypropan-2-one (109 mg). 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: CH2Cl2/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, 140 mg) in methanol (20 mL) is treated with sodium borohydride (30 mg) at 0° C., stirred 1 h at 0° C. and 2 h 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: CH2Cl2/MeOH/NH4OH 95/5/0.5): Rf=0.12.
Example 278
N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine
278A
To a solution of 2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethylamine (130 mg) in acetonitrile (2 mL) is added N,N′-bis-Boc-guanylpyrazole (112 mg) and diisopropylethylamine (0.066 mL) at room temperature. The mixture is heated at 50° C. for 5 h. 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 (1.5 mL) 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 N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine as the dihydrochloride salt.
m/z: [M+H]+=439.0
278B
2-{3-[(1H-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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidine-



1-carboxamidine hydrochloride







1H NMR (DMSO-d6): 7.48-7.38 (m, 2H), 7.34 (s, 1H), 7.32-7.20 (m, 2H), 7.17-7.00 (m, 3H),


5.78 (s, 1H), 3.98 (sl, 1H), 3.92 (sl, 1H), 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine, dichlorhydrate
293A
To a solution of 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}but-3-ynylamine (50 mg) in methanol (2.5 mL) is added platinum oxide (8 mg). 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine.
m/z: [M+H]+=393.1; [M+Na]+=415.2
293B
4-{3-[(1H-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:











Example
Product







238
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butan-1-ol







1H NMR: 7.98 (d, 2H), 7.87 (d, 1H), 7.50-7.25 (m, 6H), 7.13 (d, 1H), 5.88 (s, 1H),


3.81-3.70 (m, 1H), 7.70-7.60 (m, 2H), 3.98-2.80 (m, 2H), 2.65 (t, 2H), 2.43 (s, 3H),


2.22-1.50 (m, 10H), 1.34 (t, 1H)








396
2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-4-yl-ethyl)phenyl]methyl}-1H-



benzimidazole







1H NMR: 7.65-7.50 (m, 2H), 7.35-7.15 (m, 5H), 7.03 (d, 1H), 5.85 (s, 1H), 3.75 (t, 2H),


3.65-3.50 (m, 1H), 3.45-3.30 (m, 2H), 2.90-2.65 (m, 4H), 2.58-2.45 (m, 2H), 2.28 (s, 3H),


2.28-2.10 (m, 2H), 2.10-1.65 (m, 5H), 1.65-1.35 (m, 4H)









Following compounds are prepared according to the general methods:















General



Example
Product
methods
m/z


















98
{3′-[benzothiazol-2-yl(1-methylpiperidin-4-
53
[M + H]+ = 454.2



yloxy)methyl]biphenyl-3-yl}acetonitrile, oxalate


139
2-[(3′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-
53
[M + H]+ = 433.1



yloxy)methyl]benzothiazole


140
2-[(1-methylpiperidin-4-yloxy)(4′-
53
[M + H]+ = 483.2



trifluoromethylbiphenyl-3-yl)methyl]benzothiazole


141
2-[(1-methylpiperidin-4-yloxy)(2′,3′,4′-trifluorobiphenyl-
53
[M + H]+ = 468.6



3-yl)methyl]benzothiazole


143
{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)-
53
[M + H]+ = 530.2



methyl]biphenyl-4-yl}carbamic acid tert-butyl ester


320
N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A,
[M + H]+ = 421.0



yloxy)methyl]phenyl}propyl)guanidine, trihydrochloride
249, 149A


321
N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A,
[M + H]+ = 421.2



yloxy)methyl]phenyl}propyl)guanidine, trihydrochloride
249, 149A
[M + Na]+ = 443.2


344
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
293, 194
[M + H]+ = 421.2



yloxy)methyl]phenyl}hexylamine


346
N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A,
[M + H]+ = 459.2



yloxy)methyl]phenyl}hex-5-ynyl)guanidine,
249, 149A



hydrochloride


355
N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A,
[M + H]+ = 463.2



yloxy)methyl]phenyl}hexyl)guanidine, trihydrochloride
249, 149A
[M + Na]+ = 485.3


358
N-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A,
[M + H]+ = 445.2



yloxy)methyl]phenyl}pent-4-ynyl)guanidine,
249, 149A
[M + Na]+ = 467.3



hydrochloride


372
N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
278A,
[M + H]+ = 448.1



yloxy)methyl]phenyl}but-3-ynyl)guanidine,
249, 149A



dihydrochloride


393
N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A,
[M + H]+ = 431.1



yloxy)methyl]phenyl}but-3-ynyl)guanidine,
249, 149A



hydrochloride


397
N-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A,
[M + H]+ = 449.2



yloxy)methyl]phenyl}pentyl)guanidine, hydrochloride
249, 149A
[M + Na]+ = 471.2


418
N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A,
[M + H]+ = 417.1



yloxy)methyl]phenyl}prop-2-ynyl)guanidine,
249, 149A



hydrochloride


426
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278A,
[M + H]+ = 443.1



yloxy)methyl]phenylethynyl}azetidine-1-carboxamidine
249, 149A
[M + Na]+ = 465.4









Example 298
(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethyl)urea
298A
To a solution of 2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethylamine
(50 mg) in ethanol (0.5 mL) in a screw-cap tube is added potassium cyanate (15 mg). 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)urea melting at 136° C.
298B
2-{3-[(1H-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







299
(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-



yloxy)methyl]phenyl-sulfanyl}ethyl)(4,5-dihydrothiazol-



2-yl)amine







1H NMR (DMSO-d6): 12.37 (sl, 1H), 7.53-7.38 (m, 3H),


7.27-6.95 (m, 5H), 5.80 (s, 1H), 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)








317
(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-



yloxy)methyl]-phenylsulfanyl}ethyl)(4,5-dihydro-1H-



imidazol-2-yl)amine







1H NMR (DMSO-d6): 12.90 (sl, 1H), 10.80 and 10.40 (sl, 1H),


8.58-8.42 (m, 1H), 7.53-7.38 (m, 3H), 7.27-6.95 (m, 5H), 5.93 (s, 1H),


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)








347
1-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}ethyl)-3-isopropylthiourea







1H NMR: 10.43 (sl, 1H), 7.72-7.50 (m, 3H), 7.35-7.20 (m, 5H),


6.45-6.15 (m, 2H), 5.83 (s, 1H), 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, 1H),


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-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-pentyl)isoindole-1,3-dione (200 mg) 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 (0.5 ml), 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-[(1H-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 (200 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), thioacetic acid 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentyl ester (209 mg), diisopropylethylamine (170 μL), potassium phosphate (105 mg), water (0.05 mL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 48 h, 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylpentyl)isoindole-1,3-dione that is used without further purification.
Example 307
N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine
307A
To a solution of 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}but-3-ynylamine (290 mg) in acetonitrile (4.5 mL) is added N,N′-bis-Boc-guanylpyrazole (255 mg) and diisopropylethylamine (0.15 mL) 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 (100 mg) is then dissolved in 1,2-dichloroethane (2 mL); phenol (149 mg) and chlorotrimethylsilane (0.2 mL) are added and the solution is heated at 50° C. for 20 h. 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 N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine.
1H NMR: 7.54 (sl, 2H), 7.32 (s, 1H), 7.27-7.19 (m, 6H), 5.67 (s, 1H), 3.70-3.52 (m, 1H), 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-[(1H-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 (20 mg) is washed with pentane and diluted with anhydrous N,N-dimethylformamide (5 mL). 1H-1,2,3-triazole is then added. After stirring at room temperature for 15 min, the mixture is treated with 2[[3-(4-chloro-butoxy)phenyl]-(1-methyl-piperidin-4-yloxy)methyl]benzothiazole (223 mg) 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: CH2Cl2/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 1B.
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: CH2Cl2/MeOH/NH4OH 90/10/0.5): Rf=0.22.
Example 318
N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethyl)-N′-cyanoguanidine
318A
To a solution of 2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethylamine (50 mg) in isopropanol (1 mL) in a screw-cap tube is added diphenylcyanocarbonimidate (30 mg). 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 (2 mL) 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 N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N′-cyanoguanidine melting at 65° C.
318B
2-{3-[(1H-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}-1H-benzimidazole
338A
To a solution of 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (407 mg) in dichloromethane (2 mL) 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}-1H-benzimidazole.
1H NMR: 10.0 (sl, 1H), 7.60 (s, 1H), 7.70-7.45 (m, 2H), 7.40-7.20 (m, 5H), 6.06 (s, 1H), 5.87 (s, 1H), 3.50 (t, 2H), 3.65-3.45 (m, 1H), 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-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-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]-phenylsulfanyl}-butyl)-carbamic acid tert-butyl ester (140 mg) is dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.4 mL) 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 (0.5 ml), and the precipitate is filtered and dry to give 4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine, oxalate melting at 108° C.
359B
(4-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)-carbamic acid tert-butyl ester
A screw-cap tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (200 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg), thioacetic acid S-(4-tert-butoxycarbonylaminobutyl) ester (180 mg), potassium phosphate (200 mg), water (0.01 mL) and 1,4-dioxane (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 48 h, 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-[(1H-benzimidazol-2-yl)-(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)carbamic acid tert-butyl ester that is used without further purification.
Example 376
2-[(1-methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1H-benzimidazole
376A
To a solution of 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylethynyl}piperidine-1-carboxylic acid tert-butyl ester (160 mg) in 1,2-dichloroethane (10 mL) are added phenol (940 mg) and chlorotrimethylsilane (1.26 mL). 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]-1H-benzimidazole.
1H NMR: 9.80 (sl, 1H), 7.50 (s, 1H), 7.80-7.50 (m, 2H), 7.45-7.20 (m, 5H), 5.84 (s, 1H), 3.65-3.50 (m, 1H), 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-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylethynyl}-piperidine-1-carboxylic acid tert-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 (150 mg) in a mixture of water (1 mL), 1,4-dioxane (1 mL) and methanol (1 mL) is added 1N sodium hydroxide solution (0.6 mL). The reaction mixture is stirred at room temperature for 2 hours. After neutralization to pH 7 with addition of 1N 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.
1H NMR: 7.97 (d, 1H), 7.86 (dd, 1H), 7.53-7.24 (m, 6H), 6.32 (dd, 1H), 6.27 (dd, 1H) 5.30 (s, 1H), 3.71 (t, 2H), 3.77-3.60 (m, 1H), 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:












Example
Product
General methods







156
2-[[3-(2,5-difluorobenzyloxy)phenyl](1-methylpiperidin-4-
1A, 168B



yloxy)methyl]benzothiazole, oxalate







1H NMR of the base (CDCl3): 7.96 (d, 1H), 7.85 (d, 1H), 6.90-7.50 (m, 9H), 5.86 (s, 1H),


5.10 (s, 2H), 3.83 (m, 1H), 2.97 (m, 2H), 2.83 (m, 2H), 2.61 (s, 3H), 2.20 (m, 2H), 1.93 (m, 2H).









263
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
259A, 150



yloxy)methyl]phenylsulfanyl}acetamide







1H NMR (DMSO-d6): 8.03 (s, 1H), 7.86 (d, 1H), 7.61 (sl, 1H), 7.48-7.18 (m, 6H), 7.11 (sl, 1H),


5.95 (s, 1H), 3.57 (s, 2H), 3.57-3.45 (m, 1H), 2.62-2.40 (m, 2H), 2.07 (s, 3H), 2.07-1.72 (m,


4H), 1.70-1.35 (m, 2H)









309
N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-
307A, 194A



methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine







1H NMR: 7.65-7.55 (m, 2H), 7.38 (s, 1H), 7.30-7.15 (m, 4H), 7.01 (d, 1H), 5.79 (s, 1H),


3.70-3.55 (m, 1H), 3.18-2.95 (m, 4H), 2.55-2.30 (m, 4H), 2.44 (s, 3H), 2.15-1.95 (m, 2H),


1.95-1.70 (m, 2H), 1.65-1.50 (m, 4H), 1.49 (s, 9H)









313
N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-
307A, 194A



methylpiperidin-4-yloxy)methyl]phenyl}propyl)amine







1H NMR: 7.68-7.58 (m, 2H), 7.52 (s, 1H), 7.30-7.15 (m, 4H), 7.01 (d, 1H), 5.79 (s, 1H),


3.85-3.70 (m, 1H), 3.45-3.18 (m, 4H), 2.78-2.50 (m, 4H), 2.62 (s, 3H), 2.20-1.60 (m, 6H), 1.46 (s,


9H)









335
N-tert-butoxycarbonyl-N′-(-{3-[(1H-benzimidazol-2-yl)(1-
307A, 194A



methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine,



hydrochloride







1H NMR: 8.95 (sl, 1H), 7.68-7.58 (m, 2H), 7.41 (s, 1H), 7.32-7.15 (m, 4H), 7.01 (d, 1H),


5.78 (s, 1H), 3.92-3.82 (m, 1H), 3.70-3.25 (m, 4H), 3.20-2.70 (m, 4H), 2.81 (s, 3H), 2.52 (t, 2H),


2.30-1.85 (m, 4H), 1.70-1.50 (m, 2H), 1.49 (s, 9H), 1.35-1.20 (m, 2H)









336
N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-
307A, 194A



methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine







1H NMR: 7.68-7.58 (m, 2H), 7.41 (s, 1H), 7.32-7.15 (m, 4H), 7.01 (d, 1H), 5.78 (s, 1H),


4.27 (s, 2H), 3.92-3.82 (m, 1H), 3.10-2.80 (m, 2H), 2.37 (s, 3H), 2.65-2.30 (m, 2H), 2.15-1.90 (m,


2H), 1.90-1.65 (m, 2H), 1.46 (s, 9H)









345
N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-
307A, 194A



methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine







1H NMR (DMSO-d6): 10.91 (sl, 1H), 8.71 (sl, 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)









351
4-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
370A, 272A



yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic acid tert-
and 1B



butyl ester, oxalate







1H NMR of the base (CDCl3): 7.96 (d, 1H), 7.82 (d, 1H), 7.50-7.20 (m, 3H), 7.07 (m, 2H),


6.79 (d, 1H), 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)









353
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
376A, 189



yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxamidine,



hydrochloride







1H NMR (DMSO-d6): 10.7 and 10.45 (sl, 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)









357
N-tert-butoxycarbonyl-N′-(5-{3-[(1H-benzimidazol-2-yl)(1-
307A, 194A



methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine







1H NMR (DMSO-d6): 12.55 (sl, 1H), 8.67 (sl, 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)









383
2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-
258



yloxy)phenyl]methyl}benzothiazole, dioxalate







1H NMR of the base (CDCl3): 7.98 (d, 1H), 7.87 (d, 1H), 7.46-7.20 (m, 3H), 7.09 (m, 2H),


6.80 (d, 1H), 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,


2H), 2.28 (s, 3H), 2.20-1.70 (m, 8H)









390
5-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-
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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione
385A
To a solution of 2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethylamine (150 mg) in diethylether (10 mL) 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 (2 mL) 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione melting at 161° C.
385B
2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethylamine can be prepared according to the method described in example 249.
Example 386
[[3-(6-aminohex-1-ynyl)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
386A
A solution of 2-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)-methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione (230 mg) and hydrazine hydrate (120 μL) in ethanol (3 mL) 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](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine melting at 79° C.
386B
2-(5-{3-[(1H-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 [(1H-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]-1H-benzimidazole
398A
To a solution of 2-((1-methylpiperidin-4-yloxy){3-[3-(1-trityl-1H-imidazol-4-yl)propylsulfanyl]phenyl}methyl)-1H-benzimidazole (200 mg) in 1,2-dichloroethane (7 mL) are added phenol (270 mg) and chlorotrimethylsilane (0.37 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/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]-1H-benzimidazole.
1H NMR: 7.72-7.40 (m, 4H), 7.25-7.15 (m, 5H), 6.82 (s, 1H), 5.84 (s, 1H), 3.60-3.45 (m, 1H), 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-1H-imidazol-4-yl)propylsulfanyl]phenyl}-methyl)-1H-benzimidazole can be prepared according to the method described in example 359A.
Example 401
N-acetyl-N′-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine
401A
To a solution of N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethyl)guanidine.dihydrochloride (100 mg) in dry acetonitrile (1 mL) is added acetic anhydride (64 mg) 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-N′-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine.
1H NMR (DMSO-d6): 12.40 (sl, 1H), 7.55-7.40 (m, 1H), 7.40-7.20 (m, 3H), 7.20-7.05 (m, 4H), 5.81 (s, 1H), 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).
401B
N-(2-{3-[(1H-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, 150 mg), copper(I) iodide (15 mg), deanol (1 mL), potassium carbonate (306 mg), azetidin-3-ol, hydrochloride (88 mg). The tube is evacuated, filled with argon and sealed. After stirring at 60° C. for 100 h, 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 117° C.
Example 411
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, 100 mg) and aqueous 1N sodium hydroxide in methanol (1 mL) is stirred at room temperature for 30 min. 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 110° C.
Example 412
2-[{3-[2-(1H-imidazol-4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
412A
To a solution of 2-{(1-methylpiperidin-4-yloxy)[3-(1-trityl-1H-imidazol-4-ylethynyl)phenyl]methyl}-1H-benzimidazole (260 mg) in 1,2-dichloroethane (7 mL) are added phenol (374 mg) and chlorotrimethylsilane (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 (3 mL) and palladium on charcoal (8 mg). 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-(1H-imidazol-4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.
1H NMR (methanol-d4): 7.65-7.55 (m, 3H), 7.40-7.15 (m, 6H), 6.70 (s, 1H), 5.85 (s, 1H), 3.80-3.70 (m, 1H), 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-1H-imidazol-4-ylethynyl)phenyl]methyl}-1H-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}-1H-benzimidazole
416A
To a solution of 1,2,3-triazole (66 mg) in DMF (0.6 mL) is added sodium hydride (25 mg). After gas evolution ceased, 2[[3-(5-chloropent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (50 mg) 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}-1H-benzimidazole.
1H NMR: 9.43 (sl, 1H), 7.83-7.68 (m, 1H), 7.60 (s, 2H), 7.52 (s, 1H), 7.50-7.20 (m, 6H), 5.84 (s, 1H), 4.61 (t, 2H), 3.68-3.50 (m, 1H), 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]-1H-benzimidazole can be obtained according to the synthetic method described in example 189.
Following compounds are prepared analogously:











Example
Product







417
2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-1-ylpent-1-



ynyl)phenyl]methyl}-1H-benzimidazole







1H NMR: 9.77 (sl, 1H), 7.83-7.68 (m, 1H), 7.70 (s, 1H), 7.61 (s, 1H),


7.52 (s, 1H), 7.50-7.35 (m, 2H) 7.35-7.20 (m, 4H), 5.84 (s, 1H),


4.58 (t, 2H), 3.70-3.55 (m, 1H), 2.90-2.75 (m, 2H), 2.47 (t, 2H),


2.32 (s, 3H), 2.40-2.15 (m, 4H), 2.15-1.70 (m, 4H)








409
2-[[3-(5-imidazol-1-ylpent-1-ynyl)phenyl](1-methylpiperidin-



4-yloxy)methyl]-1H-benzimidazole







1H NMR: 10.90 (sl, 1H), 7.85-7.68 (m, 1H), 7.69 (s, 1H), 7.60 (s, 1H),


7.37 (dt, 1H), 7.40-7.20 (m, 5H), 7.11 (s, 1H), 7.00 (s, 1H), 5.84 (s, 1H),


4.17 (t, 2H), 3.68-3.50 (m, 1H), 2.88-2.70 (m, 2H), 2.48 (t, 2H),


2.30 (s, 3H), 2.29-1.90 (m, 4H), 1.90-1.50 (m, 4H)









Example 421
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine
421A
To a solution of 5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}pent-4-ynylamine (200 mg) in N,N-dimethylformamide (1.8 mL) are added water (0.05 mL), potassium hydroxide (42 mg) and palladium(II) acetate. The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 24 h, 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine.
1H NMR: 7.75-7.58 (m, 2H), 7.42-7.10 (m, 6H), 6.45 (d, 1H), 5.90 (s, 1H), 5.72 (dt, 1H), 3.68-3.50 (m, 1H), 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),
421B
5-{3-[(1H-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
423A
A solution of crude (1-{3-[benzothiazol-2-yl-(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (289 mg) in dichloromethane (3 mL) and trifluoroacetic acid (2.5 mL) is stirred at room temperature for one night. The mixture is concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous 1N 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, 200 mg), copper(I) iodide (7 mg), 2-isobutyrylcyclohexanone (25 mg), cesium carbonate (280 mg), 3-(Boc-amino)pyrrolidine (160 mg) and anhydrous N,N-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 tert-butyl ester.
Example 432
432A
2-(5-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-pentyl)isoindole-1,3-dione
To a solution of 5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-ol (35 mg) in tetrahydrofuran are added triphenylphosphine (31 mg) and phthalimide (18 mg). The reaction mixture is cooled to 0° C. and diethyl azodicarboxylate (31 μL) 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentyl)isoindole-1,3-dione (example 305B).
432B
5-{3-[(1H-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-[(1H-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. 1H NMR: 7.68-7.48 (m, 2H), 7.35-6.95 (m, 8H), 5.89 (s, 1H), 3.83-3.50 (m, 3H), 3.50-3.35 (m, 1H), 3.25-3.10 (m, 1H), 2.82-2.62 (m, 3H), 2.59-2.45 (m, 1H), 2.26 (s, 3H), 2.24-1.95 (m, 3H), 1.92-1.50 (m, 5H).
Example 437
N-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine
437A
To a solution of 2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine (example 437B, 230 mg) in acetonitrile (15 mL) is added is added N,N′-bis-Boc-guanylpyrazole (172 mg) and diisopropylethylamine (1 equivalent) at room temperature. The mixture is stirred at room temperature for 3 h. 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 (8 mL) 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-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl) guanidine trihydrochloride as a white crystalline solid melting at 170° C.
437B
2-{3-[(5-Fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine
To a solution of (2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)carbamic acid tert-butyl ester (example 437C, 386 mg) in chloroform (10 mL) are added phenol (750 mg) and chlorotrimethylsilane (814 mg). The mixture is heated at reflux for 2 h. The solvent and volatiles are removed under reduced pressure. The residue is basified by adding a solution of 1N 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-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine.
1H NMR: 8.5-9 (sl, 1H), 7.53 (s, 1H), 7.32-7.20 (m, 5H), 7.08-6.98 (m, 1H), 5.84 (s, 1H), 3.70-3.50 (m, 1H), 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-1H-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-1H-benzimidazole (example 437D, 418 mg), palladium bis(dibenzylideneacetone) (30 mg), Xantphos (30 mg), (2-mercaptoethyl)carbamic acid tert-butyl ester (1 equivalent), diisopropylethylamine (180 μL) and 1,4-dioxane (6 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 98/2 to 95/5) to afford (2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)carbamic acid tert-butyl ester. 1H NMR: 11.07 (sl, 1H), 7.69-7.59 (m, 1H), 7.39-7.36 (m, 1H), 7.30-7.15 (m, 2H), 7.04-6.91 (m, 2H), 5.83 (s, 1H), 5.30 (sl, 1H), 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-1H-benzimidazole
A mixture of (3-bromophenyl)(5-fluoro-1H-benzimidazol-2-yl)methanol (example 437E, 3.30 g) and 1-methylpiperidin-4-ol (2.37 g) in methanesulfonic acid (10 mL) is heated overnight in a sealed tube at a temperature close to 140° 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-1H-benzimidazole. 1H NMR: 9.92 (sl, 1H), 7.60 (s, 1H), 7.55-6.85 (m, 6H), 5.80 (s, 1H), 3.65-3.50 (m, 1H), 2.80-2.65 (m, 2H), 2.34 (s, 3H), 2.15-1.65 (m, 6H).
437E
(3-Bromophenyl)(5-fluoro-1H-benzimidazol-2-yl)methanol could be synthesized using the method described in example 449B.
Example 438
438A
5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine oxalate
A solution of 2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione (example 438B, 170 mg) and hydrazine hydrate (200 μL) in ethanol (2.5 mL) 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-1H-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-1H-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-1H-benzimidazole (example 437D, 418 mg), PEPPSi-sono catalyst (19 mg), copper (I) iodide (38 mg), N-pentynylphthalimide (428 mg), diethylamine (880 μL) and N,N-dimethylformamide (1.5 mL). 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 (10 mg) and N-pentynylphthalimide (214 mg) are added, and the reaction mixture is heated at 80° C. for 24 h. 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-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione. 1H NMR: 9.65 (sl, 1H), 7.84-7.65 (m, 4H), 7.54 (s, 1H), 7.48-6.95 (m, 4H), 5.84 (s, 1H), 3.90 (t, 2H, J=6.9 Hz), 3.65-3.50 (m, 1H), 2.85-2.70 (m, 2H), 2.52 (t, 2H, J=7.0 Hz), 2.32 (s, 3H), 2.28-1.50 (m, 8H).














General


Example
Product
methods







439
6-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-
438



methylpiperidin-4-yloxy)methyl]phenyl}hex-



5-ynylamine oxalate







mp = 146° C.









440
4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-
432, 150



methylpiperidin-4-yloxy)methyl]phenyl-



sulfanyl}butylamine oxalate







mp = 160° C.









441
N-(3-{3-[(1H-benzimidazol-2-yl)(1-
278, 432,



methylpiperidin-4-yloxy)methyl]phenyl-
150



sulfanyl}propyl)guanidine, dihydrochloride







mp = 318° C.









Example 443
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-phenyl}pyrrolidin-3-one, oxalate
To a solution of oxalyl chloride (317 μL) in dichloromethane (8 mL) at −78° C. is added DMSO (517 μL). After 15 min, a solution of 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol (example 406, 958 mg) in dichloromethane (18 mL) is slowly added at the same temperature. After 45 min triethylamine (2 mL) 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° C.












Example
Product
General methods







444
N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278, 432,



yloxy)methyl]phenylsulfanyl}butyl)guanidine, dihydrochloride
150







1H NMR: (methanol-d4): 7.65-7.50 (m, 2H), 7.45 (s, 1H), 7.40-7.15 (m, 5H), 5.84 (s, 1H),


3.70-3.55 (m, 1H), 3.10 (t, 2H, J = 6.6 Hz), 3.00-2.80 (m, 4H), 2.5-2.30 (m, 5H), 2.08-1.75 (m, 4H),


1.70-1.55 (m, 4H).









445
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
359B



yloxy)methyl]phenylsulfanyl}pentan-1-ol







1H NMR (methanol-d4): 9.90 (sl, 1H), 7.75-7.70 (m, 1H), 7.42-7.35 (m, 2H), 7.32-7.15 (m, 5H),


5.84 (s, 1H), 3.70-3.48 (m, 3H), 2.89 (t, 2H, J = 6.6 Hz), 2.80-2.62 (m, 2H), 2.24 (s, 3H),


2.15-1.42 (m, 12H).









446
N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
401



yloxy)methyl]phenylsulfanyl}ethyl)-N-(2,2-



dimethylpropionyl)guanidine







1H NMR: 12.34 (sl; 1H), 7.51 (d, 1H, J = 6.75 Hz), 7.48-7.40 (m, 2H), 7.30-7.20 (m, 3H),


7.20-7.05 (m, 2H), 6.65 (sl, 1H), 5.81 (s, 1H), 3.50-3.25 (m, 3H), 3.18-3.05 (m, 2H), 2.07 (m, 3H),


2.00-1.75 (m, 4H), 1.65-1.45 (m, 2H), 1.00 (s, 9H).









447
2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-
165C, B,



benzimidazole
210, 165D







mp = 90° C.









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, 500 mg), copper(I) iodide (9 mg), 2,2,6,6-tetramethylheptane-3,5-dione (37 mg), cesium carbonate (701 mg), 3-hydroxypyridine (125 mg), powdered 4A molecular sieves (200 mg) and anhydrous N,N-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-1H-benzimidazole, oxalate
449A
2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1H-benzimidazole is prepared from 3-bromophenyl(5-fluoro-1H-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-1H-benzimidazole, oxalate melting at 70° C.
449B
A mixture of (3-bromophenyl)hydroxyacetic acid (3.7 g) and 4-fluoro-ortho-phenylenediamine (2 g) in 5N aqueous hydrochloric solution (3.2 mL) is heated under reflux for 15 h 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-1H-benzimidazol-2-yl)methanol.
Example 455
4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline
To a solution of 2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-benzimidazole (example 447, 200 mg) in methanol (5 mL) and a solution of 5N hydrochloric acid in isopropanol (0.2 mL) is added 10% palladium on carbon (50 mg). 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline hydrochloride as a cream-colored solid melting at 185° C.
The following example is made using the same method:












Example
Product
mp







456
4-[(1H-benzimidazol-2-yl)(piperidin-4-
190° C.



yloxy)methyl]aniline, hydrochloride









The following example are made using the method of example 436











Example
Product
















459
N-(2-amino-ethyl)-2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-



methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide







1H NMR: 7.70-7.52 (m, 2H), 7.50-6.90 (m, 7H), 5.85 (s, 1H),


4.75 (s, 2H), 3.85-3.45 (m, 3H), 3.45-3.30 (m, 1H), 3.25-3.05 (m, 1H),


2.80-2.60 (m, 3H), 2.57-2.42 (m, 1H), 2.25 (s, 3H), 2.20-1.95 (m, 3H),


1.90-1.55 (m, 3H).









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, 170 mg) in tetrahydrofuran (3 mL) is treated with cesium fluoride (612 mg) and trifluoromethyltrimethylsilane (595 μL). After stirring for 2 h, the mixture is hydrolyzed with 1N 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. 1H NMR of the base (CDCl3): 7.96 (d, 1H), 7.86 (d, 1H), 7.45-7.20 (m, 3H), 6.91 (d, 1H), 6.73 (s, 1H), 6.51 (d, 1H), 5.85 (s, 1H), 3.77-3.30 (m, 5H), 2.69 (m, 2H), 2.36 (m, 1H), 2.25 (s, 3H), 2.20-1.70 (m, 7H).
Example 468
2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
To a solution of triphenylphosphine oxide (2.2 mmoles) in 4 mL CH2Cl2 cooled at 0° C. 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide (Example 436) (250 mg, 0.55 mmole) in 2 mL CH2Cl2 is added dropwise. The reaction mixture is allowed to reach room temperature and stirred for 1.5 h. The organic phase is washed with 1N 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-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole melting at 62° C. (déc.); MS, [M+H]+=436.1.
The following example is made using the same method












Example
Product
mp







463
2-[[3-(4,5-dihydro-1H-imidazol-2-
80° C.



ylmethylsulfanyl)phenyl](1-methylpiperidin-4-



yloxy)methyl]-5-fluoro-1H-benzimidazole









Example 469
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1H-benzimidazole
469A
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1H-benzimidazole is prepared from 3-bromophenyl(5,6-difluoro-1H-benzimidazol-2-yl)methanol according to general procedure 272A, solid melting at 70° C.
469B
A mixture of (3-bromophenyl)hydroxyacetic acid (809 mg) and 4,5-difluoro-ortho-phenylenediamine (500 mg) in 5N aqueous hydrochloric solution (2 mL) is heated under reflux for 15 h 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-1H-benzimidazol-2-yl)methanol.
Example 472
2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole, dioxalate
A solution of 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 51, 260 mg) in anhydrous acetonitrile (10 mL) is treated with 60% sodium hydride (47 mg) for 1 h at room temperature. The mixture is then cooled to 0° C. and iodomethane (36 μL) is introduced. After stirring for 15 h, 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-1H-benzimidazole, dioxalate, melting at 76° C.
Example 479
2-amino-5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-1,5-dihydroimidazol-4-one
479A
2-amino-5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-1,5-dihydroimidazol-4-one
To a solution of 3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-2-(N,N′-bis-tert-butoxycarbonyl)guanidinopropionic acid methyl ester (260 mg) in dichloromethane (2.6 mL) is added dropwise trifluoroacetic acid (1 mL). The reaction mixture is stirred at room temperature for 28 h.
Solvents are removed under reduced pressure. The residue is basified by adding 1N 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl-methyl}-1,5-dihydroimidazol-4-one.
MS, [M+H]+=465.1; [M+Na]+=487.1.
479B
3-{3-[(1H-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. 1H NMR: 11.35 and 11.13 (sl, 1H), 10.25 and 10.06 (sl, 1H), 9.04 and 8.90 (d, 1H, J=7.5 Hz), 7.82-7.70 (m, 2H), 7.52-7.18 (m, 6H), 5.89 and 5.84 (s, 1H), 5.58-5.30 (m, 1H), 5.25-5.90 (m, 1H), 4.65-4.40 (m, 1H), 3.82-3.05 (m, 6H), 2.95-2.75 (m, 2H), 2.38 (sl, 3H), 2.252-1.60 (m, 6H), 1.60-1.30 (m, 18H).
479C
2-Amino-3-{3-[(1H-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. 1H NMR: 9.74 and 9.67 (sl, 1H), 7.80-7.55 (m, 2H), 7.48-7.15 (m, 7H), 5.84 (s, 1H), 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).
479D
3-{3-[(1H-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]-1H-benzimidazole (example 72A) and N-Boc-Cysteine methyl ester using the method described in example 150; mixture of diastereomers. 1H NMR: 10.66 and 9.83 (sl, 1H), 7.90-7.70 (m, 2H), 7.50-7.35 (m, 2H), 7.35-7.18 (m, 5H), 5.87 and 5.85 (s, 1H), 5.58-5.30 (m, 1H), 4.65-4.40 (m, 1H), 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-1H-benzimidazole
481A
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-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-1H-benzimidazole.
481B
To a solution of 4-[(3-bromophenyl)carboxymethoxy]piperidine-1-carboxylic acid tert-butyl ester (general procedure 165D+saponification)(1 g) in acetonitrile (10 mL) are added 3,4,5-trifluorobenzene-1,2-diamine (470 mg), 2-chloro-1-methylpyridinium iodide (802 mg) 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 (15 mL) 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-1H-benzimidazole.
Example 497
1-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, dioxalate
A solution of 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 51, 260 mg) in anhydrous acetonitrile (10 mL) is treated with 60% sodium hydride (47 mg) for 30 min at room temperature. 1-Bromo-2-ethoxyethane (84 μL) is then introduced. After warming at 60° C. for 8 h, 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]-1H-benzimidazole, dioxalate, melting at 88° C.
Example 505
505A
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzylidene}-2-iminoimidazolidin-4-one
To a solution of 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-benzaldehyde (example 505C, 200 mg) in a mixture of ethanol-water (8:2) (3 mL) is added thiohydantoin (70 mg) and piperidine (57 μL). The reaction mixture is heated at 55° C. for 5 h. 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 (6 mL) and 30% solution of aqueous ammonia (1.1 mL) and tert-butylhydroperoxide (90 μL) 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzylidene}-2-iminoimidazolidin-4-one. MS, [M+H]+=431.1; [M+Na]+=453.1
505B
3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde
To a solution of 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-benzonitrile (example 172, 740 mg) in 80% aqueous formic acid (3 mL) is added platinum(IV) oxide (48 mg). The reaction mixture is heated at 60° C. for 7 h, then at room temperature for 2 days. As the reaction is not complete, 80% aqueous formic acid (3 mL) and platinum (IV) oxide (48 mg) 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 1N sodium hydroxide and extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated to give 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde. 1H NMR: 9.99 (s, 1H), 9.67 (sl, 1H), 8.01 (s, 1H), 7.85-7.65 (m, 2H), 7.60-7.40 (m, 2H), 7.32-7.15 (m, 3H), 5.95 (s, 1H), 3.65-3.50 (m, 1H), 2.82-2.65 (m, 2H), 2.26 (s, 3H), 2.20-1.65 (m, 6H).
Example 507
4-{3-[(1H-benzimidazol-2-yl)(1-methylazetidin-3-ylmethoxy)methyl]-phenylsulfanyl}butylamine, oxalate. Compound made from example 506 using methods described in examples 150, 432. 1H NMR (methanol-d4)(base): 7.65-7.40 (m, 3H), 7.40-7.10 (m, 5H), 5.69 (s, 1H), 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, 1H).
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) (2.4 g), ortho-aminophenol (1.03 g) in xylene (25 mL) is refluxed for 4 h 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]-1H-benzimidazole
To a solution of {3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol (example 528B, 320 mg) in dichloromethane (3 mL) is added triethylamine (0.16 mL). The reaction mixture is cooled to 0° C., and methanesulfonyl chloride (84 μL) is added dropwise. The reaction mixture is stirred at room temperature for 3 h, then cooled to 0° C. and sodium thiomethoxide (191 mg) is added. After one night at room temperature, methanol (2 mL) 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]-1H-benzimidazole. MS, [M+H]+=382.1;
528B
{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol
To a solution of 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde (example 505B, 310 mg) in methanol (4 mL) is added portionwise sodium borohydride (50 mg). The reaction mixture is stirred at room temperature for 15 minutes then heated at reflux for 3 h. 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-phenyl}methanol. 1H NMR: 9.85 (sl, 1H), 7.78-7.65 (m, 1H), 7.50-7.12 (m, 7H), 5.87 (s, 1H), 4.64 (s, 2H), 3.62-3.45 (m, 1H), 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]-1H-benzimidazole
To a solution of 1,2-phenylenediamine (213 mg) in toluene (2 mL) 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, 358 mg) in toluene (2 mL) 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 1N 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 (5 mL) 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]-1H-benzimidazole melting at 189° C.
530B
(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, 480 mg) in methanol (5 mL) 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. 1H NMR: 7.62 (s, 1H), 7.50-7.35 (m, 2H), 7.30-7.15 (m, 1H), 5.75 (sl, 1H), 4.77 (s, 1H), 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, 2.2 g) in acetonitrile (50 mL) 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. 1H NMR (dmso-d6): 8.75-8.65 (m, 2H), 7.98-7.88 (m, 2H), 7.78 (s, 1H), 7.63-7.51 (m, 2H), 7.42-7.30 (m, 1H), 6.20 (s, 1H), 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, 3 g) in dichloroethane (50 mL) are added 4-mercaptopyridine (2 equivalents) and [Ir(COD)Cl]2 (20 mg). 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. 1H NMR: 8.50-8.35 (m, 2H), 7.68 (s, 1H), 7.55-7.45 (m, 2H), 7.35-7.20 (m, 1H), 7.20-7.05 (m, 2H), 5.08 (s, 1H), 3.77 (s, 3H).
530E
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, 7.5 g) in dimethylsulfoxide (35 mL) is added copper(II)cyanide (150 mg), 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. 1H NMR: 7.47 (s, 1H), 7.45-7.35 (m, 1H), 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]-1H-benzimidazole, enantiomer B
A solution of racemic 2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (10 mg/mL) in a mixture of heptane/isopropanol (90/10) containing diethylamine (0.1%) is injected (30×100 μL) onto an analytical Chiralpak AD-H, 250×4.6 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 210 nm. The enantiomer B has a retention time of 13.2 min. Collection affords 2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole enantiomer B with a chromatographic enantiomeric purity of 97.4%.
Example 534
2-[(2,6-difluoro-3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
534A
2-[(2,6-Difluoro-3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (solid melting at 185° C.) is prepared according to general procedure 172A from (1H-benzimidazol-2-yl)(2,6-difluoro-3-methoxyphenyl)methanol.
534B
A solution of (2,6-difluoro-3-methoxyphenyl)[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol (1.4 g) in tetrahydrofuran (20 mL) is refluxed for 15 h with tetrabutylammonium fluoride (10 mL of a 1M 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 (1H-benzimidazol-2-yl)-(2,6-difluoro-3-methoxyphenyl)methanol.
534C
To a solution of 2,4-difluoro-1-methoxybenzene (156 mg) in tetrahydrofuran (5 mL) at −78° C. is added a 2M solution of lithium diisopropylamide in THF (540 μL). After stirring for 45 min a solution of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde (which can be prepared according to US2003/220341 or U.S. Pat. No. 6,476,041 for example) (300 mg) in tetrahydrofuran (5 mL) 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)-1H-benzimidazol-2-yl]methanol.
Example 549
ethyl (6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate, oxalate
To a cooled solution of 6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine (example 480, 22 mg) 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-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate, oxalate melting at 90° C.
Example 550
2-[(1H-indol-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
550A
2-[(1-Benzenesulfonyl-1H-indol-6-yl)(1-methyl-piperidin-4-yloxy)methyl]-1H-benzimidazole (150 mg) and sodium hydroxide (excess) in methanol are refluxed for 3 h. 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-[(1H-indol-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate, melting at 170° C.
550B
2-[(1-Benzenesulfonyl-1H-indol-6-yl)(1-methyl-piperidin-4-yloxy)methyl]-1H-benzimidazole is prepared according to general procedures 172A and 172B from 1-benzenesulfonyl-1H-indole-6-carbaldehyde.
Example 556
2-[benzo[b]thiophen-6-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
556A
2-[Benzo[b]thiophen-6-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate melting at 160° C. is prepared according to general procedures 272A and 534B from benzo[b]thiophen-6-yl[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol.
556B
To a suspension of magnesium (86 mg) in tetrahydrofuran is added a solution of 6-bromobenzo[b]thiophene (which can be prepared according to WO2006/107784) (500 mg) in tetrahydrofuran. After reflux for 3 h, a solution of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde (which can be prepared according to US2003/220341 or U.S. Pat. No. 6,476,041 for example) (635 mg) in tetrahydrofuran is added to the Grignard reagent at room temperature. After stirring for 12 h, 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)-1H-benzimidazol-2-yl]methanol.
Example 559
2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, enantiomer B
A solution of racemic 2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 523) (10 mg/mL) in a mixture of heptane/isopropanol (90/10) containing diethylamine (0.1%) is injected (30×100 μL) onto an analytical Chiralpak AD-H, 250×4.6 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 210 nm. The enantiomer B has a retention time of 13.9 min. Collection affords 2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, enantiomer B with a chromatographic enantiomeric purity of 99.3%
Example 561
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol
561A
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (solid melting at 118-120° C.) is prepared from 2-[(1H-benzimidazol-2-yl)hydroxymethyl]phenol according to general procedure 1A.
561B
To a solution of 1-pyrrolidin-1-ylmethyl-1H-benzimidazole (6 g) in tetrahydrofuran (40 mL) at −78° C., is added a 2.3M solution of butyllithium in hexanes (13 mL). The mixture is stirred for 25 minutes. Salicaldehyde (1.82 g) 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 trituration in dichloromethane to afford 2-[(1H-benzimidazol-2-yl)hydroxymethyl]phenol.
Example 562
2-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol
A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 70 mg), 2-hydroxybenzophenone (30 mg) in ethanol (4 mL) is refluxed for 4 h. 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.15.
Example 563
5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol
A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 50 mg), 3-methyl-1,2-cyclopentanedione (11.8 mg) in ethanol (2 mL) is refluxed for 2 h. The mixture is then cooled, diluted with water and 1N 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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.30.
Example 564
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, enantiomer B
Resolution of racemic 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 78) with (1R)-(−)-10-camphorsulfonic acid (0.45 eq) in ethyl acetate affords after several recrystallizations enantiopure 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, enantiomer B (solid melting at 85° C.). HPLC analysis: analytical Chiralpak AD-H, 250×4.6 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 10.4 min.
Example 565
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine, enantiomer A
5-{3-[(1H-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]-1H-benzimidazole, enantiomer A (prepared according example 564 with (1S)-(+)-camphorsulfonic acid).
Example 566
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine, enantiomer B
5-{3-[(1H-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]-1H-benzimidazole, enantiomer B (example 564).
Example 567
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole, enantiomer A
Resolution of racemic 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole with (1S)-(+)-10-camphorsulfonic acid (0.5 eq) in ethyl acetate affords after several recrystallizations 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole, enantiomer A (solid melting at 89° C.). HPLC analysis: analytical Chiralpak AD-H, 250×4.6 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 8.2 min. e.e.=93.5%
Example 568
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole, enantiomer B
Resolution of racemic 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole with (1R)-(−)-10-camphorsulfonic acid (0.5 eq) in ethyl acetate affords after several recrystallizations 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole, enantiomer B (solid melting at 89° C.). HPLC analysis: analytical Chiralpak AD-H, 250×4.6 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 10.3 min. e.e.=95.5%
Example 578
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylphenol
A mixture of 2-[(1H-benzimidazol-2-yl)hydroxymethyl]-4-methylphenol (prepared according to procedure 561B) (360 mg), methanesulfonic acid (500 μL) and 1-methyl-4-piperidinol (500 mg) in 1,2-dichloroethane (20 mL) and N-methylpyrrolidinone (2 mL) is warmed at 90° C. for 2 h. 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-[(1H-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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer A
2-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer A is prepared by separation on Chiralpak AD-H from racemic 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (example 561). HPLC analysis: Chiralpak AD-H, 250×4.6 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 18.8 min. e.e.=100%
Example 627
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B
2-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B is prepared by separation on Chiralpak AD-H from racemic 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (example 561). HPLC analysis: Chiralpak AD-H, 250×4.6 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 34.3 min. e.e.=100%
Example 628
6-[(1Hbenzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol enantiomer A
By analogy with example 626 from racemic 6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol (example 601). HPLC analysis: Chiralpak AD-H, 250×4.6 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 15.8 min.
Example 629
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol enantiomer B
By analogy with example 627 from racemic 6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol (example 601). HPLC analysis: Chiralpak AD-H, 250×4.6 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 19.9 min.
Example 630
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol enantiomer A
By analogy with example 626 from racemic 6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol (example 625). HPLC analysis: Chiralpak AD-H, 250×4.6 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 13.4 min.
Example 631
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol enantiomer B
By analogy with example 627 from racemic 6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol (example 625). HPLC analysis: Chiralpak AD-H, 250×4.6 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 15.3 min.
Further examples can be prepared according to the described general methods:















General



Example
Product
methods
Melting point







442
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
194, 189, 425
139° C.



yloxy)methyl]-4-fluorophenyl}pent-4-ynylamine,



dioxalate


453
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
194, 432A,
 91° C.



yloxy)methyl]phenoxy}cyclopentylamine, oxalate
258


454
2-{[3-(3-fluoropyrrolidin-1-yl)phenyl](1-
423B
103° C.



methylpiperidin-4-yloxy)methyl}benzothiazole,



oxalate


462
5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-
194, 189, 449
200° C.



methylpyrrolidin-3-ylmethoxy)methyl]phenyl}pent-4-



ynylamine, oxalate


464
2-[(3-bromophenyl)(1-methylpyrrolidin-3-
165C, 1A, 1B
 68° C.



ylmethoxy)methyl]benzothiazole, oxalate (one



epimer)


465
2-[(3-bromophenyl)(1-methylpyrrolidin-3-
165C, 1A, 1B
 68° C.



ylmethoxy)methyl]benzothiazole, oxalate (50/50



mixture of two epimers)


466
2-{(1-methylpiperidin-4-yloxy)[3-
249, 258
 70° C.



(octahydrocyclopenta[c]pyrrol-5-



yloxy)phenyl]methyl}benzothiazole, dioxalate


467
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
249, 423B
216° C.



yloxy)methyl]phenyl}pyrrolidin-3-yl)methylamine,



dioxalate


470
4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-
150, 469
 60° C.



methylpiperidin-4-



yloxy)methyl]phenylsulfanyl}butan-1-ol


471
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
194, 432A,
126° C.



yloxy)methyl]phenyl}octahydrocyclopenta[c]pyrrol-
423B



5-ylamine, dioxalate


475
2-{[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-
272A, 272B
106° C.



yloxy)methyl}-1H-benzimidazole, oxalate


476
2-{[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-
272A, 272B
136° C.



yloxy)methyl}-1H-benzimidazole, oxalate


477
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
194, 432A,
95° C.



yloxy)methyl]phenoxy}cyclohexylamine, oxalate
258


480
6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-
194, 189, 472
113° C.



methylpiperidin-4-yloxy)methyl]phenyl}hex-5-



ynylamine, dioxalate


482
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
194, 432A,
145° C.



yloxy)methyl]phenyl}pyrrolidin-2-ylmethylamine,
423B



oxalate


483
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
249, 423B
115° C.



yloxy)methyl]phenyl}pyrrolidin-3-yl)(methyl)amine,



oxalate


484
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
423B
106° C.



yloxy)methyl]phenyl}pyrrolidin-3-yl)(dimethyl)amine,



oxalate


485
2-{[3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-
423B
131° C.



yl)phenyl](1-methylpiperidin-4-



yloxy)methyl}benzothiazole, dioxalate


486
2-[(2-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-
272A, 272B
105° C.



yloxy)methyl]-1H-benzimidazole, oxalate


487
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 272B
135° C.



yloxy)methyl]-4-fluorophenol, oxalate


489
2-{[2-fluoro-5-(2-fluoroethoxy)phenyl](1-
272A, 272B
109° C.



methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,



oxalate


490
2-[(2-fluoro-5-methylphenyl)(1-methylpiperidin-4-
272A, 272B
132° C.



yloxy)methyl]-1H-benzimidazole, oxalate


493
4-{3-[(1-methylpiperidin-4-yloxy)(5,6,7-trifluoro-1H-
305A, 305B,
110° C.



benzimidazol-2-
481



yl)methyl]phenylsulfanyl}butylamine, oxalate


495
4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-
305A, 305B,
180° C.



methylpiperidin-4-
469



yloxy)methyl]phenylsulfanyl}butylamine, oxalate


500
6-(3-{[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl](1-
194, 189, 497
103° C.



methylpiperidin-4-yloxy)methyl}phenyl)hex-5-



ynylamine, dioxalate


501
6-(3-{[1-(2-methoxyethyl)-1H-benzimidazol-2-yl](1-
194, 189, 497
109° C.



methylpiperidin-4-yloxy)methyl}phenyl)hex-5-



ynylamine, dioxalate


508
2-{[3-(3-fluoropropylsulfanyl)phenyl](1-
150
 85° C.



methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,



dioxalate


509
5-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-
272A, 272B
 70° C.



methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,



oxalate


510
4,5,6-trifluoro-2-[(2-fluoro-5-
272A, 272B
 75° C.



trifluoromethoxyphenyl)(1-methylpiperidin-4-



yloxy)methyl]-1H-benzimidazole


511
5,6-difluoro-2-[(2-fluoro-5-
272A, 272B
 9° C.



trifluoromethoxyphenyl)(1-methylpiperidin-4-



yloxy)methyl]-1H-benzimidazole


522
2-{[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl](1-
272A, 272B
204° C.



methylpiperidin-4-yloxy)methyl}-1H-benzimidazole


523
2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-
272A, 272B
211° C.



4-yloxy)methyl]-1H-benzimidazole


524
2-[(2-chloro-5-trifluoromethoxyphenyl)(1-
272A, 272B
107° C.



methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,



oxalate


526
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-
272A, 1B
 95° C.



methylpiperidin-4-yloxy)methyl]benzothiazole,



oxalate


527
2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-
272A, 272B
195° C.



yloxy)methyl]-1H-benzimidazole


529
7-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-
165C, 165A
135° C.



methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,



oxalate


531
2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-
272A, 168B
125° C.



4-yloxy)methyl]benzothiazole, oxalate


532
2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-
272A, 1B
158° C.



yloxy)methyl]benzothiazole, oxalate


535
2-[(3-ethoxy-2,6-difluorophenyl)(1-methylpiperidin-
534
130° C.



4-yloxy)methyl]-1H-benzimidazole


536
2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-
525
114° C.



4-yloxy)methyl]benzoxazole, oxalate


537
2-[(1-methylpiperidin-4-yloxy)(4-
272A, 272B
 86° C.



trifluoromethylphenyl)methyl]-1H-benzimidazole


540
2-[(2-fluoro-4-trifluoromethylphenyl)(1-
272A, 272B
 91° C.



methylpiperidin-4-yloxy)methyl]-1H-benzimidazole


541
2-[(2,4-dimethylphenyl)(1-methylpiperidin-4-
272A, 272B
120° C.



yloxy)methyl]-1H-benzimidazole


542
2-[(3-methoxyphenyl)(1-methylpiperidin-4-
272A, 272B
 83° C.



yloxy)methyl]-1H-benzimidazole


543
2-[chroman-7-yl(1-methylpiperidin-4-yloxy)methyl]-
272A, 272B
128° C.



1H-benzimidazole


545
2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-
525
110° C.



yloxy)methyl]benzoxazole, oxalate


547
2-[(3,5-bis-trifluoromethylphenyl)(1-methylpiperidin-
272A, 272B
130° C.



4-yloxy)methyl]-1H-benzimidazole, oxalate


548
5-fluoro-2-[(2-fluoro-4-methylphenyl)(1-
272A, 272B
 90° C.



methylpiperidin-4-yloxy)methyl]-1H-benzimidazole


551
2-[(2,3-difluoro-4-methylphenyl)(1-methylpiperidin-
272A, 272B
 80° C.



4-yloxy)methyl]-1H-benzimidazole


552
2-[(3-chloro-4-methylphenyl)(1-methylpiperidin-4-
272A, 272B
 86° C.



yloxy)methyl]-1H-benzimidazole


553
ethyl 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-
549
118° C.



methylpiperidin-4-yloxy)methyl]benzimidazole-1-



carboxylate, oxalate


554
2-[(3-fluoro-4-methylphenyl)(1-methylpiperidin-4-
272A, 272B
 92° C.



yloxy)methyl]-1H-benzimidazole


555
2-[(5-bromo-2-fluorophenyl)(1-methylpiperidin-4-
272A, 272B
232° C.



yloxy)methyl]-1H-benzimidazole


557
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
194, 189, 555
195° C.



yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine,



oxalate


558
5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-
194, 189,
 90° C.



methylpiperidin-4-yloxy)methyl]phenyl}pent-4-
272A, 272B



ynylamine


560
ethyl (5-{3-[(1H-benzimidazol-2-yl)(1-
549, 442
 87° C.



methylpiperidin-4-yloxy)methyl]-4-



fluorophenyl}pent-4-ynyl)carbamate


569
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
185° C.



yloxy)methyl]-4-chlorophenol


570
ethyl (5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-
189, 272A,
 95° C.



yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-
272B



ynyl)carbamate


571
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
132° C.



yloxy)methyl]-4-trifluoromethoxyphenol


572
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
142° C.



yloxy)methyl]-4-fluorophenol


573
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
1A, 561B
146° C.



yloxy)methyl]-4-methoxyphenol


574
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
1A, 561B
145° C.



yloxy)methyl]-5-methylphenol


575
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
145° C.



yloxy)methyl]-4-bromophenol


576
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
213° C.



yloxy)methyl]-4-ethoxyphenol


577
2-[(1H-indol-7-yl)(1-methylpiperidin-4-yloxy)methyl]-
550A, 1A,
110° C.



1H-benzimidazole
272B


579
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
142° C.



yloxy)methyl]-4,6-difluorophenol


580
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
161° C.



yloxy)methyl]-4,6-dichlorophenol


581
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
145° C.



yloxy)methyl]-6-fluorophenol


582
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
129° C.



yloxy)methyl]-3-fluorophenol


583
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
198° C.



yloxy)methyl]-4,5-difluorophenol


584
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
140° C.



yloxy)methyl]-5-fluorophenol


585
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
142° C.



yloxy)methyl]-5-chlorophenol


586
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
111° C.



yloxy)methyl]-6-methylphenol


587
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
138° C.



yloxy)methyl]-4-methylsulfanylphenol


588
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
116° C.



yloxy)methyl]-4-ethylsulfanylphenol


589
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
140° C.



yloxy)methyl]biphenyl-4-ol


590
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
139° C.



yloxy)methyl]-4-tert-butylphenol


591
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
120° C.



yloxy)methyl]-4-propylphenol


592
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
112° C.



yloxy)methyl]-6-methoxyphenol


593
2-[(1H-benzimidazol-2-yl)(1-methy-piperidin-4-
578
136° C.



yloxy)methyl]-3-fluoro-5-methylphenol


594
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
145° C.



yloxy)methyl]-3-chlorophenol


595
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
144° C.



yloxy)methyl]-6-fluoro-4-methylphenol


596
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
120° C.



yloxy)methyl]-4-benzylphenol


598
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
135° C.



yloxy)methyl]-4-trifluoromethylphenol


599
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
146° C.



yloxy)methyl]-4-chloro-6-fluorophenol


600
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
146° C.



yloxy)methyl]-5-fluoro-3-methylphenol


601
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
148° C.



yloxy)methyl]-2-fluoro-3-methylphenol


602
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
152° C.



yloxy)methyl]indan-5-ol


603
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
120° C.



yloxy)methyl]-4-propoxyphenol


604
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
130° C.



yloxy)methyl]-4-(1-methyl-1-phenylethyl)phenol


605
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
222° C.



yloxy)methyl]-4-(2-fluoroethoxy)phenol


606
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
114° C.



yloxy)methyl]-4-(3-fluoropropoxy)phenol


607
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
111° C.



yloxy)methyl]-4-fluoro-6-methylphenol


608
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
132° C.



yloxy)methyl]-6-fluoro-4-methoxyphenol


609
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
140° C.



yloxy)methyl]-4-phenoxyphenol


610
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
108° C.



yloxy)methyl]-4-fluoro-6-methoxyphenol


611
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
139° C.



yloxy)methyl]-4,5-dimethylphenol


612
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
128° C.



yloxy)methyl]-4-(3-fluoropropylsulfanyl)phenol


613
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
1A, 561B
102° C.



yloxy)methyl]-4-fluoro-5-methylphenol


614
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
127° C.



yloxy)methyl]-4-(2-fluoroethylsulfanyl)phenol


615
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
129° C.



yloxy)methyl]-2-hydroxybiphenyl


616
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
105° C.



yloxy)methyl]-6-ethylphenol


617
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
272A, 561B
144° C.



yloxy)methyl]-5-trifluoromethylphenol


618
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
1A, 561B
189° C.



yloxy)methyl]-4-hydroxyphenol


619
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
125° C.



yloxy)methyl]-5,6,7,8-tetrahydro-1-naphthol


620
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
126° C.



yloxy)methyl]-6-trifluoromethoxyphenol


621
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
133° C.



yloxy)methyl]-5-trifluoromethoxyphenol


622
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
163° C.



yloxy)methyl]-2-fluoro-3,4-dimethylphenol


623
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
 97° C.



yloxy)methyl]-3-fluoro-2-methylphenol


624
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
146° C.



yloxy)methyl]-2,4-difluoro-3-methylphenol


625
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
578
184° C.



yloxy)methyl]-2,3-difluorophenol









Further examples can be prepared according to the described general methods:















General



Example
Product
methods
TLC







450
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-
165C, 249,
0.22(A)



yloxy)methyl]phenyl}-azetidin-3-
423B



yl)dimethylamine, oxalate


452
1-{3-[(1H-benzimidazol-2-yl)(1-
423B
0.18(D)



methylpiperidin-4-



yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate


461
2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-
272A, 272B,
0.04(D)



yloxy)phenyl]methyl}-1H-benzimidazole,
258



dioxalate


496
2-[(5-chloro-2-fluorophenyl)(1-
272A, 272B
0.14(B)



methylpiperidin-4-yloxy)methyl]-1H-



benzimidazole, oxalate


498
2-[(2-fluoro-5-trifluoromethylphenyl)(1-
272A, 272B
0.25(A)



methylpiperidin-4-yloxy)methyl]-1H-



benzimidazole, oxalate


503
6-{3-[(1-ethyl-1H-benzimidazol-2-yl)(1-
194, 189,
0.08(E)



methylpiperidin-4-yloxy)methyl]phenyl}hex-5-
472



ynylamine, oxalate


504
2-[(2-fluoro-5-methoxyphenyl)(1-
165C, 449A
0.33(E)



methylpyrrolidin-3-ylmethoxy)methyl]-1H-



benzimidazole, oxalate


517
2-[(1-methylpiperidin-4-yloxy)(3-
272A, 272B
0.36(A)



trifluoromethylsulfanylphenyl)methyl]-1H-



benzimidazole, oxalate


518
2-[(4-fluoro-3-trifluoromethoxyphenyl)(1-
272A, 272B
0.32(A)



methylpiperidin-4-yloxy)methyl]-1H-



benzimidazole, oxalate


519
2-[(2-fluoro-5-propoxyphenyl)(1-
272A, 272B
0.33(A)



methylpiperidin-4-yloxy)methyl]-1H-



benzimidazole, oxalate


597
4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-
578
0.20(A)



4-yloxy)methyl]phenol





Eluent A: CH2Cl2/MeOH/NH4OH 90/10/0.5


Eluent B: CH2Cl2/MeOH/NH4OH 95/5/0.5


Eluent C: CH2Cl2/MeOH 90/10


Eluent D: CH2Cl2/MeOH/NH4OH 90/10/1


Eluent E: CH2Cl2/MeOH/NH4OH 80/20/0.5






Further examples can be prepared according to the described general methods:














General


Example
Product
methods







491
2-{[3-(3,3-difluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-
272A,



yloxy)methyl}-1H-benzimidazole, dioxalate
272B







1H NMR of the base (CDCl3): 9.90 (sl, 1H), 7.69 (sl, 1H), 7.18 (m, 3H), 6.86 (d, 1H), 6.64 (s,


1H), 6.43 (d, 1H), 5.80 (s, 1H), 3.65-3.35 (m, 5H), 2.67 (m, 2H), 2.38 (m, 3H), 2.22 (s, 3H),


2.20-1.60 (m, 5H)









492
2-{[3-(5-fluorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1-
423B



methylpiperidin-4-yloxy)methyl}benzothiazole, dioxalate







1H NMR of the base (CDCl3): 7.96 (d, 1H), 7.85 (d, 1H), 7.15-7.50 (m, 3H), 6.90 (d, 1H),


6.80 (s, 1H), 6.57 (d, 1H), 5.85 (s, 1H), 5.25 (d, 1H), 3.66 (m, 1H), 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).









451
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
432, 150



yloxy)methyl]phenylsulfanyl}hexylamine, oxalate







1H NMR (base): 7.65-7.48 (m, 2H), 7.43 (s, 1H), 7.30-7.15 (m, 5H), 5.85 (s, 1H),


3.60-3.45 (m, 1H), 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).









457
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
359B



yloxy)methyl]phenylsulfanylmethyl}oxazolidin-2-one







mp = 109° C.









458
N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278, 432,



yloxy)methyl]phenylsulfanyl}hexyl)guanidine, dihydrochloride
150







1H NMR (dmso-d6): 7.65-7.48 (m, 2H), 7.43 (s, 1H), 7.30-7.15 (m, 5H), 5.85 (s, 1H),


3.60-3.45 (m, 1H), 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).









473
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
437B,



yloxy)methyl]phenylsulfanyl}but-2-enylamine
359B,







MS, [M = H]+ = 423.2









474
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
437B,



yloxy)methyl]phenylsulfanyl}but-2-enylamine, oxalate
359B,


478
N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
401



yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine







MS, [M + H]+ = 509.2; [M + Na]+ = 531.1









488
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
437B, 53



yloxy)methyl]phenyl}allylamine







mp = 183° C.; MS, [M + H]+ = 377.3; [M + Na]+ = 399.1









494
cis-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
437B,



yloxy)methyl]phenylsulfanylmethyl}cyclopropylmethylamine
359B







mp = 99° C.; MS, [M + H]+ = 437.1; [M + Na]+ = 459.2









499
N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-
278,



yloxy)methyl]phenyl}allyl)guanidine, trihydrochloride
437B,




359B







MS, [M + H]+ = 419.2; [M + Na]+ = 441.3









502
2-[(azetidin-3-ylmethoxy)(3-bromophenyl)methyl]-1H-benzimidazole
210, 165D, E







mp = 104° C.









506
2-[(3-bromophenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-
165C,



benzimidazole
437B, 210,




165D, E







MS, 79Br [M + H]+ = 386.1; [M + Na]+ = 408.0; MS, 80Br [M + H]+ = 388.0; [M + Na]+ = 410.0









512
2-[(2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-
272A, 1B



benzimidazole



mp = 210° C.


513
2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-
272A, 1B



benzimidazole







mp = 85° C.









514
2-[(5-ethylsulfanyl-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-
150, 272A,



1H-benzimidazole
1B







mp = 90° C.









515
2-[(azetidin-3-ylmethoxy)(2-fluoro-5-trifluoromethoxyphenyl)methyl]-
165B, A,



1H-benzimidazole, oxalate
D, E







1H NMR (base): 7.57-7.62 (m, 2H), 7.38-7.52 (m, 1H), 7.25-7.11 (m, 4H), 6.07 (s, 1H),


3.99-3.90 (m, 2H), 3.80-3.74 (m, 2H), 3.64-3.51 (m, 2H), 2.88-3.00 (m, 1H).









516
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylazetidin-3-
165C, B,



ylmethoxy)methyl]-1H-benzimidazole, oxalate
A, D, E







1H NMR (base): 7.65-7.48 (m, 2H), 7.38-7.33 (m, 1H), 7.25-7.10 (m, 4H), 6.04 (s, 1H),


3.89-3.70 (m, 2H), 3.44-3.48 (m, 1H), 3.32-3.38 (m, 3H), 2.52-2.76 (m, 1H), 2.44 (m, 3H)









520
2-[(3-ethylsulfanyl-2,6-difluorophenyl)(1-methylpiperidin-4-
150, 272A,



yloxy)methyl]-1H-benzimidazole
1B







mp = 150° C.









521
2-[(2,2-difluorobenzo[1,3]dioxol-5-yl)(1-methylpiperidin-4-
272A, 1B



yloxy)methyl]-1H-benzimidazole







MS, [M + H]+ = 402.1









538
2-[(piperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole
165B, A,




D, E







1H NMR: 9.50 (sl, 1H), 7.75 (sl, 1H), 7.48 (sl, 1H), 7.38-7.22 (m, 5H), 7.12-7.05 (m, 1H),


5.98 (s, 1H), 3.75-3.60 (m, 1H), 3.20-3.05 (m, 2H), 2.72-2.55 (m, 2H), 2.10-1.85 (m, 2H),


1.70-1.45 (m, 2H)









539
2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole
165C, B,




A, D, E







MS, [M + H]+ = 328.03









544
2-[(piperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole
165B, A,




D, E







mp = 185° C.









546
2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole
165C, B,




A, D, E







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 300 g 15 minutes at 4° C. Pellets are resuspended in buffer I Tris-HCl 50 mM, MgCl2 10 mM, NaCl 140 mM, pH=7.4 supplemented by Leupeptin 10 μg/mL, Phenyl Methyl Sulphonyl Fluoride (PMSF) 0.1 mM, Aprotinin 2 μg/mL and Pepstatin 2 μM (or a 1/50 dilution of a mix of protease inhibitors). The obtained suspension is stirred gently and submitted to a 25-26×g mechanic pressure exerted through a syringe. The cell lysate is then centrifuged at 300 g 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.

    
    
        GTPγ [35S] Binding
    
    


Defreezed membranes are diluted at a final concentration of 5 μg/180 μL/well in buffer I supplemented by GDP 10 μM and distributed in 96 well polystyrene microplate. GTPγ [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 μl wash to stop the reaction.
The filter-bound radioactivity is measured in a liquid scintillation counter Microbeta TRILUX® with 50 μl of scintillation fluid.
GTPγ [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 300 g 15 minutes at 4° C. Pellets were resuspended in buffer I Tris-HCl 50 mM, MgCl2 10 mM, NaCl 140 mM, 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 25-26×g mechanic pressure exerted through a syringe. The cell lysate is then centrifuged at 300 g 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 20 μg/180 μL/well in a binding buffer containing 50 mM Tris/HCl, 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 μM 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 μl of ice cold incubation binding buffer.
The filter-bound radioactivity was measured in a liquid scintillation counter Microbeta TRILUX® with 50 μl 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 described hereabove have been evaluated in the GTPγ [35S] assay or in the [3H] histamine binding assay and have been found active with a Ki or IC50 under 1000 nM.














Example
Activity



















1
B



2
A



3
B



4
A



5
B



6
B



7
B



8
C



9
C



10
C



11
C



12
B



13
B



14
A



15
B



16
C



17
A



18
B



19
B



20
B



21
B



22
C



23
C



24
A



25
C



26
C



27
C



28
B



29
A



30
B



31
C



32
B



33
B



34
B



35
A



36
B



37
A



38
B



39
B



40
C



41
C



42
C



43
B



44
A



45
C



46
B



47
C



48
B



49
A



50
C



51
C



52
A



53
B



54
B



55
C



56
B



57
C



58
B



59
C



60
C



61
C



62
C



63
B



64
A



65
C



66
A



67
C



68
B



69
C



70
B



71
B



73
B



74
B



75
C



76
B



77
B



78
B



79
B



80
B



81
B



82
B



83
B



84
A



85
B



86
B



87
B



88
C



89
B



90
B



91
C



92
B



93
B



94
C



95
C



96
B



97
B



98
B



99
B



100
B



101
C



102
C



103
B



104
C



105
C



106
B



107
C



108
B



109
B



110
B



111
C



112
A



113
C



114
B



115
B



116
B



117
C



118
C



119
B



120
A



121
B



122
B



123
A



124
C



125
C



126
B



127
B



128
B



129
C



130
B



131
B



132
B



133
B



134
B



135
B



136
B



137
B



138
B



139
C



140
B



141
B



142
B



143
B



144
C



145
B



146
B



147
B



148
B



149
C



150
B



151
B



152
C



153
C



154
B



155
B



156
C



157
B



158
C



159
C



160
C



161
C



162
C



163
C



164
B



165
B



166
C



167
C



168
B



169
A



170
B



171
C



172
B



173
B



174
B



175
B



176
C



177
B



178
B



179
B



180
C



181
C



182
C



183
B



184
B



185
C



186
A



187
C



188
C



189
B



190
B



191
B



192
B



193
B



194
B



195
B



196
C



197
C



198
C



199
B



200
B



201
C



202
C



203
A



204
B



205
A



206
B



207
A



208
B



209
B



210
A



211
B



212
A



213
B



214
B



215
B



216
B



217
B



218
C



219
A



220
C



221
B



222
B



223
B



224
B



225
B



226
B



227
C



228
C



229
C



231
B



232
A



233
B



234
B



235
A



236
B



237
B



238
A



239
A



240
B



241
B



242
A



243
B



244
B



245
B



246
B



247
B



248
B



249
B



250
B



251
A



252
A



253
C



254
C



255
C



256
C



257
A



258
B



259
B



260
C



261
B



262
B



263
A



264
B



265
B



266
B



267
C



268
B



269
C



270
A



271
C



272
A



273
A



274
B



275
B



276
C



277
B



278
C



279
A



280
B



281
A



282
A



283
C



284
B



285
A



286
B



287
C



288
A



289
C



290
B



291
B



292
B



293
B



294
C



295
B



296
B



297
B



298
A



299
A



300
B



301
C



302
C



303
B



304
C



305
C



306
B



307
A



308
B



309
B



310
B



311
B



312
B



313
B



314
C



315
A



316
B



317
A



318
C



319
C



320
C



321
C



322
A



323
A



324
B



325
C



326
C



327
B



328
C



330
B



331
B



332
A



333
B



334
B



335
B



336
B



337
C



338
B



339
B



340
C



341
B



342
B



343
B



344
B



345
B



346
B



347
A



348
A



349
B



350
A



351
A



352
B



353
B



354
C



355
B



356
A



357
B



358
C



359
C



360
A



361
A



362
A



363
B



364
A



365
B



366
C



367
B



368
C



369
A



370
A



371
C



372
C



373
C



374
C



375
A



376
A



377
B



378
A



379
A



380
B



381
C



382
C



383
B



384
B



385
B



386
C



387
C



388
A



389
B



390
C



391
A



392
A



393
C



394
A



395
B



396
A



397
B



398
B



399
B



400
C



401
B



402
B



403
B



404
B



405
B



406
C



407
C



408
B



409
B



410
B



411
A



412
A



413
B



414
B



415
B



416
B



417
A



418
C



419
A



421
C



422
C



423
B



424
B



425
C



426
B



427
B



428
B



429
B



430
C



431
C



433
C



435
C



436
C



437
C



438
C



439
C



440
C



441
C



442
C



443
C



444
B



445
B



446
B



447
A



448
B



449
C



450
A



451
B



452
B



453
C



454
C



455
C



456
A



457
C



458
B



459
C



460
A



461
B



462
B



463
A



464
C



465
C



466
C



467
C



468
B



469
A



470
B



471
B



472
B



473
C



474
C



475
B



476
C



477
A



478
B



479
C



480
B



481
A



482
C



483
B



484
C



485
A



486
C



487
C



488
A



489
C



490
B



491
A



492
A



493
C



494
C



495
C



496
B



497
A



498
B



499
C



500
B



501
B



502
A



503
B



504
C



505
A



506
B



507
C



508
C



509
C



510
B



511
B



512
C



513
C



514
C



515
A



516
B



517
C



518
A



519
C



520
B



521
A



522
C



523
C



524
B



525
B



526
C



527
C



528
B



529
B



530
A



531
C



532
B



533
C



534
B



535
B



536
C



537
A



538
A



539
B



540
B



541
C



542
C



543
C



544
A



545
B



546
B



547
A



548
C



549
A



550
C



551
B



552
B



553
A



554
B



555
C



556
C



557
C



558
C



559
C



560
B



561
C



562
C



563
B



564
C



565
B



566
C



567
B



568
C



569
C



570
B



571
C



572
C



573
B



574
C



575
C



576
C



577
B



578
C



579
A



580
A



581
C



582
C



583
B



584
C



585
C



586
C



587
C



588
C



589
A



590
A



591
B



592
B



593
C



594
C



595
B



596
C



597
A



598
B



599
B



600
C



601
C



602
B



603
B



604
B



605
C



606
B



607
A



608
B



609
B



610
A



611
C



612
C



613
C



614
C



615
B



616
C



617
C



618
C



619
B



620
C



621
C



622
B



623
C



624
C



625
C



627
C







A: Ki or IC50 <1000 nM



B: Ki or IC50 <300 nM



C: Ki or IC50 <30 nM

## Claims

1. A combination of a compound of formula (I) and one or more therapeutic agent(s),
wherein said compound of formula (I) being:




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), phthalimido, 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, cyanoalkyl, 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; and
wherein said one or more therapeutic agent(s) selected from the group consisting of:
Histamine H1, H2 or H3 receptor antagonists,
Leukotriene antagonists,
5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists
CX1- and α2-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, and
mucolytics or anti-tussive agents.

2. The combination according to claim 1, wherein the H1 receptor antagonist is selected from the group consisting of cetirizine, desloratadine, bepotastine and doxepin.

3. The combination according to claim 1, 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, alkoxycarbonylheterocyclyl, 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), phthalimido, 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.

4. The combination according to claim 1, wherein X represents NH or S.

5. The combination according to claim 1, wherein HetAr is phenyl.

6. The combination according to claim 1, wherein R represents methyl.

7. The combination according to claim 1, wherein B represents a single bond.

8. The combination according to claim 1, 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), phthalimido, 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.

9. The combination according to claim 1, wherein the compound of formula (I) is 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-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-methylpiperidin-4-yloxy)(3-phenoxy-phenyl)methyl]benzothiazole
5-methyl-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole
2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazole
2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylphenyl)methyl]benzothiazole
2-[(2,3-dihydrobenzofuran-5-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole
2-[(4-fluoro-3-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
[benzothiazol-2-yl(4-fluoro-3-methyl-phenyl)methyl](1-methylpiperidin-4-yl)amine
(benzothiazol-2-yl-p-tolylmethyl)(1-methylpiperidin-4-yl)amine
[(benzofuran-2-yl)(benzothiazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
2-[(3-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
[(1H-benzimidazol-2-yl)phenylmethyl](1-methylpiperidin-4-yl)amine
2-[(3-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[benzothiazol-2-yl(3-fluoro-5-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[benzothiazol-2-yl(3-fluoro-5-methylphenyl)methyl](1-methylpiperidin-4-yl)amine
2-[(3-benzyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[benzofuran-5-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(3-ethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
[benzothiazol-2-yl(3-iodophenyl)methyl](1-methylpiperidin-4-yl)amine
2-[(1-methylpiperidin-4-yloxy)(3-propoxyphenyl)methyl]-1H-benzimidazole
[(1H-benzimidazol-2-yl)(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
(benzothiazol-2-ylpyridin-3-ylmethyl)(1-methylpiperidin-4-yl)amine
2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole
{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxymethyl]biphenyl-3-yl}methanol
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
[benzothiazol-2-yl(1H-pyrrol-2-yl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-trifluoromethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-ethylphenyl)methyl](1-methylpiperidin-4-yl)amine
3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol
2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]benzothiazole
[(1H-benzimidazol-2-yl)(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-isopropylphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-isobutoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(3-methylbutoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester
trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester
[(1H-benzimidazol-2-yl)(3-cyclohexyl methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-fluorophenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-hexylphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine
2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
[benzothiazol-2-yl(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-ethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-phenoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}methanol
3′-[(1H-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]-1H-benzimidazole
1-{3-[(1H-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
[benzothiazol-2-yl(3-cyclohexylmethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)biphenyl-3-ylmethyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-pentyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
2-[(2′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1-methylpiperidin-4-yloxy)(3′-nitrobiphenyl-3-yl)methyl]benzothiazole
{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}acetonitrile
2-[(3′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
[benzothiazol-2-yl(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
(benzothiazol-2-ylbiphenyl-3-ylmethyl)(1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(4-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(3-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(2-phenoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
[benzothiazol-2-yl(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine
1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}ethanone
2-[(3′-fluoro-biphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}ethanone
[benzothiazol-2-yl(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine
[(3-allyloxyphenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
2-[(1-methylpiperidin-4-yloxy)(2′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole
2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole
2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]-1H-benzimidazole
{(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
2-[(2′-chlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol
{(1H-benzimidazol-2-yl)[3-(4-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(3-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol
{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol
2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]benzothiazole
{(1H-benzimidazol-2-yl)[3-(2-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(4-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1-methylpiperidin-4-yl)amine
[(3-azidophenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
{(1H-benzimidazol-2-yl)[3-(2-ethoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-pent-4-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamic acid tert-butyl ester
2-[(3′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]benzothiazole
2-[(1-methylpiperidin-4-yloxy)(2′,3′,4′-trifluorobiphenyl-3-yl)methyl]benzothiazole
2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamic acid tert-butyl ester
[(1H-benzimidazol-2-yl)(3-furan-2-ylphenyl)methyl](1-methylpiperidin-4-yl)amine
[(1H-benzimidazol-2-yl)(3-but-3-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(4-methylpentyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
2-[(1-methylpiperidin-4-yloxy)(3-pyrazol-1-ylphenyl)methyl]benzothiazole
2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
{(1H-benzimidazol-2-yl)[3-(2,5-difluoro-benzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(3-ethylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid methyl ester
2-[(3-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2[[3-(2,5-difluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-{3-[(1H-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-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]-1H-benzimidazole
5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole
5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole
2-[(2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole
2[[3-(3-fluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile
2[[3-(furan-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
((1H-benzimidazol-2-yl)-{3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine
{(1H-benzimidazol-2-yl)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
2[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(3,3,3-trifluoro-propoxy)phenyl]methyl}benzothiazole
2-[(4-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
{(1H-benzimidazol-2-yl)[3-(2-fluoro-ethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine
((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)ethoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine
2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethoxy-biphenyl-3-yl)methyl]-1H-benzimidazole
2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(3-benzo[1,3]dioxol-5-ylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2[[3-(3-methoxybenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentan-2-one
2-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl-benzyloxy)phenyl]methyl}benzothiazole
4-[benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1,1-dimethylpiperidinium
2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol
2-[(1-methylpiperidin-4-yloxy)-o-tolyl-methyl]-1H-benzimidazole
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine
2-[(3-ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)phenyl]methyl}benzothiazole
3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzonitrile
2-{(1-methylpiperidin-4-yloxy)[3-(1H-[1,2,3]triazol-4-yl)phenyl]methyl}-1H-benzimidazole
3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]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]-1H-benzimidazole
2-[(3-methanesulfonylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(4-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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]-1H-benzimidazole
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrimidin-2-ol
2-[(3-tert-butylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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]-N-benzyl-N-methylbenzamide
3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-propylbenzamide
2-[(2,4-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
[(1H-benzimidazol-2-yl)(4′-methoxy-biphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine
3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-methyl-N-phenylbenzamide
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine
2-[(3-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(4-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol
2-[(3-azidophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole
{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butan-1-ol
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-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]-1H-benzimidazole
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1-ol
1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2-ol
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol
2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine
2-{(1-methylpiperidin-4-yloxy)[3-(2-methylsulfanyl-ethoxy)phenyl]methyl}benzothiazole
2-[(1-methylpiperidin-4-yloxy)(2-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole
2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole
2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-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-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol
2-(1-{3-[(1H-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-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-N-methylacetamide
2-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole
2-[(3-bromo-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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-methylpiperidin-4-yloxy)[3-(pyridin-4-ylmethoxy)phenyl]methyl}benzothiazole
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butan-1-ol
2[[3-(furan-2-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzyloxy}propan-2-one
2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine
2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole
[(1H-benzimidazol-2-yl)-p-tolyl-methyl](1-methylpiperidin-4-yl)amine
2-[(3-ethylsulfanyl-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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-methoxyethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine
(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)methyl-amine
2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole
2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine
2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}benzothiazole
2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-ylmethoxy)phenyl]methyl}benzothiazole
2-[(3-Cyclohexylmethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propane-1,2-diol
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamine
2-{3-[benzothiazol-2-yl(1-ethyl-piperidin-4-yloxy)methyl]phenoxy}ethylamine
2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine
6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine
2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-urea
(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-thiazol-2-yl)amine
2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamine
N-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propylamine
N-tert-butoxycarbonyl-N′-(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-methyl-1H-imidazol4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]benzothiazole
N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine
N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine
N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine
2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}-1H-benzimidazole
3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamine
N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-1H-imidazol-2-yl)amine
N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N′-cyanoguanidine
6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine
N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine
N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine
2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}benzothiazole
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol
6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamine
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine
4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid tert-butyl ester
4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid tert-butyl ester
2-{(1-methylpiperidin-4-yloxy)[3-(2-piperazin-1-yl-ethoxy)phenyl]methyl}benzothiazole
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamine
2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(4-piperidin-1-yl-butoxy)phenyl]methyl}-1H-benzimidazole
2-[(2-fluoro-3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
N-tert-butoxycarbonyl-N′-(-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine
N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine
2-{(1-methylpiperidin-4-yloxy)[3-(1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1H-benzimidazole
N-tert-butoxycarbonyl-N′-(5-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-5-ynyl)guanidine
N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine
N-tert-butoxycarbonyl-N′-(6-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine
N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine
4-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butyl)piperazine-1-carboxylic acid tert-butyl ester
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamine
N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine
N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine
1-(2-{3-[(1H-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-methylpiperidin-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 tert-butyl ester
2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-phenylsulfanyl}ethylamine
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxamidine
2[[3-(2-chloroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine
2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-1-yl-ethoxy)phenyl]methyl}-1H-benzimidazole
N-tert-butoxycarbonyl-N′-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine
N-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine
4-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic acid tert-butyl ester
(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)acetic acid tert-butyl ester
4-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic acid tert-butyl ester
N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine
N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine
N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine
[[3-(4-aminobutoxy)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propylamine
4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic acid tert-butyl ester
(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)acetic acid tert-butyl ester
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamine
N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine
N-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine
N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine
(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamino)acetic acid tert-butyl ester
2-[(1-methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-ylmethoxy)phenyl]methyl}benzothiazole
2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-3-ylmethoxy)phenyl]methyl}benzothiazole
2-[[3-(1-methylpiperidin-3-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
2-[(1-methylpiperidin-4-yloxy)(3-piperidin-3-ylethynyl-phenyl)methyl]-1H-benzimidazole
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine
2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole
2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol
3-amino-4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione
[[3-(6-aminohex-1-ynyl)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine
{[3-(4-aminobutoxy)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine
2-[(3-azetidin-3-ylethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol
5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol
4-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic acid tert-butyl ester
2-[[3-(2-azetidin-3-ylethyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidine-1-carboxamidine
2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-4-yl-ethyl)phenyl]methyl}-1H-benzimidazole
N-(5-{3-[(1H-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]-1H-benzimidazole
N-tert-butoxycarbonyl-W-(4-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamine
N-acetyl-N′-(2-{3-[(1H-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-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}azetidin-3-ol
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methanol
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ylamine
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol
N-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)acetamide
2[[3-(5-imidazol-1-ylpent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(5-pyrazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol
2-[{3-[2-(1H-imidazol-4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
acetic acid 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-yl ester
2-[(3-bromo-phenyl)(1-methyl-pyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-yloxy)phenyl]methyl}benzothiazole
2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-2-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole
N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine
N1-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)butane-1,4-diamine
{[3-(6-aminohex-1-ynyl)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-en-1-ol
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine
2-[(2,5-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2-fluoro-5-iodo-phenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylethynyl}azetidine-1-carboxamidine
4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol
2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine
2-[[3-(3-fluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-enylamine
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (enantiomer A)
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (enantiomer B)
N-(2-aminoethyl)-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide
N-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine
2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione
6-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine oxalate
4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine oxalate
N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propyl)guanidine, dihydrochloride
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-one, oxalate
N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)guanidine, dihydrochloride
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-ol
N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-(2,2-dimethylpropionyl)guanidine
2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-benzimidazole
2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl}benzothiazole, oxalate
2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1H-benzimidazole, oxalate
4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline
4-[(1H-benzimidazol-2-yl)(piperidin-4-yloxy)methyl]aniline, hydrochloride
N-(2-amino-ethyl)-2-{3-[(5-fluoro-1H-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-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1H-benzimidazole
2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole, dioxalate
2-amino-5-{3-[(1H-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-1H-benzimidazole
1-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, dioxalate
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde
4-{3-[(1H-benzimidazol-2-yl)(1-methylazetidin-3-ylmethoxy)methyl]phenylsulfanyl}butylamine, oxalate
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole, oxalate
{3-[(1H-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]-1H-benzimidazole, enantiomer B
2-[(2,6-difluoro-3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
ethyl (6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate, oxalate
2-[(1H-indol-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
2-[benzo[b]thiophen-6-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, enantiomer B
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol
2-[(1H-benzimidazol-2-yl)hydroxymethyl]phenol
2-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol
5-(6-{3-[(1H-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]-1H-benzimidazole, enantiomer B
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine, enantiomer A
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine, enantiomer B
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole, enantiomer A
2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole, enantiomer B
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer A
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol enantiomer A
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol enantiomer B
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol enantiomer A
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol enantiomer B
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-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-1H-benzimidazol-2-yl)(1-methylpyrrolidin-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-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methylamine, dioxalate
4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-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-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, oxalate
4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}cyclohexylamine, oxalate
6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine, dioxalate
1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-ylmethylamine, oxalate
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)(methyl)amine, oxalate
(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]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-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol, oxalate
2-{[2-fluoro-5-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, oxalate
2-[(2-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
4-{3-[(1-methylpiperidin-4-yloxy)(5,6,7-trifluoro-1H-benzimidazol-2-yl)methyl]phenylsulfanyl}butylamine, oxalate
4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine, oxalate
6-(3-{[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine, dioxalate
6-(3-{[1-(2-methoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine, dioxalate
2-{[3-(3-fluoropropylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, dioxalate
5-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
4,5,6-trifluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
5,6-difluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1 H-benzimidazole
2-{[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole
2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2-chloro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate
2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
7-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate
2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate
2-[(3-ethoxy-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole, oxalate
2-[(1-methylpiperidin-4-yloxy)(4-trifluoromethylphenyl)methyl]-1H-benzimidazole
2-[(2-fluoro-4-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2,4-dimethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[chroman-7-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole, oxalate
2-[(3,5-bis-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
5-fluoro-2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2,3-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(3-chloro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-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]-1H-benzimidazole
2-[(5-bromo-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate
5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine
ethyl (5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}pent-4-ynyl)carbamate
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chlorophenol
ethyl (5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)carbamate
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethoxyphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methoxyphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-methylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-bromophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethoxyphenol
2-[(1H-indol-7-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-difluorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-dichlorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-difluorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-chlorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylsulfanylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethylsulfanylphenol
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-ol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-tert-butyl phenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methoxyphenol
2-[(1H-benzimidazol-2-yl)(1-methy-piperidin-4-yloxy)methyl]-3-fluoro-5-methylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-chlorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-ethylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-benzylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chloro-6-fluorophenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-3-methylphenol
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]indan-5-ol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propoxyphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(1-methyl-1-phenylethyl)phenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethoxy)phenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropoxy)phenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-methoxyphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-phenoxyphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methoxyphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-dimethylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropylsulfanyl)phenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-5-methylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethylsulfanyl)phenol
3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-hydroxybiphenyl
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-ethylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethylphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-hydroxyphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7,8-tetrahydro-1-naphthol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-trifluoromethoxyphenol
2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethoxyphenol
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3,4-dimethylphenol
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluoro-2-methylphenol
6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,4-difluoro-3-methylphenol
6-[(1H-benzimidazol-2-yl)(1-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-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate
2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}-1H-benzimidazole, dioxalate
2-[(5-chloro-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
2-[(2-fluoro-5-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
6-{3-[(1-ethyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine, oxalate
2-[(2-fluoro-5-methoxyphenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole, oxalate
2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylsulfanylphenyl)methyl]-1H-benzimidazole, oxalate
2-[(4-fluoro-3-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
2-[(2-fluoro-5-propoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate
4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol
2-{[3-(3,3-difluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, dioxalate
2-{[3-(5-fluorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole, dioxalate
6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexylamine, oxalate
5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}oxazolidin-2-one
N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexyl)guanidine, dihydrochloride
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine
4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine, oxalate
N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine
3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allylamine
cis-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropylmethylamine
N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allyl)guanidine, trihydrochloride
2-[(azetidin-3-ylmethoxy)(3-bromophenyl)methyl]-1H-benzimidazole
2-[(3-bromophenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole
2-[(2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(5-ethylsulfanyl-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(azetidin-3-ylmethoxy)(2-fluoro-5-trifluoromethoxyphenyl)methyl]-1H-benzimidazole, oxalate
2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole, oxalate
2-[(3-ethylsulfanyl-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(2,2-difluorobenzo[1,3]dioxol-5-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole
2-[(piperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole
2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole
2-[(piperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole
2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole
as well as their enantiomers, diastereomers, mixtures thereof and pharmaceutically acceptable salts, free forms, tautomers, hydrates and solvates.