3-OR 4-Monosubstituted phenol and thiophenolderivatives useful as H3 ligands
The present invention relates to 3- or 4-monosubstituted phenol and thiophenol derivatives of general formula : in which R, X, Y, Z, m and p have the meanings indicated below, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. Histamine H3 receptors are found inter alia on presynaptic terminals of peripheral nerves, where they modulate autonomic neurotransmission and modulate a variety of end organ responses under control of the autonomic nervous system. They are also heteroreceptors, modulating the release of numerous other neurotransmitters such as dopamine, glutamate, noradrenaline, serotonin, GABA, acetylcholine, some peptides and co-transmitters. Recently numerous histamine H3 receptor ligands have been developed. An overview of the current advance in H3 ligand research and patenting is given in H3 receptor ligands are believed to be suitable for the treatment of various diseases including both disorders of the central nervous system and inflammatory disorders. Examples of diseases where treatment with H3 ligands is believed to be useful are inflammatory bowel disease, Crohn's disease, colitis ulcerosa, sleep disorders, migraine, dyskinesia, stress-induced anxiety, psychotic disorders, epilepsy, Cognition deficiency diseases such as Alzheimer's disease or mild coginitive impairment, depression, mood disorders, schizophrenia, anxiety disorders, attention-deficit hyperactivity disorder (ADHD), psychotic disorders, obesity, dizziness, epilepsy, motion sickness, vertigo, respiratory diseases such as 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, nasal congestion and allergic congestion. Although H3 ligands are known there is still a need to provide new H3 ligands that are good drug candidates. In particular, preferred compounds should bind potently to the histamine H3 receptor whilst showing little affinity for other receptors. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favourable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects. In this context, the present invention concerns new substituted phenol and thiophenol derivatives of general formula (1) : or a pharmaceutically acceptable salt and/or thereof wherein : It has been found that these compounds are H3 ligands and are thus particularly useful for the treatment of H3-related diseases such as neurologic disorders, or inflammatory, respiratory and allergic diseases, disorders and conditions. In the present description the following definitions are used, unless otherwise specified. "halo" denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo. "(C1-Cx)alkyl" denotes a saturated, straight-chain or branched hydrocarbon group having from 1 to x carbon atoms and includes for example (when x= 4) methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl and further (when x=6) pentyl, I-pentyl, n-pentyl and hexyl. This also applies if the alkyl group carries substituents or is a substituent for another group, e.g. in -S-(C1-C4)alkyl, -O-(C1-C4)alkyl, - SO2-(C1-C4)alkyl, -SO-(C1-C4)alkyl, -CH2-O-(C1-C4)alkyl, -C(O)O(C1-C4)alkyl, (C1-C4)alkylamino, [(C1-C4)alkyl]2amino, -(C1-C4)alkyl-phenyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, -C(O)(C1-C4)alkyl. "(C1-C4)alkoxy" denotes straight-chain and branched alkoxy groups and includes for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. "(C2-C6)alkylene" denotes a divalent radical derived from straight-chain or branched alkane containing from 2 to 6 carbon atoms. Examples of (C2-C6)alkylene radicals are methylene, ethylene (1,2-ethylene or 1,1-ethylene), trimethylene (1,3-propylene), tetramethylene (1,4-butylene), pentamethylene and hexamethylene. "hydroxy(C1-C4)alkyl" radicals are alkyl radicals substituted by hydroxy. They can contain 1 or several hydroxy substituents, if not stated otherwise. Examples of suitable hydroxy(C1-C4)alkyl radicals are hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl. "(C3-C6)cycloalkyl" denotes a saturated monocyclic carbocyclic group having 3 to 6 carbon atoms and includes for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In the case where the (C1-Cx)alkyl radicals are substituted by halo, such radical can contain 1 or several halogen atoms, if not stated otherwise. Said halo is preferably a fluoro, a chloro, a bromo or a iodo, in particular fluoro or chloro. For example in a fluoro-substituted alkyl radical, a methyl group can be present as a difluoromethyl or a trifluoromethyl group. "saturated heterocycle" denotes a saturated monocyclic group having 4 to 7 ring members, which contains 1 nitrogen atom and optionally a further heteroatom selected from nitrogen, oxygen and sulphur. Examples of saturated heterocycles are azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazepanyl and azepanyl. het1 and het2 are monocyclic or bicyclic heteroaromatic groups having 5 to 10 ring members, which contain 1, 2, 3 or 4 heteroatom(s) selected from nitrogen, oxygen and sulphur. In particular the heteroaromatic group contains either (a) 1 to 4 nitrogen atoms, (b) one oxygen atom or one sulfur atom or (c) 1 oxygen atom or 1 sulfur atom and 1 or 2 nitrogen atoms. het2 is preferably C-linked, which means that the group is linked to the adjacent atom by a ring carbon atom. het1 can be C-linked or N-linked. The heteroaryl group can be unsubstituted, monosubstituted or disubstituted, as indicated in the definition of X and R2 hereabove for general formula (1) according to the present invention. Examples of heteroaryl groups include, but are not limited to thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiadiazinyl, isobenzofuranyl, benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolyl, cinnolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, pyrrolopyrazinyl, pyrrolopyridinyl, and imidazopyridinyl. Preferred definitions for het1 and het2 will follow hereafter. In the general formula (1) according to the present invention, when a radical is mono- or poly-substituted, said substituent(s) can be located at any desired position(s), unless otherwise stated. Also, when a radical is polysubstituted, said substituents can be identical or different, unless otherwise stated. According to a preferred aspect of the invention, X is selected from -CN, -CH2OH, -C(O)OH, -CH2-NR1R2, -C(O)NR3R4, -CH2-het1 and het1, het1 in both -CH2-het1 and het1 being optionally substituted once or twice by (C1-C4)alkyl, more preferably X is selected from -CH2-NR1R2, -CONR3R4, -CH2-het1 and het1, het1 in both -CH2-het1 and het1 being optionally substituted once or twice by (C1-C4)alkyl, wherein R1, R2, R3, R4 and het1 are as previously defined. het1 is preferably selected from a 5 or 6 membered monocyclic heteroaromatic group, or a 9 membered bicyclic heteroaromatic group, each heteroaromatic group containing 1 to 3 nitrogen atoms, or 1 to 2 nitrogen atoms and 1 oxygen atom, or 1 nitrogen atom and 1 sulphur atom, and each heteroaromatic group being optionally substituted once or twice by (C1-C4)alkyl, and preferably, optionally substituted once or twice by (C1-C2)alkyl. More preferably, X is thiazolyl, benzimidazolylmethyl-, pyridinyl, oxazolyl, imidazopyridinylmethyl-, pyrimidinyl, imidazolyl, imidazolylmethyl- or triazolylmethyl-, said thiazolyl, benzimidazolylmethyl-, pyridinyl, oxazolyl, imidazopyridinylmethyl-, pyrimidinyl, imidazolyl, imidazolylmethyl- and triazolylmethyl- each being optionally substituted with one methyl group. R1 is preferably hydrogen, methyl or ethyl. R2 is preferably selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted by one or two substituents independently selected from -S-(C1-C4)alkyl, -O-(C1-C4)alkyl, -SO2-(C1-C4)alkyl, and phenyl, said phenyl being optionally substituted by one or two substituents independently selected from halo, hydroxy, cyano, (C1-C4)alkyl and (C1-C4)alkoxy, (C3-C6)cycloalkyl, het2 optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl and (C1-C4)alkoxy, wherein het2 is defined as above, -SO2-R5 wherein R5 is selected from the group consisting of (C1-C4)alkyl, [(C1-C4)alkyl]2amino, phenyl, and -(C1-C4)alkyl-phenyl, wherein said phenyl is optionally substituted by 1 substituent independently selected from halo and cyano and -C(O)-R6 wherein R6 is selected from the group consisting of (C1-C4)alkyl, ((C1-C4)alkyl]2amino, amino, and -(C1-C4)alkyl-phenyl, said phenyl being optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl and (C1-C4)alkoxy. More preferably R2 is selected from the group consisting of (C1-C3)alkyl optionally substituted by -O-(C1-C3)alkyl, preferably methoxy, (C3-C5)cycloalkyl, het2, wherein het2 is preferably selected from the group consisting of 5 or 6 membered monocyclic heteroaromatic ring systems containing 1 to 2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulphur atom, said het2 being optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl and (C1-C4)alkoxy, preferably (C1-C4)alkyl, SO2-R5 wherein R5 is selected from the group consisting of (C1-C4)alkyl, [(C1-C4)alkyl]2amino, phenyl, and -(C1-C4)alkyl-phenyl, wherein said phenyl is optionally substituted by 1 substituent independently selected from halo and cyano and wherein R5 is preferably (C1-C4)alkyl, C(O)-R6 wherein R6 is selected from the group consisting of (C1-C4)alkyl, ((C1-C4)alkyl]2amino, amino, and -(C1-C4)alkyl-phenyl, said phenyl being optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl and (C1-C4)alkoxy, and wherein R6 is preferably (C1-C4)alkyl. In another aspect of the invention, R2 is preferably (C1-C3)alkyl optionally substituted by methoxy. het2 is preferably selected from the group consisting of 5 or 6 membered monocyclic heteroaromatic ring systems containing 1 or 2 nitrogen atoms. In another aspect of the invention, R2 is preferably a pyridazinyl group. According to a further preferred aspect of the invention R1 and R2 form together with the N atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocycle wherein one C atom may be replaced by N, O, S, SO or SO2 and wherein said saturated heterocycle is optionally substituted by one or two groups independently selected from hydroxy, halo, =O, (C1-C4)alkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, -SO2(C1-C4)alkyl, -C(O)(C1-C4)alkyl, [(C1-C4)alkyl]2amino, -C(O)NH2, C(O)O(C1-C4)alkyl and pyrrolidinone, more preferably R1 and R2 form together with the N atom to which they are attached a 5- or 6-membered saturated heterocycle selected from or optionally substituted by one or two groups independently selected from hydroxy, fluoro, hydroxymethyl, methoxymethyl, SO2(C1-C4)alkyl, -C(O)(C1-C4)alkyl, -CONH2, and pyrrolidinone. Even more preferably, R1 and R2 form together with the N atom to which they are attached a morpholinyl group. Preferably R3 and R4 are each independently selected from hydrogen and (C1-C4)alkyl or R3 and R4 form together with the N atom to which they are attached a 4, 5 or 6 membered saturated heterocycle wherein one C atom may be replaced by N or O and wherein said saturated heterocycle is optionally substituted by (C1-C4)alkyl. More preferably, R3 and R4 are selected independently from hydrogen, methyl and ethyl, or R3 and R4 form together with the N atom to which they are attached a pyrrolidinyl, piperidinyl, piperazinyl or azetidinyl ring, (each pyrrolidinyl, piperidinyl, piperazinyl and azetidinyl ring being optionally methyl substituted). Preferably, Y is selected from CH2, CH(OH), O and C=O, more preferably Y is O. Preferably, Z is O Preferably m is equal to 1 or 2 and p is equal to 2, more preferably m and p are both 2. In one preferred aspect of the invention R is a group of formula : wherein * represents the attachment point to Z, L is a (C2-C5)alkylene and R7 and R8 are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C1-C6)alkyl or R7 and R8 form together with the N atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocycle wherein one C atom is optionally replaced by N, O, S, SO or SO2 and wherein said saturated heterocycle is optionally substituted by one or two groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, C(O)O(C1-C4)alkyl, -C(O)-(C1-C4)alkyl-NH2, -C(O)NH2 and halo. Examples of the 4-, 5-, 6- or 7-membered saturated heterocycle are : or Even more preferably, R7 and R8 form together with the N atom to which they are attached a morpholinyl or oxazepanyl group. In another preferred aspect, R7 and R8 form together with the N atom to which they are attached a 4-, 5- or 6-membered saturated heterocycle, optionally substituted by one or two (C1-C4)alkyl, preferably methyl. In another more preferred aspect, the saturated heterocycle is a pyrrolidinyl group, optionally substituted by one or two methyl groups. Preferably, L is propylene. According to another preferred aspect of the invention R is a group of formula: wherein * represents the attachment point to Z, the N-containing ring is a 4- or 6-membered saturated heterocycle, n is an integer equal to 0 or 1, and R9 represents a substituent selected from hydrogen, C1-C4)alkyl and (C3-C6)cycloalkyl. Preferably, R9 is isopropyl or cyclobutyl. When one of the groups in the compound of formula (1) is substituted by halo, generally fluoro or chloro, in particular fluoro is preferred. Particularly preferred compounds of the invention include those in which each variable in formula (1) is selected from the suitable and/or preferred groups for each variable. Even more preferable compounds of the invention include those where each variable in formula (1) is selected from the more preferred or most preferred groups for each variable. According to a particular aspect of the invention the following compounds are excluded from the invention: compounds of formula (1), wherein Y is O, Z is O, R is a group of formula : wherein R10 is hydrogen or (C1-C4)alkyl, R11 is (C1-C4)alkoxy, hydroxy or N((C1-C4)alkyl)2 and X is -CN, - CH2OH, -CH2-O-(C1-C4)alkyl, -C(O)OH, -C(O)O(C1-C4)alkyl, -CONR3R4 or CH2NR1R2 wherein R1 is hydrogen or a (C1-C4)alkyl group and R2 is either hydrogen, (C1-C4)alkyl (optionally substituted by phenyl) or -C(O)(C1-C4)alkyl. In another emdodiment of the present invention, there is provided a compound of formula (1) selected from: Particularly preferred compounds of formula (1) are as described in the Examples section hereafter. Where the salt form is obtained in the Examples, a compound of the present invention includes the free base thereof, for example: In another embodiment of the invention, particularly preferred examples are: Pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see " Pharmaceutically acceptable salts of compounds of formula (1) may be prepared by one or more of three methods: All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see Hereinafter all references to compounds of formula (1) include references to salts, solvates and complexes thereof and to solvate and complexes of salts thereof. The compounds of the invention may also exist as polymorphs and crystal habits thereof, prodrugs and isomers (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (1). Certain compounds of formula (1) may themselves act as prodrugs of other compounds of formula (1). Metabolites of compounds of formula (1), may also be formed Compounds of formula (1) containing one or more asymmetric carbon atoms_can exist as two or more stereoisomers. Where structural isomers are interconvertible The compounds of the present invention may also exist as stereoisomers, geometric isomers and tautomeric forms and may exhibit more than one type of isomerism, and mixtures of one or more thereof. Acid addition or base salts wherein the counterion is optically active, for example, Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, " The compounds of the present invention may also exist as pharmaceutically acceptable isotopically-labelled compounds of formula (1) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and16N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulphur, such as35S. Certain isotopically-labelled compounds, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, Substitution with heavier isotopes such as deuterium, Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Position Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO. The phenol and thiophenol derivatives of formula (1) can be prepared using conventional procedures such as by the following illustrative methods in which R, X, Y, Z, m, p, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as previously defined unless otherwise stated. The compounds of formula (1), wherein X is -CH2NR1R2, may be prepared from compounds of formula (2) using standard techniques for functional group interconversion known to those skilled in the art, for example as described in These techniques include: These transformations can be performed sequentially to prepare compounds in which R1 and R2 are as here above defined. The compounds of formula (2) may be prepared by reduction of the corresponding cyano derivatives of formula (3) : with a suitable reducing agent (e.g. LiAlH4 or hydrogen gas in the presence of a catalyst such as PtO2) in a suitable solvent (e.g. Et2O/dichloromethane, tetrahydrofuran or isopropanol) at between room temperature and reflux. The compounds of formula (3) above correspond actually to the compounds of formula (1) wherein X is a CN group. The compounds of formula (3) wherein Z is O may be prepared by alkylation of the corresponding hydroxy derivatives of formula (4) : with a derivative of formula R-RLG wherein RLG is a leaving group such as halo, mesylate or tosylate, in the presence of a base (e.g. potassium carbonate) and optionally in the presence of an additive (e.g. potassium iodide) in a suitable solvent (e.g. dimethylformamide) at between room temperature and reflux. When R is a group of formula: as previously defined, then the derivative of formula R-RLG may be prepared by alkylation of the corresponding amino derivative of formula NHR7R8 with a derivative of formula RLG-L-RLG and a base (e.g. NaOH, Na2CO3, K2CO3, Cs2C03), optionally in the presence of an additive (e.g. potassium iodide) in a suitable solvent (e.g. N,N-dimethylformamide, acetonitrile, acetone/H2O) at between room temperature and reflux. The amino derivative of formula NHR7RB is either commercial or made using procedures known to the skilled person. When R is a group of formula : as previously defined, then the derivative of formula R-RLG is either commercial or may be prepared using literature procedures well-known to the skilled person. The compounds of formula (4) may be prepared by deprotection of the corresponding derivatives of formula (5) wherein Z is O: wherein RP is a protecting group (e.g. methyl, deprotected with BBr3 in dichloromethane at between 0°C and room temperature). The compounds of formula (5) are either commercial or may be prepared by double alkylation of the compounds of formula (6) : wherein RP is as previously defined, with the compounds of formula (7) : wherein RLG is as previously defined, and a base (e.g. NaH), optionally in the presence of an additive (e.g. potassium iodide) in a suitable solvent (e.g. N,N-dimethylformamide, N-methyl pyrrolidinone) at between room temperature and reflux. The compounds of formula (6) and (7) are each either commercially available or made using literature procedures well-known to the skilled person. Compounds of formula (3), wherein Z represents S may be prepared from compounds of formula (5) wherein Z represents S and RP is Me by a Pummerer rearrangement, followed by alkylation of the resulting intermediate with a derivative of formula R-RLG. The reaction is achieved by treatment of the compound of formula (5) with a suitable oxidant (e.g.m-CPBA) in a suitable solvent (e.g. dichloromethane) at 0°C to provide the corresponding sulphide. Treatment of this intermediate with trifluoroacetic anhydride in the presence of a suitable base (e.g. 2,6-lutidine) in a suitable solvent (e.g. acetonitrile) at about -15°C, followed by reaction with R-RLG, in the presence of a base (e.g. triethylamine, potassium carbonate) in a suitable solvent (e.g. N,N-dimethylformamide) at between 0°C and room temperature provides the compound of formula (3). Alternatively, the compounds of formula (3) wherein Z is O may be prepared by alkylation of the compounds of formula (4) with the alcohol derivative of formula ROH, which is either commercial or made using literature procedures well-known to the skilled person, using Mitsunobu reagents such as PPh3 and DIAD in a suitable solvent (e.g. THF) at between 0°C and reflux. Persons skilled in the art will appreciate that, in order to obtain compounds of formula (1) in an alternative or more convenient manner, the individual process steps mentioned in this section may be performed in a different order. For example compounds of formula (1) wherein Z is O and X is -CH2NR1R2, may be prepared by alkylation of the compounds of formula (8) : with a derivative of formula R-RLG or ROH as previously defined, using conditions analogous to those decribed for the preparation of compounds of formula (3). The compounds of formula (8) may be prepared by deprotection of the compounds of formula (9) : wherein RP is as previously defined, using conditions appropriate for the protecting group and the nature of R1 and R2 (e.g. using NaSMe in dimethylformamide at 130°C wherein RP is methyl and R1 and R2 are (C1-C4)alkyl). The compounds of formula (9) may be prepared from the corresponding amino derivatives of formula (10) using analogous conditions to those described for the preparation of compounds of formula (1) from compounds of formula (2). The compounds of formula (10) may be prepared from compounds of formula (5) wherein Z is O using analogous reduction conditions to those described for the preparation of compounds of formula (2) from compounds of formula (3). A further example of performing the individual process steps described in this section in a different order to obtain compounds of formula (1) in an alternative or more convenient manner, is the preparation of compounds of formula (1) wherein Z is O by double alkylation of the compounds of formula (11) : with the compounds of formula (7) as previously defined, using analogous conditions described for the preparation of compounds of formula (5) from compounds of formula (6). The compounds of formula (11) may be prepared from the corresponding hydroxy derivatives of formula (12) : using analogous conditions described for the preparation of compounds of formula (3) from compounds of formula (4). The compounds of formula (12) are either commercial or made using literature procedures well-known to the skilled person. An example of performing the individual process steps described in this section in a different order to obtain compounds of formula (1) wherein Z is O and R is a group of formula : is the preparation of these compounds by reaction of the compounds of formula (13) : wherein RLG is as previously defined, with the amino derivatives of formula NHR7R8 using analogous conditions to those previously described for the preparation of R-RLG. Alternatively, the same transformation can be achieved by heating the compounds of formula (13) with the amino derivatives of formula NHR7R8 and a base (e.g. diisopropylethylamine) in a suitable solvent (e.g. N-methylpyrrolidinone) at 150-200°C for 5-10 min using a microwave oven. Alternatively, the compounds of formula (1) wherein Z is O, X is -CH2NR1R2 and R1 and R2 are hydrogen or an optionally substituted (C1-C4)alkyl or together with the N atom to which they are attached form an optionally substituted 4-, 5- or 6-membered saturated heterocycle wherein a C atom may be replaced by N, O, S, SO or SO2, may be prepared by reductive amination of the compounds compounds of formula (14) : with the amino derivative of formula HNR1R2 and a reducing agent (e.g. NaHB(OAc)3), optionally in the presence of a Lewis acid (e.g. Ti(OiPr)4) in a suitable solvent (e.g. EtOH) at between 0°C and reflux. The compounds of formula (14) may be prepared by reduction of the compounds of formula (3) wherein Z is O with a reducing agent (e.g. diisobutylaluminium hydride) in a suitable solvent (e.g. toluene) at between -78°C and room temperature (about 20°C). Alternatively, the compounds of formula (14) may be prepared by oxidation of the compounds of formula (1) wherein Z is O and X is -CH2OH, using an oxidant (e.g. pyridinium chlorochromate) in a suitable solvent (e.g. dichloromethane) at between 0°C and reflux. The compounds of formula (1) wherein X is -CH2OH, may be prepared by reduction of the compounds of formula (1) wherein X is -C(O)O(C1-C4)alkyl, with a reducing agent (e.g. LiAlH4) in a suitable solvent (e.g. tetrahydrofuran) at between -78°C and reflux. The compounds of formula (1) wherein X is -C(O)O(C1-C4)alkyl, may be prepared by esterification of the compounds of formula (1) wherein X is COOH, using the standard procedures well-known to the skilled person. For example, the esterification can be achieved by using a reagent capable of activating a carboxylic acid (e.g. thionyl chloride) and HO(C1-C4)alkyl, optionally in the presence of an additional solvent (e.g. dichloromethane) at between 0°C and reflux. The compounds of formula (1) wherein X is C(O)OH, may be prepared by hydrolysis of the compounds of formula (3) as previously defined with a mineral acid (e.g. concentrated aqueous HCl), optionally in the presence of a suitable co-solvent (e.g. dioxane), at between 0°C and reflux. The compounds of formula (1) wherein m and p are both equal to 2, Z is O and Y is CH(OH), may be prepared by reduction of the compounds of formula (1) wherein m and p are both equal to 2 and Y is C=O, with a reducing agent (e.g. LiAlH4) in a suitable solvent (e.g. Et2O) at between 0°C and reflux. The compounds of formula (1) wherein m and p are both equal to 2, Z is O and Y is C=O, may be prepared by treatment of the compounds of formula (15) : with sodium chloride in a suitable solvent (e.g. dimethylsulphoxide/water) at between 100°C and reflux. The compounds of formula (15) may be prepared by treatment of the compounds of formula (16) : with a base (e.g. NaH) in a suitable solvent (e.g. 1,2-dimethoxyethane) at between room temperature and reflux. The compounds of formula (16) may be prepared by alkylation of the compounds of formula (11) as previously defined with methyl acrylate and a base (e.g. benzyltrimethylammonium hydroxide) in a suitable solvent (e.g. methanol/acetonitrile) at between room temperature and reflux. The compounds of formula (1) wherein X is -CONH2, may be prepared by treatment of the compounds of formula (3) as previously defined with polyphosphoric acid or boron trifluoride-acetic acid complex at between room temperature and 100°C. The compounds of formula (1) wherein X is -CONR3R4, may be prepared by reaction of the compounds of formula (1) wherein X is COOH, sequentially with a reagent capable of activating a carboxylic acid (e.g. thionyl chloride,) and then with the amino derivative of formula HNR3R4, in a suitable solvent (e.g. dichloromethane) at between 0°C and reflux. Alternatively the acid may be treated with the amine of formula HNR3R4, in the presence of a coupling agent (e.g. TBTU, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), optionally in the presence of a suitable additive (e.g. 1-hydroxybenzotriazole) and base (e.g. triethylamine) in a suitable solvent (e.g. dichloromethane, N,N-dimethylformamide) at room temperature. Compounds of formula (1) wherein X is CH2NR1R2 may be prepared by reduction of compounds of formula (1) wherein X is -CONR3R4 and NR1R2 equals NR3R4, with a reducing agent (e.g. lithium aluminium hydride) in a suitable solvent (e.g. tetrahydrofuran, ether) at between room temperature and 50°C. The compounds of formula (1) wherein X is -CH2-O-(C1-C4)alkyl may be prepared by alkylation of the compounds of formula (1) wherein X is -CH2-OH, with a derivative of formula RLG(C1-C4)alkyl, wherein RLG is as previously defined, and a base (e.g. NaH) in a suitable solvent (e.g. dimethylformamide) at between room temperature and reflux. The compounds of formula (1) wherein X is -CH2-O-het2 may be prepared by alkylation of the compounds of formula (1) wherein X is -CH2-OH, with a derivative of formula RLGHet2, by palladium catalysed cross-coupling with a haloheteroaromatic compound, using a suitable palladium source (e.g. tris(dibenzylideneacetone)palladium (0)), optionally in the presence of a chelating ligand (e.g. BINAP) and in the presence of a suitable base (e.g. sodium tert-butoxide) in a solvent (e.g. toluene), at between room temperature and reflux. Compounds of formula (1) wherein X is het1, may be prepared from compounds of formula (1) wherein X is COOH, or alternatively from compounds of formula (3) or (14) using methods known to those skilled in the art, such as those described in general heterocyclic texts such as For example, compounds of formula (1) where X is optionally substituted 2-thiazolyl and Z is O may be prepared by treating compounds of formula (17) : with a suitable reagent (e.g. bromoacetaldehyde dimethyl acetal, chloroacetone) and HCl in a suitable solvent (e.g. EtOH) at reflux. Compounds of formula (17) may be prepared by reacting compounds of formula (3) wherein Z is O with diethyldithiophosphate and water at 60°C. Compounds of formula (1) wherein X is -CH2-het1, and where said het1 is N-linked, may be prepared from compounds of formula (1) wherein X is -CH2-NH2 using methods known to those skilled in the art, such as those described in general heterocyclic texts such as Compounds of formula (1) wherein X is -CH2-het1, and where said het' is C-linked, may be prepared from compounds of formula (1) wherein X is -COOH by a two step process of CH2 homologation using the Arndt-Eistert synthesis ( The compounds of formula (1) and their precursors which contain a sulphide group can be oxidised to the corresponding sulphoxides or sulphones using standard techniques well-known to those skilled in the art, for example as described in It will be appreciated by those skilled in the art that, certain compounds of formula (1) may be converted to alternative compounds of formula (1) using standard chemical transformations. Examples of these include, acylation and sulphonation of amine functions (e.g see examples 166, 229, 230), reductive amination reactions (e.g. see examples 167, 168), alkylation (e.g. see example 228) or hydrogenation of halo atoms (e.g. see examples 202, 203). It will be appreciated by those skilled in the art that, in the course of carrying out the processes described above, the functional groups of intermediate compounds may need to be protected by protecting groups. These functional groups include hydroxyl, amino and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl and diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), alkyl (e.g. methyl or methoxyethyl) and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable [protecting groups for carboxylic acid include (C1-C4)alkyl or benzyl esters. The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore. The introduction and removal of protecting groups is fully described in Also, the compounds of formula (1) as well as intermediates for the preparation thereof, can be purified according to various well-known methods such as recrystallisation and chromatography. The compounds of formula (1), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutically active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the histamine H3 receptor is involved or in which agonism or antagonism of this receptor may induce benefit. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. According to another aspect of the invention, there is provided a pharmaceutical composition including a compound of the formula (1) or a pharmaceutically acceptable salt and/or solvate thereof, as defined in any one of the preceding claims, together with a pharmaceutically acceptable excipient. Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function. The compound of formula (1) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula (1) may be in the form of multiparticulate beads. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %. Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents. Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula (1) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly( The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free ( Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying. Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1µg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1µl to 100µl. A typical formulation may comprise a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 µg to 4000 µg of the compound of formula (1). The overall daily dose will typically be in the range 1 µg to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day. The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. In as much as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid. For administration to human patients, the total daily dose of the compounds of the invention is typically in the 0.001 mg to 2000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 1 mg to 2000 mg, while an intravenous dose may only require from 0.01 mg to 100 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment. According to another embodiment of the present invention, the compounds of the formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result. The second and more additional therapeutic agents may also be a compound of the formula (1), or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more histamine H3 receptor ligands known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents. As used herein, the terms "co-administration", "co-administered" and "in combination with", referring to the compounds of formula (1) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following: Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, include, but are by no means limited to : According to the present invention, combination of the compounds of formula (1) with : The compounds of formula (1) have the ability to interact with the H3 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the H3 receptor plays in the physiology of all mammals. According to this invention H3 ligands are meant to include H3 receptor antagonists, agonists and inverse agonists. For the preferred indications to be treated according to the invention, H3 antagonists are believed to be most suitable. In another aspect of the invention there is provided a compound of the formula (1) as defined in herein, or a pharmaceutically acceptable salt and/or solvate thereof, for use as a medicament. A further aspect of the present invention relates to the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions in which the H3 receptor is involved. More specifically, the present invention also concerns the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of : The compounds of formula (1) of the invention are particularly suitable for the treatment of allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic congestion. A still further aspect of the present invention also relates to the use of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug being a H3 ligand. In particular, the present inventions concerns the use of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of H3-mediated diseases and/or conditions, in particular the diseases and/or conditions listed above. Another aspect of the invention relates to the use of a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof, for the manufacture of a medicament for the treatment of female sexual dysfunction, including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder, or for the treatment of male sexual dysfunction including male desire disorders, male erectile dysfunction or male orgasmic disorders such as premature ejaculation. The following examples illustrate the preparation of phenol and thiophenol derivatives of the formula (1) : 4-Methoxyphenylacetonitrile (10g, 67.9mmol) in DMF (50ml) was added slowly to a suspension of NaH (5.04g, 150mmol) in DMF (50ml) at 0°C under N2. The reaction was allowed to warm up to room temperature and stirred for 30 min. The reaction was cooled to 0°C and bis(2-chloroethyl)ether (10.7g, 74.7mmol)) in DMF (100ml) was added dropwise over 80 min. The reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction was quenched with water (200ml) and extracted with ethyl acetate (3x300ml). The combined organic extracts were washed with water (2x200ml), brine (200ml), dried over MgSO4, filtered, washed with ethyl acetate and concentrated Boron tribromide (1M in DCM, 262ml) was added to a solution of 4-(4-methoxyphenyl)-tetrahydro-2H-pyran-4-carbonitrile (14.7g, 67.9mmol) in DCM (294ml) at 0°C under N2 keeping the temperature below 5°C. The reaction was allowed to warm to room temperature and stirred for 48hours. The mixture was cooled to -10-0°C with dry ice acetone and quenched with saturated aqueous sodium bicarbonate (294ml). The mixture was allowed to warm to room temperature and stirred for 1hour. The mixture was separated and the aqueous extracted with DCM (3x250ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated To a stirred suspension of LiAlH4 (79g, 2.08mol, 5eq) in THF (900ml) at 0 to 5°C under an atmosphere of nitrogen was added 4-(4-methoxyphenyl)- tetrahydro-2H-pyran-4-carbonitrile (90g, 0.414mol) in THF (900ml) over a 25 minutes maintaining the temperature at 5 to 10°C. The reaction mixture was allowed to warm to ambient temperature and stirred until complete. Sodium hydroxide (2N, 850ml) was added dropwise, the resulting solids filtered and washed with THF (2x800ml), the organics concentrated To a solution of {[4-(4-methoxyphenyl)-tetrahydro-2H-pyran-4-yl]methyl}amine (60g, 0.271mol) in H2O (444mL) and AcOH (213ml) was charged formaldehyde (37%ww solution in H2O, 408 mL) and the mixture cooled to 0 to 5°C. Sodium triacetoxyborohydride (345g, 1.626mol, 6eq) was added portion wise while maintaining the temperature below 12°C. The mixture was stirred at ambient temperature until complete. Sodium hydroxide (2M, 1000ml) was added slowly and the mixture extracted with DCM (4x250ml). The organic extracts were dried over MgSO4, filtered and concentrated To a suspension of Sodium thiomethoxide (49.2g, 0.702mol, 5eq) in DMF (140ml) was added {[4-(4methoxyphenyl)-tetrahydro-2H-pyran-4-yl]methyl}dimethylamine (35g, 0.140mol) and the resulting mixture was heated to 130°C. Once complete, allowed to cool to ambient temperature and saturated aqueous NH4Cl (525ml) was added. The resultant was extracted with EtOAc (3x500ml), dried over MgSO4, filtered and concentrated 3-Methoxyphenylacetonitrile (10g, 67.9mmol) in DMF (50ml) was added slowly to a suspension of NaH (5.04g, 150mmol) in DMF (50ml) at 0°C under N2. The reaction was allowed to warm to room temperature and stirred for 30mns. The reaction was cooled to 0°C and bis(2-chloroethyl)ether (10.7g, 74.7mmol) in DMF (100ml) was added dropwise over 80 min. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water (500ml) and extracted with ethyl acetate (3x100ml). The combined organic extracts were washed with brine (3x50ml), dried over MgSO4, filtered, washed with ethyl acetate and concentrated To a stirred suspension of LiAlH4 (3.7 g, 96.7 mmol) in diethyl ether (100 mL) cooled at 0°C was added dropwise a solution of 4-(3-methoxyphenyl)-tetrahydro-pyran-4-carbonitrile (4.2 g, 19.3 mmol) in diethyl ether (100 mL). After being stirred at room temperature for 30 min, the reaction mixture was refluxed for another 15 min. The mixture was cooled to 10°C and water, sodium hydroxide (15% w/v in water, 0.48 mL) and water again were successively added dropwise. After being stirred for 15 min at room temperature, the mixture was filtered over diatomaceous earth and concentrated. The residue was purified with flash chromatography (DCM/MeOH: 95/5) to provide [4-(3-methoxyphenyl)tetrahydro-pyran-4-yl]methylamine (4 g, 94%). A mixture of [4-(3-methoxyphenyl)tetrahydro-pyran-4-yl]methylamine (0.51 g, 2.3 mmol), acetic acid (0.535 mL, 9.2 mmol), sodium triacetoxyborohydride (0.974 g, 4.6 mmol), 37% solution of formaldehyde in water (0.55 mL) and DCM (40 mL) was stirred 72 h at ambient temperature. The organic phase was washed twice with water. Concentrated NaOH was added to the aqueous phase (pH 12) and the mixture was extracted twice with (dichloromethane. The organic extracts were dried over Na2SO4, filtered and concentrated To a suspension of Sodium thiomethoxide (0.42 g, 6 mmol) in DMF (1.2 mL) was added N-{[4-(3-methoxyphenyl)tetrahydro-pyran-4-yl]methyl}-N,N-dimethylamine (0.3 g, 1.2 mmol) and the resulting mixture was heated to 65°C for 7 h, allowed to cool to ambient temperature and quenched with saturated aqueous NH4Cl (6 mL). The mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated Amine (1eq.) was charged to a reaction flask followed by acetone (3vol or 20vol), 5M NaOH solution (1.2eq.) and 1-bromo-3-chloropropane (1.5 eq. or 3eq.). The reaction was stirred overnight at room temperature. The phases were separated and the acetone layer concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), chloride (378mg, 2,13mmol), DMF (10ml), water (17ml) and K2CO3 (1.18g, 8.52mmol) was heated to 130°C. Cooled to ambient temperature, water (40ml) added, extracted with EtOAc (3x25ml) and the combined organic extracts washed with water (2x25ml). The organics were dried over MgSO4, filtered and concentrated Pyrrolidine (10g, 0.14mol), acetone (28ml), 5M NaOH solution (21ml) and 1-bromo-3-chloropropane (24.4g, 0.15mol) were stirred together under N2 for 8hours. The organic layer was separated and concentrated Alkylation of 3-[4-(dimethylamino)methyltetrahydro-2H-pyran-4-yl]phenol (0.1 g, 0.425 mmol) with 1-(3-chloropropyl)pyrrolidine (0.125 g, 0.85 mmol) according to general procedure B gave the desired compound after purification by flash chromatography (0.030 g, 20%).1H NMR (400MHz, CDCl3) 2(R),5(R)-trans-Dimethyl-pyrrolidine (0.75g, 7.56mmol), acetone (15ml, 20vol), 5M NaOH solution (1.8ml, 1.2eq.) and 1-bromo-3-chloropropane (3.57g, 22.7mmol, 3eq.) were reacted together according to general procedure A to give the title compound (0.5g, 38%) as a yellow oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (330mg, 1.43mmol), 1-(3-chloro-propyl)-2,5-trans-dimethyl-pyrrolidine (221mg, 1.26mmol), DMF (7.6ml) and K2CO3 (790mg, 5.72mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM, MeOH, NH3) to give the title compound as a yellow oil (180mg, 34%).1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.87 (d, 2H), 4.08-3.95 (m, 2H), 3.79-3.70 (m, 2H), 3.59-3.49 (m, 2H), 3.11-3.00 (m, 2H), 2.77 (m, 1H), 2.54 (m, 1H), 2.40 (s, 2H), 2.14-1.81 (m, 8H), 1.96 (s, 6H), 1.44-1.31 (m, 2H), 0.97 (d, 6H). 2-Methylpyrrolidine (0.9g, 10.6mmol), acetone (18ml, 20vol), 5M NaOH solution (2.50ml) and 1-bromo-3-chloropropane (5g, 31.8mmol, 3eq) were reacted together according to general procedure A to give the title compound (1g, 59%) as a pale yellow oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), 1-(3-chloro-propyl)-2-methyl-pyrrolidine (344mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.52mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM, MeOH, NH3) to give the title compound as a yellow oil (120mg, 16%).1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.87 (d, 2H), 4.08-3.96 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.18 (td, 1H), 2.98 (m, 1H), 2.40 (s, 2H), 2.29 (m, 1H), 2.20 (m, 1H), 2.16-1.62 (m, 10H), 1.96 (s, 6H), 1.42 (m, 1H), 1.09 (d, 3H). 2,6-cis-Dimethyl-piperidine (1.0g, 8.83mmol), K2CO3 (1.52g, 1.25eq.) and 3-bromopropanol (6.14g, 44.2mmol, 4vol) were reacted together at 100°C for 2hours. The reaction was allowed to cool to room temperature, diluted with DCM (20ml) and quenched with 2M HCl solution (20ml). The aqueous was extracted with DCM (2 x 20ml) and basified to pH 14 with 2M NaOH solution (∼15ml). The aqueous was extracted with DCM (3 x 20ml). The combined DCM layers were dried over MgSO4, filtered washed with DCM and concentrated 1-(Propan-1'-ol)-2,6-cis-dimethyl-piperidine (1.22g, 7.12mmol) was dissolved in DCM (24ml) and cooled to 0-5°C under N2. Thionyl chloride (1.04ml, 14.25mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 30mins. The reaction was quenched with 2M HCl solution (25ml). The aqueous was extracted with DCM (25m1) and basified to pH 14 with 5M NaOH solution (∼25ml). The aqueous was extracted with TBME (3 x 25ml). The combined organic layers were dried over MgSO4, filtered washed with TBME and concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), 1-(3-chloro-propyl)-2,6-cis-dimethyl-piperidine (410mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.52mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM, MeOH, NH3) to give the title compound as a yellow oil (280mg, 33.9%).1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.85 (d, 2H), 3.93 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.95 (t, 2H), 2.51-2.36 (m, 2H), 2.40 (s, 2H), 2.14-2.04 (m, 2H), 1.96 (s, 6H), 1.93-1.82 (m, 4H), 1.74-1.51 (m, 3H), 1.41-1.21 (m, 3H), 1.13 (d, 6H). Thiomorpholine (5g, 49mmol), acetone (15ml, 3vol), 5M NaOH solution (11.8ml) and 1-bromo-3-chloropropane (11.6g, 73.5mmol, 1.5eq.) were reacted together according to general procedure A to give the title compound (8.5g, 96%) as a pale yellow oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1000mg, 4.25mmol), 4-(3-chloro-propyl)-thiomorpholine (764mg, 2,13mmol), DMF (20ml), and K2CO3 (2,34g, 17mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant DCM:MeOH:NH3 (95:5:1) to give the title compound (320mg, 20%).1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 3.99 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.79-2.64 (m, 8H), 2.55 (t, 2H), 2.40 (s, 2H), 2.16-2.04 (m, 2H), 2.01-1.82 (m, 4H), 1.97 (s, 6H). Dimethyl-{4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-pyran-4-ylmethyl}amine (300mg, 0.792mmol) and TFA (0.99ml) were cooled to 0 to 5 °C and trifluoro-peracetic acid (4M, 0.77ml) [4M solution prepared by the addition of 27.5% H2O2 (0.94ml) to TFA (1.56ml)] was added and the reaction stirred for six hours at 0 to 5°C. The mixture was diluted with DCM (6ml), basified with NaOH (2M, 8ml) and extracted with DCM (2x20ml). The DCM extracts were dried over MgSO4, filtered and concentrated Dimethyl-{4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-pyran-4-ylmethyl}amine (300mg, 0.792mmol) and TFA (0.99ml) were cooled to 0 to 5°C and trifluoro-peracetic acid (4M, 0.77ml) was added and the reaction allowed to warm to ambient temperature overnight. The mixture was diluted with DCM (6ml), basified with NaOH (2M, 8ml) and extracted with DCM (2x20ml). The DCM extracts were dried over MgSO4, filtered and concentrated 4-Hydroxypiperidine (3g, 30mmol), acetone (60ml, 20vol), 5M NaOH solution (7.2ml) and 1-bromo-3-chloropropane (14.2g, 90mmol, 3eq.) were reacted together according to general procedure A to give the title compound (1.5g, 28%) as a pale yellow oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), 1-(3-chloro-propyl)-piperidin-4-ol (378mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.52mmol) were reacted together according to general procedure B. The isolated material was dissolved in EtOAc (30ml), washed with NaOH (2M, 2x20ml) and water (25ml), dried over MgSO4 filtered and concentrated 4-Methoxy-piperidine (1.5g, 13mmol), acetone (30ml, 20vol), 5M NaOH solution (3.13ml) and 1-bromo-3-chloropropane (6.14g, 39mmol, 3eq.) were reacted together according to general procedure A to give the title compound (1.5g, 60%) as a pale yellow oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), 1-(3-chloro-propyl)-4-methoxy-piperidine (410mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.62mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM: MeOH: NH3) to give the title compound as a yellow oil (415mg, 50%).1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.34 (s, 3H), 3.22 (m, 1H), 2.83-2.71 (m, 2H), 2.51 (t, 2H), 2.40 (s, 2H), 2.23-1.81 (m, 10H), 1.97 (s, 6H), 1.67-1.53 (m, 2H). 4-Piperidine ethanol (0.9g, 7.5mmol), acetone (18ml, 20vol), 5M NaOH solution (1.8ml) and 1-bromo-3-chloropropane (3.54g, 22.5mmol, 3eq.) were reacted together according to general procedure A to give the title compound (0.6g, 37%) as an orange oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (288mg, 1.22mmol), 2-[1-(3-chloro-propyl)-piperidin-4-yl]-ethanol (252mg, 1.22mmol), DMF (8ml) and K2CO3 (674mg, 4.88mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:4:1) provided the title compound (180mg, 36%) as an off white solid.1H NMR (400MHz, CDCl3) N-Boc-4-(2-hydroxy-ethyl)-piperidine (5g, 21.8mmol) in THF (25ml) was added to a suspension of NaH (1.47g, 43.7mmol) in THF (75ml) at 0°C under N2. The reaction was stirred for 1 hour at 0°C and Mel (2.72ml, 43.7mmol) added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100ml) and extracted with DCM (3 x 100ml). The combined DCM layers were dried over MgSO4, filtered, washed with DCM and concentrated 4-(2-Methoxy-ethyl)-piperidine hydrochloride (1.5g, 8.4mmol), acetone (30ml, 20vol), 5M NaOH solution (6.03ml, 3.6eq.) and 1-bromo-3-chloropropane (3.96g, 25.1mmol, 3eq.) were reacted together according to general procedure A to give the title compound (1.6g, 88%) as a pale yellow oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), 1-(3-chloro-propyl)-4-(2-methoxy-ethyl)-piperidine (466mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.52mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:4:1) provided the title compound (409mg, 46%) as a yellow oil.1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 3.99 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.41 (t, 2H), 3.33 (s, 3H), 2.97-2.86 (m, 2H), 2.49 (t, 2H), 2.40 (s, 2H), 2.15-1.78 (m, 8H), 1.97 (s, 6H), 1.74-1.17 (m, 7H). Piperidine-4-carboxylic acid amide (0.5g, 3.90mmol), acetone (1.5ml, 3vol), 5M NaOH solution (1.20ml, 1.2eq.) and 1-bromo-3-chloropropane (0.50ml, 5.04mmol, 1eq.) were reacted together according to general procedure A to give the title compound (0.16g, 20%) as a pale yellow oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), 1-(3-chloro-propyl)-piperidine-4-carboxylic acid amide (436mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.52mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM: MeOH: NH3) to give the title compound as a white solid (175mg, 20%).1H NMR (400MHz, CDCl3) δ 7.21 (d, 2H), 6.86 (d, 2H), 5.44 (br s, 1H), 5.25 (br s, 1H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.03-2.93 (m, 2H), 2.51 (t, 2H), 2.40 (s, 2H), 2.22-1.66 (m, 13H), 1.97 (s, 6H). Piperazine-1-carboxylic acid ethyl ester (3.0g, 18.9mmol), K2CO3 (2.8g, 1.1eq.), DMF (30ml, 10vol) and 1-bromo-3-chloropropane (1.8ml, 18.9mmol, 1eq.) were reacted together at room temperature overnight. The reaction was quenched with water (100ml) and extracted with DCM (3 x 50ml). The combined DCM extracts were dried over MgSO4, filtered washed with DCM and concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid ethyl ester (499mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.52mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant (10%MeOH in DCM) the title compound (276mg, 26%).1H NMR (400MHz, CDCl3) δ 7.21 (d, 2H), 6.86 (d, 2H), 4.14 (q, 2H), 4.01 (t, 2H), 3.75 (dt, 2H), 3.60-3.42 (m, 6H), 2.54 (t, 2H), 2.47-2.36 (m, 4H), 2.40 (s, 2H), 2.16-1.82 (m, 6H), 1.97 (s, 6H), 1.26 (t, 3H). Diethyl-amine (7.27ml, 70mmol), acetone (15ml, 3vol), 5M NaOH solution (16.8ml, 1.2eq.) and 1-bromo-3-chloropropane (16.5g, 105mmol, 1.5eq.) were reacted together according to general procedure A to give the title compound (6.2g, 59%) as a colourless oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), (3-chloro-propyl)-diethylamine (319mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.52mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant (3%EtOH: 1%NH3 in DCM) gave the title compound as a pale yellow clear oil (160mg, 22%).1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.61 (t, 2H), 2.54 (q, 4H), 2.40 (s, 2H), 2.15-1.82 (m, 6H), 1.97 (s, 6H), 1.02 (t, 6H). 2-Ethylamino ethanol (6.2g, 70mmol), acetone (18ml, 3vol), 5M NaOH solution (16.8ml, 1.2eq.) and 1-bromo-3-chloropropane (16.5g, 105mmol, 1.5eq.) were reacted together according to general procedure A to give the title compound (4.5g, 39%) as a colourless oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), 2-[(3-chloro-propyl)-ethylamino]-ethanol (353mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.52mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM: MeOH: NH3) to give the title compound as a white solid (150mg, 19%).1H NMR (400MHz, CDCl3) δ 7.21 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.60-3.49 (m, 4H), 2.68 (t, 2H), 2.62 (t, 2H), 2.59 (q, 2H), 2.40 (s, 2H), 2.14-1.82 (m, 6H), 1.97 (s, 6H), 1.62 (br s, 1H), 1.03 (t, 3H). Isopropylmethylamine (4g, 56mmol), acetone (12ml, 3vol), 5M NaOH solution (13.44ml, 1.2eq.) and 1-bromo-3-chloropropane (13.22g, 84mmol, 1.5eq.) were reacted together according to general procedure A to give the title compound (4.8g, 66%) as a colourless oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500mg, 2.13mmol), (3-chloro-propyl)-isopropyl-methyl-amine (318mg, 2,13mmol), DMF (10ml) and K2CO3 (1.18g, 8.52mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:3:1) provided the title compound (200mg, 43%) as a white solid.1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.87 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.83 (sep, 1H), 2.55 (t, 2H), 2.40 (s, 2H), 2.22 (s, 3H), 2.14-2.05 (m, 2H), 1.96 (s, 6H), 2.00-1.82 (m, 4H), 1.00 (d, 6H). Pyrrolidine (10.4g, 0.15mol), acetone (200ml), 5M NaOH solution (35ml) and 1-bromo-2-chloroethane (62.9g, 0.44mol) were reacted together according to general procedure A. The crude mixture was purified by column chromatography eluting with ethyl acetate to give the title compound (2.0g, 10%) as a pale yellow oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (389mg, 1.65mmol), 1-(2-chloro-ethyl)-pyrrolidine (210mg, 1.57mmol), DMF (4.5ml) and K2CO3 (885g, 6.40mmol) was heated to 130°C for 30 minutes. The mixture was cooled to ambient temperature; water (9ml) was added and the mixture was extracted with EtOAc (3 x 4.5ml). The organic phase was washed with brine (10ml), NaOH solution (2M, 10ml) and water (10ml). The organic layer was dried over MgSO4, filtered and concentrated Pyrrolidine (3.0g, 42mmol), acetone (60ml), 5M NaOH solution (10ml) and 1-bromo-3-chloro-2-methylpropane (21.7g, 0.13mol) were reacted together according to general procedure A to give the title compound (3.9g, 58%) as a pale yellow oil. 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (0.91g, 3.87mmol), 1-(3-chloro-2-methyl-propyl)-pyrrolidine (500mg, 3.10mmol), DMF (5ml) and K2CO3 (2.14g, 15.50mmol) were reacted together according to general procedure B. The organic phase was washed with 2M NaOH (3 x 20ml), water (2 x 20ml), dried over MgSO4, fitered and concentrated 4-Hydroxypiperidine (2.13g, 21.1mmol), K2CO3 (5.83g, 2eq.), 2-bromopropane (11.2g, 91mmol, 4.3eq.) and MeOH (21.3ml) were refluxed together overnight. The reaction was allowed to cool to room temperature and quenched with 2M HCl solution (40ml) and extracted with TBME (40ml). The aqueous phase was basified to pH 14 with 2M NaOH solution and extracted with DCM (9 x 50ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated 1-Isopropyl-4-hydroxypiperidine (1g, 6.98mmol), DCM (10ml) and triethylamine (1.08ml, 7.68mmol) were cooled to 0-5°C and mesyl chloride (0.54ml, 6.98mmol) was added dropwise under N2. The reaction was allowed to warm to room temperature and stirred for 1hour. The reaction was quenched with sat. NaHC03 (20ml) and the aqueous phase extracted with DCM (2 x 5ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (532mg, 2.26mmol) in DMF (2ml) was added to a solution of NaH (100mg, 2.5mmol) in DMF (2ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-isopropyl-piperidin-4-yl ester (400mg, 1.81mmol) in DMF (1.3ml) was slowly added. The reaction was heated to 75°C and stirred for 6hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20ml), water (10ml) and 5M NaOH solution (10ml). The organic layer was washed with 2.5M NaOH (2 x 20ml), brine (2 x 20ml), dried over MgSO4, filtered and concentrated 4-Hydroxypiperidine (2.08g, 21.2mmol), K2CO3 (5.86g, 2eq.), cylopentylbromide (11.51g, 77.6mmol, 3.7eq.) and MeOH (20.8ml) were refluxed together overnight. The reaction was allowed to cool to room temperature and quenched with 2M HCl solution (40ml) and extracted with TBME (40ml). The aqueous phase was basified to pH 14 with a 2M NaOH solution and extracted with DCM (4 x 50ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated 1-Cyclopentyl-4-hydroxypiperidine (1g, 5.91mmol), DCM (10ml) and triethylamine (0.91m, 6.5mmol) were cooled to 0-5°C and mesyl chloride (0.46ml, 5.91 mmol) was added dropwise under N2. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with sat. NaHCO3 (20ml) and the aqueous phase extracted with DCM (2 x 5ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (487mg, 2.07mmol) in DMF (2ml) was added to a solution of NaH (100mg, 2.5mmol) in DMF (2ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-cyclopentyl-piperidin-4-yl ester (409mg, 1.65mmol) in DMF (1.5ml) was slowly added. The reaction was heated to 75°C and stirred for 6hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20ml), water (10ml) and 5M NaOH solution (10ml). The organic layer was washed with 2.5M NaOH (2 x 20ml), brine (2 x 20ml), dried over MgSO4, filtered and concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (730mg, 3.10mmol), 3-chloro-1-bromopropane (980mg, 6.20mmol), DMF (10ml) and K2CO3 (1.72g, 12.40mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH (20: 1) provided a mixture of bromo and chloro phenoxy ether (250mg) which was used in the next stage. The mixture (250mg) was refluxed with isopropyl amine (34°C) (10ml, 40vol) for 7 days. The reaction was concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.5g, 6.38mmol), 1-bromo-4-chlorobutane (1.5ml, 12.77mmol), DMF (20ml) and K2CO3 (3.5g, 25.53mmol) were reacted together according to general procedure B. Purification of a fraction of the crude (900mg) by chromatography on alumina, eluant ethyl acetate:heptanes (12: 88) provided a mixture of bromo and chloro phenoxy ether (220mg) which was used in the next stage. The purified mixture (220mg, 0.68mmol) and pyrrolidine (0.17ml, 2.03mmol) were refluxed in EtOH (3ml, 15vol) overnight. The reaction was concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1eq.), alcohol (R-OH) (0.8eq.) and PPh3 (1eq.) were mixed together in THF (10vol) and cooled to 0°C under N2. DIAD (1eq.) in THF (10vol) was added slowly to the reaction and allowed to warm to room temperature overnight. The reaction was quenched with 2M HCl solution (10vol) and extracted with ethyl acetate (3 x 10vol). The aqueous phase was basified to pH 14 with NaOH (~30vol) and extracted with ethyl acetate (3 x 10vol). The organic phase was dried over MgSO4, filtered and concentrated Pyrrolidine (1.82g, 25mmol), K2CO3 (3.0g, 1.04eq.), 3-bromo-2,2-dimethyl-propan-1-ol (8.45g, 50mmol, 2eq.) were heated together at 90°C overnight. The reaction was allowed to cool to room temperature and quenched with 2M HCl solution (50ml) and extracted with TBME (3 x 50ml). The aqueous phase was basified to pH 14 with 2M NaOH solution and extracted with DCM (3 x 50ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (0.28g, 1.19mmol), 2,2-dimethyl-3-pyrrolidin-1-yl-propan-1-ol (0.15g, 0.96mmol), PPh3 (0.31 g, 1.19mmol), THF (3ml) and DIAD (0.24ml, 1.19mmol) were reacted together according to general procedure C. The crude material was subjected to chromatography on silica eluting with DCM :MeOH :NH3 (97 :2 :1) to provide the title compound (85mg, 24%) as an off-white solid.1H NMR (400MHz, CDCl3) δ 7.23 (d, 2H), 6.91 (d, 2H), 3.84-3.69 (m, 4H), 3.69-3.54 (m, 2H), 2.67-2.56 (m, 4H), 2.50 (s, 2H), 2.44 (s, 2H), 2.18-2.08 (m, 2H), 2.01 (s, 6H), 1.92 (ddd, 2H), 1.79-1.67 (m, 4H), 1.04 (s, 6H). Pyrrolidine (2ml, 24mmol), THF (20ml) and methyl vinylketone (2.5ml, 31mmol) were mixed together and stirred overnight. NaBH4 (1.17g, 31mmol) was added to the reaction mixture and stirred for 3hours. The reaction was quenched with water (20ml) and extratcted with TBME (2 x 20ml). The combined organic extracts were dried over MgSO4, filtered, washed with TBME and concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.03g, 4.40mmol), 4-pyrrolidin-1-yl-butan-2-ol (0.5g, 3.50mmol), PPh3 (1.15g, 4.40mmol), THF (10ml) and DIAD (0.86ml, 4.40mmol) were reacted together according to general procedure C. The crude product was purified by preparative HPLC, eluting with acetonitrile/water/0.1%TFA as a gradient, to give the title compound as a yellow oil (125mg, 10%).1H NMR (400MHz, CDCl3) δ 7.19 (d, 2H), 6.86 (d, 2H), 4.43 (m, 1H), 3.75 (dt, 2H), 3.60-3.51 (m, 2H), 2.67-2.46 (m, 6H), 2.40 (s, 2H), 2.14-2.04 (m, 2H), 1.97 (s, 6H), 1.93-1.73 (m, 8H), 1.31 (d, 3H). Pyrrolidine (28.15g, 0.4mol), toluene (200ml), catalytic p-TsOH (200mg) and ethyl acetoacetate (20g, 0.15mol) were refluxed together in a Dean-Stark apparatus under N2 for 3hours. The reaction was cooled to room temperature and concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (925mg, 3.93mmol), 3-pyrrolidin-1-yl-butan-1-ol (450mg, 3.14mmol), PPh3 (1.03g, 3.93mmol), THF (9ml) and DIAD (0.77ml, 3.93mmol) were reacted together according to general procedure C. The crude material was subjected to chromatography on silica eluting with DCM :MeOH (99.5 :0.5) to provide the title compound (268mg, 24%) as a colourless oil.1H NMR (400MHz, CDCl3) δ 7.21 (d, 2H), 6.88 (d, 2H), 4.11-3.97 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.66-2.52 (m, 5H), 2.40 (s, 2H), 2.19-2.05 (m, 3H), 1.96 (s, 6H), 1.93-1.70 (m, 7H), 1.16 (d, 3H). 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (405mg, 1.72mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethanol (178mg, 1.38mmol), PPh3 (451mg, 1.72mmol), THF (8ml) and DIAD (348mg, 1.72mmol) were reacted together according to general procedure C. The crude product was subjected to chromatography on alumina eluting with ethyl acetate :heptane (50 :50) to provide the title compound (130mg, 27%) as a colourless oil.1H NMR (400MHz, CDCl3) δ 7.21 (d, 2H), 6.87 (d, 2H), 4.09-3.95 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.09 (m, 1H), 2.40 (s, 2H), 2.35 (s, 3H), 2.30-1.99 (m, 6H), 1.96 (s, 6H), 1.93-1.63 (m, 6H). 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (2g, 9.86mmol), 1-(3-chloro-propyl)-pyrrolidine (2.33g, 15.78mmol), DMF (40ml) and K2CO3 (5.45g, 39.44mmol) were reacted together according to general procedure E. The crude reaction product was diluted with 2M HCl solution (200ml) and washed with ethyl acetate (3 x 50ml). The aqueous phase was basified to pH 14 with 2M NaOH (200ml) and extracted with ethyl acetate (4 x 50ml). The combined organic extracts were dried over MgSO4, filtered, washed with ethyl acetate and concentrated Alternatively, 4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile can be prepared by the following steps: 4-Hydroxybenzylcyanide (20 g, 0.15 mol) was dissolved in DMF (500 mL) and then K2CO3 (41.4 g, 0.3 mol) and Nal (7.8 g, 0.052 mol) were added followed by dropwise addition of 3-(1-pyrrolidine)-propylchloride (26.5 g, 0.18 mol) at 60 °C. Heating was continued at 90 °C for 3 h and then the mixture was heated overnight at 60 °C. 3-(1-Pyrrolidine)-propylchloride (10 g, 0.067 mol) was again added as the reaction was not complete and heating was continued for a further 6 h. The reaction mixture was concentrated and taken up in EtOAc. The organic layer was washed with water, finally with brine. Crude [4-(3-pyrrolidin-1-ylpropoxy)phenyl]acetonitrile was purified by DCM/MeOH 9.5/0.5 over a silica gel column. Yield: 25.5g (70 %).1H-NMR (400 MHz, CDCl3) δ 1.77 (m, 4H); 1.98 (m, 2H); 2.50 (m, 4H); 2.59 (t, 2H); 3.66 (s, 2H); 4.00 (t, 2H); 6.87(d, 2H); 7.19(d, 2H). NaH (14.6 g, 0.61 mol) was suspended in DMF (100 mL). [4-(3-Pyrrolidin-1-ylpropoxy)phenyl]acetonitrile (25.5 g, 0.10 mol) was dissolved in DMF (100 mL) and added dropwise to the ice-cooled suspension of NaH. The reaction mixture was stirred at room temperature for 30 min followed by dropwise addition of 2-bromoethylether (36.2 g, 0.16 mol) in DMF (200 mL) in ice-cold condition. The reaction mixture was poured into ice-cold water. The solid was filtered, washed with water, dried and the resulting solid was washed with 5 % EtOAc in hexane to give the title compound (22 g, 67 %). To a stirred suspension of LiAlH4 (1.81g, 47.7mmol, 5eq) in Et2O/DCM (1:1, 30mL) at 0 to 5°C under a nitrogen atmosphere was added 4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (3g, 9.55 mmol) in Et2O/DCM (1:1, 30mL) over 15 minutes maintaining the temperature at 5 to 10°C. The reaction mixture was allowed to warm up to ambient temperature and stirred until complete. Sodium hydroxide (2N, 15mL) was added dropwise and the resulting solids were filtered, washed with Et2O/DCM (1:1, 6 x 50mL) and concentrated To a mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (2.5g, 7.86 mmol), acetic acid (6ml), and water (12.5ml) was added formaldehyde (11.5ml) and stirred for 15 minutes. STAB (10g, 4.72mmol) was added portionwise and stirred for one hour. Sodium hydroxide (2M, 100ml) was added slowly to attain a pH of 9. The resulting mixture was extracted with DCM (3x100ml) and the combined organic phases were dried over MgSO4, filtered and concentrated A mixture of 4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-carbonitrile ( 1.0 g, 5 mmol), 1-(3-chloropropyl)piperidine ( 1.2 g, 7.5 mmol) obtained following the procedure described in the A mixture of 4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (1.45 g, 4.4 mmol), isopropanol (12 mL), concentrated HCl (350µL), and PtO2 (115 mg) was stirred and hydrogenated to 50°C overnight at atmospheric pressure. The mixture was filtrated over diatomaceous earth and concentrated. The residue was dissolved in DCM /MeOH mixture and washed with NaOH (1M). The organic layers were dried over Na2SO4, filtered and concentrated, purified by flash chromatography (10 g silica gel, DCM/ MeOH (10% NH3)) to provide the title compound as free base (0.650 g, 44.5%). This was then converted to the dihydrochloride salt.1H NMR (400MHz, DMSO-D6) δ 10.66 (bs, 1H), 7.74 (bs, 3H), 7.32 (d, 2H), 6.97 (d, 2H), 4.07 (t, 2H), 3.73-3.65 (m, 2H), 3.47-3.28 (m, 4H), 3.18-3.10 (m, 2H), 2.98-2.81 (m, 4H), 2.25-2.16 (m, 2H), 2.14-2.06 (m, 2H), 1.90-1.67 (m, 7H), 1.44-1.31 (m, 1H). To (0.50 g, 1.5 mmol) of {4-[4-(3-Piperidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine dihydrochloride was added 1.5 mL of formaldehyde (37% w/w solution in H2O). 1.9 mL of formic acid was added and the mixture was heated to 100°C for 1.5 h. After cooling, water was added and the mixture extracted with ether. NaOH was added to the aqueous phase and the mixture extracted 3 times with ether. The organic extracts were washed with brine, dried over Na2SO4 filtered and concentrated To a solution of 1-(4-methoxyphenyl)cyclohexanecarbonitrile (2 g, 9.29 mmol) in DCM (40 mL) at 0°C under N2 was added dropwise BBr3 (2.63 mL, 27.87 mmol). The reaction was allowed to warm to room temperature and stirred for 48hours. The mixture was stirred for 3 hours at 0°C and quenched with water (30 mL). The mixture was separated and the organic layer was washed with a saturated aqueous solution of NaHCO3 then water. The combined organic extracts were dried over Na2SO4, filtered, concentrated 1-(4-Hydroxyphenyl)cyclohexanecarbonitrile (1.70 g, 8.45 mmol), 1-(3-chloro-propyl)-pyrrolidine (1.87 g, 12.67 mmol), acetone (50 mL), sodium iodide (0.444 g, 2.96 mmol) and K2CO3 (5.45g, 39.44 mmol) were heated to 50°C overnight. The solvent was evaporated and the crude product was taken into DCM, washed with 0.5N NaOH, extracted with 0.5N HCl solution and washed with DCM. The aqueous layer was basified with 0.5N NaOH and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, washed with DCM and concentrated To a stirred suspension of LiAlH4 (0.607 g, 16 mmol) in diethyl ether (15 mL) cooled at 0°C was added dropwise a solution of 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarbonitrile (1 g, 3.2 mmol) in diethyl ether (10 mL). After being stirred at room temperature for 30 min, the reaction mixture was refluxed for another 30 min. The mixture was cooled to 0°C and water (1.38 mL), a 5N aqueous solution of sodium hydroxide (1.38 mL) and water (5.52 mL) again were successively added dropwise. After being stirred for 15 min at room temperature, the mixture was filtered over diatomaceous earth and concentrated. The crude {1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methylamine (0.961 g, 95%) was used in the next step without further purification. To {1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methylamine (0.96 g, 3 mmol) was added formic acid (5 mL) followed by formaldehyde (37% w/w solution in H2O, 0.915 mL, 33 mmol). The mixture was refluxed for 3 h and allowed to stir overnight at room temperature. It was then diluted with DCM, basified to pH 12 with an aqueous solution of NaOH and the mixture was extracted with DCM. The organic extracts were dried over Na2SO4, filtered, concentrated A solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 A suspension of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 Anhydrous tetrahydrofuran (141 ml, 10vol) was charged rapidly onto stirred and cooled (0-5°C) lithium aluminium hydride (6.2g, 0.1634mol, 0.44wt) under nitrogen. The resulting slurry was cooled to 0-5°C and then a solution of methyl 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 Pyridinium chlorochromate (20.3g, 0.09415mol), 1.69wt) was charged to a stirred suspension of celite (24g, 2wt) and {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 A solution of the 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 A solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 To a solution of 4-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-thiomorpholine (200mg, 0.494mmol) in TFA (0.67ml) at 5 to 10°C was added dropwise a solution of trifluoro-peracetic acid [4M solution prepared by the addition of 27.5% H2O2 (0.94ml) to TFA (1.56ml)] and stirred at 5 to 10°C for 1 hour. The reaction mixture was diluted with DCM (5ml) and NaOH (5M solution, 4ml) was added to attain pH14. The mixture was extracted with DCM ((2x5ml), the combined DCM extracts were washed with saturated aqueous brine (10ml), dried over MgSO4, filtered and concentrated To a solution of 4-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-thiomorpholine (230mg, 0.56mmol) in TFA (0.77ml) at 0 to 5°C was added dropwise a solution of trifluoro-peracetic acid [4M solution prepared by the addition of 27.5% H2O2 (0.94ml) to TFA (1.56ml)]. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0 to 5°C, diluted with DCM (5ml) and quenched with NaOH (5M solution, 5ml) to attain pH14. The mixture was extracted with DCM (4x5ml), the combined DCM extracts were dried over MgSO4, filtered and concentrated 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-Piperazine-1-carboxylic acid tert-butyl ester (1.0g, 5.4mmol), acetic acid (3ml) and water (5ml) were mixed together. Potassium cyanate (2.25g, 27.7mmol) was added portionwise as a solution in water (5ml) and stirred for 4 hours, during which time a solid precipitated. The solid was filtered, re-dissolved in DCM (20ml), dried over MgSO4, filtered, the filter cake washed with DCM (5vol) and concentrated 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (10.83 g, 34.05 mmol) and triethylamine (10.31 g, 102.16 mmol) in dry dichloromethane at 0 ° C was added dropwise a solution of di- To a stirred solution of LiAlH4 (2.59 g, 68.18 mmol) in dry THF at 0° C was added dropwise a solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-pyran-4-ylmethyl}carbamic acid To a solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.629 mmol) in dichloroethane (5 mL) under nitrogen atmosphere was added acetic acid (45 mg, 1.258 mmol), triethylamine (76 mg, 1.258 mmol) and 3-(methylthio)propanal (108 mg, 1.04 mmol). The mixture was stirred for 30 min and a solution of NaHB(OAc)3 (236 mg, 1.15 mmol) in dichloroethane (5 mL) was added. After stirring at room temperature overnight, the reaction mixture was filtered over celite, concentrated To a solution of methyl-(3-methylsulfanyl-propyl)-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (170 mg, 0.404 mmol) in DCM (10 mL) under nitrogen atmosphere at 0°C was added TFA (0.240 mL, 3.2 mmol) followed by meta-chloroperbenzoic acid (70% pure, 199 mg, 0.808 mmol). The reaction mixture was stirred overnight allowing it to warm up to room temperature. It was quenched with an aqueous solution of Na2S2O3. The organic layer was separated and washed with an aqueous solution of NaHCO3. The organic layer was then dried over sodium sulphate, filtered, concentrated and purified by column chromatography on silica gel eluting with DCM:MeOH:NH3 (89.9:10:0.1) to give the title compound.1H NMR (400MHz, CDCl3) δ 7.18 (d, 2H), 6.88 (d, 2H), 4.03 (t, 2H), 3.78 - 3.73 (m, 2H), 3.53 - 3.48 (m, 2H), 2.82 (s, 3H), 2.69-2.73 (m, 2H), 2.65 (m, 2H), 2.55 (m, 4H), 2.47 (s, 2H), 2.22 (t, 2H), 2.12 - 2.09 (m, 2H), 1.89-2.05 (m, 5H), 1.68-1.85 (m, 8H). To a solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (400 mg, 1.256 mmol) in dichloroethane (10 mL) under nitrogen atmosphere was added acetic acid (180.5 mg, 2.76 mmol), triethylamine (306.4 mg, 2.76 mmol) and acetone (80.2 mg, 1.38 mmol). The mixture was stirred for 1 h at ambient temperature and NaHB(OAc)3 (601 mg, 2.76 mmol) was added. After stirring overnight, the reaction mixture was filtered over celite, concentrated To isopropyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}-amine (258 mg, 0.71 mmol) was added formaldehyde (37% w/w solution in H2O, 1 mL) and formic acid (1.5 mL).The resulting mixture was heated to 60°C overnight. After cooling, H2O and ethyl acetate were added. The aqueous layer was separated, basified with 30% NaOH and extracted 3 times with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated To a solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (254 mg, 0.798 mmol) in dichloroethane (5 mL) under nitrogen atmosphere were added acetic acid (37 mg, 1.6 mmol), triethylamine (97 mg, 1.6 mmol) and cyclopentanone (10 mg, 1.19 mmol). The mixture was stirred for 30 min at ambient temperature and NaHB(OAc)3 (204 mg, 1.6 mmol) was added at 0°C. After stirring overnight, the reaction mixture was filtered over celite, concentrated To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (150 mg, 0.47 mmol) and 1-bromo-4-chloroethane (54.2 µL, 0.47 mmol) in anhydrous acetonitrile (5 mL) was added potassium carbonate (65 mg, 0.47 mmol). The mixture was heated to 60°C overnight then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH:NH3 (94:5:1) to give the title compound (40 mg, 23 % yield).1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.73 -3.78 (m, 2H), 3.57-3.53 (m, 2H), 2.65 -2.61 (m, 4H), 2.53 (m, 4H), 2.20 (m, 4H), 2.10-1.88 (m, 6H), 1.56 (m, 4H). To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (207 mg, 0.65 mmol) and bis(2-bromoethyl)ether (82 µL, 1.3 mmol) in anhydrous acetonitrile (10 mL) was added potassium carbonate (180 mg, 1.3 mmol). The mixture was heated to 60°C overnight then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (97:3) with 10% NH3 to give the title compound (90 mg, 23 % yield).1H NMR (400MHZ, CDCL3) δ 7.22 (d, 2H), 6.83 (d, 2H), 4.04 (m, 2H), 3.73 (m, 2H), 3.51 (m, 6H), 3 (m, 6H), 2.38 (m, 2H), 2.25 (m, 2H), 2.13 - 2.03 (m, 10H), 1.88 (m, 2H). Methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (150 mg, 0.45 mmol) was treated with (2-bromoethyl)benzene (100 mg, 0.54 mmol) and potassium carbonate (187 mg, 1.35 mmol) in a sealed tube under microwave (Smith Personal Synthesiser) (55°C) for 80 min. The reaction mixture was taken in DCM (10 mL) and water (5 mL). The organic layer was separated and washed twice with water and brine. The combined organic extracts were dried over Na2SO4, filtered, concentrated This example was prepared from methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine similarly to the procedure used for example 59. 1H NMR (400MHz, CDCl3) δ 7.28-7.19 (m, 7H), 6.87 (d, 2H), 4.00 (t, 2H), 3.69-3.65 (m, 2H), 3.53-3.48 (t, 2H), 3.29 (s, 2H), 2.61 (t, 2H), 2.54-2.50 (m, 6H), 2.10-2.07 (m, 2H), 2.01-1.97 (m, 2H), 1.93-1.88 (m, 2H), 1.86 (s, 3H), 1.78-1.76 (m, 4H). To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetra-hydropyran-4-ylmethyl}amine (150 mg, 0.45 mmol) and 2-bromoethylmethylether (43 µL, 0.45 mmol) in anhydrous acetonitrile (5 mL) was added potassium carbonate (62.4 mg, 0.45 mmol). The mixture was heated to 60°C overnight then to 80°C for a day and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) with 10% NH3 to give the title compound as an oil (69 mg, 18% yield).1H NMR (400MHz, CDCl3) δ 7.20 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.78 - 3.48 (m, 4H), 3.29 (t, 2H), 3.27 (s, 3H), 2.67 (t, 2H), 2.59 (m, 4H), 2.48 (s, 2H), 2.39 (t, 2H), 2.11-2.00 (m, 4H), 1.98 (s, 3H), 1.92 - 1.85 (m, 2H), 1.84-1.80 (m, 4H). To a solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (150 mg, 0.45 mmol) and 2-chloropyrymidine (52 mg, 0.45 mmol) in anhydrous acetonitrile (5 mL) was added potassium carbonate (62 mg, 0.45 mmol). The mixture was heated to 60°C overnight then refluxed for 2 days, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (97:3) with 10% NH3 to give the title compound (40 mg, 22% yield).1H NMR (400MHz, CDCl3) δ 8.24 (m, 2H), 7.20 (d, 2H), 6.88 (d, 2H), 6.42 (m, 1H), 4.02 (m, 2H), 3.80 (m, 4H), 3.52 (t, 2H), 2.59 (m, 9H), 2.01 (m, 8H), 1.79 (s, 3H). To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (200 mg, 0.628 mmol) and triethylamine (106 µL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of mesyl chloride (58 µL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (140 mg, 56 %).1NMR (400MHz, CDCl3) To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (200 mg, 0.628 mmol) and triethylamine (106 µL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of α-toluenesulfonylchloride (143 mg, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (207 mg, 69 %).1H NMR (400MHZ, CDCL3) δ 7.27-7.22 (M, 3H), 7.16-7.14 (M, 2H), 7.07 (D, 2H), 6.83 (D, 2H), 4.05 (S, 2H), 3.95 (T, 2H), 3.68-3.63 (M, 2H), 3.55 (T, 1H), 3.49-3.44 (M, 2H), 3.01 (D,2H), 2.57 (T,2H), 2.47 (S,4H), 2.02-1.93 (M, 4H), 1.78-1.72 (M, 6H). To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (100 mg, 0.314 mmol) and triethylamine (0.1 mL, 0.63 mmol) in anhydrous dichloromethane (3 mL) under nitrogen atmosphere at 0°C was added 3-cyanobenzenesulfonylchloride (100 mg, 0.47 mmol). The reaction mixture was stirred for 2 h allowing it to warm up to room temperature. It was then diluted with dichloromethane and quenched with water. The organic layer was separated and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound.1H NMR (400MHz, CDCl3) δ 7.97 (s, 1H), 7.93-7.91 (d, 1H), 7.83-7.81 (d, 1H), 7.62-7.58 (m, 1H), 7.11-7.09 (d, 2H), 6.89-6.86 (d, 2H ), 4.06-4.03 (m, 3H), 3.77-3.72 (m, 2H), 3.56-3.51 (m, 2H),3.08 (br s,2H), 2.70-2.67 (m, 2H), 3.08 (br s,4H), 2.08-2.01 (m, 4H), 1.85-1.82 (m, 6H). To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (100 mg, 0.314 mmol) and triethylamine (0.1 mL, 0.63 mmol) in anhydrous dichloromethane (3 mL) under nitrogen atmosphere at 0°C was added 2-fluorobenzenesulfonylchloride (91 mg, 0.47 mmol). The reaction mixture was stirred for 2 h allowing it to warm up to room temperature. It was then diluted with dichloromethane and quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (120 mg, 80%).1H NMR (400MHz, CDCl3) δ 7.86-7.82 (t, 1H), 7.58-7.52 (m, 1H), 7.28-7.24 (m, 1H), 7.13-7.12 (m, 3H), 6.90-6.88 (m, 2H), 4.19 (m, 1H), 4.05-4.02 (t, 2H), 3.73-3.70 (m, 2H), 3.56-3.51 (t, 2H), 3.10-3.08 (d, 2H), 2.66-2.62 (t, 2H), 2.54 (m, 4H), 2.06-1.99 (m, 4H), 1.85-1.8 (m, 6H). To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 µL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of mesyl chloride (56 µL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (175 mg, 71 %).1NMR (400MHz, CDCl3) δ 7.22 (d, 2H), 6.92-6.90 (d, 2H), 4.03 (t, 2H), 3.83-3.78 (m, 2H), 3.52 (t, 2H), 3.16 (s, 2H), 2.68 (s, 3H), 2.64 (t, 2H), 2.54 (m, 4H), 2.19-2.15 (m, 5H), 2.05-1.91 (m,4H), 1.81-1.78 (m, 4H). To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (200 mg, 0.628 mmol) and triethylamine (106 µL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of dimethylsulfamoyl chloride (81 µL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (207 mg, 77 %).1H NMR (400MHZ, CDCL3) δ 7.19 (D, 2H), 6.93-6.91 (D, 2H), 4.05 (T, 2H), 3.78-3.76 (M, 2H), 3.59-3.54 (M, 2H), 3.17-3.15 (D, 2H), 2.76-2.70 (M, 12H), 2.15-2.06 (M, 4H), 1.90-1.87 (M, 6H). To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (200 mg, 0.628 mmol) and triethylamine (106 µL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of acetyl chloride (54 µL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (102 mg, 45 %).1H NMR (400MHz, CDCl3) δ 7.18 (d, 2H), 6.94 (d, 2H), 4.97 (s, 1H), 4.05 (t, 2H), 3.80 (m, 2H), 3.59 (m, 2H), 3.46 (d, 2H), 2.66 (t, 2H), 2.57 (m, 4H), 2.03 (m, 4H), 1.80 (m,8H). To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 µL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of acetyl chloride (52 µL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound (86 mg, 36 %).1H NMR (400MHz, CDCl3) δ Shows rotomers 7.19-7.13 (2d, 2H), 6.91-6.88 (d, 2H), 4.05-4.02 (m, 2H), 3.85-3.80 (m, 2H), 3.56-3.45 (m, 4H), 2.67-2.65 (m, 2H), 2.60-2.56 (m, 4H), 2.32-1.96 (several multiplets, 12H). To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (200 mg, 0.63 mmol) and triethylamine (93 µL, 0.66 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere at 0°C was added dropwise a solution of phenylacetyl chloride (93 µL, 0.66 mmol) in anhydrous dichloromethane (2 mL). After stirring for 3 h at 0°C, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (98:2) to give the title compound (34 mg, 12 %).1H NMR (400MHz, CDCl3) δ 7.32-7.31 (m, 3H), 7.12-7.10 (m, 2H), 6.89-6.87 (d, 2H), 6.76-6.74 (d, 2H), 4.91 (t, 1H), 4.02 (t, 2H), 3.79-3.74 (m, 2H), 3.53-3.51 (m, 2H), 3.47 (s, 2H), 3.37-3.35 (d, 2H), 2.62 (m, 6H), 2.08-2.06 (m, 2H), 1.93-1.85 (m, 6H), 1.76-1.74 (m, 2H). To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (200 mg, 0.63 mmol) and triethylamine (106 µL, 0.754 mmol) in anhydrous dichloromethane (9 mL) under nitrogen atmosphere was added dropwise a solution of dimethylcarbamoylchloride (69 µL, 0.754 mmol) in anhydrous dichloromethane (1 mL). After stirring for 3 h at 0°C, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound (80 mg, 32 %).1H NMR (400MHz, CDCl3) δ 7.13 (d, 2H), 6.86 (d, 2H), 3.98 (t, 2H), 3.84 (t, 1H), 3.74 (m, 2H), 3.52 (m, 2H), 3.36 (d, 2H), 2.69 (s, 6H), 2.65 (m, 2H), 2.57 (m, 4H), 2.02-1.95 (m,4H), 1.84-1.78 (m, 6H). To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 µL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of dimethylcarbamoylchloride (67 µL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) followed by DCM:MeOH:NH3 (90:5:5) to give the title compound (84 mg, 39 %).1H NMR (400MHz, CDCl3) δ 7.19 (d, 2H), 6.90-6.88 (d, 2H), 4.03 (t, 2H), 3.81-3.78 (m, 2H), 3.56-3.52 (m, 4H), 2.70 (s, 6H), 2.66 (t, 2H), 2.29 (s, 3H), 2.05-2.01 (m, 4H), 1.86-1.81 (m, 6H). To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (200 mg, 0.63 mmol) and acetic acid (108 µL, 1.89 mmol) in water (12 mL) was added portionwise potassium cyanate (153 mg, 1.89 mmol). After stirring overnight, the reaction mixture was quenched with a 0.1N aqueous solution of NaOH. The organic layer was separated and the aqueous layer extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) followed by DCM:MeOH (90:10) and DCM:MeOH:NH3 (90:5:5) to give the title compound (25 mg, 11 %).1H NMR (400MHz, CDCl3) δ 7.18 (d, 2H), 6.92-6.90 (d, 2H), 4.24 (s, 2H), 4.17 (t, 1H), 4.03 (t, 2H), 3.84-3.79 (m, 2H), 3.61-3.55 (m, 2H), 3.36-3.35 (d, 2H), 2.63 (t, 2H), 2.53 (m, 4H), 2.07-1.97 (m, 4H), 1.88-1.79 (m, 6H). A three-neck reaction vessel was charged with [4-(3-pyrrolidin-1-ylpropoxy)phenyl]acetonitrile (7g, 28.6 mmol), benzyltrimethylammonium hydroxide (40% in methanol, 1.3 mL) in acetonitrile (185 mL). The solution was heated to reflux and methyl acrylate (25 mL, 286 mmol) was added dropwise. After refluxing for 5 hr, the mixture was concentrated to half, diethyl ether was added and the organics were washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash-chromatography to provide 4-cyano-4-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-heptanedioic acid dimethyl ester (8.8 g, 74%). To a solution of 4-cyano-4-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-heptanedioic acid dimethyl ester (8.8 g, 21.1 mmol) in 1,2-dimethoxyethane (176 mL) was charged portions of NaH (60% dispersion, 2.55 g, 63.4 mmol). The reaction mixture was heated to reflux. After 4.5 hr, the % of solvent were evaporated and the mixture cooled to 20°C with an ice bath and quenched with water (100 mL), HCl 1N (100 mL). The aqueous layer was extracted with ether (100 mL). After basification with NaOH the aqueous phases were extracted with dichloromethane. The combined organics were washed with water, dried over Na2SO4, filtrered and concentrated to provide 5-cyano-2-oxo-5-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarboxylic acid methyl ester (6.6 g , 81%) as an oil. To a solution of 5-cyano-2-oxo-5-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarboxylic acid methyl ester (6.6 g, 17 mmol) and dimethylsulfoxide (128 mL) was added water (8.0 mL) and sodium chloride (6.4 g, 109 mmol). The reaction mixture was heated to 142-146°C. After 5 hr, the mixture was concentrated and the residue was dissolved in DCM (120 mL), washed with water (100 mL), and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (70 g silica gel, eluant : gradient of DCM/MeOH 95/5 to 90/10) providing 4-oxo-1-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarbonitrile as a crystallizing oil (2.2 g 45.5 %). After crystallization in ether, 0.2g of analytical sample were obtained. To a stirred suspension of LiAlH4 (0.59 g, 15 mmol, 10 eq) in diethyl ether (8 mL) was added dropwise at ambient temperature a solution of 4-oxo-1-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarbonitrile (0.5 g, 1.5 mmol) in diethyl ether (25 mL). The reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to 0°C and, successively, a solution of water, sodium hydroxide (15% w/v, 0.68 mL) and water again were carefully added dropwise. After being stirred for 15 min at room temperature, the mixture was filtered over diatomaceous earth and concentrated. The residue was purified by flash chromatography (10 g silica gel, DCM/ MeOH (10% NH3 ) to provide the title compound (0.27 g, 54%) as an oil. To 4-aminomethyl-4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-cyclohexanol (0.26 g, 0.78 mmol) was added 0.8 mL of formaldehyde (37% w/w solution in H2O). 1 mL of formic acid was added and the mixture was heated to about 100°C for 20 min. After cooling, water was added and the mixture extracted with ether. NaOH was added at the aqueous phase and the mixture extracted 3 times with ether. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated Starting phenol (3.69mmol), chloride (5.90mmol), DMF (15ml) and K2CO3 (14.83mmol) was heated to 130°C until the reaction is complete (1 to 2 hrs). Cooled to ambient temperature, water (30ml) was added, extracted with EtOAc (3x9ml) and the combined organic extracts were washed with NaOH (2M, 2x25ml). The organics were dried over MgSO4, filtered and concentrated 4-(3-Hydroxy-phenyl)-tetrahydro-2H-pyran-4-carbonitrile (1.03g, 5.10mmol), 1-(3-chloro-propyl)-pyrrolidine (600mg, 4.08mmol), DMF (6.8ml) and K2CO3 (2.82g, 20.4mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3 x 50ml), brine (3 x 50ml), dried over MgSO4, fitered and concentrated 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (318mg, 1.56mmol), 1-(3-chloropropyl)-2,5-trans-dimethyl-pyrrolidine (250mg, 1.42mmol), DMF (5ml) and K2CO3 (785mg, 5.70mmol) were reacted together according to general procedure E. The crude was dissolved in ethyl acetate (20ml), washed with brine (2 x 10ml), dried over MgSO4, filtered and concentrated 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (315mg, 1.55m mol), 1-(3-chloropropyl)-2-methyl-pyrrolidine (400mg, 2.48mmol), DMF (6ml) and K2CO3 (833mg, 6.03mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (450mg, 88%) as an orange oil.1H NMR (400MHz, CDCl3), δ 7.37 (d, 2H), 6.93 (d, 2H), 4.12-3.99 (m, 4H), 3.89 (td, 2H), 2.35-1.62 (m, 14H), 1.42 (m, 1H), 1.09 (d, 3H). 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (750mg, 3.69m mol), 4-(3-chloropropyl)-thiomorpholine (1.06g, 5.91mmol), DMF (15ml) and K2CO3 (2.05g, 14.83mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:3:1) provided the title compound (365mg, 29%) as an off white solid.1H NMR (400MHz, CDCl3), δ 7.37 (d, 2H), 6.93 (d, 2H), 4.12-4.04 (m, 2H), 4.01 (t, 2H), 3.89 (td, 2H), 2.77-2.64 (m, 8H), 2.54 (t, 2H), 2.16-1.99 (m, 4H), 1.95 (p, 2H). Sodium perborate tetrahydrate (221 mg, 1.43mmol) and glacial acetic acid (5ml) was heated to 50 to 60°C and 4-[4-(3-Thiomorpholin-4-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile (500mg, 1.43mmol) was added in one portion and the heating was maintained for 3 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was added to ice water (15ml) and extracted with EtOAc (3x5ml), which was discarded. The aqueous phase was basified to pH 8-9 with 2M sodium hydroxide and extracted with DCM (3x25ml), dried over MgSO4, filtered and concentrated To a solution of 4-[4-(3-Thiomorpholin-4-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile (500mg, 1.44mmol) in TFA (1.65ml) at 0 to 5°C was added drop wise a solution of trifluoro-peracetic acid (4M in TFA, 0.72ml). The reaction was allowed to warm to room temperature and stirred for 3 hours. A further portion of trifluoro-peracetic acid (4M in TFA, 0.097ml) [4M solution prepared by the addition of 27.5% H2O2 (0.94ml) to TFA (1.56ml)] was added to the reaction and stirred overnight. The reaction mixture was cooled to 0 to 5°C, diluted with DCM (20ml) and quenched with NaOH (5M solution, 12ml) to attain pH10. The mixture was extracted with DCM (3 x 20ml), the combined DCM extracts were dried over MgSO4, filtered and concentrated 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 -[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-Piperazine-1-carboxylic acid 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-{3-[4-(4-Cyano-tetrahydro-pyran-4-yl)-phenoxy]-propyl}-piperazine-1-carboxylic acid 4-[4-(3-Piperazin-1-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile (265mg, 0.81 mmol), DCM (10.6ml), HOBT (120mg, 0.89mmmol), FMoc (L)-aniline (277mg, 0.89mmol) and EDCI.HCl (171mg, 0.89mmol) were stirred at ambient temperature overnight. Water (10ml) was added and stirred for one hour, the mixture was filtered and the organic phase separated and washed with water (10ml), the organic phase was dried over MgSO4, filtered and concentrated 2-(Methylamino)-ethanol (1.0g, 13.3mmol), acetone (20ml, 20vol), 5M NaOH solution (3.19ml, 1.2eq.) and 1-bromo-3-chloropropane (6.28g, 39.9mmol, 3eq.) were reacted together according to general procedure A to give the title compound (1.14g, 55%) as a colourless oil. 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (800mg, 3.94mmol), 2-[(3-chloropropyl)-methyl-amino]-ethanol (595mg, 3.94mmol), DMF (8ml) and K2CO3 (2.18g, 15.76mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3.x 20ml), water (2x 20ml), dried over MgSO4, fitered and concentrated 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (790mg, 3.87mmol), 1-(3-chloro-2-methyl-propyl)-pyrrolidine (500mg, 3.10mmol), DMF (5ml) and K2CO3 (2.14g, 15.50mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3 x 20ml), water (2 x 20ml), dried over MgSO4, fitered and concentrated Pyrrolidine (28.15g, 0.4mol), toluene (200ml), catalytic p-TsOH (200mg) and ethyl acetoacetate (20g, 0.15mol) were refluxed together with a Dean-Stark apparatus under N2 for 3hours. The reaction was cooled to room temperature and concentrated 3-Pyrrolidin-1-yi-butan-1-ol (1.0g, 7mmol) was dissolved in DCM (20ml). The reaction was cooled to 0-5°C and thionyl chloride (1.65g, 14mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1.0g, 4.9mmol), 1-(3-chloro-1-methyl-propyl)-pyrrolidine (780mg, 3.90mmol), DMF (20ml) and K2CO3 (2.71g, 19.60mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3 x 20ml), water (2 x 20ml), dried over MgSO4, fitered and concentrated 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1.0g, 4.9mmol), 2-(2-chloro-ethyl)-1-methylpyrrolidine (722mg, 3.90mmol), DMF (20ml) and K2CO3 (2.71g, 19.60mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3 x 20ml), water (2 x 20ml), dried over MgSO4, fitered and concentrated 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (459mg, 2.26mmol) in DMF (2ml) was added to a solution of NaH (100mg, 2.5mmol) in DMF (2ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-isopropyl-piperidin-4-yl ester (400mg, 1.81mmol) in DMF (1.3ml) was slowly added. The reaction was heated to 75°C and stirred for 6hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20ml), water (10ml) and 5M NaOH solution (10ml). The organic layer was washed with 2.5M NaOH (2 x 20ml), brine (2 x 20ml), dried over MgSO4, filtered and concentrated 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (459mg, 2.26mmol) in DMF (2ml) was added to a solution of NaH (100mg, 2.5mmol) in DMF (2ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-cyclopentyl-piperidin-4-yl ester (447mg, 1.81 mmol) in DMF (1.3ml) was slowly added. The reaction was heated to 75°C and stirred for 6hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20ml), water (10ml) and 5M NaOH solution (10ml). The organic layer was washed with 2.5M NaOH (2 x 20ml), brine (2 x 20ml), dried over MgSO4, filtered and concentrated 4-(4-hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (3.4 g, 16.73 mmol) was taken in DMF (75 ml) and then Cs2CO3 (4.84 g, 25.095 mmol) was added followed by dropwise addition of 1-bomo-3-chloroproprane (2.45 ml) at 60 °C. The heating was continued at 60 °C overnight. First the reaction mixture was concentrated and quenched by adding water and extracted with ethyl acetate. The compound was purified by coloumn chromatography (0-14 %, ethyl acetate-hexane). Yield: 3.3 g (70 % of a 10:3 mixture of chloro and bromo compound). A mixture of halide (0.7 mmol), Cs2CO3 (0.350 g, 1.07 mmol), potassium iodide (0.180 g, 1.07 mmol) and amines (NR7R8) (1.07 mmol) in DMF (7 mL) was heated to 70°C overnight. The mixture was cooled to ambient temperature, water was added, and the resulting mixture was extracted with dichloromethane and the organic extracts were dried over Na2SO4, filtered and concentrated The compound was obtained according the general procedure F, using morpholine as amine. The hydrochloride salt as analytical sample was prepared with ether/HCl 2M in dichloromethane and crystallization in ether. Yield = 34%1H NMR (400MHz, DMSO-D6) δ 1.95-2.12 (m, 4H); 2.16-2.25 (m, 2H); 3.01-3.12 (m, 2H); 3.19-3.27 (m, 2H); 3.40-3.48 (m, 2H); 3.60-3.69 (t, 2H); 3.80-3.89 (m, 2H); 3.91-4.03 (m, 4H); 4.08-4.13 (m, 2H); 7.20 (d, 2H); 7.46 (d, 2H); 11.33 (bs, 1H) The compound was obtained according the general procedure F, using 1-methylpiperazine as amine. The hydrochloride salt as analytical sample was prepared with ether/HCl 1 M in dichloromethane and triturated with pentane. Yield = 57%1H NMR (400MHz, DMSO-D6) δ 11.85 (bs, 1H), 7.46 (d, 2H), 7.02 (d, 2H), 4.13 -4.07 (m, 2H), 4.03 -3.96 (m, 2H), 3.84-3.18 (m, 12H), 2.87-2.78 (m, 3H), 2.24-2.13 (m, 2H), 2.11-1.96 (m, 4H). The compound was obtained according the general procedure F, using 2-methylpiperidine as amine. The hydrochloride salt as analytical sample was prepared with ether/HCl 1 M in dichloromethane and trituration with pentane. Yield = 28%1H NMR (400MHz, DMSO-D6) δ 10.22 (bs, 1H), 7.46 (d, 2H), 7.01(d, 2H), 4.13-4.06 (m, 2H), 4.03-3.96 (dd, 2H), 3.69-3.60 (t, 2H), 3.48-3.38 (m, 1H), 3.25-3.06 (m, 3H), 3.01-2.90 (m, 1H), 2.21-1.95 (m, 7H), 1.88-1.57 (m, 5H), 1.56-1.39 (m, 1H), 1.32 (d, 2H), 1.24 (d, 1H). The compound was obtained according the general procedure F, using 3-methylpiperidine as amine. The hydrochloride salt as analytical sample was prepared with ether/HCl 1M in dichloromethane and trituration with pentane. Yield = 52%1H NMR (400MHz, DMSO-D6) δ 10.32 (bs, 1H), 7.46 (d, 2H), 7.01 (d, 2H), 4.11-4.05 (t, 2H), 4.03-3.96 (dd, 2H), 3.69-3.60 (t, 2H), 3.48-3.35 (m, 2H), 3.19-3.11 (m, 2H), 2.82-2.72 (m, 1H), 2.58-2.45 (m, 1H), 2.24-2.16 (m, 2H), 2.12-1.90 (m, 5H), 1.85-1.70 (m, 3H), 1.12-1.02 (m, 1H), 0.89 (d, 3H). The compound was obtained according the general procedure F, using 4-methylpiperidine as amine. The hydrochloride salt as analytical sample was prepared with ether/HCl 1M in dichloromethane and trituration with pentane. Yield = 60%1H NMR: (400MHz, DMSO-D6) δ 10.18 (bs, 1H), 7.46 (d, 2H), 7.01 (d, 2H), 4.11-4.05 (t, 2H), 4.03-3.96 (dd, 2H), 3.69-3.60 (t, 2H), 3.49-3.42 (m, 2H), 3.19-3.11 (m, 2H), 2.94-2.83 (m, 2H), 2.22-2.13 (m, 2H), 2.11-1.95 (m, 4H), 1.81-1.73 (m, 2H), 1.65-1.54 (m, 1H), 1.53-1.41 (m, 2H), 0.91 (d, 3H). The compound was obtained according the general procedure F, using hexamethyleneimine as amine. The hydrochloride salt as analytical sample was prepared with ether/HCl 1M in dichloromethane and trituration with ether. Yield = 9%1H NMR (400MHz, DMSO-D6) δ 10.54 (bs, 1H), 7.41 (d, 2H), 7.01(d, 2H), 4.11-4.05 (t, 2H), 4.03-3.96 (dd, 2H), 3.69-3.60 (dt, 2H), 3.41-3.30 (m, 2H), 3.24-3.17 (m, 2H), 3.16-3.06 (m, 2H), 2.24-2.16 (m, 2H), 2.12-1.95 (m, 4H), 1.92-1.76 (m, 4H), 1.72-1.52 (m, 4H). The compound was obtained according the general procedure F, using 4,4-difluoropiperidine hydrochloride as amine (add (C2H5)3N to obtain the free base ). The hydrochloride salt as analytical sample was prepared with ether/HCl 1M in dichloromethane and trituration with ether. Yield = 9%1H NMR : (400MHz, DMSO-D6) δ 10.28 (bs, 1H), 7.46 (d, 2H), 7.01(d, 2H), 4.12-4.07 (t, 2H), 4.03-3.96 (dd, 2H), 3.69-3.59 (dt, 4H), 3.33-3.25 (m, 2H), 3.21-3.11 (m, 2H), 2.39-2.27 (m, 2H), 2.27-2.17 (m, 2H), 2.12-1.95 (m, 4H). 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1.5g, 7.39mmol), 1-bromo-4-chlorobutane (1.7ml, 14.77mmol), DMF (20ml) and K2CO3 (4.1g, 29.56mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant ethyl acetate:heptanes (33:66) provided a mixture of bromo and chloro phenoxy ether (1.3g, 60%) which was used in the next stage. A portion of the mixture (0.5g, 1.70mmol) and pyrrolidine (0.42ml, 5.11mmol) were refluxed in EtOH (5ml, 10vol) overnight. The reaction was concentrated 1-(4-Hydroxyphenyl)cyclohexanecarbonitrile (2.0 g, 10 mmol) was taken in acetone (150 mL) and then Cs2CO3 (8.1 g, 25 mmol) was added followed by dropwise addition of 1,3 dibromopropane (5.1 mL, 50 mmol). The mixture was heated for 3 h at 70°C. After cooling and filtration, the mixture was concentrated and the residue was purified by flash chromatography (50 g silica gel, DCM) to provide the title compound (2.8 g, 87%). Note: presence of allyl derivative as impurity. A mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile (0.660 g, 2.0 mmol), amine (NR7R8) (0.260g, 3.0 mmol), sodium carbonate (0.320 g, 3 mmol), potassium iodide (20 mg) and 20 mL of butanol was heated for 4 h at 100°C. After cooling, water was added to quench the reaction and the mixture was extracted with DCM. The organics extracts were washed with a saturated aqueous solution of NaHCO3, water and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (DCM and DCM / MeOH (10% NH3) to provide (0.440 g, 67%). A mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile (0.660 g, 2.0 mmol), piperidine (0.260g, 3.0 mmol), sodium carbonate (0.320 g, 3 mmol), potassium iodide (20 mg) and 20 mL of butanol was heated for 4 h at 100°C according to general procedure G. After cooling, water was added to quench the reaction and the mixture was extracted with DCM. The organics extracts were washed with a saturated aqueous solution of NaHCO3, water and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (DCM and DCM / MeOH (10% NH3) to provide the title compound (0.440 g, 67%).1H NMR (400MHz, CDCl3) δ 7.37 (d, 2H), 6.90(d, 2H), 4.00 (t, 2H), 2.49-2.36 (m, 6H), 2.17-2.09 (m, 2H), 1.97 (qt, 2H), 1.88-1.67 (m, 7H), 1.62-1.55 (m, 4H), 1.47-1.40 (m, 2H), 1.32-1.20 (m, 1H). 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1eq.), alcohol (R-OH) (0.8eq.) and PPh3 (1eq.) were mixed together in THF (10vol) and cooled to 0°C under N2. DIAD (1eq.) in THF (10vol) was added slowly to the reaction and allowed to warm to room temperature overnight. The reaction was quenched with 2M HCl solution (10vol) and extracted with ethyl acetate (3 x 10vol). The aqueous was basified to pH 14 with NaOH (∼30vol) and extracted with ethyl acetate (3 x 10vol). The organics were dried over MgSO4, filtered and concentrated 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1.29g, 6.4mmol), 2,2-dimethyl-3-pyrrolidin-1-yl-propan-1-ol (0.8g, 5.1mmol), PPh3 (1.67g, 6.4mmol), THF (16ml) and DIAD (1.25ml, 6.4mmol) were reacted together according to general procedure H. The crude material was subjected to chromatography on silica eluting with DCM :MeOH (98 :2). The resulting solid was slurried in TBME:heptanes (1:2, 1ml) to provide the title compound (120mg, 5%) as a white solid.1H NMR (400MHz, CDCl3), δ 7.37 (d, 2H), 6.94 (d, 2H), 4.12-4.03 (m, 2H), 3.89 (td, 2H), 3.71 (s, 2H), 2.57 (br s, 4H), 2.47 (s, 2H), 2.15-1.99 (m, 4H), 1.70 (brs, 4H), 1.00 (s, 6H). 4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (400 mg, 1.27 mmol) was treated with polyphosphoric acid at 80°C overnight. After allowing the mixture to cool to room temperature, ethyl acetate and water were added. The organic layer was separated. The aqueous layer was basified to pH 10 with concentrated NaOH and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, concentrated A solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 A suspension of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 Anhydrous tetrahydrofuran (141ml, 10vol) was charged rapidly onto stirred and cooled (0-5°C) lithium aluminium hydride (6.2g, 0.1634mol, 0.44wt) under nitrogen (Note: very exothermic). The resulting slurry was cooled to 0-5°C and then a solution of methyl 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 To a suspension of NaH (60%, 0.574 g, 14.35 mmol) in DMF (8 mL) at 0°C was added dropwise [4-(3-pyrrolidin-1-ylpropoxy)phenyl]acetonitrile (1 g, 4.10 mmol) in DMF (3 mL). The reaction mixture was stirred at 0°C for 5 min than at room temperature for 30 min. After cooling to 0°C, 1,4-dibromobutane (0.980 mL, 8.2 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature then heated to 50°C overnight. It was poured into ice-cold water and extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated A three neck reaction vessel was charged with [4-(3-pyrrolidin-1-ylpropoxy)phenyl]acetonitrile (7g, 28.6 mmol), benzyltrimethylammonium hydroxide (40% in methanol, 1.3 mL) in acetonitrile (185 mL). The solution was heated to reflux and methyl acrylate (25 mL, 286 mmol) was added dropwise. After refluxing for 5 hr, the mixture was concentrated to half, diethyl ether was added and the organics were washed with HCl 1N and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash-chromatography to provide 4-cyano-4-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-heptanedioic acid dimethyl ester (8.8 g, 74%).1H NMR (400MHz, CDCl3) To a solution of 4-cyano-4-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-heptanedioic acid dimethyl ester (8.8 g, 21.1 mmol) in 1,2-dimethoxyethane (176 mL) was charged portions of NaH (60% dispersion, 2.55 g, 63.4 mmol). The reaction mixture was heated to reflux. After 4.5 hr, the ¾ of solvent were evaporated and the mixture cooled to 20°C with an ice bath and quenched with water (100 mL), HCl 1N (100 mL). The aqueous layer was extracted with ether (100 mL). After basification with NaOH the aqueous phases were extracted with dichloromethane. The combined organics were washed with water, dried over Na2SO4, filtrered and concentrated to provide 5-cyano-2-oxo-5-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarboxylic acid methyl ester (6.6 g, 81%) as an oil.1H NMR (400MHz, CDCl3) δ 12.2 (bs, 1 H); 7.33 (d, 2H); 6.95 (d, 2H); 4.08-4.00 (m, 2H); 3.75 (s, 3H); 2.95 (d, 1H); 2.80-2.70 (m, 1H); 2.65-2.60 (m, 2H); 2.50-2.42 (m, 6H); 2.30-2.15 (m, 2H); 2.05-1.95 (m, 2H); 1.90-1.85 (m, 4H). To a solution of 5-cyano-2-oxo-5-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarboxylic acid methyl ester (6.6 g, 17 mmol) and dimethylsulfoxide (128 mL) was added water (8.0 mL) and sodium chloride (6.4 g, 109 mmol). The reaction mixture was heated to 142-146°C. After 5 hr, the mixture was concentrated and the residue was dissolved in DCM (120 mL), washed with water (100 mL), and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (70 g silica gel, eluant: gradient of DCM/MeOH 95/5 to 90/10) providing 4-oxo-1-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarbonitrile as a crystallizing oil (2.2 g, 45.5%). After crystallization in ether, 0.2g of analytical sample were obtained.1H NMR (400MHz, CDCl3) To a stirred suspension of LiAlH4 (0.070 g, 1.85 mmol, 5 eq) in diethyl ether (1.9 mL) was added dropwise at 0°C a solution of 4-oxo-1-[4-(3-pyrrolidin-1-ylpfopoxy)-phenyl]-cyclohexanecarbonitrile (0.12 g, 0.37 mmol) in diethyl ether (5.5 mL). The reaction mixture was stirred at ambient temperature for 4 h .The reaction mixture was cooled to 0°C and, successively, a solution of water, sodium hydroxide (15% w/v, 0.08 mL) and water again were carefully dropped. After being stirred for 15 min at room temperature, the mixture was filtered over diatomaceous earth and concentrated. The residue was purified by flash chromatography (10 g silica gel, DCM/ MeOH (10% NH3) to provide 0.050 g of title compound.1H NMR (400MHz,DMSO-D6) Pure enantiomers of 2-methyl pyrrolidine can be obtained by resolution with +/- tartaric acid as described in 3-Bromopropan-l-ol (5.28 mL, 58.4 mmol) was added to a solution of (R)-2-methylpyrrolidine (7.1 g, 58.4 mmol) in water (200 mL). KOH (7.53 g, 134 mmol) was then added and the mixture stirred at ambient temperature for 48 hours. The reaction mixture was then extracted with dichloromethane (5 x 80 mL) and ethyl acetate (5 x 80 mL). The combined organic extracts were dried using MgSO4, filtered and concentrated Sodium hydride (80 % dispersion in mineral oil, 940 mg, 0.024 mmol) was added in two portions at 0 °C to a solution of A solution of trifluoroacetic acid (2.5 ml) in dichloromethane (5 mL) was added slowly at 0 °C to a solution of (3R)-1-Benzyl-3-methoxypyrrolidine was prepared as described in the following patent A solution of (3R)-1-Benzyl-3-methoxypyrrolidine (2.35 g, 12.3 mmol) in methanol (50 mL) containing concentrated HCl (1 mL) was hydrogenated at ambient temperature at 50 psi in the presence of a catalytic amount of 10 % Pd(OH)2 on carbon (250 mg, 10% w/w). The reaction mixture was filtered over celite and rinsed with dichloromethane (60 mL) and methanol (60 mL) to remove the catalyst. The organic layer was basified with NaOH (2.0M, 10 mL) and extracted with diethylether (3 x 30 mL). The aqeous layer was further acidified to pH3 using concentrated HCl, concentrated Step 1: 1-Benzyl-2,2-dimethylpyrrolidine was prepared according to the procedure described in the following reference. Step 2: A solution of 1-Benzyl-2,2-dimethylpyrrolidine (1.02g, 5.40 mmol) in ethanol (80 mL) and concentrated HCl (0.5 mL) was hydrogenated over 20 % Pd(OH)2 (100 mg, 10 % w/w) at 60 psi at ambient temperature for 4 hours. The reaction mixture was filtered over arbocel to remove the catalyst and a further 2 mL of concentrated HCl was added to the crude product. The reaction mixture was then concentrated The free base of cis-2,5-dimethylpyrrolidine was prepared as described by K2CO3 (3.02 g, 21.9 mmol) was added to a solution of 1-(4-hydroxyphenyl)cyclohexanecarbonitrile (4.0 g, 19.9 mmol) in DMF (50 mL). 1-bromo-3-chloroproprane (1.97 ml, 19.9 mmol) was then added dropwise and the reaction heated at 60°C overnight. The reaction mixture was concentrated, quenched by adding water (50 mL), extracted with dichloromethane (2 x 50 mL) and the organic extracts were dried over Na2SO4, filtered and concentrated A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (2.00g, 7.20 mmol), Cs2CO3 (2.58 g, 7.20 mmol), potassium iodide (0.20 g, 1.20 mmole) and (R)-(-)-2-(methoxymethyl)pyrrolidine (1.07 mL, 8.60 mmol) in NMP (20 mL) was heated to 75°C overnight. The reaction mixture was cooled to ambient temperature, concentrated A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (200 mg, 0.72 mmol), A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (200 mg, 0.72 mmol), A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (150 mg, 0.54 mmol), A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (150 mg, 0.54 mmol), To a stirred suspension of LiAlH4 (1.0M in diethyl ether, 13.7 ml, 13.7 mmol) at 0°C under an atmosphere of nitrogen was added 1-(4-{3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]propoxy}phenyl)cyclohexanecarbonitrile (0.980 g, 2.7 mmol) in Et2O (15 mL) over 15 minutes maintaining the temperature at 5 to 10°C. The reaction mixture was allowed to warm up to ambient temperature for 20 minutes then refluxed for 30 minutes until complete. The reaction mixture was cooled to 0°C, water (0.5 mL) was added followed by NaOH (2.0M, 1.5 mL) and water (0.5 mL). Ethyl acetate (5 mL) was added and the mixture filtered through a short pad of celite, eluting with ethyl acetate (2 x 15 mL). The organic washings were dried over Na2SO4 and concentrated To a stirred suspension of LiAlH4 (1.0M in diethyl ether, 1.46 ml, 1.46 mmol) at 0°C under an atmosphere of nitrogen was added a solution of 1-(4-{3-[(3 To a stirred solution of ({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclo-hexyl}methyl)amine (0.60 g, 1.90 mmol) and A solution of To a stirred suspension of LiAlH4 (1.0M in diethyl ether, 0.4 ml, 0.40 mmol) at 0°C under an atmosphere of nitrogen was added 1-{4-[3-(2,2-dimethylpyrrolidin-1-yl)propoxy]phenyl}cyclohexanecarbonitrile (27 mg, 0.079 mmol) in Et2O (15 mL) over 15 minutes maintaining the temperature at 5 to 10°C. The reaction mixture was allowed to warm up to ambient temperature for 20 minutes then refluxed for 30 minutes until complete. The reaction mixture was cooled to 0°C, water (0.5 mL) was added followed by NaOH (2.0M, 1.5 mL) and water (0.5 mL). Ethyl acetate (5 mL) was added and the mixture filtered through a short pad of celite, eluting with ethyl acetate (2 x 15 mL) and concentrated A solution of Acetyl chloride (14 µL, 0.20 mmol) was added dropwise to a solution of Ethanesulfonyl chloride (43 µL, 0.456 mmol) was added dropwise to a solution of triethylamine (58 µL, 0.418 mmol) and n-Propylsulfonyl chloride (33 µL, 0.289 mmol) was added dropwise to a solution of triethylamine (37 µL, 0.265 mmol) and Methanesulfonyl chloride (19 µL, 0.24 mmol) was added dropwise to a solution of triethylamine (31 µL, 0.22 mmol) and Ethanesulfonyl chloride (26 µL, 0.28 mmol) was added dropwise to a solution of triethylamine (35 µL, 0.25 mmol) and LiAlH4 (1.0M in diethylether, 4.72 mL, 4.72 mmol) was added dropwise at 0°C to a solution of ( A solution of LiAlH4 (1.0M in diethylether, 1.20 mL, 0.60 mmol) was added dropwise at 0°C to a solution of A solution of 4-(4-hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (203 mg, 1.0 mmol) and tri-n-butylphosphine (299 µL, 1.20 mmol) in toluene (6 mL) were added to a solution of 3-[(2R)-2-methylpyrrolidin-1-yl]propan-1-ol (172 mg, 1.20 mmol) in toluene (6 mL) and tetrahydrofuran (2 mL) at ambient temperature. 1'1-azobis( A solution of 4-(4-{3-[(2 4-[4-(4-Piperidinyloxy)phenyl]tetrahydro-2 4-[4-(1-Isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile (50 mg, 0.152 mmol) was combined with boron trifluoride-acetic acid complex (500 µL, 3.6 mmol) and stirred at ambient temperature for 18 hours, followed by 65°C for 3 hours. The reaction mixture was allowed to cool and then basified with saturated NaHCO3 solution (15 mL). The product was extracted with dichloromethane (2 x 35 mL). The combined organic extracts were dried using Na2SO4 filtered and concentrated 4-[4-(1-Isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile (1g, 3 mmol) and concentrated hydrochloric acid (10 mL) were combined and heated at reflux for 44 hours. Reaction mixture was concentrated 4-(4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl)tetrahydro-2 4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (2g, 6.4 mmol), diethyl dithiophosphate (15 mL, 8.9 mmol), and water (1.5 mL) were combined and stirred at ambient temperature for 5 hours, 55 °C for 2 hours then 70°C for 2 hours. The reaction mixture was diluted with dichloromethane (100mL) and basified to pH 8 with a saturated solution of NaHCO3 in water, and solid NaHCO3. The layers were separated, and further dichloromethane (100 mL) was used to extract the product. The combined organics were dried using Na2SO4, filtered and concentrated 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbothioamide (150 mg, 0.43 mmol), bromoacetaldehyde diethylacetal (67 µL, 0.43 mmol), concentrated hydrochloric acid (5 drops) and ethanol were combined and heated at reflux for 5 hours. The reaction mixture was concentrated To a stirred solution 4-[4-(1-isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile (2.5 g, 7.62 mmol) in dry diethyl ether (15 ml) at 0°C was added dropwise a solution of LiAlH4 (1.0M solution in Et2O, 22.87 ml, 22.9 mmol). Reaction stirred at 0°C for 30 mins, then warmed up to ambient temperature overnight under a nitrogen atmosphere until complete. The reaction was cooled to 0°C, water (0.9 ml) was added dropwise followed by sodium hydroxide (2.0M, 0.9 ml) and water (2.7 ml). Dichloromethane (25 ml) and methanol (1 ml) were added and the mixture filtered through a short pad of arbocel, eluting with 2% methanol in dichloromethane (200 ml). The organic washings were dried over Na2SO4 and concentrated To a stirred solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 To a stirred solution of To a stirred, solution of To a stirred solution of To a stirred solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 To a stirred solution of To a stirred solution of To a solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (100 mg, 0.301 mmol) in toluene (2 ml) was added ethyl-4-bromobutyrate (43 µl, 0.301 mmol), A mixture of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (100 mg, 0.314 mmol), 2-chloropyrimidine (50 mg, 0.346 mmol) and A solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 The title compound (320mg, 74%) was prepared from 4-[4-(1-isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile and diethyl dithiophosphate similarly to the procedure used for intermediate 50. LRMS APCI+ m/z 363+. The title compound (320mg, 74%) was prepared from 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 O-(1 The title compound (60mg, 48%) was prepared from 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 (4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 The title compound (20mg, 5%) was prepared from (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine and 3-iodopyridine similarly to the procedure used for example 152.1H NMR (400 MHz, CDCl3) δ 1.12 (d, 6H), 1.88-1.95 (m, 4H), 2.10-2.21 (m, 4H), 2.51 (m, 2H), 2.83-2.88 (m, 3H), 3.22-3.27 (m, 3H), 3.55-3.59 (m, 2H), 3.77-3.82 (m, 2H), 4.35 (m, 1H), 6.73 (d, 1H), 6.93 (d, 2H), 7.00 (t, 1H), 7.24 (d, 2H), 7.87-7.90 (m, 2H). HRMS ESI+ m/z 410.2791+. 4-Hydroxypiperidine (2.41g, 23.8mmol), cyclobutanone (5g, 71.4mmol) and acetic acid (1.36ml, 23.8mmol) were stirred in tetrahydrofuran (35ml) at 0°C for 1.5 hours. Sodium triacetoxyborohydride (10.1g, 47.7mmol) was then added at 0°C and the reaction mixture stirred at 0°C for 1 hour. The mixture was warmed to room temperature and stirred for 1 hour, then heated to 40°C for 18 hours. The reaction was concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (0.75g, 3.19mmol), 1-cyclobutylpiperidin-4-ol (0.45g, 2.90mmol), PPh3 (0.84g, 3.19mmol), THF (10ml) and DIAD (0.66ml, 3.19mmol) were reacted together similarly to general procedure C. The crude material was subjected to chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:0.2) to provide the title compound (114mg, 11 %) as an off-white solid.1H NMR (400MHz, CD3OD) δ 1.71-1.77 (m, 4H), 1.85-1.90 (m, 4H), 1.94 (s, 6H), 1.99-2.06 (m, 4H), 2.12-2.16 (m, 2H), 2.20-2.28 (m, 2H), 2.45 (s, 2H), 2.58-2.70 (m, 2H), 2.79 (m, 1H), 3.46-3.53 (m, 2H), 3.72-3.75 (m, 2H), 4.39 (m, 1H), 6.91 (d, 2H), 7.26 (d, 2H). HRMS ESI+ m/z 373.2846+. DIAD (9.8ml, 47.3mmol) was added dropwise over 10 minutes to a solution of ethyl-4-hydroxy phenylacetate (7.7g, 42.7mmol), 1-cyclobutylpiperidin-4-ol (6.58g, 42.5mmol) and PPh3 (12.3g, 47mmol) in THF (150ml) at 0°C. The reaction mixture was then stirred at room temperature for 18 hours. The reaction was concentrated NaH (60% dispersion in oil, 800mg, 20mmol) was added at 0°C to a solution of ethyl {4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}acetate (2g, 6.3mmol) in THF (25ml) and Sodium hydroxide (200mg, 5mmol) was added to a solution of ethyl 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 The compounds of the following tabulated Examples of the general formula were prepared using 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 The title compound (223mg, 50%) was prepared from 4-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}tetrahydro-2 The title compound (92mg, 39%) was prepared from 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 The title compound (155mg, 83%) was prepared from 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 The title compound (1.05g, 100%) was prepared from 4-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}tetrahydro-2 The title compound (31mg, 25%) was prepared from 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 The title compound (25mg, 31%) was prepared from 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 The title compound (28mg, 18%) was prepared from 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 To a stirred solution of 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine (160mg, 0.41mmol) and The title compound (78mg, 44%) was prepared from 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine and acetone similarly to the procedure used for example 54.1H NMR (400MHz, CDCl3) δ 0.98 (d, 6H), 1.77-1.80 (m, 4H), 1.86-1.93 (m, 2H), 1.98-2.02 (m, 2H), 2.06-2.09 (m, 2H), 2.20-2.22 (m, 4H), 2.34-2.36 (m, 6H), 2.50-2.54 (m, 5H), 2.62 (t, 2H), 3.52 (t, 2H), 3.71-3.75 (m, 2H), 4.02 (t, 2H), 6.85 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 430.3417+. The title compound (26mg, 14%) was prepared from 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine and cyclopropane carboxaldehyde similarly to the procedure used for example 54.1H NMR (400MHz, CDCl3) δ 0.02 (q, 2H), 0.43 (q, 2H), 0.76 (m, 1H), 1.74-1.76 (m, 4H), 1.83-1.89 (m, 2H), 1.95-1.99 (m, 2H), 2.03-2.06 (m, 3H), 2.13 (d, 2H), 2.19-2.21 (m, 4H), 2.26-2.40 (m, 5H), 2.47-2.51 (m, 4H), 2.59 (t, 2H), 3.49 (t, 2H), 3.68-3.72 (m, 2H), 3.98 (t, 2H), 6.82 (d, 2H), 7.17 (d, 2H). HRMS ESI+ m/z 442.3412+. The title compound (169mg, 51%) was prepared from {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine free base and cyclopropane carboxaldehyde similarly to the procedure used for example 54. 3 equivalents of cyclopropane carboxaldehyde were required for the synthesis of this Example.1H NMR (400MHz, CDCl3) δ -0.04 (q, 4H), 0.39 (q, 4H), 0.71-0.76 (m, 2H), 1.80-1.86 (m, 4H), 1.94-2.12 (m, 6H), 2.16 (d, 4H), 2.55-2.72 (m, 8H), 3.51 (t, 2H), 3.75-3.79 (m, 2H), 4.04 (t, 2H), 6.88 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 427.3306+. The compounds of the following tabulated Examples of the general formula were prepared using methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine and the appropriate aldehydes or ketones similarly to the procedure used for example 54. The compounds of the following tabulated Examples of the general formula were prepared using 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid, the appropriate amines and O-(1 Methoxyacetyl chloride (55µl, 0.6mmol) was added dropwise at 0°C to a solution of 1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)piperazine of example 181 (200mg, 0.5mmol) and The compounds of the following tabulated Examples of the general formula were prepared using lithium aluminium hydride, the amides of examples 182, 183, 184 and intermediate 60 similarly to the procedure used for example 142. {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (300mg, 0.94mmol), 2-fluoronitrobenzene (100µl, 0.95mmol) and potassium carbonate (150mg, 1.08mmol) were stirred together at room temperature in A solution of 2-nitro- The compounds of the following tabulated Examples of the general formula were prepared using {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine and the appropriate bromo or iodopyridines similarly to the palladium coupling procedure used for example 152. A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (150 mg, 0.47mmol), 1-methylbenzimidazole-2-sulfonic acid (83.4mg, 0.39mmol) and A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (100 mg, 0.31mmol), 4,6-dichloropryrimidine (46.8mg, 0.31mmol) and A solution of 6-chloro- A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (300 mg, 0.94mmol), 1,4-dichlorophthalazine (188mg, 0.94mmol) and The title compound (86mg, 51%) was prepared from 4-chloro- A mixture of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 Trimethylsilylacetylene (0.9ml, 6mmol) was added at room temperature to a solution of 4-[3-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile (200mg, 0.6mmol) and dicarbonylcyclopentadienyl cobalt (12mg, 0.07mmol) in toluene (3ml). Tetrabutylammonium fluoride (1.54g, 6mmol) was added portionwise over 10 minutes. The reaction mixture was then stirred at room temperature under visible light under nitrogen for 12 days. The reaction mixture was concentrated Tosylmethyl isocyanide (370mg, 1.89mmol) was added to a solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500mg, 1.58mmol) and potassium carbonate (652mg, 4.73mmol) in methanol (7ml). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was partitioned between ethyl acetate (2x75ml) and water (20ml). The organic layers were combined, dried over sodium sulphate, filtered and concentrated The title compound (75mg, 60%) was prepared from {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanol and 4-bromopyridine similarly to the procedure used for example 152.1H NMR (400MHz, CDCl3) δ 1.76-1.82 (m, 4H), 1.98-2.04 (m, 2H), 2.12-2.17 (m, 4H), 2.49-2.58 (m, 4H), 2.61-2.66 (m, 2H), 3.54-3.60 (m, 2H), 3.81-3.85 (m, 2H), 3.87 (s, 2H), 4.03 (t, 2H), 6.71 (d, 2H), 6.91 (d, 2H), 7.29 (d, 2H), 8.36 (d, 2H). HRMS ESI+ m/z 397.2479+. 1-Bromo-3-chloropropane (0.42ml, 4.25mmol) was added to a solution of 4-(4-dimethylaminomethyltetrahydro-pyran-4-yl)-phenol (1.0g, 4.25mmol) and potassium carbonate (1.5g, 10.8mmol) in A mixture of 1-{4-[4-(3-chloropropoxy)phenyl]tetrahydro-2 This amine was described in patent The compounds of the following tabulated examples of the general formula were prepared using 1-{4-[4-(3-chloropropoxy)phenyl]tetrahydro-2 (1-Benzhydryl-azetidin-3-yl)-methanol (3.07g, 12.1 mmol) was dissolved in dichloromethane (60ml). The reaction was cooled to 0-5°C and thionyl chloride (1.07ml, 14.6mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was concentrated 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.15g, 5.65mmol), 1-benzhydryl-3-chloromethylazetidine hydrochloride (1.58g, 5.13mmol), This intermediate was hydrogenated in ethanol (20ml) for 4 hours at 60°C at atmospheric pressure in the presence of 10% Pd/C (300mg). The reaction mixture was filtered through Arbocel® and rinsed with ethanol and water. The filtrate was concentrated Cyclopentyl bromide (0.17ml, 1.54mmol) and 5M aqueous sodium hydroxide (0.34ml, 1.68mmol) were added to a solution of 1-{4-[4-(azetidin-3-ylmethoxy)phenyl]tetrahydro-2 A mixture of 1-{4-[4-(3-chloropropoxy)phenyl]tetrahydro-2 The title compound (30mg, 12%) was prepared using 4-[4-(3-chloro-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile and (S)-(+)-2-pyrrolidine methanol similarly to the procedure used for example 208.1H NMR (400MHz, CDCl3) δ 1.79-1.85 (m, 3H), 1.94 (m, 1H), 2.01-2.12 (m, 7H), 2.41 (m, 1H), 2.58 (m, 1H), 2.78 (m, 1H), 3.08 (m, 1H), 3.33 (m, 1H), 3.49 (m, 1H), 3.71 (d, 1H), 3.88 (t, 2H), 4.04-4.09 (m, 4H), 6.92 (d, 2H), 7.38 (d, 2H). HRMS ESI+ m/z 345.2167+. The title compound (1.58g, 92%) was prepared using 4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile and lithium aluminium hydride similarly to the procedure used for intermediate 51. LRMS APCI+ m/z 351+. The title compound (1.16g, 100%) was prepared using 1-{4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanamine and acetic anhydride similarly to the procedure used for example 140.1H NMR (400MHz, CDCl3) δ 1.82-1.86 (m, 2H), 1.87 (s, 3H), 2.00-2.04 (m, 4H), 2.58-2.85 (m, 10H), 3.45 (d, 2H), 3.56-3.61 (m, 2H), 3.79-3.84 (m, 2H), 4.02 (t, 2H), 4.97 (brs, 1H), 6.91 (d, 2H), 7.19 (d, 2H). LRMS APCI+ m/z 393+. The title compound (492mg, 44%) was prepared using 4-(4-Methoxyphenyl)-tetrahydro-2H-pyran-4-carbonitrile (10g, 46mmol) was heated at reflux for 18 hours in concentrated hydrochloric acid (100mL). The reaction mixture was extracted with dichloromethane (2x100mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated The title compound (515mg, 77%) was prepared using 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid, N-methyl-piperazine and O-(1 The title compound (428mg, 93%) was prepared using 1-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]carbonyl}-4-methylpiperazine and lithium aluminium hydride similarly to the procedure used for example 142. HRMS ESI+ m/z 305.2220+. To a suspension of sodium thiomethoxide (660mg, 9.4mmol) in N,N-dimethylformamide (2ml) was added 1-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methyl}-4-methylpiperazine (410mg, 1.3mmol) in N,N-dimethylformamide (3ml). The reaction mixture was heated to 130°C under nitrogen for 18 hours. The mixture was then allowed to cool down to room temperature and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate (2x30ml). The combined organic extracts were dried over sodium sulphate, filtered and concentrated The title compound (72mg, 14%) was prepared using 4-{4-[(4-methylpiperazin-1-yl)methyl]tetrahydro-2 The title compound (3.1g, 87%) was prepared using 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid, morpholine and O-(1 The title compound (2.48g, 87%) was prepared using 4-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]carbonyl}morpholine and lithium aluminium hydride similarly to the procedure used for example 142. HRMS ESI+ m/z 292.1897+. The title compound (1.70g, 75%) was prepared using 4-{[4-(4-methoxyphenyl)tetrahydro-2 The title compound (52mg, 12%) was prepared using 4-[4-(morpholin-4-ylmethyl)tetrahydro-2H-pyran-4-yl]phenol, 1-isopropyl-4-hydroxypiperidine (step1 of intermediate 21), PPh3 and DIAD similarly to the procedure used for intermediate 55.1H NMR (400MHz, CD3OD) δ 1.09 (d, 6H), 1.74-1.80 (m, 2H), 1.83-1.90 (m, 2H), 1.98-2.04 (m, 2H), 2.12-2.18 (m, 6H), 2.40 (s, 2H), 2.47 (t, 2H), 2.75 (m, 1H), 2.80-2.85 (m, 2H), 3.47-3.54 (m, 6H), 3.71-3.77 (m, 2H), 4.36 (m, 1H), 6.90 (d, 2H), 7.28 (d, 2H). HRMS ESI+ m/z 403.2951+. The title compound (1.09g, 66%) was prepared using 4-[4-(morpholin-4-ylmethyl)tetrahydro-2H-pyran-4-yl]phenol, (1-benzhydryl-azetidin-3-yl)-methanol, PPh3 and DIAD similarly to the procedure used for intermediate 55. HRMS ESI+ m/z 513.3103+. A solution of 4-{[4-(4-{[1-(benzhydryl)azetidin-3-yl]methoxy}phenyl)tetrahydro-2H-pyran-4-yl]methyl}-morpholine (1.0g, 1.95 mmol) in ethanol (10mL) was hydrogenated for 16 hours at room temperature at 60 psi in the presence of Pd(OH)2/C (150mg, 15% w/w). 2N Hydrochloric acid (few drops) was added and the reaction mixture hydrogenated for 16 hours at 60°C at 60 psi. The reaction mixture was basified with aqueous sodium carbonate and the mixture filtered over Arbocel® and rinsed with ethanol. The filtrate was concentrated The compounds of the following tabulated examples of the general formula were prepared using 4-({4-[4-(azetidin-3-ylmethoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-morpholine, the appropriate ketones and sodium triacetoxyborohydride similarly to the procedure used for example 54. The title compound (5.5g, 77%, solid after trituration in pentane) was prepared using 4-(methylthio)phenylacetonitrile, bis(2-bromoethyl)ether, sodium hydride and potassium iodide similarly to the procedure used for intermediate 56. Microanalysis: Found: C, 66.62; H, 6.46; N, 5.97%. C13H15NOS requires C, 66.92; H, 6.48; N, 6.00%. A solution of meta-chloroperbenzoic acid (5.08g, 22.66mmol) in dichloromethane (30ml) was added dropwise over 15 minutes at 0°C to a solution of 4-[4-(methylthio)phenyl]tetrahydro-2 2,6-Lutidine (3.33ml, 28.6mmol) was added to a solution of 4-[4-(methylsulfinyl)phenyl]tetrahydro-2H-pyran-4-carbonitrile (2.3g, 9.23mmol) in acetonitrile (70ml). The mixture was cooled in an ice-acetone bath and trifluoroacetic anhydride (3.87ml, 27.69mmol) added slowly. The solution was stirred at this temperature under nitrogen for 3 hours. The reaction mixture was then concentrated The title compound (2.42g, 91%) was prepared using 4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2H-pyran-4-carbonitrile and lithium aluminium hydride similarly to the procedure used for intermediate 51. LRMS APCI+ m/z 335+. Microanalysis: Found: C, 64.08; H, 8.79; N, 7.447%. C19H30N2OS.0.33DCM requires C, 64.04; H, 8.52; N, 7.73%. Formaldehyde (37%w/w solution in water, 650µl, 7.58mmol) was added to a solution of 1-(4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2H-pyran-4-yl)methanamine (1.0g, 3.03mmol) in tetrahydrofuran (10ml). Acetic acid (173µl, 3.03mmol) was then added and the mixture stirred at room temperature for 10 minutes. The mixture was cooled to 0°C and sodium triacetoxyborohydride (1.6g, 7.57mmol) was added in 2 portions. The mixture was then warmed to room temperature and stirred for 18 hours. The reaction was quenched with water and concentrated 4-{4-[(3-Pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2H-pyran-4-carbonitrile (1g, 3.03mmol) was heated at reflux in concentrated hydrochloric acid (10ml) for 18 hours. More hydrochloric acid (11ml) was added and the mixture heated at reflux for a further 18 hours. The reaction mixture was then concentrated The title compound (228mg, 40%) was prepared using 4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2H-pyran-4-carboxylic acid and pyrrolidine similarly to the procedure used for example 149. HRMS ESI+ m/z 403.2403+. The title compound (58mg, 27%) was prepared using 1-[3-({4-[4-(pyrrolidin-1-ylcarbonyl)tetrahydro-2 The title compound (contaminated with ammonium chloride) was prepared using 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarbonitrile and concentrated hydrochloric acid similarly to the procedure used for intermediate 80. LRMS ESI+ m/z 332+. The title compound (200mg, 16%) was prepared using 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarboxylic acid and 4-hydroxypiperidine similarly to the procedure used for example 149. HRMS ESI+ m/z 415.2943+. The title compound (90mg, 46%) was prepared using 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}carbonyl)piperidin-4-ol and lithium aluminium hydride similarly to the procedure used for example 142.1H NMR (400MHz, CDCl3) δ 1.29-1.55 (m, 10H), 1.64-1.69 (m, 2H), 1.77-1.81 (m, 4H), 1.90-2.06 (m, 4H), 2.10-2.13 (m, 2H), 2.23 (s, 2H), 2.26-2.30 (m, 2H), 2.51-2.54 (m, 4H), 2.62 (t, 2H), 3.51 (m, 1H), 4.01 (t, 2H), 6.83 (d, 2H), 7.25 (d, 2H). HRMS ESI+ m/z 401.3154+. The title compound (10mg, 8%) was prepared using 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarboxylic acid and 1-methylpiperazine similarly to the procedure used for example 149.1H NMR (400MHz, CD3OD) δ 1.32 (m, 1H), 1.64-1.69 (m, 7H), 1.81-1.85 (m, 4H), 1.98-2.03 (m, 2H), 2.05-2.13 (m, 4H), 2.15 (s, 3H), 2.25-2.28 (m, 2H), 2.59-2.62 (m, 4H), 2.69 (t, 2H), 3.33-3.42 (m, 4H), 4.01 (t, 2H), 6.90 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 414.3107+. The title compound (351mg, 19%) was prepared using 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarboxylic acid and piperazine similarly to the procedure used for example 149. LRMS APCI+ m/z 400+. The title compound (187mg, 59%) was prepared using 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}carbonyl)piperazine and lithium aluminium hydride similarly to the procedure used for example 142.1H NMR (400MHz, CDCl3) δ 1.30-1.33 (m, 3H), 1.46-1.54 (m, 4H), 1.78-1.81 (m, 4H), 1.98-2.05 (m, 4H), 2.09-2.12 (m, 6H), 2.23 (s, 2H), 2.53-2.57 (m, 4H), 2.62-2.71 (m, 6H), 4.01 (t, 2H), 6.83 (d, 2H), 7.26 (d, 2H). LRMS APCI+ m/z 386+. The title compound (73mg, 73%) was prepared using 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl) piperazine and acetic anhydride similarly to the procedure used for example 166.1H NMR (400MHz, CDCl3) δ 1.31-1.34 (m, 3H), 1.48-1.53 (m, 5H), 1.82-1.85 (m, 4H), 1.99 (s, 3H), 2.02-2.07 (m, 4H), 2.13-2.17 (m, 4H), 2.28 (s, 2H), 2.58-2.64 (m, 4H), 2.70 (t, 2H), 3.20 (t, 2H), 3.41-3.43 (m, 2H), 4.01 (t, 2H), 6.83 (d, 2H), 7.25 (d, 2H). HRMS ESI+ m/z 428.3264+. Methanesulphonic acid anhydride (49mg, 0.28mmol) was added at 0°C to a solution of 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl) piperazine (90mg, 0.23mmol) and pyridine (47µl, 0.58mmol) in dichloromethane (1 ml). The reaction was stirred at 0 °C for 10 minutes, then allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (20ml) and aqueous sodium carbonate (20ml). The layers were separated. The organic layer was dried over sodium sulphate, filtered and concentrated Bis-(2-chloroethyl)amine hydrochloride (10g, 56mmol) was stirred vigourously in a mixture of dichloromethane (150ml) and aqueous 10% sodium hydroxide (50ml). Di- The title compound (1.8g, 53%) was prepared using [4-(3-pyrrolidin-1-ylpropoxy)phenyl]acetonitrile, Acetyl chloride (27µl, 0.37mmol) was added dropwise to a solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile (90mg, 0.28mmol) and triethylamine (78µl, 0.56mmol) in dichloromethane (3ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (15ml) and washed with water (15ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x10ml). The organics were combined, washed with brine, dried over sodium sulphate, filtered and concentrated The title compound (80mg, 76%) was prepared from 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile, formaldehyde and sodium triacetoxyborohydride similarly to the procedure used for example 54.1H NMR (400MHz, CD3OD) δ 1.81-1.85 (m, 4H), 1.97-2.15 (m, 6H), 2.37 (s, 3H), 2.45 (t, 2H), 2.58-2.62 (m, 4H), 2.68 (t, 2H), 2.99 (d, 2H), 4.04 (t, 2H), 6.96 (d, 2H), 7.42 (d, 2H). LRMS APCI+ m/z 328+. Microanalysis: Found: C, 73.01; H, 8.94; N, 12.81%. C20H29N3O requires C, 73.36; H, 8.93; N, 12.83%. The title compound (45mg, 58%) was prepared from 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile, acetone and sodium triacetoxyborohydride similarly to the procedure used for example 54.1H NMR (400MHz, CD3OD) δ 1.12 (d, 6H), 1.81-1.84 (m, 4H), 1.99-2.14 (m, 6H), 2.58-2.69 (m, 8H), 2.82 (m, 1H), 3.02 (d, 2H), 4.04 (t, 2H), 6.96 (d, 2H), 7.42 (d, 2H). HRMS ESI+ m/z 356.2691+. A mixture of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile (68mg, 0.22mmol), 2-bromoethylmethylether (21 µl, 0.22mmol), solid sodium bicarbonate (84mg, 1.0mmol) and potassium iodide (5mg, catalytic) was heated at 50°C in acetonitrile (1ml) for 18 hours. The reaction mixture was concentrated A solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine (350 mg, 1.05 mmol), glycolaldehyde dimer (130 mg, 1.05 mmol) and AcOH (0.15 ml, 2.1 mmol) in DCM (5 ml) was stirred at room temperature for 18 hours. Saturated aqueous sodium carbonate (10 ml) and DCM (10 ml) were added and the mixture was shaken and partitioned. The aqueous phase was extracted with DCM (2x10 ml) and the combined organics dried (K2CO3), filtered and concentrated A mixture of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine (115 mg, 0.35 mmol), (1-Ethoxy-cyclopropoxy)-trimethylsilane (360 mg, 2.0 mmol), AcOH (0.2 ml, 3.5 mmol), NaCNBH3 (110 mg, 1.75 mmol) and 4A molecular sieves (100 mg) in MeOH (5 ml) was heated to reflux for 18 hours. The mixture was cooled, concentrated 1H NMR (400MHz, CDCl3) δ 0.15 (m, 2H), 0.29 (m, 2H), 1.68 (m, 1H), 1.70-1.90 (m, 6H), 1.85 (s, 3H), 2.00-2.10 (m, 4H), 2.60 (m, 4H), 2.65 (s, 2H), 2.68 (m, 2H), 3.50 (t, 2H), 3.76 (m, 2H), 4.01 (t, 2H), 6.85 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 373.2844+. A mixture of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (482 mg, 1.50 mmol), 1,2-dibromoethane (0.13 ml, 1.50 mmol) and K2CO3 (420 mg, 3.0 mmol) in acetonitrile (50 ml) was heated to 70°C for 3 days. The mixture was concentrated A solution of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (159 mg, 0.50 mmol) and dimethyl 2,2-diethoxyethyldithioimido-carbonate (120 mg, 0.50 mmol, ARKIVOC 2001, viii, 34-39) in AcOH (5 ml) was heated at reflux for 8 h. The mixture was concentrated To a solution of 2-(methylthio)-1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazole (90 mg, 0.22 mmol) in EtOH (4 ml) and water (1ml) was added Raney Nickel (50% slurry in water) in 200 mg aliquots every 30 min. After 3 h all starting material had been consumed. The mixture was filtered through Arbocel® with EtOH (200 ml) and concentrated A solution of 4-(4-hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (5g, 25mmol), t-butyldimethylsilyl chloride (4.46g, 29mmol) and imidazole (2.34g, 34mmol) were stirred in DMF (15ml) at room temperature. After 30 minutes, a yellow suspension was observed. The reaction was partitioned between ether (75ml) and water (100ml). The ether was then washed further with water (4x50ml), dried over sodium sulphate, filtered and concentrated To a stirred solution of 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)tetrahydro-2H-pyran-4-carbonitrile (3.5g, 11mmol) in THF (35ml) at 0°C was added dropwise lithium aluminium hydride (1M solution in ether, 44ml, 44mmol). The reaction was allowed to warm up to room temperature and stirred for 4 hours until complete. The reaction mixture was cooled to 0°C, water (1.66 mL) was added followed by NaOH (2.0M, 1.66 mL) and water (4.97 mL). The mixture was filtered through a short pad of celite, eluting with dichloromethane:methanol (97:3, 150ml) and concentrated 1-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)tetrahydro-2H-pyran-4-yl]methanamine (3.65g, 11.4mmol), 2-bromopyridine (910µl, 9.48mmol), tris(dibenzylideneacetone)dipalladium(0) (471mg, 0.455mmol), 2,2'-bis(diphenylphosphino)1,1'-binaphyl (567mg, 0.910mmol) and sodium N-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)tetrahydro-2H-pyran-4-yl]methyl}pyridin-2-amine (2.099g, 5.27mmol) and tetrabutylammonium fluoride (1M solution in THF, 5.80ml, 5.80mmol) were stirred in THF (20ml) at room temperature for 24 hours until complete. THF was removed 4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (220mg, 0.775mmol), 1-bromo-4-chlorobutane (146mg, 0.852mmol) and potassium carbonate (118mg, 0.852mmol) were stirred in DMF (1ml) at 60°C for 24 hours until complete. Reaction was partitioned between ethyl acetate (50ml) and water (75ml). The organic layer was separated and washed further with water (2x30ml), then dried over sodium sulphate, filtered and concentrated A mixture of N-({4-[4-(4-chlorobutoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-2-amine (180mg, 0.481mmol), pyrrolidine (80µl, 0.963mmol), sodium carbonate (102mg, 0.963mmol) and sodium iodide (4mg, 0.024mmol) were stirred in butanol (5ml) at 100°C for 24 hours until complete. Butanol was removed 4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (200mg, 0.704mmol), 3-chloropropylpiperidine hydrochloride (152mg, 0.775mmol) and potassium carbonate (204mg, 1.48mmol) were stirred in DMF (1ml) at 45°C for 24 hours until complete. The reaction was then partitioned between ethyl acetate (40ml) and water (40ml). The organic layer was separated, dried over sodium sulphate and concentrated To a solution of 4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (250mg, 0.881mmol), 1-ethylpiperidin-4-ol (103mg, 0.8mmol) and triphenylphosphine (231mg, 0.881mmol) in THF (5ml) at 0°C under nitrogen was added dropwise diisopropyl azodicarboxylate (95% solution, 183µl, 0.881mmol). Reaction was stirred for 10 minutes then warmed to room temperature for 72 hours until complete. THF was removed To a solution of N-methylcyclobutanamine (1g, 3.89mmol) and potassium carbonate (1.18g, 8.56mmol) in acetonitrile (20ml) at 0°C was added 1-bromo-3-chloropropane (383µl, 3.89mmol). Reaction was warmed to room temperature and stirred for 24 hours. Solid removed by filtration and filtrate concentrated 4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (386mg, 1.36mmol), N-(3-chloropropyl)-N-methylcyclobutanamine (241 mg, 1.496mmol) and potassium carbonate (280mg, 2.03mmol) were stirred in DMF (2ml) at 45°C for 24 hours until complete. Reaction was partitioned between ethyl acetate (40ml) and saturated sodium bicarbonate solution (50ml), then the organic layer washed with water (50ml). Organic layer separated and dried over sodium sulphate, filtered and concentrated To a cooled solution of 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile (1.16g, 3.53mmol) in dichloromethane (12ml) at -78°C under nitrogen, was added dropwise diisobutylaluminium hydride (1M solution in dichloromethane, 12.38ml, 12mmol) keeping the temperature below -60°C. Reaction stirred at -78°C for 40 minutes, then at -20°C for 1 hour before allowing to warm to room temperature. After 1 hour, reaction cooled and quenched with 2M HCl (13.2ml) and basified with sodium carbonate to pH 8, and filtered though a short pad of celite eluting with dichloromethane:methanol (99:1 by volume). Reaction then partitioned between dichloromethane (50ml) and water (50ml), and organic layer washed with a further portion of water (50ml) before being separated, dried over sodium sulphate, filtered and concentrated 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carbaldehyde (50mg, 0.151 mmol), ammonium acetate (116mg, 1.51mmol) and 2,3-butanedione (13mg, 0.151mmol) in acetic acid (1ml) heated in a Smith Personal Synthesiser microwave for 900 seconds at 180°C. Acetic acid removed To a stirred solution of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (390mg, 1.2mmol) in acetonitrile (~5mL), was added Hunig's base (230µL, 1.35mmol, 1.1eq.) and 4-ethoxy-3-nitropyridine hydrogen chloride (250mg, 1.2mmol, 1eq.) and the mixture stirred at reflux for 72 hours. To this a further portion of 4-ethoxy-3-nitropyridine hydrogen chloride (50mg, 0.24mmol, 0.2eq.) was added and the mixture stirred at reflux for a further 24 hours. The reaction mixture was then concentrated To a stirred solution of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (320mg, 1.0mmol) in acetonitrile (~5mL), was added Hunig's base (190µL, 1.1mmol, 1.1eq.) and 2-chloro-3-nitropyridine (175mg, 1.1mmol, 1.1eq.) and the mixture stirred at reflux for 4 hours. The reaction mixture was then concentrated A solution of (3-Nitro-pyridin-4-yl)-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-amine (200mg, 0.45 mmol) in ethanol (~5mL) was hydrogenated for 4 hours at room temperature at 40 psi in the presence of 10% Pd/C (20mg, 10%w/w). The reaction mixture was filtered over Arbocel® and rinsed with ethanol. The filtrate was concentrated N*4*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine (60mg, 0.15mmol) and acetic anhydride (~1mL) were stirred at reflux for 18 hours. The reaction mixture was quenched with ~1mL water, then basified with dilute sodium carbonate solution then extracted with DCM (2 x 20mL). The organics were combined, dried over sodium sulphate, filtered and concentrated A solution of (3-Nitro-pyridin-2-yl)-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-amine (465mg, 1.06 mmol) in ethanol (~10mL) was hydrogenated for 4 hours at room temperature at 40 psi in the presence of 10% Pd/C (45mg, 10%w/w). The reaction mixture was filtered over Arbocel® and rinsed with ethanol (30mL), 2M HCl (20mL) and EtOH (30mL). The filtrate was concentrated N*4*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine (280mg, 0.68mmol), trimethylorthoformate (5mL) and formic acid (0.5mL) were stirred at 40°C for 18 hours then at 60°C for 24 hours, then at 80°C for 24 hours. The reaction mixture was concentrated N*2*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-2,3-diamine (350mg, 0.85mmol), trimethylorthoformate (5mL) and formic acid (0.5mL) were stirred at 40°C for 3 hours. The reaction mixture was concentrated Trifluoro-methanesulfonic acid 2-nitro-pyridin-3-yl ester (1.1g, 4.1mmo), {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (1.3g, 4.1mmol) and Hunig's base (1.7mL, 9.8mmol) were stirred at 60°C for 72 hours. The mixture was diluted with DCM (30mL) and washed with water (10mL). The DCM layer was dried over sodium sulphate, filtered and concentrated To a solution of this residue in methanol (10mL) was added methyl viologen dichloride hydrate (5mg, 0.02mmol) and a solution of sodium dithionite (1.07g, 6.13mmol) and NaHCO3 (940mg, 11.2mmol) in water (10mL). The mixture was stirred at room temperature for 10 minutes and then extracted with DCM (2 x 30mL). The organics were dried over sodium sulphate, filtered and concentrated This green solid, trimethylorthoformate (5mL) and formic acid (0.5mL) were stirred at room temperature for 18 hours. The reaction mixture was concentrated A mixture of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (500mg, 1.57mmol), 3,4,5-Trichloro-pyridazine (403mg, 2.20mmol) and potassium carbonate (240mg, 1.73mmol) in acetonitrile (5mL) were stirred at room temperature for 72 hours. The mixture was concentrated A solution of this oil and sodium hydroxide (110mg, 2.7mmol) in ethanol (~5mL) was hydrogenated for 18 hours at room temperature at 50 psi in the presence of 10% Pd/C (60mg, 10%w/w). The reaction mixture was filtered over Arbocel® and rinsed with ethanol. The filtrate was concentrated A solution of 4-[4-(3-morpholino-4-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile (2.0g, 6.05mmol) in concentrated hydrochloric acid (30mL, 10vol) was heated at reflux for 16h. The solution was cooled to room temperature affording a precipitate. This was filtered, washed with water (~5mL) and diethyl ether (~10mL) and then dried to give the title compound (1.34g, 57%) as a pale orange solid. LRMS (APCI-) 348 (M-H+)-. Microanalysis: Found: C, 58.16; H, 7.30; N, 3.45%. C19H28NO5Cl. 0.3H2O requires C, 58.32; H, 7.37; N, 3.58%. O-(1 O-(1 To a stirred solution of 4-(3-{4-[4-(morpholin-4-ylcarbonyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)morpholine (160mg, 0.38 mmol) in THF (4 mL) at 0°C was added dropwise a solution of LiAlH4 (1.0M solution in Et2O, 1.15 mL, 1.15 mmol). The reaction mixture was stirred at 0°C for 20mins then heated at reflux for 1.5 hours. The reaction was then cooled to 0°C, water (0.10 ml) was added dropwise followed by sodium hydroxide (2.0M, 0.10 ml) and water (0.30 ml). The mixture was filtered through a short pad of celite, eluting with 1% methanol in dichloromethane (15 ml) and the organic washings concentrated The title compound (252mg, 77%) was prepared from N-methyl-4-[4-(3-morpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide and a solution of LiAlH4 (1.0M solution in Et2O) similarly to the procedure used for 4-(3-{4-[4-(morpholin-4-y(methyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)morpholine.1H NMR (400 MHz, CD3OD) δ 1.85-2.00 (m, 6H), 2.12 (m, 2H), 2.24 (s, 3H), 2.45 (m, 4H), 2.53 (t, 2H), 2.63 (s, 2H), 3.57 (m, 2H), 3.70-3.80 (m, 6H), 4.01 (t, 1H), 6.88 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 349.2477+. To a stirred solution of N-methyl-1-{4-[4-(3-morpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanamine (230mg, 0.66mmol) in methanol (2mL) was added methanesulfonyl-ethene (64µL, 0.72mmol) and the mixture stirred at room temperature for 18 hours. The mixture was concentrated in A solution of 2-methyl-pyrazine (580µL, 6.4mmol) in THF (4mL) was added to 4.7mL of 1.5M lithium diisopropylamide : THF complex in hexanes at -40°C and the resulting deep red solution stirred at -40°C for 0.5 hours. A solution of 4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (1.00g, 3.2mmol) in THF (5mL) was added at -40°C and the reaction mixture stirred at this temperature for 0.5 hours, then at room temperature for 18 hours. A further 1 equivalent of lithium diisopropylamide complex was then added and the reaction mixture stirred at reflux for 24 hours.. The mixture was cooled to room temperature, water (10mL) added and the mixture concentrated A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile and 4-[4-(3-bromo-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile (7.5g, 27mmol), K2CO3 (9.6g, 70mmol) and azetidine hydrochloride (4.0g, 43mmol) in acetonitrile (80mL) was heated at 40°C for 18 hours. The mixture was concentrated A solution of 4-[4-(3-azetidin-1-yipropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (1.1g, 3.7mmol) in concentrated hydrochloric acid (15mL, 10vol) was heated and stirred at reflux for 24 hours. The solution was cooled to room temperature and then concentrated O-(1 To a stirred solution of 4-({4-[4-(3-azetidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)morpholine (120mg, 0.31mmol) in THF (1 mL) at 0°C was added dropwise a solution of LiAlH4 (1.0M solution in Et2O, 1.00mL, 1.00mmol). The reaction mixture was stirred at 0°C for 20mins then heated at reflux for 3 hours. The reaction was then cooled to 0°C, water (0.10 ml) was added dropwise followed by sodium hydroxide (2.0M, 0.10 ml) and water (0.30 ml). The mixture was filtered through a short pad of celite, eluting with 1% methanol in dichloromethane (15 ml) and the organic washings concentrated 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (6.18g, 30.4mmol), (1-benzhydryl-azetidin-3-yl)-methanol (7g, 28mmol), PPh3 (8g, 30.4mmol), and DIAD (69mL, 30.4mmol), were reacted together similarly to general procedure C. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate:diethylamine (50:45:5 to 0:95:5) to provide the title compound (5.03g, 41%) as a yellow solid. LRMS APCI+ m/z 439+. 4-(4-{[1-(diphenylmethyl)azetidin-3-yl]methoxy}phenyl)tetrahydro-2H-pyran-4-carbonitrile (0.605g, 1.38mmol), palladium hydroxide (0.08g), concentrated hydrochloric acid (0.115mL, 1.38mmol), and ethanol (8mL) were combined and hydrogenated for 18 hours at 40°C at 40psi. The mixture was filtered through Arbocel® and rinsed with ethanol. The filtrate was concentrated 4-[4-(azetidin-3-ylmethoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (0.2g, 0.73mmol) was dissolved in THF (2mL). Cyclobutanone (0.06mL, 0.80mmol) and acetic acid (0.042mL, 0.73mmol) were added. The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.311g, 1.47mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with 10% aqueous sodium carbonate (5mL) then extracted with DCM (2 x 50mL). The organics were combined, dried over sodium sulphate, filtered and concentrated 4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile (0.29g, 0.89mmol), was dissolved in THF (5mL). The solution was cooled to 0°C under nitrogen. Lithium aluminiumhydride (2.7mL, 1.0M solution in diethyl ether) was added dropwise. The reaction was stirred at 0°C for 30 minutes, then warmed up to ambient temperature for 4 hours under a nitrogen atmosphere until complete. The reaction was cooled to 0°C, water (0.1mL) was added dropwise followed by sodium hydroxide (2.0M, 0.1mL) and water (0.3mL). The mixture was filtered (using dichloromethane:methanol (90:10) ) through celite. The organics were dried over sodium sulphate, filtered and concentrated 1-(4-(4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl)tetrahydro-2H-pyran-4-yl)methanamine (0.175g, 0.53mmol) was dissolved in toluene (5mL), 2-bromopyridine (0.051mL, 0.53mmol), 2,2'-bis(diphenylphosphino)-1,1'binapthyl (0.013g, 0.02mmol) and sodium tert-butoxide (0.076g, 0.79mmol) were added. The reaction mixture was purged with nitrogen, tris(dibenzylideneacetone)dipalladium(0) (0.011g, 0.01mmol) was added. The mixture was heated under nitrogen at 70°C for 18 hours. The reaction mixture was diluted with water (20mL) and extracted with DCM (2 x 30mL). The combined organics were dried over sodium sulphate, filtered and concentrated 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid amide (0.561g, 1.69mmol) and N-[(dimethylamino)methylene]-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide (0.15g, 0.39mmol), hydrazine hydrate (0.048mL, 0.98mmol) and acetic acid (1mL) were combined and heated at 100°C for 1.5 hours. The reaction mixture was concentrated N-[(dimethylamino)methylene]-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide (0.34g, 0.88mmol), methyl hydrazine (0.116mL, 2.19mmol) and acetic acid (1mL) were combined and heated at 100°C for 2 hours. The reaction mixture was diluted with water (10mL), solid sodium carbonate was added until the mixture was pH9. Dichloromethane (2 x 50mL) was used to extract. The combined organics were dried over sodium sulphate, filtered and concentrated 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2 Triphenylphosphine (0.203g, 0.78mmol), iodine (0.198g, 0.78mmol) and triethylamine (0.217mL, 1.56mmol) were dissolved in dichloromethane (5mL). The mixture was stirred at room temperature for 10 minutes. N'-formyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbohydrazide (0.145g, 0.39mmol) in dichloromethane (5mL) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (100mL) and washed with water (25mL). The organic was dried over sodium sulphate, filtered and concentrated 4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (0.5g, 3.1mmol), ethylenediamine (1.5mL, 22mmol), copper (II) acetate (0.07g, 0.3mmol) and N-methylpyrrolidinone (1.5mL) were combined and subjected to microwave (Smith Personal Synthesiser) irradiation at 220°C for 1 hour. The reaction mixture was concentrated Dimethylsulphoxide (0.156mL, 2.19mmol) and dichloromethane (15mL) were combined and cooled to - 78°C under nitrogen, oxalyl chloride (0.191 mL, 2.19mmol) was added and the reaction mixture was stirred at -78°C under nitrogen for 1 hour. A solution of 2-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-4,5-dihydro-1H-imidazole (0.314g, 0.88mol) in dichloromethane (15mL) was added slowly. The reaction was stirred at -78°C for 1 hour. Triethylamine (0.611mL, 4.4mmol) was then added and the reaction was stirred for a further hour. The reaction mixture allowed to warm to room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100mL) and washed with an aqueous ammonia solution (20mL). The organic was dried over sodium sulphate, filtered and concentrated (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2 The product from step 1 (0.162g, 0.34mmol) and sodium hydroxide (0.033g, 0.82mmol) were dissolved in ethanol (3mL). 10% Palladium on charcoal (0.02g) was added. The mixture was hydrogenated for 18 hours at room temperature at 50 psi. The reaction mixture was filtered through Arbocel®, the filtrate was concentrated 4-[4-(3-Chloro-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (5.3 g, 19 mmol) was taken in acetonitrile (30 ml), to which was added Hunig's base (6 g, 47 mmol) and homo-morpholine hydrogen chloride (2.8 g, 20 mmol). This solution was heated at reflux for 18 hours. The solvent was removed 4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (900 mg, 26 mmol) was dissolved in THF (5ml) and cooled to 0°C under nitrogen. Lithium aluminium hydride (1M in EtO2, 7.8 ml, 78mmol) was added dropwise and left to stir for 10 minutes before heating to reflux for 18 hours. The solution was cooled to 0°C before quenching with water (0.78 ml), followed by sodium hydroxide (2M, 0.78ml) and finally water (2.4 ml). The resulting slurry was filtered through Arbocel®, washing through with DCM (2 x 10ml). The filtrate was concentrated C-{4-[4-(3-[1,4]Oxazepan-4-yi-propoxy)-phenyl]-tetrahydro-pyran-4-yl}-methylamine (150 mg, 0.43 mmol) and 1-Bromo-2-(2-bromo-ethoxy)-ethane (110 mg, 0.47 mmol) were dissolved in acetonitrile (10 ml) and K2CO3 (130 mg, 0.95 mmol) was added. The solution was heated at 60°C for 18 hours before filtering the solution to remove to the solid K2CO3. The filtrate was concentrated C-{4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-yl}methylamine (210 mg, 0.48 mmol) was added to a solution of 2-bromopyridine (70 mg, 0.42 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), BINAP (126 mg, 2 mmol) and sodium 4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (1 g, 29 mmol) was dissolved in concentrated hydrochloric acid (15ml) and heated at 90°C for 24 hours, and the solvent was then removed 4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid guanidine (1.2 g, 0.88 mmol of free acid) was dissolved in DMF (5 ml), to which was added N-BOC piperidine (200 mg, 1.06 mmol), HBTU (400 mg, 1.06 mmol) and Hunig's base (129 mg, 1.06 mmol). The reaction was stirred at room temperature for 3 hours before adding saturated sodium bicarbonate solution (15ml) and extracting the product into EtOAc (15 ml). The organic layer was washed with brine (15 ml), dried over Na2SO4 and concentrated 4-{4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (260 mg, 0.48 mmol) was dissolved in a solution of hydrogen choride in dioxane (4M, 5 ml) and was stirred at room temperature for 2 hours. The solvent was removed 4-(3-{4-[4-(piperazin-1-ylcarbonyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)-1,4-oxazepane (45 mg, 0.1 mmol) was dissolved in DCM (3 ml), to which was added formaldyhyde (37% w/w in H2O, 12 mg, 0.12 mmol) and acetic acid (8 mg, 0.12 mmol) and was stirred at room temperature for 30 minutes before adding STAB (25 mg, 0.12 mmol). The solution was allowed to stir for a further 45 minutes before washing the solution with saturated sodium bicarbonate (10 ml), followed by brine (10 ml). The organic layer was dried over Na2SO4 and concentrated A mixture of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine (200mg, 0.63mmol), A mixture of (1-benzhydrylazetidin-3-yl)methanol (4.0g, 15.8mmol), acetone (20ml), 2-propanol (80ml), c.HCl (1.5ml) and Pd(OH)2 was hydrogenated at 50psi/50° for 18 hours. The reaction mixture was filtered through Arbocel® and concentrated (1-isopropylazetidin-3-yl)methanol hydrochloride (2.6g, 15.7mmol) was dissolved in dichloromethane (50ml) and cooled to 0°C. Thionyl chloride (1.4ml, 19.2mmol) was added dropwise over 5 min. The reaction mixture was then stirred whilst warming to ambient temperature. Stirred at ambient temperature for 48 hours. The reaction mixture was concentrated 3-(chloromethyl)-1-isopropylazetidine hydrochloride (2.8g, 15.2mmol), 4-(4-hydroxyphenyl)tetrahydropyran-4-carbonitrile (3.1g, 15.2mmol) and potassium carbonate (8.5g, 61.6mmol) were combined in DMF (40ml) and stirred at 50° for 2 hours. Potassium iodide (0.5g 3.0mmol) was added and the mixture was stirred at 50° for 18 hours then at 90-95° for a further 5 hours. The reaction mixture was concentrated A solution of 4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile (1.8g, 5.73mmol) in THF (80ml) was cooled to 0°C under an atmosphere of nitrogen. A solution of lithium aluminium hydride (1.0M solution in Et2O, 17ml, 17mmol) was added dropwise over 5 min. The mixture was stirred whilst warming to ambient temperature over 18 hours. The reaction was cooled to 0°C and quenched with water (0.5ml) then 2M NaOH (0.5ml) and then water (1.5ml). Celite® (3g) was added and the mixture stirred at ambient temperature for 0.5 hour. Diluted with ethyl acetate (50ml), filtered and concentrated 1-(4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine was stirred with 2-bromopyridine (60µl, 0.63mmol), tris(dibenzylideneacetone)djpalladium(0) (15mg, 0.018mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (19mg, 0.036mmol) and sodium 1H NMR (400MHz, CDCl3) δ 8.02 (d, 1H), 7.31 (t, 1H), 7.25 (d, 2H), 6.91 (d, 2H), 6.50 (t, 1H), 6.20 (d, 1H), 4.09 (d, 2H), 3.99 (t, 1H), 3.82 (m, 2H), 3.59 (m, 2H), 3.48 (d, 2H), 3.45 (m, 2H), 3.03 (m, 2H), 2.88 (m, 1H),2.33 (m, 1H), 2.13 (m, 2H), 1.92 (m, 2H), 0.93 (d, 6H). LRMS ESI+ m/z 396 [M+H]+ HRMS ESI+ m/z 396.2639 [M+H]+ To a solution of 4-[4-(3-Pyrrolidin-1-ylpropoxy)-phenyl]tetrahydropyran-4-carbonitrile (2.0g, 6.37mmol) in diethyl ether (30ml) and THF (5ml) was added methyl lithium/lithium bromide complex (1.5M solution in diethyl ether, 4.5ml, 6.75mmol), the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was quenched by adding water (5ml) and concentrated 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}ethanone_(500mg, 1.51 mmol) was dissolved in dimethylformamide dimethylacetal (3ml) and heated in a sealed tube microwave reactor (Smiths Personal Synthesizer) at 150°C for 1800 seconds then at 170°C for 2400 seconds. The reaction mixture concentrated The crude intermediate was dissolved in ethanol (10ml), formamidine acetate (320mg, 3.07mmol) and sodium ethoxide (21% w/v solution in ethanol, 1.0ml, 3.09mmol) were added and the mixture stirred at ambient temperature for 1.5 hours then heated at 70°C for 2 hours. Formamidine acetate (500mg, 4.80mmol) was added and stirred at 70°C for 18 hours. Formamidine acetate (500mg, 4.80mmol) and potassium carbonate (2.0g, 14.5mmol) were added and stirred at reflux for 5 hours. Formamidine acetate (500mg, 4.80mmol) was added and stirred at reflux for 18 hours. The reaction mixture was partitioned between DCM (80ml) and 10% Na2CO3 (50ml), the organics were dried over Na2SO4, filtered and concentrated 2-Aminopropionaldehyde dimethyl acetal (0.2g, 1.7mmol), thiocarbonyldiimidazole (0.36g, 2.0mmol) and triethylamine (0.23ml, 1.7mmol) were stirred in DMF (2.0ml) at ambient temperature for 30 minutes before heating to 50°C for 18 hours. {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (540mg, 1.7mmol) was added and stirred at ambient temperature for 4 hours. 2M HCl (6ml) was added, stirred at 70°C for 18 hours, then c.HCl (1.0ml) was added and the mixture stirred at 110°C for 18 hours. The reaction mixture was cooled and partitioned between ethyl acetate (100ml) and dilute aqueous sodium carbonate (50ml). The organics were dried over Na2SO4 and concentrated 4-methyl-1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazole-2-thiol (0.6g, 1.44mmol) was dissolved in ethanol (20mL), water (5mL) was added, and the mixture was cooled in ice. Raney nickel (4g) was added, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was filtered though Arbocel® and concentrated 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 1.6 mmol) and TosMIC (340 mg, 1.7 mmol) were dissolved in EtOH (20 ml), to which NaCN (12 mg, 0.25 mmol) was added. The solution immediately turned pale yellow and was allowed to stir for 2 hours at room temperature. The solvent was removed The 5-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-yl}-4-(toluene-4-sulfonyl)-4,5-dihydro-oxazole (500 mg) was dissolved in EtOH saturated with ammonia ( 7ml) before heating in a bomb at 110°C for 18 hours. The solvent was removed A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile (3.0 g, 10.7 mmol), potassium iodide (100 mg, 0.60 mmol) and ethylmethylamine (5.0 ml, 58.3 mmol) in acetonitrile (30 mL) was heated to 60°C overnight. The mixture was cooled, concentrated Lithium aluminium hydride (9.93 ml of a 1 M solution in tetrahydrofuran, 9.93 mmol) was added to a solution of 4-(4-{3-[ethyl(methyl)amino]propoxy}phenyl)tetrahydro-2H-pyran-4-carbonitrile (2.0 g, 6.6 mmol) in tetrahydrofuran (10 ml) at 0°C under N2. The reaction mixture was warmed to room temperature over 18 h and then quenched by the sequential addition of water (0.4 ml), 2M NaOH solution (0.4 ml) and water (0.4 ml). The mixture was filtered through arbocel and concentrated To a stirred solution of 3-{4-[4-(aminomethyl)tetrahydro-2H-pyran-4-yl]phenoxy}-N-ethyl-N-methylpropan-1-amine (500 mg, 1.6 mmol) and bis(2-bromoethyl)ether (345 mg, 1.5 mmol) in anhydrous acetonitrile (50 mL) was added potassium carbonate (450 mg, 3.3 mmol). The mixture was heated to 60°C overnight then concentrated Compounds were evaluated using a cell based functional assay measuring cAMP through β-lactamase reporter gene activity. A stable cell line was generated from HEK-293 cells expressing a CRE β-lactamase reporter gene and transfected with human histamine H3 receptor cDNA. Cells were seeded at a density of 500,000 cells/ml, and grown overnight in MEM (Invitrogen) supplemented with 1% dialysed FBS (Sigma), 2mM glutamine (Sigma), 1mM sodium pyruvate (Sigma), 0.1mM non essential amino acids (Invitrogen) and 25mM HEPES (Sigma) in poly D lysine coated 384 well plates (BD Biosciences). H3 receptor agonist imetit (Tocris) dose dependently inhibited 10µM forskolin (Calbiochem) stimulated synthesis of cAMP measured after 4.5hours by β-lactamase cleavage of CCF4-AM dye (Invitrogen). For IC50 determination, test compounds were prepared in PBS (Sigma) and DMSO (Sigma) at a dose response of 5x10-10 to 5x10-5M with a final DMSO concentration in the assay of 0.5%. Cells were incubated for 15 minutes plus/minus compound and their ability to permit 10µM forskolin-stimulated cAMP synthesis in the presence of 1 nM imetit was measured as described above. Functional Ki values were calculated from the IC50 of compounds tested as antagonists based on an experimentally determined imetit EC50 (represented in the equation as Kd) of 350pM, and an imetit concentration of 1nM, according to the Cheng-Prussoff equation where Ki = (IC50)/(1+([L]/Kd)). All the examples were tested in the assay described above and found to have a Ki value of less than 5 µM. Most of the examples have a Ki value of less than 100 nM. The data for some of said preferred compounds are given below by way of example: The invention relates to 3- or 4-monosubstituted phenol and thiophenol derivatives of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. Said 3- or 4-monosubstituted phenol and thiophenol derivatives are H3 ligands and are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions. A compound of the formula (1) :
or a pharmaceutically acceptable salt and/or solvate (including hydrate) thereof wherein :
the substituent of formula -Z-R is in the meta or para position of the phenyl group; X is selected from -CN, -CH2OH, -CH2-O-(C1-C4)alkyl, -C(O)OH, -C(O)O(C1-C4)alkyl, -CH2-NR1R2, -C(O)NR3R4, -CH2-O-het2, -CH2-het1 and het1, the group het1 in both -CH2-het1 and het1 being optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl, -S-(C1-C4)alkyl and (C1-C4)alkoxy; R1 is hydrogen or (C1-C4)alkyl optionally substituted by (C3-C8)cycloalkyl; R2 is selected from the group consisting of :
hydrogen, (C1-C6)alkyl optionally substituted by one or two substituents independently selected from (C3-C6)cycloalkyl, hydroxy, -S-(C1-C4)alkyl, -O-(C1-C4)alkyl, -SO2(C1-C4)alkyl, -SO-(C1-C4)alkyl, halo, het1, amino, (C1-C4)alkylamino, [(C1-C4)alkyl]2amino and phenyl, said phenyl being optionally substituted by one or two substituents independently selected from halo, hydroxy, cyano, (C1-C4)alkyl and (C1-C4)alkoxy, (C3-C6)cycloalkyl, het2, optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl, NH2 and (C1-C4)alkoxy, -SO2-R5 wherein R5 is selected from the group consisting of (C1-C4)alkyl, amino, (C1-C4)alkylamino, [(C1-C4)alkyl]2amino, phenyl and -(C1-C4)alkyl-phenyl, said phenyl being optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl and (C1-C4)alkoxy, and -C(O)-R6 wherein R6 is selected from the group consisting of (C1-C4)alkyl, amino, (C1-C4)alkylamino, [(C1-C4)alkyl]2amino, phenyl and -(C1-C4)alkyl-phenyl, said phenyl being optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl and (C1-C4)alkoxy; or R1 and R2 form together with the N atom to which they are attached a 3-, 4-, 5-, 6- or 7-membered saturated heterocycle wherein one C atom may be replaced by N, O, S, SO or SO2 and wherein said saturated heterocycle is optionally substituted by one or two groups independently selected from hydroxy, halo, =O, (C1-C4)alkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, -SO2(C1-C4)alkyl, -C(O)(C1-C4)alkyl, [(C1-C4)alkyl]2amino, amino, (C1-C4)alkylamino, -C(O)NH2, C(O)O(C1-C4)alkyl and pyrrolidinone; R3 and R4 are each independently selected from hydrogen, (C3-C6)cycloalkyl, and (C1-C4)alkyl, said (C3-C6)cycloalkyl and (C1-C4)alkyl being optionally substituted by amino, (C1-C4)alkylamino, [(C1-C4)alkylhamlno or (C3-C6)cycloalkyl, or R3 and R4 form together with the N atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocycle wherein one C atom may be replaced by N or O and wherein said saturated heterocycle is optionally substituted by (C1-C4)alkyl, [(C1-C4)alkyl]2amino, amino, (C1-C4)alkylamino, or -C(O)(C1-C4)alkyl, said -C(O)(C1-C4)alkyl being optionally substituted by methoxy or ethoxy, Y is selected from CH2, CH(OH), O, C=O and N, said N being substituted by H, (C1-C4)alkyl, C(O)(C1-C4)alkyl or (C1-C4)alkoxy(C1-C4)alkyl; Z is selected from O, S, SO and SO2; m and p are both integers which are independently 1, 2 or 3, with the condition that m+p is equal to or less than 4 so that the ring formed by :
is a 4-, 5- or 6-membered ring; and R is either a group of formula :
wherein * represents the attachment point to Z, L is a straight chain or branched (C2-C6)alkylene and R7 and R3 are each independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C1-C6)alkyl or R7 and R8 form together with the N atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocycle wherein one C atom is optionally replaced by N, O, S, SO or SO2 and wherein said saturated heterocycle is optionally substituted by one or two groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, C(O)O(C1-C4)alkyl, -C(O)-(C1-C4)alkyl-NH2, -C(O)NH2, halo, amino, (C1-C4)alkylamino and [(C1-C4)alkyl]2amino, or R is a group of formula:
wherein * represents the attachment point to Z, the N-containing ring is a 4- to 7-membered saturated heterocycle, n is an integer equal to 0, 1 or 2, and R9 represents a substituent selected from hydrogen, (C1-C4)alkyl, hydroxy(C1-C6 alkyl) and (C3-C6)cycloalkyl; het1 is selected from monocyclic or bicyclic heteroaromatic groups having 5 to 10 ring members, which contain 1, 2, 3 or 4 heteroatom(s) selected from nitrogen, oxygen and sulphur and het2 is selected from monocyclic or bicyclic heteroaromatic groups having 5 to 10 ring members, which contain 1, 2, 3 or 4 heteroatom(s) selected from nitrogen, oxygen and sulphur. A compound of formula (1) as defined in claim 1, wherein X is selected from -CH2-NR1R2, -C(O)NR3R4, -CH2-het1 and het1, het1 being optionally substituted once or twice by (C1-C4)alkyl, wherein R1, R2, R3, R4 and het1 are as previously defined in claim 1. A compound of formula (1) as defined in claim 2, wherein X is -CH2-het1 or het1, and het1 is selected from a 5 or 6 membered monocyclic heteroaromatic group or a 9 membered bicyclic heteroaromatic group, each heteroaromatic group containing 1 to 3 nitrogen atoms, or 1 to 2 nitrogen atoms and 1 oxygen atom, or 1 nitrogen atom and 1 sulphur atom, and each heteroaromatic group being optionally substituted once or twice by (C1-C4)alkyl. A compound of formula (1) as defined in claim 3, wherein X is thiazolyl, benzimidazolylmethyl-, pyridine oxazolyl, imidazopyridinylmethyl-, pyrimidinyl, imidazolyl, imidazolylmethyl- or triazolylmethyl-, said thiazolyl, benzimidazolylmethyl-, pyridinyl, oxazolyl, imidazopyridinylmethyl-, pyrimidinyl, imidazolyl, imidazolylmethyl- and triazolylmethyl- each being optionally substituted with one methyl group. A compound of formula (1) as defined in claim 1 or claim 2, wherein R1 is hydrogen, methyl or ethyl. A compound of formula (1) as defined in claim 1, claim 2 or claim 5, wherein R2 is selected from the group consisting of
hydrogen,
(C1-C6)alkyl optionally substituted by one or two substituents independently selected from -S-(C1-C4)alkyl, -O-(C1-C4)alkyl, -SO2-(C1-C4)alkyl, and phenyl, said phenyl being optionally substituted by one or two substituents independently selected from halo, hydroxy, cyano, (C1-C4)alkyl and (CH-C4)alkoxy,
(C3-C6)cycloalkyl,
het2 optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl and (C1-C4)alkoxy, wherein het2 is defined as in claim 1,
-SO2-R5 wherein R6 is selected from the group consisting of (C1-C4)alkyl, [(C1-C4)alkyl]2amino, phenyl, and -(C1-C4)alkyl-phenyl, wherein said phenyl is optionally substituted by 1 substituent independently selected from halo and cyano and
-C(O)-R6 wherein R6 Is selected from the group consisting of (C1-C4)alkyl, ((C1-C4)alkyl]2amino, amino, and -(C1-C4)alkyl-phenyl, said phenyl being optionally substituted by one or two substituents independently selected from halo, cyano, (C1-C4)alkyl and (C1-C4)alkoxy. A compound of formula (1) as defined in claim 6, wherein R2 is selected from the group consisting of
(C1-C3)alkyl optionally substituted by -O-(C1-C3)alkyl,
(C3-C5)cycloalkyl,
het2, wherein het2 is selected from the group consisting of 5 or 6 membered monocyclic heteroaromatic groups containing 1 to 2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulphur atom, said het2 being optionally substituted by (C1-C4)alkyl,
SO2-R5 wherein R6 is (C1-C4)alkyl and
C(O)-R6 wherein R6 is (C1-C4)alkyl. A compound of formula (1) as defined in claim 7, wherein R2 is (C1-C3)alkyl optionally substituted by methoxy. A compound of formula (1) as defined in claim 7, wherein R2 is het2, and het2 is selected from the group consisting of 5 or 6 membered monocyclic heteroaromatic groups containing 1 or 2 nitrogen atoms. A compound of formula (1) as defined in claim 9, wherein R2 is a pyridazinyl group. A compound of formula (1) as defined in claim 1 or claim 2, wherein R1 and R2 form together with the N atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocycle wherein one C atom may be replaced by N, O, S, SO or SO2 and wherein said saturated heterocycle is optionally substituted by one or two groups independently selected from hydroxy, halo, =O, (C1-C4)alkyl, -(C1-C4)alkyl(C3-C6)cycloalkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, -SO2(C1-C4)alkyl, -C(O)(C1-C4)alkyl, [(C1-C4)alkyl]2amino, -C(O)NH2, C(O)O(C1-C4)alkyl and pyrrolidinone. A compound of formula (1) as defined in claim 11, wherein R1 and R2 form together with the N atom to which they are attached a morpholinyl group. A compound of formula (1) as defined in claim 1 or claim 2, wherein R3 and R4 are each independently selected from hydrogen and (C1-C4)alkyl or R3 and R4 form together with the N atom to which they are attached a 4, 5 or 6 membered saturated heterocycle wherein one C atom may be replaced by N or O and wherein said saturated heterocycle is optionally substituted by (C1-C4)alkyl. A compound of formula (1) as defined in claim 13, wherein R3 and R4 are selected Independently from hydrogen, methyl and ethyl, or R3 and R4 form together with the N atom to which they are attached a pyrrolidinyl, piperidinyl, piperazinyl or azetidinyl ring, each pyrrolidinyl, piperidinyl, piperazinyl and azetidinyl ring being optionally methyl substituted. A compound of formula (1) as defined in any one of the preceding claims, wherein Y is selected from CH2, CH(OH), O and C=O. A compound of formula (1) as defined in claim,15, wherein Y is O. A compound of formula (1) as defined in any one of the preceding claims, wherein Z is O. A compound of formula (1) as defined in any one of the preceding claims, wherein m and p are both 2. A compound of formula (1) as defined in any one of the preceding claims, wherein R is a group of formula :
wherein * represents the attachment point to Z, L is a (C2-C5)alkylene and R7 and R8 are each independently selected from hydrogen, (C1-C8)alkyl, (C3-C6)cycloalkyl, hydroxy(C1-C6)alkyl or R7 and R8 form together with the N atom to which they are attached a 4-, 5-, 6- or 7-membered saturated heterocycle wherein one C atom is optionally replaced by N, O, S, SO or SO2 and wherein said saturated heterocycle is optionally substituted by one or two groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C1-C4)alkyl, hydroxy, C(O)O(C1-C4)alkyl, -C(O)-(C1-C4)alkyl-NH2, -C(O)NH2 and halo. A compound of formula (1) as defined in claim 19, wherein R7 and R8 form together with the N atom to which they are attached a morpholinyl or oxazepanyl group. A compound of formula (1) as defined in claim 19, wherein R7 and R8 form together with the N atom to which they are attached a 4-, 5- or 6-membered saturated heterocycle, optionally substituted by one or two (C1-C4)alkyl groups. A compound of formula (1) as defined in claim 21, wherein the saturated heterocycle is a pyrrolidinyl group, optionally substituted by one or two methyl groups. A compound of formula (1) as defined in claim 19, wherein R7 and R8 are (C1-C3)alkyl. A compound of formula (1) as defined in any one of claims 19 to 23, wherein L is propylene. A compound of formula (1) as defined in any one of claims 1 to 18, wherein R is a group of formula:
wherein * represents the attachment point to Z, the N-containing ring is a 4- or 6-membered saturated heterocycle, n is an integer equal to 0 or 1, and R9 represents a substituent selected from hydrogen, (C1-C4)alkyl and (C3-C5)cycloalkyl. A compound of formula (1) as defined in claim 25, wherein R9 is isopropyl or cyclobutyl. A compound of formula (1) according to claim 1 which is selected from:
N-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-methanesulfonamide; {4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-urea; 4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]tetrahydro-2H-pyran-4-carboxylic acid amide; 4-{4-[(-1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxamide; 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-tetrahydro-2H-pyran-4-carboxamide; N-{[4-(4-{3-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-propoxy}phenyl)tetrahydro-2H-pyran-4-yl]-methyl}-N-methylmethanesulfonamide; and N*4*-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine. A pharmaceutical composition including a compound of the formula (1) or a pharmaceutically acceptable salt and/or solvate thereof, as defined in any one of the preceding claims, together with a pharmaceutically acceptable excipient. A compound of the formula (1) as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt and/or solvate thereof, for use as a medicament. The use of a compound of the formula (1) according to any one of claims 1 to 27 or a pharmaceutically acceptable salt and/or solvate thereof, for the manufacture of a medicament for the treatment of sleep disorders, migraine, dyskinesia, stress-induced anxiety, psychotic disorders, epilepsy, Cognition deficiency diseases, depression, mood disorders, schizophrenia, anxiety disorders, attention-deficit hyperactivity disorder (ADHD), psychotic disorders, obesity, dizziness, vertigo, epilepsy, motion sickness, inflammatory diseases, adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic congestion, male sexual dysfunction or female sexual dysfunction. The use of a compound of the formula (1) according to claim 30 wherein the cognition deficiency disease is Alzheimer's disease or mild cognitive impairment. A combination of a compound of formula (1) as defined in any one of claims 1 to 27, and another pharmacologically active agent A combination as claimed in claim 32, wherein the other pharmacologically active agent is a histamine H1 receptor antagonist A compound of the formula (1) as defined in any one of claims 1 to 27 or a pharmaceutical acceptable salt and/or solvate thereof, for use in treating the diseases, disorders and conditions as defined in claims 30 and 31.
Another embodiment of the invention is an intermediate as described herein.
where each part may be administered by either the same or different route.EXAMPLES
glossary
APCI atmospheric pressure chemical ionisation Arbocel® filter agent BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl BOC br broad CDI carbonyldiimidazole δ chemical shift d doublet Δ heat DCM dichloromethane DIAD diisopropyl azodicarboxylate DMF DMSO dimethylsulfoxide EDCI see WSCDI ESI+ electrospray ionisation positive scan ESI- electrospray ionisation negative scan h hours HBTU O-(1 HOAT 1-hydroxy-7-azabenzotriazole HOBT 1-hydroxybenzotriazole HPLC high pressure liquid chromatography Hunig's base Diisopropylethylamine m/z mass charge ratio min minutes MS mass spectrum NH3 0.88 ammonia aqueous solution NMM NMR nuclear magnetic resonance q quartet s singlet STAB sodium triacetoxyborohydride t triplet TBME TBTU 2-(1H-benzotriazot-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TosMIC Tosylmethyl isocyanide WSCDI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Intermediate 1: 4-(4-methoxyphenyl)-tetrahydro-2H-pyran-4-carbonitrile
Intermediate 2: 4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile
Intermediate 3: 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol
Intermediate 4: 3-{4-[(dimethylamino)methyl]tetrahydro-pyran-4-yl}phenol
General procedure A for the synthesis of chlorides (R-RLGwherein RLGis chloride):
General procedure B:
Intermediate 5: 1-(3-Chloro-propyl)-pyrrolidine
Example 1: Dimethyl-{4-[3-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-pyran-4-ylmethyl}amine
Intermediate 6: 1-(3-Chloro-propyl)-2(R),5(R)-trans-dimethyl-pyrrolidine
Example 2: (4-{4-[3-(2,5-Dimethylpyrrolidin-1-yl)propoxy]pheny}tetra-hydro-pyran-4-ylmethyl)dimethylamine
Intermediate 7: 1-(3-Chloro-propyl)-2-methyl-pyrrolidine
Example 3: Dimethyl-(4-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-tetrahydro-pyran-4-ylmethyl)-amine
Intermediate 8: 1-(3-Chloro-propyl)-2,6-cis-dimethyl-piperidine
Example 4: (4-{4-[3-(2,6-Dimethylpiperidin-1-yl)propoxy]phenyl}tetra-hydro-pyran-4-ylmethyl)dimethyl-amine
Intermediate 9: 4-(3-Chloro-propyl)-thiomorpholine
Example 5: Dimethyl-{4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetra-hydro-pyran-4-ylmethyl}amine
Example 6: Dimethyl-(4-{4-[3-(1-oxothiomorpholin-4-yl)propoxy]phenyl}-tetrahydropyran-4-ylmethyl)amine
Example 7: (4-14-[3-(1,1-Dioxo-thiomorpholin-4-yl)propoxylphenyl]tetra-hydro-pyran-4-ylmethyl)dimethyl-amine
Intermediate 10: 1-(3-Chloro-propyl)-piperidin-4-ol
Example 8: 1-{3-[4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenoxy]-propyl}-piperidin-4-ol
Intermediate 11: 1-(3-Chloro-propyl)-4-methoxy-piperidine
Example 9: (4-{4-[3-(4-Methoxy-piperidin-1-yl)-propoxy]-phenyl}-tetrahydro-pyran-4-ylmethyl)-dimethyl-amine
Intermediate 12: 2-[1-(3-Chloro-propyl)-piperidin-4-yl]-ethanol
Example 10: 2-(1-{3-[4-(4-Dimethylaminomethyltetrahydropyran-4-yl)phenoxy]propyl}piperidin-4-yl)ethanol
Intermediate 13:1-(3-Chloro-propyl)-4-(2-methoxy-ethyl)-piperidine
Example 11: [4-(4-{3-[4-(2-Methoxy-ethyl)-piperidin-1-yl]-propoxy}-phenyl)-tetrahydro-pyran-4-ylmethyl]-dimethyl-amine
Intermediate 14:1-(3-Chloro-propyl)-piperidine-4-carboxylic acid amide
Example 12: 1-{3-[4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenoxy]-propyl}-piperidine-4-carboxylic acid amide
Intermediate 15: 4-(3-Chloro-propyl)-piperazine-1-carboxylic acid ethyl ester
Example 13:{3-[4-(4-Dimethylaminomethyltetrahydropyran-4-yl)phenoxy]-propyl}piperazine-1-carboxylic acid ethyl ester
Intermediate 16 : (3-Chloro-propyl)-diethyl-amine
Example 14: {3-[4-(4-Dimethylaminomethyltetrahydropyran-4-yl)phenoxy]-propyl}diethyl-amine
Intermediate 17: 2-[(3-Chloro-propyl-ethyl-amino]-ethanol
Example 15: 2-({3-[4-(4-Dimethylaminomethyltetrahydropyran-4-yl)-phenoxy]propyl}ethylamino) ethanol
Intermediate 18: (3-Chloro-propyl)-isopropyl-methyl-amine
Example 16: {3-[4-(4-Dimethylaminomethyltetrahydropyran-4-yl)phenoxyl-propyl} isopropylmethylamine
Intermediate 19: 1-(2-chloro-ethyl)-pyrrolidine
Example 17: Dimethyl-{4-[4-(2-pyrrolidin-1-ylethoxy)phenyl]tetrahydro-pyran-4-ylmethyl}amine
Intermediate 20: 1-(3-Chloro-2-methyl-propyl)-pyrrolidine
Example 18: Dimethyl-{4-[4-(2-methyl-3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-amine
Intermediate 21: Methanesulfonic acid 1-isopropyl-piperidin-4-yl ester
Example 19: {4-[4-(1-Isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-ylmethyl}dimethyl-amine
Intermediate 22: Methanesulfonic acid 1-cyclopentyl-piperidin-4-yl ester
Example 20: {4-[4-(1-Cyclopentylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-ylmethyl}dimethylamine
Example 21: {3-[4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenoxy]-propyl}-isopropylamine
Example 22: Dimethyl-{4-[4-(4-pyrrolidin-1-ylbutoxy)phenyl]tetrahydro-pyran-4-ylmethyl}amine
General procedure C:
Intermediate 23: 2,2-Dimethyl-3-pyrrolidin-1-yl-propan-1-ol
Example 23: {4-[4-(2,2-Dimethyl-3-pyrrolidin-1-yl-propoxy)-phenyl]-tetra-hydropyran-4-ylmethyl}-dimethyl-amine
Intermediate 24: 4-Pyrrolidin-1-yl-butan-2-ol
Example 24: Dimethyl-{4-[4-(1-methyl-3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine
Intermediate 25: 3-Pyrrolidin-1-yl-butan-1-ol
Example 25: Dimethyl-{4-[4-(3-pyrrolidin-1-yl-butoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-amine
Example 26: Dimethyl-(4-{4-[2-(1-methylpyrrolidin-2-yl)ethoxy]phenyl}-tetrahydropyran-4-ylmethyl)amine
Example 27: 4-[4-(3-Pprrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile
Example 28: {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine dihydrochloride
Example 29: Dimethyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydro-pyran-4-ylmethyl}amine
Example 30: 4-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile
Example 31: {4-[4-(3-Piperidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl} methylamine dihydrochloride
Example 32: Dimethyl-{4-[4-(3-piperidin-1-ylpropoxy)phenyl]tetrahydro-pyran-4-ylmethyl}amine dihydrochloride
Intermediate 26: 1-(4-hydroxyphenyl)cyclohexanecarbonitrile
Example 33: 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarbonitrile
Example 34: N-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl)-N,N-dimethylamine
Intermediate 27: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde
General procedure D:
Example 35: (1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperidin-4-yl)-methanol
Example 36: 1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperidin-4-ol
Example 37: 1-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-piperidine-4-carboxylic acid amide
Example 38: 1-Methyl-4-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-piperazine
Example 39: 1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine
Example 40: 1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}pyrrolidin-3-ol
Example 41: (R)-2-Methoxymethyl-1-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyrrolidine
Example 42: (S)-2-Methoxymethyl-1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}pyrrolidine
Example 43: 1-(1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperidin-4-yl)pyrrolidin-2-one
Example 44: 4-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-thiomorpholine
Example 45: 4-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}thiomorpholine-1-oxide
Example 46: 4-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-thiomorpholine 1,1-dioxide
Example 47: 4-{4-[4-(3-Pyrrolidin-1-yl-propoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine-1-carboxylic acid ethyl ester
Intermediate 28: Piperazine-1-carboxylic acid amide hydrochloride
Example 48: 4-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine-1-carboxylic acid amide
Example 49: 1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperidine
Example 50: 4,4-difluoro-1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetra-hydropyran-4-ylmethyl}piperidine
Example 51: methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine
Example 52: methyl-(3-methylsulfanyl-propyl)-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine
Example 53: (3-methanesulfonyl-propyl)-methyl-{4-[4-(3-pyrrolidin-1-yl-propoxy)phenyl]tetrahydropyran-4-ylmethyl}amine
Example 54: isopropyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydro-pyran-4-ylmethyl}amine
Example 55: isopropyl-methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine
Example 56: cyclopentyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetra-hydropyran-4-ylmethyl}amine
Example 57:1-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}pyrrolidine
Example 58: 4-{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}-morpholine
Example 59 : methyl-phenethyl-{4-4-{3-pyrrolidin-1-ylpropoxy)phenyl]tetra-hydropyran-4-ylmethyl}amine
Example 60 : methyl-benzyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetra-hydropyran-4-ylmethyl}amine
Example 61 : (2-methoxyethyl)-methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]tetrahydropyran-4-ylmethyl}amine
Example 62: methyl-pyrymidin-2-yl-{4-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-tetrahydropyran-4-ylmethyl}amine
Example 63: N-{4-4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-methanesulfonamide
Example 64: C-Phenyl-N-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetra-hydropyran-4-ylmethyl}-methanesulfonamide
Example 65: 3-Cyano-N-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-benzenesulfonamide
Example 66: 2-Fluoro-N-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-benzenesulfonamide
Example 67: N-methyl-N-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetra-hydropyran-4-ylmethyl}-methanesulfonamide
Example 68 : N'-{[4-(4-(3-Pyrrolidin-1-yl-propoxy)-phenyl)tetrahydro-2
Example 69: N-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-acetamide
Example 70: N-methyl-N-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-acetamide
Example 71: 2-Phenyl-N-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-acetamide
Example 72: 1,1-Dimethyl-3-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-urea
Example 73: 1,1,3-Trimethyl-3-{4-[4-(3-pyrrolidin-1-yl-propoxyl-phenyl]-tetrahydro-pyran-4-ylmethyl}-urea
Example 74: {4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-urea
Intermediate 29: 4-aminomethyl-4-[4-(3-pyrrolidin-1-yl-propoxy)phenyl]-cyclohexanol
Example 75: 4-dimethylaminomethyl-4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-cyclohexanol
General procedure E:
Example 76: 4-[3-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile
Example 77: 4-{4-[3-(2,5-Dimethylpyrrolidin-1-yl)propoxy]phenyl}-tetra-hydropyran-4-carbonitrile
Example 78: 4-{4-[3-(2-Methylpyrrolidin-1-yl)-propoxy]-phenyl}tetra-hydropyran-4-carbonitrile
Example 79: 4-[4-(3-Thiomorpholin-4-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrite
Example 80: 4-{4-[3-(1-Oxo-thiomorpholin-4-yl)-propoxy]-phenyl}-tetra-hydropyran-4-carbonitrile
Example 81: 4-{4-[3-(1,1-Dioxo-1λ6-thiomorpholin-4-yl)propoxy]-phenyl}tetrahydro-pyran-4-carbonitrile
Example 82: 4-{4-[3-(4-Hydroxypiperidin-1-yl)propoxy]phenyl}tetrahydro-pyran-4-carbonitrile
Example 83: 4-(4-{3-[4-(2-Hydroxyethyl)-piperidin-1-yl]propoxy}phenyl)-tetrahydro-pyran-4-carbonitrile
Example 84: 1-{3-[4-(4-Cyano-tetrahydro-pyran-4-yl)-phenoxy]-propyl}-piperidine-4-carboxylic acid amide
Example 85: 4-{3-[4-(4-Cyanotetrahydropyran-4-yl)-phenoxy]propyl}-piperazine-1-carboxylic acid ethyl ester
Intermediate 30: 4-(3-Chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester
Example 86: 4-{3-[4-(4-Cyano-tetrahydro-pyran-4-yl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester
Example 87: 4-[4-(3-Piperazin-1-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile
Example 88: 4-(4-{3-[4-(2-Aminopropionyl)piperazin-1-yl]propoxy}phenyl)-tetrahydropyran-4-carbonitrile
Intermediate 31: 2-[(3-Chloro-propyl)-methyl-amino]-ethanol
Example 89: 4-(4-{3-[(2-Hydroxyethyl)methylamino]propoxy}-phenyl)tetra-hydropyran-4-carbonitrile
Example 90: 4-[4-(2-Pyrrolidin-1-ylethoxy)phenyl]tetrahydropyran-4-carbonitrile
Example 91: 4-[4-(2-Methyl-3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydro-pyran-4-carbonitrile
Intermediate 32:1-(3-Chloro-1-methyl-propyl)-pyrrolidine hydrochloride
Step 2:
Example 92: 4-[4-(3-Pyrrolidin-1-ylbutoxy)phenyl]tetrahydropyran-4-carbonitrile
Example 93: 4-{4-[2-(1-Methylpyrrolidin-2-yl)ethoxy]phenyl}tetrahydro-pyran-4-carbonitrile
Example 94: 4-[4-(1-Isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile
Example 95: 4-[4-(1-Cyclopentylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile
Intermediates 33 and 34: 4-[4-(3-chloro-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile and 4-[4-(3-bromo-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile
General procedure F:
Example 96: 4-[4-(3-morpholino-4-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile
Example 97: 4-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]phenyl}tetrahydro-pyran-4-carbonitrile
Example 98: 4-{4-[3-(2-methyl-piperidin-1-yl)-propoxy]phenyl}-tetrahydro-pyran-4-carbonitrile
Example 99: 4-{4-[3-(3-methyl-piperidin-1-yl)-propoxy]phenyl}-tetrahydro-pyran-4-carbonitrile
Example 100: 4-{4-[3-(4-methyl-piperidin-1-yl)-propoxy]phenyl}-tetrahydro-pyran-4-carbonitrile
Example 101: 4-[4-(3-azepan-1-ylpropoxy)phenyl]tetrahydropyran-4-carbonitrile
Example 102: 4-{4-[3-(4,4-difluoro-piperidin-1-yl)-propoxy]phenyl}-tetra-hydropyran-4-carbonitrile
Example 103: 4-[4-(5-Pyrrolidin-1-ylpentyloxy)phenyl]tetrahydropyran-4-carbonitrile
Intermediate 35: 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile
General procedure G:
Example 104: 1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-cyclohexane-carbonitrile
General procedure H:
Example 105: 4-[4-(2,2-Dimethyl-3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-pyran-4-carbonitrile
Example 106: 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid amide
Example 107: 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Intermediate 36: Methyl 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Example 108: {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanol
Example 109: 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclo-pentane-carbonitrile
Example 110: 4-oxo-1-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexane-carbonitrile
Example 111: 4-hydroxy-1-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]cyclo-hexanecarbonitrile
Intermediate 37: (
Intermediate 38: 3-[(2
Intermediate 39:
Intermediate 40: (3
Intermediate 41: (3
Intermediate 42: (3
Intermediate 43: 2,2-Dimethylpyrrolidine
Intermediate 44: (2
Intermediates 45 and 46: 1-[4-(3-bromo-propoxy)phenyl]cyclohexane-carbonitrile and 1-[4-(3-chloro-propoxyl-phenyl]-cyclohexane-carbonitrile
Example 112: 1-(4-{3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]propoxy}-phenyl)cyclohexanecarbonitrile
Example 113:1-(4-{3-[(3
Example 114:1-(4-{3-[(3
Example 115: 4-(4-{3-[(2
Example 116: 1-{4-[3-(2,2-dimethylpyrrolidin-1-yl)propoxy]phenyl}cyclo-hexanecarbonitrile
Example 117: -1-[1-(4-{3-[(2
Example 118: {[1-(4-{3-[(3
Example 119:
Example 120: [(1-{4-[3-(2,2-dimethylpyrrolidin-1-yl)propoxy]phenyl}-cyclo-hexyl)methyl]amine
Example 121:
Example 122:
Example 123:
Example 124:
Example 125:
Example 126:
Example 127:
Example 128:
Intermediate 47: 4-(4-{3-[(2S)-2-methylpyrrolidinyl]propoxy}phenyl)-tetrahydro-2H-pyran-4-carbonitrile
Example 129: 4-(4-{3-[(2
Intermediate 48:
Intermediate 49: 4-[4-(4-piperidinyloxy)phenyl]tetrahydro-2
Example 130: 4-{4-[1-cyclobutyl-4-piperidinyl)oxy]phenyl}tetrahydro-2
Example 131: 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Example 132: 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Example 133: 4-{4-[(1-isopropylpiperidin-4-yl)oxy]pheny]-
Example 134: 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl]-
Example 135: 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl)tetrahydro-2
Intermediate 50: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Example 136: 4-metyl-2-[4-(4-(3-pyrrolidin-1-ylpropoxy)phenyl)tetrahydro-2H-pyran-4-yl]-1,3-thiazole
Example 137: 2-[4-(4-(3-pyrrolidin-1-ylpropoxy)phenyl)tetrahydro-2
Intermediate 51: (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Intermediate 52:
Example 138:
Example 139:
Example 140:
Example 141:
Example 142:
Example 143:
Example 144: 1-{[4-(4-[(1-isopropylpiperidin-4-yl)oxy]phenyl)tetrahydro-2
Example 145:
Example 146:
Example 147: 2-{[4-(4-[(1-isopropylpiperidin-4-yl)oxy]phenyl)tetrahydro-2
Intermediate 53: 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Example 148: 1-isopropyl-4-{4-[4-(1,3-thiazol-2-yl)tetrahydro-2
Example 149: 4-{4-[4-(azetidin-1-ylcarbonyl)tetrahydro-2
Example 150:
Example 151: 1-[(4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Example 152:
Example 153:
Intermediate 54: 1-cyclobutylpiperidin-4-ol
Example 154: 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Intermediate 55: ethyl {4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}acetate
Intermediate 56: ethyl 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Intermediate 57: 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Examples 155-160
155 NMe2 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}- 1H NMR (400MHz, CD3OD) δ 1.70-1.79 (m, 4H), 1.89-2.02 (m, 6H), 2.07-2.10 (m, 2H), 2.25 (d, 4H), 2.63-2.87 (m, 9H), 3.73 (t, 2H), 3.82-3.85 (m, 2H), 4.41 (m, 1H), 6.94 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 387.2637+. 25% yield 156 NHMe 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-N-methyltetrahydro-2H-pyran-4-carboxamide 1H NMR (400MHz, CD3OD) δ 1.70-1.76 (m, 4H), 1.88-2.08 (m, 8H), 2.22-2.25 (m, 2H), 2.38-2.42 (m, 2H), 2.59-2.63 (m, 2H), 2.66 (s, 3H), 2.80 (m, 1H), 3.61 (t, 2H), 3.75-3.80 (m, 2H), 4.39 (m, 1H), 6.90 (d, 2H), 7.27 (d, 2H). HRMS ESI+ m/z 373.2480+. 10% yield 157 4-[(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)carbonyl]morpholine 1H NMR (400MHz, CD3OD) δ 1.70-1.76 (m, 4H), 1.85-2.09 (m, 8H), 2.20-2.24 (m, 4H), 2.63-2.67 (m, 2H), 2.81 (m, 1H), 3.25-3.31 (m, 6H), 3.33-3.39 (m, 2H), 3.73 (t, 2H), 3.82-3.87 (m, 2H), 4.41 (m, 1H), 6.96 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 429.2740+. 20% yield 158 NH2 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxamide 1H NMR (400MHz, CD3OD) δ 1.76-1.82 (m, 2H), 1.94-2.00 (m, 4H), 2.06-2.10 (m, 4H), 2.20-2.22 (m, 2H), 2.42 (d, 2H), 2.65-2.79 (m, 2H), 2.89-2.99 (m, 2H), 3.26 (m, 1H), 3.66 (t, 2H), 3.78-3.82 (m, 2H), 4.55 (m, 1H), 6.95 (d, 2H), 7.34 (d, 2H). HRMS ESI+ m/z 359.2322+. 13% yield 159 NHiPr 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-N-isopropyltetrahydro-2H-pyran-4-carboxamide 1H NMR (400MHz, CD3OD) δ 1.04 (d, 6H), 1.70-1.77 (m, 4H), 1.88-2.00 (m, 6H), 2.05-2.08 (m, 2H), 2.20-2.26 (m, 2H), 2.42 (d, 2H), 2.60-2.68 (m, 2H), 2.81 (m, 1H), 3.62 (t, 2H), 3.77-3.82 (m, 2H), 3.99 (m, 1H), 4.39 (m, 1H), 6.90 (d, 2H), 7.28 (d, 2H). HRMS ESI+ m/z 401.2789+. 13% yield 160 NHEt 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-N-ethyltetrahydro-2H-pyran-4-carboxamide 1H NMR (400MHz, CD3OD) δ 1.01 (t, 3H), 1.69-1.75 (m, 4H), 1.88-2.01 (m, 6H), 2.04-2.07 (m, 2H), 2.16-2.28 (m, 2H), 2.41 (d, 2H), 2.56-2.68 (m, 2H), 2.79 (m, 1H), 3.15 (q, 2H), 3.62 (t, 2H), 3.76-3.80 (m, 2H), 4.38 (m, 1H), 6.89 (d, 2H), 7.28 (d, 2H). HRMS ESI+ m/z 387.2636+. 22% yield Intermediate 58: 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Example 161: 1-cyclobutyl-4-{4-[4-(1,3-thiazol-2-yl)tetrahydro-2
Example 162: 1-cyclobutyl-4-{4-[4-(4-methyl-1,3-thiazol-2-yl)tetrahydro-2
Intermediate 59: 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Example 163:
Example 164:
Example 165:
Example 166: 1-acetyl-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Example 167: 1-isopropyl-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Example 168: 1-(cyclopropylmethyl)-4-({4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-2
Example 169: 1-cyclopropyl-
Examples 170-178
170 N-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)cyclopentanamine 1H NMR (400MHz, CDCl3) δ 1.21-1.28 (m, 2H), 1.39-1.43 (m, 2H), 1.53-1.60 (m, 4H), 1.83-1.94 (m, 9H), 2.07-2.12 (m, 4H), 2.41 (s, 2H), 2.61-2.72 (m, 7H), 3.49 (t, 2H), 3.73-3.79 (m, 2H), 4.02 (t, 2H), 6.89 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 401.3162+. 53% yield 171 N-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)butan-1-amine 1H NMR (400MHz, CDCl3) δ 0.83 (t, 3H), 1.15-1.20 (m, 2H), 1.23-1.29 (m, 2H), 1.85-1.92 (m, 9H), 2.07-2.15 (m, 6H), 2.40 (s, 2H), 2.69-2.77 (m, 6H), 3.51 (t, 2H), 3.73-3.78 (m, 2H), 4.03 (t, 2H), 6.86 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 389.3153+. 57% yield 172 N-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)cyclohexanamine 1H NMR (400MHz, CD3OD) δ 1.02-1.14 (m, 6H), 1.53 (m, 1H), 1.60 (d, 2H), 1.69 (d, 2H), 1.81-1.87 (m, 6H), 1.91 (s, 3H), 1.99-2.03 (m, 2H), 2.14 (d, 2H), 2.49 (s, 2H), 2.61 (t, 4H), 2.69 (t, 2H), 3.48 (t, 2H), 3.72-3.76 (m, 2H), 4.03 (t, 2H), 6.89 (d, 2H), 7.24 (d, 2H). HRMS ESI+ m/z 415.3314+. 61% yield 173 1-cyclopentyl-N-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)methanamine 1H NMR (400MHz, CD3OD) δ 1.07-1.12 (m, 2H), 1.46-1.50 (m, 4H), 1.60-1.64 (m, 2H), 1.82-1.85 (m, 5H), 1.87-1.91 (m, 5H), 1.99-2.01 (m, 2H), 2.04 (d, 2H), 2.14 (d, 2H), 2.43 (s, 2H), 2.59-2.62 (m, 4H), 2.69 (t, 2H), 3.49 (t, 2H), 3.71-3.76 (m, 2H), 4.02 (t, 2H), 6.88 (d, 2H), 7.24 (d, 2H). HRMS ESI+ m/z 415.3313+. 44% yield 174 N-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pentan-1-amine 1H NMR (400MHz, CD3OD) δ 0.86 (t, 3H), 1.08-1.13 (m, 2H), 1.20-1.28 (m, 4H), 1.82-1.88 (m, 6H), 1.92 (s, 3H), 1.97-2.01 (m, 2H), 2.08 (t, 2H), 2.14 (d, 2H), 2.44 (s, 2H), 2.60-2.64 (m, 4H), 2.70 (t, 2H), 3.49 (t, 2H), 3.71-3.76 (m, 2H), 4.02 (t, 2H), 6.89 (d, 2H), 7.25 (d, 2H). HRMS ESI+ m/z 403.3313+. 30% yield 175 N-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)hexan-1-amine 1H NMR (400MHz, CDCl3) δ 0.87 (t, 3H), 1.13-1.20 (m, 4H), 1.23-1.29 (m, 4H), 1.83-1.91 (m, 9H), 2.06-2.13 (m, 6H), 2.40 (s, 2H), 2.58-2.72 (m, 6H), 3.51 (t, 2H), 3.73-3.77 (m, 2H), 4.02 (t, 2H), 6.85 (d, 2H), 7.19 (d, 2H). HRMS ESI+ m/z 417.3469+. 74% yield 176 N,3,3-trimethyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)butan-1-amine 1H NMR (400MHz, CDCl3) δ 0.77 (s, 9H), 1.17 (t, 2H), 1.84-1.90 (m, 6H), 1.92 (s, 3H), 2.08-2.12 (m, 6H), 2.41 (s, 2H), 2.57-2.70 (m, 6H), 3.52 (t, 2H), 3.73-3.78 (m, 2H), 4.01 (t, 2H), 6.86 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 417.3457+. 59% yield 177 2-{[methyl({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)amino]methyl}phenol 1H NMR (400MHz, CDCl3) δ 1.78 (s, 3H), 1.79-1.85 (m, 6H), 2.06-2.09 (m, 2H), 2.21 (d, 2H), 2.67-2.75 (m, 8H), 3.48-3.54 (m, 4H), 3.70-3.75 (m, 2H), 4.03 (t, 2H), 6.73 (t, 1H), 6.77 (d, 1H), 6.86 (d, 1H), 6.90 (d, 2H), 7.13 (t, 1H), 7.25 (d, 2H). HRMS ESI+ m/z 439.2943+. 30% yield 178 3-{[methyl({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)amino]methyl}phenol 1H NMR (400MHz, CD3OD) δ 1.83 (brs, 7H), 1.88-1.91 (m, 2H), 1.95-2.01 (m, 2H), 2.11-2.15 (d, 2H), 2.55 (s, 2H), 2.58-2.62 (m, 4H), 2.69 (t, 2H), 3.17 (s, 2H), 3.49 (t, 2H), 3.63-3.67 (m, 2H), 4.02 (t, 2H), 6.62 (d, 1H), 6.67 (d, 1H), 6.72 (s, 1H), 6.89 (d, 2H), 7.05 (t, 1H), 7.29 (d, 2H). HRMS ESI+ m/z 439.2941+. 68% yield Examples 179-191
179 NEt2 N,N-diethyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide 1H NMR (400MHz, CDCl3) δ 0.64-0.74 (m, 3H), 1.04-1.12 (m, 3H), 1.79-1.82 (m, 4H), 1.91-2.03 (m, 4H), 2.23 (d, 2H), 2.54-2.58 (m, 4H), 2.65 (t, 2H), 2.86-2.94 (m, 2H), 3.27-3.35 (m, 2H), 3.77-3.89 (m, 4H), 4.01 (t, 2H), 6.86 (d, 2H), 7.15 (d, 2H). HRMS ESI+ m/z 389.2789+. Microanalysis: Found: C, 69.16; H, 9.18; N, 7.05%. C23H36N2O3. 0.5H2O requires C, 69.49; H, 9.38; N, 7.05%. 68% yield 180 1-methyl-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)piperazine 1H NMR (400MHz, CDCl3) δ 1.76-1.81 (m, 4H), 1.97-2.03 (m, 8H), 2.15 (s, 3H), 2.19-2.22 (m, 2H), 2.50-2.54 (m, 4H), 2.62 (t, 2H), 3.26-3.44 (m, 4H), 3.78 (t, 2H), 3.87-3.90 (m, 2H), 4.02 (t, 2H), 6.88 (d, 2H), 7.15 (d, 2H). HRMS ESI+ m/z 416.2908+. 9% yield 181 1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4- yl}carbonyl)piperazine 1H NMR (400MHz, CDCl3) δ 1.77-1.80 (m, 6H), 1.97-2.02 (m, 4H), 2.20 (d, 2H), 2.50-2.54 (m, 6H), 2.61 (t, 2H), 3.24-3.38 (m, 4H), 3.78 (t, 2H), 3.86-3.90 (m, 2H), 4.00 (t, 2H), 6.87 (d, 2H), 7.15 (d, 2H). HRMS ESI+ m/z 402.2746+. 43% yield 182 1-propyl-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)piperazine 1H NMR (400MHz, CDCl3) δ 0.84 (t, 3H), 1.37-1.43 (m, 2H), 1.1.69-1.77 (m, 2H), 1.84-1.88 (m, 4H), 1.98-2.07 (m, 6H), 2.14-2.19 (m, 4H), 2.65-2.69 (m, 4H), 2.74 (t, 2H), 3.26-3.40 (m, 4H), 3.78 (t, 2H), 3.87-3.89 (m, 2H), 4.02 (t, 2H), 6.86 (d, 2H), 7.15 (d, 2H). HRMS ESI+ m/z 444.3196+. 71% yield 183 1-ethyl-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)piperazine 1H NMR (400MHz, CDCl3) δ 0.97 (t, 3H), 1.76-1.83 (m, 4H), 1.98-2.01 (m, 8H), 2.18 (d, 2H), 2.25 (d, 2H), 2.51-2.55 (m, 4H), 2.62 (t, 2H), 3.20-3.40 (m, 4H), 3.77 (t, 2H), 3.85-3.88 (m, 2H), 3.98-4.03 (m, 2H), 6.85 (d, 2H), 7.13 (d, 2H). HRMS ESI+ m/z 430.3047+. 81 % yield 184 1-methyl-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)-1,4-diazepane 1H NMR (400MHz, CDCl3) δ 1.75-1.81 (m, 8H), 1.98-2.03 (m, 4H), 2.14-2.29 (m, 7H), 2.51-2.54 (m, 4H), 2.62 (t, 2H), 3.12-3.24 (m, 2H), 3.54-3.65 (m, 2H), 3.77-3.88 (m, 4H), 4.01 (t, 2H), 6.88 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 430.3057+. 68% yield 185 N-[2-(dimethylamino)ethyl]-N-ethyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide 1H NMR (400MHz, CDCl3) δ 0.66-0.72 (m, 3H), 1.76-1.81 (m, 4H), 1.98-2.02 (m, 6H), 2.23-2.26 (m, 6H), 2.40-2.45 (m, 2H), 2.50-2.55 (m, 4H), 2.61 (t, 2H), 2.93-3.00 (m, 2H), 3.30-3.39 (m, 2H), 3.80 (t, 2H), 3.86-3.89 (m, 2H), 4.01 (t, 2H), 6.88 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 432.3215+. 62% yield 186 N-[2-(dimethylamino)ethyl]-N-methyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide 1H NMR (400MHz, CDCl3) δ 1.77-1.80 (m, 4H), 1.96-2.01 (m, 6H), 2.18-2.27 (m, 6H), 2.35-2.42 (m, 3H), 2.50-2.53 (m, 4H), 2.62 (t, 2H), 3.03 (s, 2H), 3.35-3.45 (m, 2H), 3.79 (t, 2H), 3.86-3.88 (m, 2H), 4.01 (t, 2H), 6.87 (d, 2H), 7.15 (d, 2H). HRMS ESI+ m/z 418.3052+. 61 % yield 187 1-(3-{4-[4-(pyrrolidin-1-ylcarbonyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)pyrrolidine 1H NMR (400MHz, CDCl3) δ 1.40-1.52 (m, 3H), 1.52-1.80 (m, 3H), 1.82-2.10 (m, 6H), 2.10-2.30 (m, 2H), 2.30-2.38 (m, 2H), 2.60-3.05 (m, 6H), 3.40-3.60 (m, 2H), 3.75-3.90 (m, 4H), 4.05 (t, 2H), 6.84 (d, 2H), 7.18 (d, 2H). LRMS APCI+m/z 387+. HRMS ESI+ m/z 387.2634[MH]+. 188 1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)piperidine 1H NMR (400MHz, CDCl3) δ 1.18-1.38 (m, 2H), 1.40-1.50 (m, 2H), 1.50-1.80 (m, 6H), 1.84-2.05 (m, 2H), 2.10-2.30 (m, 8H), 2.30-2.48 (m, 2H), 3.10-3.40 (m, 4H), 3.75-3.90 (m, 4H), 4.10 (t, 2H), 6.88 (d, 2H), 7.20 (d, 2H). LRMS APCI+ m/z 401+. HRMS ESI+ m/z 401.2670+. 189 1-(3-{4-[4-(azetidin-1-ylcarbonyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)pyrrolidine 1H NMR (400MHz, CDCl3) δ 1.80-2.00 (m, 6H), 2.00-2.20 (m, 4H), 2.20-2.30 (m, 2H), 2.60-2.82 (m, 6H), 3.50-3.65(m, 2H), 3.72-3.90(m, 4H), 3.90-4.05(m, 2H), 4.08 (t, 2H), 6.90 (d, 2H), 7.20 (d, 2H). LRMS APCI+ m/z 373+. HRMS ESI+ m/z 373.2477[MH]+. 190 N-ethyl-N-methyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide 1H NMR (400MHz, CDCl3) δ 1.00-1.20(m, 3H), 1.78-1.86(m, 4H), 1.92-2.08(m, 4H), 2.18-2.30(m, 2H), 2.45-2.60(m, 6H), 2.60-2.70(t, 3H), 3.22-3.50(m, 2H), 3.70-3.94 (m, 4H), 4.00 (t, 2H), 6.88 (d, 2H), 7.15 (d, 2H). LRMS APCI+ m/z 375+. HRMS ESI+ m/z 375.2634[MH]+. 191 N,N-dimethyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide 1H NMR (400MHz, CDCl3) δ 1.70-1.90(m, 4H), 1.92-2.10(m, 4H), 2.20-2.30(m, 2H), 2.50-2.90(m, 12H), 3.70-3.82(m, 2H), 2.82-2.92(m, 2H), 4.00 (t, 2H), 6.88 (d, 2H), 7.15 (d, 2H). LRMS APCI+m/z 361+. HRMS ESI+ m/z 361.2478[MH]+. Intermediate 60: 1-(methoxyacetyl)-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Examples 192-195
192 (from Ex 182) 1-propyl-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)piperazine 1H NMR (400MHz, CDCl3) δ 0.85 (t, 3H), 1.40-1.46 (m, 2H), 1.77-1.80 (m, 4H), 1.84-1.91 (m, 2H), 1.98-2.03 (m, 2H), 2.08 (d, 2H), 2.18-2.22 (m, 6H), 2.24-2.28 (m, 4H), 2.36 (s, 2H), 2.51-2.54 (m, 4H), 2.63 (t, 2H), 3.51 (t, 2H), 3.72-3.75 (m, 2H), 4.01 (t, 2H), 6.84 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 430.3410+. 96% yield 193 (from Ex 183) 1-ethyl-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)piperazine 1H NMR (400MHz, CDCl3) δ 1.02 (t, 3H), 1.77-1.81 (m, 4H), 1.86-1.91 (m, 2H), 1.99-2.02 (m, 2H), 2.08 (d, 2H), 2.19-2.23 (m, 4H), 2.27-2.35 (m, 6H), 2.38 (s, 2H), 2.51-2.54 (m, 4H), 2.63 (t, 2H), 3.52 (t, 2H), 3.73-3.76 (m, 2H), 4.02 (t, 2H), 6.85 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 416.3267+. 54% yield 194 (from Ex 184) 1-methyl-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1,4-diazepane 1H NMR (400MHz, CDCl3) δ 1.60 (p, 2H), 1.77-1.80 (m, 4H), 1.86-1.92 (m, 4H), 1.98-2.02 (m, 2H), 2.08 (d, 2H), 2.28 (s, 3H), 2.38-2.40 (m, 2H), 2.47-2.53 (m, 8H), 2.57 (s, 2H), 2.62 (t, 2H), 3.50 (t, 2H), 3.73-3.77 (m, 2H), 4.01 (t, 2H), 6.85 (d, 2H), 7.19 (d, 2H). HRMS ESI+ m/z 416.3265+. 13% yield 195 (from Int 60) 1-(2-methoxyethyl)-4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)piperazine 1H NMR (400MHz, CDCl3) δ 1.76-1.79 (m, 4H), 1.84-1.89 (m, 2H), 1.97-2.01 (m, 2H), 2.06 (d, 2H), 2.19-2.21 (m, 4H), 2.28-2.33 (m, 4H), 2.35 (s, 2H), 2.47 (t, 2H), 2.50-2.53 (m, 4H), 2.61 (t, 2H), 3.29 (s, 3H), 3.43 (t, 2H), 3.50 (t, 2H), 3.71-3.74 (m, 2H), 4.00 (t, 2H), 6.83 (d, 2H), 7.19 (d, 2H). HRMS ESI+ m/z 446.3374+. 31% yield Intermediate 61: 2-nitro-
Intermediate 62:
Example 196: 2-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Examples 197-200
197 N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-2-amine 1H NMR (400MHz, CDCl3) δ 1.81-1.86 (m, 4H), 1.90-1.96 (m, 2H), 2.05-2.17 (m, 4H), 2.58-2.75 (m, 6H), 3.50 (d, 2H), 3.59 (t, 2H), 3.81-3.85 (m, 2H), 4.00 (t, 1H), 4.05 (t, 2H), 6.23 (d, 1H), 6.51 (t, 1H), 6.92 (d, 2H), 7.25 (d, 2H), 7.32 (t, 1H), 8.02 (d, 1H). HRMS ESI+ m/z 396.2633+. 14% yield 198 N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-3-amine 1H NMR (400MHz, CDCl3) δ 1.80-1.84 (m, 4H), 1.88-1.94 (m, 2H), 2.03-2.07 (m, 2H), 2.19 (d, 2H), 2.56-2.63 (m, 4H), 2.66-2.70 (m, 2H), 3.24 (s, 3H), 3.57 (t, 2H), 3.77-3.82 (m, 2H), 4.05 (t, 2H), 6.74 (d, 1H), 6.93 (d, 2H), 7.01 (t, 1H), 7.24 (d, 2H), 7.88-7.91 (m, 2H). HRMS ESI+ m/z 396.2640+. 13% yield 199 6-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-3-amine 1H NMR (400MHz, CDCl3) δ 1.83 (d, 7H), 1.94-2.01 (m, 2H), 2.04 (t, 2H), 2.24 (d, 2H), 2.2.58-2.62 (m, 4H), 2.68 (t, 2H), 2.98 (t, 1H), 3.29 (d, 2H), 3.59 (t, 2H), 3.79-3.83 (m, 2H), 4.04 (t, 2H), 6.85 (d, 1H), 6.94 (d, 2H), 7.27 (d, 2H), 7.86 (d, 1H), 7.92 (s, 1H). HRMS ESI+ m/z 410.2793+. 11 % yield 200 4-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-3-amine 1H NMR (400MHz, CDCl3) δ 1.81-1.83 (m, 4H), 1.87-1.94 (m, 2H), 2.05 (t, 2H), 2.18 (d, 2H), 2.38 (s, 3H), 2.58-2.61 (m, 4H), 2.69 (t, 2H), 3.10 (t, 1H), 3.20 (d, 2H), 3.56 (t, 2H), 3.77-3.82 (m, 2H), 4.05 (t, 2H), 6.69 (dd, 1H), 6.87 (d, 1H), 6.93 (d, 2H), 7.24 (d, 2H), 7.78 (s, 1H). HRMS ESI+ m/z 410.2793+. 13% yield Example 201: 1-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-benzimidazol-2-amine
Intermediate 63: 6-chloro-
Example 202:
Intermediate 64: 4-chloro-
Example 203:
Example 204: 2-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Example 205: 2-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Example 206: 5-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Example 207: 4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2
Intermediate 65: 1-{4-[4-(3-chloropropoxy)phenyl]tetrahydro-2
Example 208:
Intermediate 66:
Examples 209-211
209 N, N-dimethyl-1-(4-{4-[3-(4-methyl-1,4-diazepan-1-yl)propoxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine 1H NMR (400MHz, CDCl3) δ 1.77-1.91 (m, 6H), 1.94 (s, 6H), 2.04-2.08 (m, 2H), 2.33 (s, 3H), 2.38 (s, 2H), 2.57-2.65 (m, 6H), 2.70-2.73 (m, 4H), 3.52 (t, 2H), 3.70-3.75 (m, 2H), 3.98 (t, 2H), 6.84 (d, 2H), 7.18 (d, 2H). LRMS APCI+ m/z 390+. 30% yield 210 1-[3-(4-{4-[(dimethylamino)methyl]tetrahydro-2H-pyran-4-yl}phenoxy)propyl]-N,N-dimethylazetidin-3-amine 1H NMR (400MHz, CDCl3) δ 1.62-1.90 (m, 6H), 1.96 (s, 6H), 2.11 (s, 6H), 2.40 (s, 2H), 2.63 (t, 3H), 2.80-2.86 (m, 3H), 3.52-3.56 (m, 4H), 3.72-3.76 (m, 2H), 3.96-3.99 (m, 2H), 6.85 (d, 2H), 7.20 (d, 2H). HRMS ESI+ m/z 376.2959+. 53% yield 211 Dimethyl-{4-[4-(3-[1,4]oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-amine 1H NMR (400MHz, CDCl3) δ 1.85-2.04 (m, 12H), 2.11 (M, 2H), 2.42 (s, 2H), 2.7-2.8 (m, 6H), 3.55 (t, 2H), 3.72-3.82 (m, 6H), 4.02 (t, 2H), 6.87 (d, 2H), 7.22 (d, 2H) HRMS ESI+ m/z 377.2792+ 35% yield Intermediate 67: 1-benzhydryl-3-chloromethyl-azetidine hydrochloride
Example 212: 1-(4-{4-[(1-cyclopentylazetidin-3-yl)methoxy]phenyl}tetrahydro-2
Example 213:
Example 214: 4-(4-{3-[(2
Intermediate 68: 1-{4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanamine
Example 215:
Example 216:
Intermediate 69: 4-(4-methoxyphenyl)tetrahydro-2
Intermediate 70: 1-{[4-(4-methoxyphenyl)tetrahydro-2
Intermediate 71: 1-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methyl}-4-methylpiperazine
Intermediate 72: 4-{4-[(4-methylpiperazin-1-yl)methyl]tetrahydro-2
Example 217: 1-[(4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]-4-methylpiperazine
Intermediate 73: 4-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]carbonyl}morpholine
Intermediate 74: 4-{[4-(4-methoxyphenyl)tetrahydro-2
Intermediate 75: 4-[4-(morpholin-4-ylmethyl)tetrahydro-2
Example 218: 4-[(4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2
Intermediate 76: 4-{[4-(4-{[1-(benzhydryl)azetidin-3-yl]methoxy}phenyl) tetrahydro-2
Intermediate 77: 4-({4-[4-(azetidin-3-ylmethoxy)phenyl]tetrahydro-2
Examples 219-221:
219 cyclopentyl 4-[(4-{4-[(1-cyclopentylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]morpholine 1H NMR (400MHz, CDCl3) δ 1.32-1.37 (m, 2H), 1.49-1.53 (m, 2H), 1.58-1.69 (m, 4H), 1.83-1.89 (m, 2H), 2.08-2.15 (m, 6H), 2.38 (s, 2H), 2.74 (m, 1H), 2.91 (m, 1H), 3.03 (t, 2H), 3.45 (t, 2H), 3.49-3.54 (m, 6H), 3.72-3.76 (m, 2H), 4.04 (d, 2H), 6.84 (d, 2H), 7.22 (d, 2H). HRMS ESI+ m/z 415.2946+. 92% yield 220 isopropyl 4-[(4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]morpholine 1H NMR (400MHz, CDCl3) δ 0.92 (d, 6H), 1.83-1.90 (m, 2H), 2.09-2.14 (m, 6H), 2.31 (m, 1H), 2.38 (s, 2H), 2.85 (m, 1H), 3.03 (t, 2H), 3.41 (t, 2H), 3.49-3.54 (m, 6H), 3.72-3.76 (m, 2H), 4.06 (d, 2H), 6.85 (d, 2H), 7.22 (d, 2H). HRMS ESI+ m/z 389.2791+. 61% yield 221 cyclobutyl 4-[(4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]morpholine 1H NMR (400MHz, CDCl3) δ 1.62-1.75 (m, 2H), 1.82-1.90 (m, 4H), 1.93-1.99 (m, 2H), 2.09-2.15 (m, 6H), 2.38 (s, 2H), 2.88 (m, 1H), 3.07 (t, 2H), 3.14 (m, 1H), 3.40 (t, 2H), 3.49-3.55 (m, 6H), 3.72-3.77 (m, 2H), 4.07 (d, 2H), 6.85 (d, 2H), 7.22 (d, 2H). HRMS ESI+ m/z 401.2791+. HRMS ESI+ m/z 401.2791+. Intermediate 78: 4-[4-(methylthio)phenyl]tetrahydro-2H-pyran-4-carbonitrile
Intermediate 79: 4-[4-(methylsulfinyl)phenyl]tetrahydro-2H-pyran-4-carbonitrile
Example 222: 4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2
Intermediate 80: 1-(4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2
Example 223:
Example 224:
Intermediate 81: 4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2
Intermediate 82: 1-[3-({4-[4-(pyrrolidin-1-ylcarbonyl)tetrahydro-2
Example 225: 1-[3-({4-[4-(pyrrolidin-1-ylmethyl)tetrahydro-2
Intermediate 83: 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl] cyclohexanecarboxylic acid
Intermediate 84: 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl} carbonyl)piperidin-4-ol
Example 226: 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl) piperidin-4-ol
Example 227: 1-methyl-4-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl} carbonyl)piperazine
Intermediate 85: 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)pheny]cyclohexyl} carbonyl)piperazine
Example 228: 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexy}methyl)piperazine
Example 229: 1-acetyl-4-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl} methyl)piperazine
Example 230: 1-(methylsulfonyl)-4-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl] cyclohexyl}methyl)piperazine
Intermediate 86:
Intermediate 87:
Example 231: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile
Example 232: 1-acetyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile
Example 233: 1-methyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile
Example 234: 1-isopropyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile
Example 235: 1-(2-methoxyethyl)-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl] piperidine-4-carbonitrile
Example 236: 2-[methyl({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)amino]ethanol
Example 237: N-methyl-N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)cyclopropanamine
Example 238: 1-(3-{4-[4-(aziridin-1-ylmethyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)pyrrolidine
Example 239: 2-(methylthio)-1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4 yl}methyl)-1H-imidazole
Example 240: 1-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-1H-imidazole
Intermediate 88: 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)tetrahydro-2H-pyran-4-carbonitrile
Intermediate 89: 1-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)tetrahydro-2H-pyran-4-yl]methanamine
Intermediate 90: N-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)tetrahydro-2H-pyran-4-yl]methyl}pyridin-2-amine
Intermediate 91: 4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol
Intermediate 92: N-({4-[4-(4-chlorobutoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-2-amine
Example 241 : N-({4-[4-(4-pyrrolidin-1-ylbutoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-2-amine
Example 242: N-({4-[4-(3-piperidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridin-2-amine
Example 243: N-[(4-{4-[(1-ethylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridin-2-amine
Intermediate 93: N-(3-chloropropyl)-N-methylcyclobutanamine
Example 244: N-{[4-(4-{3-[cyclobutyl(methyl)amino]propoxy}phenyl)tetrahydro-2H-pyran-4-yl]methyl}pyridin-2-amine
Intermediate 94: 4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carbaldehyde
Example 245: 4-{4-[4-(4,5-dimethyl-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-yl]phenoxy}-1-isopropylpiperidine
Intermediate 95: (3-Nitro-pyridin-4-yl)-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-amine
Intermediate 96: (3-Nitro-pyridin-2-yl)-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-amine
Intermediate 97: N*4*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine
Example 246: 2-Methyl-1-{4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-1H-imidazo[4,5-c]pyridine
Intermediate 98: N*2*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-2,3-diamine
Example 247: 1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazo[4,5-c]pyridine
Example 248: 3-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-3H-imidazo[4,5-b]pyridine
Example 249: 1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazo[4,5-b]pyridine
Example 250: N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)pyridazin-4-amine
Intermediate 99: 4-[4-(3-Morpholin-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid hydrochloride
Example 251: N-methyl-4-[4-(3-morpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide
Example 252: 4-(3-{4-[4-(morpholin-4-ylcarbonyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)morpholine
Example 253: 4-(3-{4-[4-(morpholin-4-ylmethyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)morpholine
Example 254: N-methyl-1-{4-[4-(3-morpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanamine
Example 255: N-methyl-2-(methylsulfonyl-N-({4-[4-(3-morpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)ethanamine
Example 256: 6-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-5H-pyrrolo[2,3-b]pyrazine
Example 257: 4-[4-(3-azetidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile
Example 258: 4-({4-[4-(3-azetidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)morpholine
Example 259: 4-({4-[4-(3-azetidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)morpholine
Intermediate 100: 4-(4-{[1-(diphenylmethyl)azetidin-3-yl]methoxy})phenyl)tetrahydro-2H-pyran-4-carbonitrile
Intermediate 101: 4-[4-(azetidin-3-ylmethoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile
Example 260: 4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile
Example 261: 1-(4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine
Example 262: N-[(4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridin-2-amine
Intermediate 102: N-[(dimethylamino)methylene]-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide
Example 263: 3-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-1H-1,2,4-triazole
Example 264: 1-methyl-5-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-1H-1,2,4-triazole
Intermediate 103: N'-formyl-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbohydrazide
Example 265: 2-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-1,3,4-oxadiazole
Intermediate 104: 2-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-4,5-dihydro 1H-imidazole
Example 266: 2-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-1H-imidazole
Example 267: N-[(4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridazin-4-amine
Intermediate 105: 4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile
Intermediate 106: C-{4-[4-(3-[1,4]Oxazepan-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-yl}-methylamine
Example 268: 4-(3-{4-[4-(morpholin-4-ylmethyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)-1,4-oxazepane
Example 269: N-[(4-{4-[3-(1,4-oxazepan-4-yl)propoxy]phenyl}tetrahydro-2H-pyran-4-*yl)methyl]pyridin-2-amine
Example 270: 4-(3-{4-[4-(piperazin-1-ylcarbonyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)-1,4-oxazepane
Step1:
Step 2:
Step 3:
Example 271: 4-[3-(4-{4-[(4-methylpiperazin-1-yl)carbonyl]tetrahydro-2H-pyran-4-yl}phenoxy)propyl]-1,4-oxazepane
Example 272: 4-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-4H-1,2,4-triazole
Intermediate 107: (1-isopropylazetidin-3-yl)methanol hydrochloride
Intermediate 108: 3-(chloromethyl)-1-isopropylazetidine hydrochloride
Example 273: 4-{4-[(1-isopropylazetidin-3-ylmethoxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile
Example 274: 1-(4-{4-[(1-isopropylazetidin-3-ylmethoxy)phenyl}tetrahydro-2H-pyran-4-yl)methanamine
Example 275: N-[(4-{4-[(1-isopropylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methyl]pyridin-2-amine
Intermediate 109: 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}ethanone
Example 276: 4-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}pyrimidine
Step 1.
Step 2.
Intermediate 110: 4-methyl-1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazole-2-thiol
Example 277: 4-methyl-1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)-1H-imidazole
Example 278: 4-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-1H-imidazole
Step 1:
Step 2:
Example 279: 4-[4-(4-{3-[ethyl(methyl)amino]propoxy}phenyl)tetrahydro-2H-pyran-4-ylmethyl]-morpholine
Step 1:
Step 2:
Step 3:
H3Cell Based Functional Assay
29 0.4 190 2.4 249 9.7 133 12.4 191 10.3 250 4.6 136 3.9 196 0.6 254 1.3 155 1.0 205 5.8 266 9.7 156 2.0 206 12.9 267 5.8 160 1.5 213 2.6 268 6.5 187 7.3 220 2.2 276 6.2 188 6.8 247 3.9 272 10.8 189 14.3 248 0.3