WO2013027001A1 - Compounds and their use to treat histamine h3 related disorders - Google Patents

Abstract

The present invention provides compounds of formula (1) and pharmaceutically acceptable salts thereof, wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, m, n, p, q, Q₁, Q₂, Q₃, Q₄, Q₅, Q₆, X₁, X₂, X₃, X₄, A₁ and L₁, are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Description

COMPOUNDS AND THEIR USE TO TREAT HISTAMINE H3 RELATED DISORDERS

The present invention relates to compounds and their uses, and in particular to compounds having a piperidinylalkene scaffold and their therapeutic use in the treatment or prevention of conditions having an association with the histamine H3 receptor.

The H3 receptor was first identified pharmacologically in 1983 as an autoreceptor that regulates the production of histamine (1). The receptor was later cloned in 1999 (2). It is a constitutively active G protein-coupled receptor that is expressed predominantly in the central nervous system (CNS) and modulates a variety of CNS functions both centrally and peripherally. It is expressed on the presynaptic terminals of CNS neurones and acts as a negative modulator of release of neurotransmitters such as histamine, acetylcholine, norepinephrine, serotonin and dopamine (3). Consequently, the ability of the H3 receptor to regulate the release of a wide range of neurotransmitters has fuelled research into the development of antagonists / inverse agonists which have potential in behavioural and physiological conditions, for example CNS disorders such as narcolepsy, disorders of wakefulness, cognition or attention, pain and in suppression of food intake.

Histaminergic neurones are located in the tuberomammillary nucleus of the posterior hypothalamus and project their axons into brain regions including the hypothalamus, thalamus, cerebral cortex, amygdala, and septum. Activity of histaminergic neurons is closely linked with the sleep / wake cycle and numerous reports in the literature have established that the H3 receptor plays a role in cognition and sleep / wake related processes, based on studies with known H3 receptor antagonists and their effects in animal models (4, 5, 6). H3 antagonist compound A-349821 is currently in preclinical development and has been shown to demonstrate cognition-enhancing effects in the rat (7)·

The histaminergic system is one of the targets of leptin signalling in the hypothalamus. Known H3 antagonist clobenpropit increases histamine release in the hypothalamus of mice and has the effect of reducing energy intake in both lean and obese mice (8). The role of the H3 receptor in obesity has been further substantiated through studies with antagonists thioperamide and ciproxifan and more recently with non-imidazole compounds (10).

The non-selective antagonist thioperamide has an antinociceptive effect in a number of acute pain models (11). H3 antagonists have been suggested for the treatment of neuropathic pain (12). In addition GSK207040 and GSK334429 are selective non- imidazole H3 antagonist compounds that display high affinity for both rat and human H3 receptors. Both compounds reduced tactile allodynia in the rat, suggesting H3 antagonists have therapeutic potential in the treatment of neuropathic pain (13).

In an attempt to identify compounds with improved drug-like properties, non-imidazole compounds have been at the forefront of research, for example A-349821 (7) and GS 207040 / GSK334429 (13). ABT-239 is currently being investigated for use in attention deficit hyperactivity disorder, Alzheimer's Disease and schizophrenia (14).

International patent application WO20071 13249 discloses l-[4-[(l-methyl-4- piperidinylidene)methyl]phenyl]ethanone as an intermediate towards the synthesis of a class of N-hydroxycinnamoylamides.

International patent application WO2003031412 discloses a series of [4-(l- methylethoxy)phenyI]ethylidene]piperidine derivatives as muscarinic antagonists. Wang D et al, Life Sciences (1997), 60(15), 1271- 1277 discloses 4-[(4- methoxyphenyl)methylene]- l ,2,2,6,6-pentamethylpiperidine as an intermediate towards the synthesis of [³H]benzylpempidine.

US patent US 4,166,814 discloses a series of piperidine derivatives, including 4,4' -(1,4- phenylenedimethylidyne)bis[l,2,2,6,6-pentamethyl]-piperidine, as light stabilisers for plastics.

There exists a clinical need to generate further classes of H3 antagonist and/or inverse agonist compounds that demonstrate improved drug-like properties (9). W

In accordance with a first aspect of the present invention, there is provided a compound having the Formula (1):

(1)

wherein:

Ri represents H or Cj_-6 alkyl;

R₂ represents Ci.₆ alkyl, wherein each R₂ may be the same or different;

p represents 0, 1, 2, 3 or 4;

m represents 1 or 2;

n represents 1 or 2; provided that both and m and n do not represent 2;

R₃ represents Ci-6 alkyl, -Qi-C_3-6 cycloalkyl or -Q₂-3-6 membered monocyclic heterocyclyl, wherein each may be optionally substituted by one or more substituents, independently selected from halogen, C|_-6 alkyl or C|.₆ alkoxy;

Qi and Q₂ independently represent a covalent bond or Ci_-3 alkylene;

Xi, X₂, X₃ and X4 independently represent CH or N; wherein no more than 2 of Xi, X₂, X3 and X₄ represent N;

R4, independently represents halogen, Ci_-6 alkyl, haloCi-6 alkyl, Ci-6 alkoxy or haloCi.₆ alkoxy;

q represents 0, 1 or 2;

A I represents a covalent bond or C|_-6 alkylene optionally substituted by one or more hydroxy or Ci-₆ alkoxy;

Li represents a covalent bond or -NR₆-, -0-, ^b-NR₇CO-^a, ^b-CONR₈-^a, -C(O)-, ^b- NR₇S0₂-^a, ^b-S0₂NR_s-^a, -S(0)₂-, in which ^a represents the point of attachment to Ai and b represents the point of attachment to R5;

R₆, R₇ and R₈ independently represent H or C]_-6 alkyl;

Rs represents -(CH₂)i -30Ci_₆ alkyl, or -Q3-C₃.₈ cycloalkyl, -Q₄-heteroaryl, -Q₅- heterocyclyl, -Qg-aryl; in which the C₃-₈ cycloalkyl, heteroaryl, heterocyclyl and aryl are optionally substituted with one or more R₉; wherein each R₉ may be the same or different;

when A i represents optionally substituted C|.₆ alkylene, R₅ also represents H or C|.₆ alkyl;

Q3, Q4, Q5 and Q₆ independently represent a covalent bond or C1.3 alkylene;

R₉ represents halogen, -CN, -N0₂, =0, -OR,₀, -NRnR,₂, -CORn, -C0₂R,₂, - CONR_{1 3}Ri4, -S0₂NRi₃Ri4, -NR₁₅COR₍₆, -NRi₅S0₂Ri₆, -OCONR,₃Ri₄, -NR_BC0₂R,₄, - NR,₃CONRi₃Ri4, -SR,₄, -SOR_M, -S0₂Ri₄, -OS0₂R₎₄, -C_3-6cycloaIkyl, -aryl, -heteroaryl, -heterocyclyl, or Ci-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OR10, -NR_{1 (}Ri₂, -CORu, -C0₂Ri₂, - CONR,₃R₁₄, -S0₂NR₁₃Ri4, -NR,₅COR_l5, -NR,₅S0₂Ri₆₎ -OCONR,₃Ri₄, -NR,₃C0₂R₁₄, - NRi₃CONRi₃Ri4, -SR_M, -SORj₄, -S0₂R_I4, -OS0₂Ri₄, -C₃.₆cycloalkyl, -aryl, -heteroaryl or -heterocyclyl; in which each Ci-₆ alkyl, C -6cycloalkyl, aryl, heteroaryl or heterocyclyl present as or as part of R9 is optionally substituted with one or more Rn, wherein each R_i7 may be the same or different;

Rio represents H, C].₃ alkyl or haloC_J-3 alkyl;

Rn, i2, R| , Ri4, Ris and R|₆ independently represent H or C1.3 alkyl;

Rn represents halogen, Ci_-6 alkyl, haloC|.₆ alkyl, - CN, -NO2, =0, -ORig_, C0₂R, 9, -COR,9, -NR,₉R₂₀, -CONR,₉R₂₀, -NR,₉COR_20; -NR_{I 9}S0₂R₂o or -S0₂NR₁₉R₂o;

Rj8 represents H, Ci-ealkyl or -haloCi_-6 alkyl;

Ri9 and R₂₀ independently represent H or Ci_-6alkyl;

excluding 4,4'-(l ,4-phenyIenedimethylidyne)bis[l,2,2,6,6-pentamethyl]- piperidine;

or a pharmaceutically acceptable salt thereof.

The compounds of the invention have been found to modulate the histamine H3 receptor. In particular, the compounds possess antagonist or inverse agonist properties at this receptor. Based on the high affinity for the receptor, the compounds may have the potential to display useful selectivity for the H3 receptor. Where any group in the compound of formula (1) above is referred to as being optionally substituted, this group may be unsubstituted or substituted by one or more substituents. Typically any such group will be unsubstituted, or substituted by one, two or three substituents.

In the compounds of the invention as represented by formula (1) and the more detailed description hereinafter certain of the general terms used in relation to groups or substituents thereon are to be understood to include the following atoms or groups unless otherwise specified.

The term 'halogen' as used herein refers to a fluorine, chlorine, bromine or iodine atom, unless otherwise specified.

The term 'hydroxyl' as used herein refers to -OH. The term 'C_x._y alkyl' as used herein refers to a linear or branched saturated hydrocarbon group containing from x to y carbon atoms. For example, C|_-6 alkyl refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of C| -6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert butyl, n-pentyl, isopentyl, neopentyl and hexyl. C₀alkyl indicates that the group is absent i.e. there is a direct bond between the groups.

The term 'C_x._y alkylene' as used herein refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from 'C_x._y alkyl' above. Examples of C e alkylene groups include methylene, methyl methylene, dimethylmethylene, ethylene, propylene and methylpropylene. The term 'C_x._yalkoxy' as used herein refers to an -0-C_x._y alkyl group wherein C_x-y alkyl is as defined herein. Examples of C_)- alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.

The term 'haloC_x-yalkyl' as used herein refers to a C_x-yalkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include fluoroethyl, trifluoromethyl and trifluoroethyl.

The term 'C1 -3 hydroxyalkyl' as used herein refers to a Ci-₃alkyl group as defined herein wherein at least one hydrogen atom is replaced with hydroxyl. Examples of Ci_-3 hydroxyalkyl groups include hydroxymethyl and hydroxyethyl. The term 'C_x._y cycloalkyl' as used herein refers to a saturated monocyclic hydrocarbon ring of x to y carbon atoms. For example, C₃.₈ cycloalkyl refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of C3.8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term 'heterocyclyl' refers to a 4-7 membered monocyclic ring or a 8-12 membered bicyclic, bridged or spiro-fused ring, any of which may be saturated or partially unsaturated, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen, silicon or sulphur.

Examples of such monocyclic groups include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrpfuranyl, dihydropyrany], tetrahydropyranyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyridazinyl, dihydropyridazinyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, azepanyl and oxazepanyl.

Examples of N-linked 4-7 membered monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

Examples of such 8-12 membered bicyclic, bridged or spiro-fused rings include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-lH-3- benzazepine, tetrahydroisoquinolinyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, octahydro- 1 H-isoindolyl, octahydro- lH-indolyl, octahydro- 1 H-cyclopenta[b]pyridinyl, octahydro- 1 H-cyclopenta[c]pyridinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.1]heptanyl, oxaspiro[4.5]decanyl and oxaspiro[4.4]nonanyl.

It will be appreciated that any heterocyclyl ring may be attached to the rest of the molecule through any available C or N atom. Optional substituents may be present on any available C or N atom.

The term 'heteroaryl' as used herein refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur. Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, triazinyl, tetrazinyl and the like. Examples of such bicyclic aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and imidazopyridyl.

It will be appreciated that any heteroaryl ring may be attached to the rest of the molecule through any available C or N atom. Optional substituents may be present on any available C or N atom.

When the 'heteroaryl' contains a nitrogen atom, the nitrogen atom may be oxidized. For instance, pyridyl as the 'heteroaryl' may be its N-oxide.

The term 'aryP as used herein refers to a C6-12 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl and tetrahydronaphthalenyl.

'Pharmaceutically acceptable salts' of compounds of Formula (1) of the present invention include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids. Salts with acids may, in particular, be employed in some instances. In particular, 'pharmaceutically acceptable salts' of compounds of Formula (1) of the present invention include but are not limited to acid addition salts (for example, phosphates, nitrates, sulphates, borates acetates, maleates, citrates, fumarates, succinates, methanesulfonates, benzoates, salicylates and hydrohalides), and salts of amino acids (such as glycine, alanine, valine, leucine, isoleucine, cysteine, methionine, proline). Further pharmaceutically acceptable salts include quaternary ammonium salts of the compounds of formula (1). Compounds of formula (1) and their salts may be in the form of a solvate, which is included in the scope of the invention. Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol. The compound of Formula (1) of the present invention may be in either hydrate or non- hydrate form.

General methods for the preparation of salts are well known to the person skilled in the art. Pharmaceutical acceptability of salts will depend on a variety of factors, including formulation processing characteristics and in vivo behaviour, and the skilled person would readily be able to assess such factors having regard to the present disclosure.

Where compounds of the invention exist in different enantiomeric and/or diastereoisomeric forms (including geometric isomerism about a double bond), these compounds may be prepared as isomeric mixtures or racemates, although the invention relates to all such enantiomers or isomers, whether present in an optically pure form or as mixtures with other isomers. Individual enantiomers or isomers may be obtained by methods known in the art, such as optical resolution of products or intermediates (for example chiral chromatographic separation (e.g. chiral HPLC)), or an enantiomeric synthesis approach. Similarly, where compounds of the invention may exist as alternative tautomeric forms (e.g. keto/enol, amide/imidic acid), the invention relates to the individual tautomers in isolation, and to mixtures of the tautomers in all proportions. The invention also extends to all conformational ring isomers.

In certain embodiments, the compounds of the invention bear one or more radiolabels. Such radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula (1), or may be introduced by coupling the compounds of formula (1) to chelating moieties capable of binding to a radioactive metal atom. Such radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.

In certain embodiments, Ri represents H. In other certain embodiments, R| represents Ci-3 alkyl, typically methyl.

In certain embodiments, p represents 0. In some embodiments, p represents 1. R , when present generally represents C_{) -3} alkyl, typically methyl or ethyl.

Typically, p represents 0 or 1.

In some embodiments, m represents 1. In other embodiments, m represents 2. In some embodiments, n represents 1. In other embodiments, n represents 2.

In certain embodiments, m represents 1 and n represents 1. In other certain embodiments, m represents 1 and n represents 2. In one embodiment, m represents 1 and n represents 1 or 2.

In further certain embodiments, m represents 2 and n represents 1. Qi typically represents a covalent bond or -CH₂-. Q₂ typically represents a covalent bond.

In certain embodiments, R₃ represents C)- alkyl, C_3-6 cycloalkyl, -CH₂-C₃.₆ cycloalkyl or 3-6 membered heterocycloalkyl, each of which may be optionally substituted.

Representative examples of R₃ 3-6 membered heterocycloalkyl include pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiophenyl, and tetrahydrothiopyrany 1.

Suitable R₃ optional substituents include halogen, typically fluorine.

Typical examples of R₃ include ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, - CH₂-cyclopropyl and tetrahydrofuranyl, each of which may be optionally substituted.

Specific examples of R₃ include ethyl, isopropyl, isobutyl, cyclobutyl, 3- fluorocyclobutyl, cyclopentyl, -CH₂-cyclopropyl and tetrahydrofuran-3-yl.

In one embodiment, R₃ represents Cj.6 alkyl or optionally substituted C_3-6 cycloalkyl. W

In a particular embodiment, R₃ represents optionally substituted C3.6 cycloalkyl, typically cyclobutyl or cyclopropyl. In a further particular embodiment, R₃ represents cyclobutyl.

In some embodiments, Xi represents CH. In other embodiments, Xi represents N. 5 In some embodiments, X₂ represents CH. In other embodiments, X₂ represents N. In some embodiments, X₃ represents CH. In other embodiments, X₃ represents N. In some embodiments, X₄ represents CH. In other embodiments, X₄ represents N. In some embodiments i, X₂, X3 and X₄ each represent CH.

In some embodiments, one of the groups i, X₂, X₃ or X₄ represents N and the rest 10 represent CH.

In one embodiment, R4 represents halogen.

In certain embodiments, q represents 0. Typically, q represents 0 or 1. When q is other than 0, specific R examples include fluoro or chloro.

In some embodiments Ai represents a covalent bond or a straight or branched C_]- 15 alkylene optionally substituted by one or more hydroxy.

Typical examples of Ai include a covalent bond or optionally substituted methylene, (methyl)methylene, (dimethyl)methylene, ethylene and (methyl)propylene.

Specific examples of Ai include a covalent bond, -CH₂-, -CH(OH)-, -C(C¾)₂-, C(CH₃)(OH)-, -CH(OH)CH₂-^d, -CH₂CH(OH)-^d and -(CH₂)2-C(CH3)(OH)-^d, wherein ^d 20 represents the point of attachment to the Xi, X₂, X₃, X₄ containing ring.

In one embodiment, Ai represents a covalent bond or -CH₂-.

Specific examples of L, include a covalent bond, -NH-, - N(CH₃)-, -0-, ^b-NHCO-^a, ^b- CONH-^a, -C(O)-, ^b-N(CH₃)S0₂-^a, ^b-NHS0₂-^a, ^b-S0₂NH-^a and -S(0)₂.

In one embodiment, Li represents a covalent bond. Typical examples of -L] -Ai - include a covalent bond, Ci_ alkylene, -NR6-C 1.6 alkylene- , -0-Ci.₆aIkylene-, -NR7CO-, -NR₇CO-C|.₆alkylene-, -CONRg-C,.₅ alkylene-, -C(0)-, - NR7SO2-, -NR₇S0₂-C_{1 -5}alkylene-, -S0₂NR₈-, -S(0)₂-Ci.₆alkylene-and -S(O), wherein Ci.6 alkylene, when present, is optionally substituted Specific examples of ~Li-A|- include a covalent bond, -CH₂-, -CH(OH)-,

C(C¾)(OH)-, -CH(OH)C¾-, -(CH₂)₂-C(CH₃)(OH)-, -NH-CH₂-, -N(CH₃)-CH₂-, -0- CH₂-, -0-C(CH₃)₂-, -0-(CH₂)₂-C(CH₃)(OH)-, -NHCO-, -NHCO-CH₂-, -CONH-CH₂-, - C(O)-, -NHSO2-, -NHS0₂-CH₂-, -N(CH₃)S0₂-CH₂-,-S0₂NH-, -S(0)₂-, CH₂- and - S(0)₂.

in one embodiment, R5 represents -(CH )) .30Ci-6 alkyl, or -Q3-C3-8 cycloalkyl, -Q₄- monocyclic heteroaryl, -Q₅-heterocyclyl or -Q₆-monocyclic aryl; in which the C₃.g cycloalkyl, heteroaryl, heterocyclyl and aryl are optionally substituted with one or more R9; wherein each R₉ may be the same or different; and when Ai represents optionally substituted C[.₆ alkylene, R₅ also represents H or Ci.₆ alkyl.

In a further embodiment, R₅ represents -Q -C₃-8 cycloalkyl, -Q₄-heteroaryl or -Q₅- heterocyclyl; in which the C₃.g cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with one or more R9, each of which may be the same or different.

In certain embodiments Q₃, Q₄ and Q₅ independently represent a covalent bond or methylene.

Typical examples of R5 Ca-gcycloalkyl, heteroaryl and heterocyclyl groups present when R₅ represents -Q3-C3.8 cycloalkyl, -Q4-heteroaryl or -Qs-heterocyclyl respectively include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyridazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, imidazolidinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, oxepanyl, octahydrocyclopenta[c]pyrrolyl, azabicyclo[3.2.1 ]octanyl or oxaspiro[4.5]decanyl, each of which may be optionally substituted.

R₅ is typically unsubstituted or mono- or di-substituted. R5 may also be tri-substituted. In one embodiment R₅ is unsubstituted. In another embodiment R₅ is monosubstituted. In another embodiment R₅ is disubstituted. In a further embodiment, R₅ is tri- substituted. In one embodiment, R9 represents halogen, C|.₆ alkyl, haloCi.6 alkyl, =0, -Co.₆ alkyl- OR10, -Co-6 alkyl-CORi i , -C₀.₆ alkyl-C0₂R,₂, -C₀-₆ alkyl-CONR,₃R|₄, -C₀.₆ alkyl- NRi₅CORi6, or -Co-₆alkyl-heteroaryl, wherein said Ci.₆ alkyl or -Co-aalkyl-heteroaryl is optionally substituted with one or more R17, each of which may be the same or different. Suitable heteroaryl groups present when R9 represents -Co.₆alkyl-heteroaryl include monocyclic heteroaryl groups, including thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, triazinyl and tetrazinyl, each of which may be substituted with one or more Rp, each of which may be the same or different.

Ri typically represents Ci-6 alkyl, generally methyl.

Specific examples of R9 Co-6alkyl-heteroaryl include pyrimidin-2-yl, 3-methyl- 1 ,2,4- oxadiazolyl or pyrazol- l-yl.

Specific examples of R₉ include F, -CH₃, -CH₂CH(CH₃)₂, -CF₃, =0, -OH, -OCH₃, - OCH₂CH₃, -OCH(CH₃)₂, -C(CH₃)₂OH, -CH₂OCH₃, -CH₂OH, -C(0)CH₃, -C0₂CH₃, -C0₂CH₂CH₃, -CON(CH₃)₂, -NHCOCH₃, pyrimidin-2-yl, 3-methyl- 1 ,2,4-oxadiazolyl and pyrazol- l -yl.

Specific examples of R₅ include -(CH₂)₂-OCH₃, -(CH₂)₂-OCH₂CH₃, -(CH₂)₃-OCH₃, cyclopropyl, 3-ethylcarboxylate-l -hydroxycyclobutan-l -yl, 3-methoxymethyl-l- hydroxycyclobutan-l -yl, cyclopentyl, 1 -hydroxycyclopentanl -yl, 2-(methoxy methyl)- 1- hydroxy-cyclopentan- 1 -yl, 4-methoxy- 1 -hydroxy-cycloheptan- 1 -yl, 1 - hydroxycyclohexan-l -yl, 4-methoxy-l -hydroxycyclohexan-l -yl, 3-methoxy- - hydroxycyclohexan- 1 -yl, 2-methoxy- 1 -hydroxycyclohexan- 1 -yl, 4-isopropoxy-l - hydroxycyclohexan- 1 -yl, 4-methoxy- 1 -fluorocyclohexan- 1 -yl, 4-acetylamino- 1 - hydroxycyclohexan- 1 -yl, 4-ethylcarboxylate- l -hydroxycyclohexan- l -yl, 4- (hydroxymethyl)- 1 -hydroxycyclohexan- 1 -yl, 4-(methoxymethyl)- 1 - hydroxycyclohexan- 1 - l, 4-hydroxy-4-methyl- 1 -hydroxycyclohexan- 1 -yl, 4-methoxy- 4-methyl- 1 -hydroxycyclohexan- 1-yl, 1 ,4-dimethoxycyclohexan- 1 -yl, 4-N,N- dimethylcarbamoyl- 1 -hydroxycyclohexan- 1 -yl, 4-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-l - hydroxycyclohexan- l -yl, 4-(lH-pyrazol- l -yl)-l -hydroxycyclohexan- 1 -yl, 4-ethoxy-l - hydroxycyclohexan- 1 -yl, 3-methoxy- 1 -hydroxycycloheptan- 1 -yl, cyclopentyl- methylene-, l -methylpyrazol-4-yl, l -methylpyrazol-5-yl, l ,5-dimethyl-lH-pyrazol-4-yl,

2-methylpropylpyrazol-4-yl, l ,3,5-trimethyl-l H-pyrazol-4-yl, l-methyl-5- trifluoromethyl- 1 H-pyrazol-3-y 1, 1 -methy I-3-trifluoromethyl- 1 H-pyrazol-5-yl, 1 ,2- oxazol-4-yl, 3,5-dimethyI- l,2-oxazol-4-yi, 5-methyl- l ,2-oxazol-3-yl, 5-N,N- dimethylcarbamoyl- 1 ,2-oxazol-3-y 1, 3-methyl- 1 ,2,4-oxadiazol-5-yl, 5-methyl- 1 ,3,4- oxadiazol-2-yl, 5-methyl-l,2,4-oxadiazol-3-yl, 2,4-diemthyl-l,3-thiazol-5-yl, pyridin-3- yl, pyridazin-3-yl, (2-methyl-l,3-oxazol-4-yl)-rnethylene-, (5-methyl- l ,2-oxazol-3-yl)- methylene-, pyridin-2(lH)-on-l-yl, 3-methoxy-pyridin-2(lH)-on- l-yl, 3-methyl- pyridin-2( 1 H)-on- 1 -yl, 6-methyl-3 -(trifluoromethyl)pyridi n-2( 1 H)-on- 1 -y 1, 3 - (trifluoromethyl)pyridin-2(lH)-on-l -yl, 5-(methoxymethyl)pyridin-2(lH)-on-l-yl, 3- methylcarboxylate-6-oxo-l,6-dihydropyridin-l -yl, pyridazin-3(2H)-on-2-yl, tetrahydrofuran-3-yl, 3-hydroxytetrahydrofuran-3-yl, 4-hydroxytetrahydrofuran-3-yl, tetrahydropyran-4-yl, 4-hydroxytetrahydropyran-4-yl, 2,6-dimethyl-4- hydroxytetrahydropyran-4-yI, 4-fIuorotetrahydropyran-4-yl, 3-methylimidazolidin-2- onyl, l,3-oxazolidin-2-onyl, pyrrolidin-l-yl, 2-oxopyrrolidm-l-yl, 3-methoxy-2- oxopyrrolidin-l-yl, 4-methoxy-2-oxopyrrolidin-l-yl, l -acetyl-4-hydroxypiperidin-4-yl, l-(pyrirnidin-2-yl)-4-hydroxypiperidin-4-yl, piperidin-l-yl, 4,4-difluoropiperidin-l-yI, 4-methoxypiperidin- l-yl, 2-oxopiperidin-l-yl, morpholin-4-yl, 2,6-dimethylmorpholin- 4-yl, 3-oxomorpholin-4-yl, l-acetyl-4-hydroxyazepan-4-yl, 4-hydroxyoxepan-4-yl, 5- oxo- 1 ,4-oxazepan-4-yl, 3-methoxy-3-methyl-azetidin- 1 -yl, 3-methoxy-3 -methy 1- azetidin- 1 -yl, 4-methoxytetrahydro-2H-pyran-2-yl, 4-(methoxymethyl)tetrahydro-2H- pyran-4-yl, 4-ethylcarboxylate-tetrahydropyran-4-yl, l-(propan-2-ol)tetrahydro-2H- pyran-4-yl, (tetrahydrofuran-3-yl)-methylene, 2-acetyl-4- hydroxyoctahydrocyclopenta[c]pynOl-4-yl, 8-acetyl-3-hydroxy-8- azabicyclo[3.2.1 ]octan-3-yl, 8-hydroxy-oxaspiro[4.5]decan-8-yl; and when Ai is C i.₆ alkylene, H, or methyl, isopropyl or isobutyl.

In one particular embodiment, R₅ represents 4-methoxy-l -hydroxycyclohexan-l-yl, 4- ethoxy- 1 -hydroxycyclohexan- 1 -yl, 4-methoxy-4-methyl- 1 -hydroxycyclohexan- 1 -yl, 4- isopropoxy- 1 -hydroxycyclohexan- 1 -y 1, 4-methoxy- 1 -fluorocyclohexan-1 -y 1, 4- (methoxymethyl)-l-hydroxycyclohexan-l-yl, 4-hydroxytetrahydropyran-4-yl, 4- fluorotetrahydropyran-4-yl and l ,5-dimethyl-lH-pyrazol-4-yl.

In one particular subgroup of compounds according to the invention, A| represents a covalent bond or -CH₂-, L| represents a covalent bond and R5 represents -Q₃-C3_-8 cycloalkyl, -Q₄-heteroaryl or -Q₅-heterocyclyl; in which the C₃-₈ cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with one or more R9, each of which may be the same or different.

In a further particular subgroup of compounds according to the invention, Ai represents a covalent bond or -CH -, Li represents a covalent bond and R.5 represents an optionally substituted 5 to 6 membered mo a ring of formula Rs_a:

wherein R_5a represents a C3.8 cycloalkyl or heterocyclyl ring, each optionally substituted with one or more R9; R9_a represents -C₀.₆ alkyl-ORio or -F and * represents the point of attachment to A| .

In one embodiment represents optionally substituted cyclohexyl or optionally substituted tetrahydropyran-4-yl.

R_9a typically represents -OH, -OCH₃, -C(CH₃)₂OH, -CH₂OCH₃ or -F. In one embodiment R½ represents -OH or -F.

In a further aspect of the invention, specific novel compounds include each of the novel compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts thereof. In particular embodiments the compound of formula (1) is selected from the group consisting of:

l-cyclobutyl-4-[4-(l-methyl- l H-pyrazol-4-yl)benzylidene]piperidine;

l -cyclobutyl-4-{4-[l -(2-methylpropyl)-lH-pyrazol-4-yl]benzylidene}piperidine;

l -cyclobutyl-4-[4-(3,5-dimethyl-l ,2-oxazol-4-yl)benzylidene]piperidine;

l -cyclobutyl-4-[4-(l -methyl-l H-pyrazol"5-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(2,4-dimethyl-l ,3-thiazol-5-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(l,5-dimethyl- lH-pyrazol-4-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(l,2-oxazol-4-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(l,3,5-trimethyl- l H-pyrazol-4-yl)benzylidene]piperidine;

4-[2-chloro-4-( 1 -methyl- 1 H-pyrazol-4-yl)benzylidene]- 1 -cyclobutylpiperidine; 1 -cyc!obutyl-4-[4-(3-methyl- 1 ,2,4-oxadiazol-5-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(5-methyl-l,3,4-oxadiazol-2-yl)benzylidene]piperidine;

1- cyclpbutyl-4-[4-(5-methyl-l,2,4-oxadiazol-3-yl)benzylidene]piperidine;

{4-[(l-cyclopentylpiperidin-4-ylidene)methyl]phenyl}methanol;

(4-{[l-(2-methylpropyl)piperidin-4-ylidene]methyl}phenyl)methanol;

N-{4-[(l-cyclobuty]piperidin-4-ylidene)methyl]benzyl}cyclopentanecarboxamide; N-{4-[(l -cyclobuty]piperidin-4-ylidene)methyl]benzyl}tetrahydrofuran-3-carboxamide;

2- {4-[(l-cyclobutylpiperidin-4-yIidene)methyl]phenyl}-N-cyclopentylacetamide;

2-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}-N-(tetrahydrofuran-3- yl)acetamide;

2- {4-[( 1 -cyclobutylpiperidin-4-yIidene)methyl]phenyl } - 1 -(pyrrolidin- 1 -y l)ethanone;

{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}(pyrrolidin-l -yl)methanone;

4-[(l -cyclobutylpiperidin-4-ylidene)methyl]-N-cyclopentylbenzamide;

4-[(l -cyclobutylpiperidin-4-ylidene)methyl]-N-(tetrahydrofuran-3-yl)benzamide;

4-[(l-cyclobutyIpiperidin-4-ylidene)methyl]-N-(cyclopentylmethyl)benzamide;

4-[(l-cyclobutylpiperidin-4-ylidene)methyl]-N-(tetrahydrofuran-3-ylmethyl)benzamide;

4-[(l -cyclobutylpiperidin-4-ylidene)methyl]-N-(pyridin-3-yl)benzamide;

N-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyI}pyridin-3-amine;

{3-chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}(pyrrolidin-l- yl)methanone;

{2-chloro-4-[( 1 -cyclobutyIpiperidin-4-ylidene)methyl]phenyl } (pyrrolidin- 1 - yl)methanone;

{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]-2-fluorophenyl}(pyrrolidin-l - yl)methanone;

{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]-3-fIuorophenyl}(pyrrolidin-l - yI)methanone;

{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]-3-fluorophenyl}methanol;

{3-chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyI]phenyl}methanol;

{6-[(l-cyclobutylpiperidin-4-ylidene)methyl]pyndin-3-yl}(pyrrolidin-l -yl)rnethanone; {6-[(l -cyclobutylpiperidin-4-ylidene)methyl]pyridin-3-yl}methanol;

{5 (l -cyclobutylpiperidin-4-ylidene)methyl]pyridin-2-yl}(pyrrolidin-l-yl)methanone; pyrrolidin- l-yI(4-{[l-(tetrahydrofuran-3-yl)piperidin-4-ylidene]methyl}phenyl) methanone; 1 - {4-[( 1 -cyclobutylpiperidin-4-ylidene)methy l]benzy 1 } pyridin-2( 1 H)-one;

2- {4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}pyridazin-3(2H)-one;

3- ( { -[( 1 -cyclobutylpiperidin-4-ylidene)methyl]benzyl }oxy)pyridazine;

1 - {4-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]benzy 1 } -3 -methoxypyridin-2( I H)-one; methyl l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-6-oxo-l ,6- dihydropyridine-3-carboxylate;

1 - {4-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]benzy 1 } -3 -methylpyridin-2( 1 H)-one; 1 - {4- [( 1 -cyclobutyIpiperidin-4-y lidene)methy IJbenzy 1 } -6-methyl-3 - (trifluoromethy l)pyridin-2( 1 H)-one;

1 -{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-(trifluoromethyl)pyridin- 2(lH)-one;

l-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}piperidin-2-one;

4- {4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}mo holin-3-one;

l -{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}pyrrolidin-2-one;

l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-5-(methoxymethyl)pyridin- 2(lH)-one;

(3S)- 1 - { 4-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]benzyl } -3 -methoxypyrrolidin-2- one;

(4R)-l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-4-methoxypyrrolidin-2- one;

4-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyI}-l,4-oxazepan-5-one;

l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-methylimidazolidin-2-one; 3-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-l,3-oxazolidin-2-one;

l -cyclobutyl-4-{4-[(cyclopentyloxy)methyl]benz)'lidene}piperidine;

l -cyclobutyl-4-{4-[(tetrahydrofuran-3-ylmethoxy)methyl]benzylidene}piperidine;

l-cyclobutyl-4-{4-[(cyclopentylmethoxy)methyl]benzylidene}piperidine;

l -cyclobutyl-4-{4-[(tetrahydro-2H-pyran-4-yloxy)methyl]benzylidene}piperidine;

1 -cyclobutyl-4-(4- { [(2 -methyl- 1 ,3 -oxazol-4-y i)methoxy]methyl } benzylidene) piperidine;

1 -cyclobutyl-4-(4-{[(5-methyl-l ,2-oxazol-3-yl)methoxy]methyl}benzylidene) piperidine;

3-({4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}oxy)pyridine;

1 -cyclobutyl-4-(4- { [(5-methyl- 1 ,2-oxazol -3 -yl)oxy]methyl }benzylidene)piperidine; l -cyclobutyl-4-[4-({[l -methyl-5-(trifluoromethyl)- l H-pyrazol-3- yl]oxy}methyl)benzylidene]piperidine;

l -cyclobutyl-4-[4-({[l -methyl-3-(trifluoromethyl)- lH-pyrazol-5-yl]oxy}methyl) benzylidene]piperidine;

3-({4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}oxy)-N,N-dimethyl- l ,2- oxazole-5-carboxamide;

1 -cyclobutyl-4-[4-(piperidin- 1 -ylmethyl)benzylidene]piperidine;

4-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}morpholine;

l-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-4,4-difluoropiperidine;

4- {4-[(l -cyclobutyIpί eridin-4-ylidene)methyl benzyl}-2,6-dimethylmo holine; l -cyclobutyl-4-{4-[(4-methoxypiperidin- l-yl)methyl]benzylidene}piperidine;

N- {4- [( 1 -cyclobutylpiperidin-4-y lidene)methy l]benzy 1 } -2-methoxy-N- methylethanamine;

N-(4-((l-ethylpiperidin-4-ylidene)methyl)benzyl)cyclopentanamine dihydrochloride; 1 -(4-(( 1 -cyclobutylpiperidin-4-ylidene)methyl)phenyl)ethanol;

(4-((l-cyclobutylpiperidin-4-ylidene)methyl)phenyl)(cyclopentyl)methanol;

1- (4-((l -cyclobutylpiperidin-4-ylidene)methyl)phenyl)-3-methylbutan- l -ol;

(4-(( 1 -cyclobutylpiperidin-4-ylidene)methyl)phenyl)methanol;

2- (4-((l-cyclobutyipiperidin-4-ylidene)methyl)phenyl)propan-2-ol;

1 -(4-(( 1 -Cyclobutylpiperidin-4-yIidene)methyl)phenyl)-2-methylpropan- 1 -ol;

(3-Chloro-4-((l-cyclobutylpiperidin-4-ylid6ne)methyl)phenyl)(cycIopentyl)methanol;

1 -(4-(( 1 -Cyclobuty lpiperidin-4-ylidene)methyl)phenyl)-2-cyclopentyIethanol;

l -(4-((l-Cyclobutylpiperidin-4-ylidene)methyl)phenyl)-2-cyclopropylethanol;

CycIopentyl(4- { [ 1 -(2-methylpropyl)piperidin-4-ylidene]methyl} phenyl)methanol ; Cyclopentyl(4-((l-ethylpiperidin-4-ylidene)methyl)phenyl)methanol;

Cyclopentyl(4-((l-(cyclopropylmethyl)piperidin-4-ylidene)methyl)phenyl)methanol;

1 -(4-(( 1 -Cyclobutylpiperidin-4-yIidene)methyl)phenyl)cyclopentanoI;

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}cyclohexanol;

3- {4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl} tetrahydroruran-3-ol;

4- {4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl} tetrahydro-2H-pyran-4-ol; 1 -(4- {4-[( 1 -CycIobutylpiperidin-4-ylidene)methyl]pheny 1} -4-hydroxypiperidin- 1 - yl)ethanone; 01

N-(4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4- hydroxycyclohexyl)acetamide;

Ethyl 4- { 4-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]phenyI }-4- hydroxycyclohexanecarboxylate;

l-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methoxycyclohexanol;

4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-l -( yrimidin-2-yl)piperidin-4- ol;

1 - {4-[(l -cyciobutylpiperidin-4-ylidene)methyl]phenyl} -4- (hydroxymethy l)cy clohexanol ;

1 -[4- { 4-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]phenyl } -4- hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl]ethanone;

I-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-(3-methyl-l ,2,4-oxadiazol-5- yl)cyclohexanol;

1 -(4- {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methy ljphenyl } -4-hydroxyazepan- 1 - yl)ethanone;

l -(3-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-3-hydroxy-8- azabicyclo[3.2.1]oct-8-yl)ethanone;

Ethyl 3-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}-3- hydroxycyclobutanecarboxylate;

{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}(tetrahydro-2H-pyran-4- yl)methanol;

4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-hydroxy-N,N- dimethylcyclohexanecarboxamide;

l -{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}- l-(l -methyl- lH-pyrazoI-4- yl)ethanol;

4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-2,6-dimethyltetrahydro-2H- pyran-4-ol;

4-{3-Chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran- 4-01;

l-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methoxy-4- methylcyclohexanol;

l-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyI}-4-methylcyclohexane-l ,4-diol; l - {4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4- (methoxymethyl)cyclohexanol;

l - {4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-ethoxycyclohexanol;

8-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl} -l -oxaspiro[4.5]decan-8-ol; l -{3-Chloro-4-[(l -cyclobutylpiperidin-4-ylidene)met yl]phenyl}-4- methoxycyclohexanol;

1 - {4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-(propan-2- yloxy)cyclohexanol;

2- {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl} -4-methoxybutan-2-ol;

1 - {4- [( 1 -cycIobutylpiperidin-4-ylidene)methyl]phenyl } -3 -

(methoxymethyl)cyclobutanol;

1 -{ -[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]pheny 1 } -3 -methoxycyclohexanol ; l -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-(l H-pyrazol-l - yl)cyc!ohexanol

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-2-methoxycyclohexanol;

4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}oxepan-4-ol;

l -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl} -3-methoxycycloheptanol;

{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-l -(tetrahydrofuran-3-yl)ethanol; l-{4-[(l -Cyclobuty[piperidin-4-ylidene)methyl]phenyI}-2- (methoxymethyl)cyclopentanol;

l -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methoxycycloheptanol;

1 - { -[( 1 -cyclopentylpjperidin-4-ylidene)methyl]pheny] } -4-methoxycyclohexanol;

4- { - [( 1 -Cy clopenty Ipi eri din-4-y li dene)methy ljpheny 1 } tetrahydro-2H-pyran-4-ol ;

4-Methoxy- l-(4-{ [l -(propan-2-yl)piperidin-4-ylidene]methyI}phenyl)cyclohexanol; 4-(4-{[l -(propan-2-yl)piperidin-4-y!idene]methyl}phenyl)tetrahydro-2H-pyran-4-ol;

1 -(4- { [ 1 -(Cyclopropylmethyl)piperidin-4-ylidene]methyl } phenyl)-4- methoxycyclohexanol;

1 - (4-((l -Cyclobutylpiperidin-4-ylidene)methyl)phenyl)propan-2-ol;

2- (4-((l-Cyclobutylpiperidm-4-ylidene)methyl)phenyl)-l -cyctopentylethanol;

1 -(4-(4-(( 1 -Cyclobutylpiperidin-4-y!idene)methyl)benzyl)-4-hydroxypiperidin- 1 - yl)ethanone;

l -(4-((l -Cyclobuty)piperidin-4-ylidene)methyl)benzyl)cyclopentanol;

l -Cyclopentyl-2-(4-((l -ethylpiperidin-4-ylidene)metbyl)phenyl)ethanol; 2-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl phenyl}-l -(tetrahydrofuran-3- yl)ethanol;

4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]benzyl}tetrahydro-2H-pyran-4-ol; 4-{4-[(l-CyclobutyIpiperidin-4-ylidene)methyl -3-fluorobenzyl}tetrahydro-2H-pyran- 4-oI;

1- {4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]benzyl}-4-methoxycyclohexanol; 4-(4-{[l-(Tetrahydrofuran-3-yl)piperidin-4-ylidene methyl}benzyl)tetrahydro-2H- pyran-4-oI

4-(4-{[l-(3-Fluorocyclobutyl)piperidin-4-ylidene]methyl}benzyl)tetrahydro-2H-pyran- 4-ol;

2- {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } - 1 -(tetrahydro-2H-pyran-4- yl)ethanol;

3- {4-[(l-Cyclobutylpiperidin-4-ylidene)methy]]benzyl}tetrahydrofuran-3-ol;

4- {4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydrofuran-3-ol;

l-{4-[(E)-(l-Cyclobutylazepan-4-ylidene)methyl]phenyl}-4-methoxycyclohexanol; l-{4-[(Z)-(l-Cyclobutylazepan-4-ylidene)methyl]phenyl}-4-methoxycyclohexanol;

4-{4-[(E)-(l-Cyclobutylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol;

4-{4-[(Z)-(l-Cyclobutylazepan-4-ylidene)methyI]phenyl}tetrahydro-2H-pyran-4-ol;

4-(4-{(E)-[l-(Propan-2-yl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4-ol; 4-(4-{(Z)-[l -(Propan-2-yl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4-ol;.

4-{4-[(E)-(l-Cyclobutylazepan-4-ylidene)methyl]benzyl}tetrahydro-2H-pyran-4-ol;

4-{4-[(E)-(l-Cyclopentylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol;

4-{4-[(Z)-(l -cyclopentylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol;

4-(4-{(E)-[l -(Cyclopropylmethyl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H- pyran-4-ol;

4-(4-{(Z)-[l -(Cyclopropylmethyl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H- pyran-4-ol;

4-(4-{(E)-[l-(2-MethyIpropyl)azepan-4-ylidene]methyl}phenyI)tetrahydro-2H-pyran-4- ol;

4-(4-{(Z)-[l -(2-Methylpropyl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4- ol;

4-{4-[(E)-(l-Ethylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol;

l-{6-[(l-Cyclobutylpiperidin-4-ylidene)methyl]pyridin-3-yl}-4-methoxycyclohexanol; 4-({5-[(l-Cyclobutylpiperidin-4-ylidene)methyl]pyridin-2-yl}methyl)tetrahydro-2H- pyran-4-ol;

1 - { 5-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]pyridin-2-yl }-4-methoxycyclohexanol; l-Cyclobutyl-4-{4-[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]benzylidene}piperidine; l-CyclobutyI-4-[4-(4-fluorotetrahydro-2H-pyran-4-yl)benzylidene]piperidine;

1 -Cyclobutyl-4-[4-( 1 -fluoro-4-methoxycyclohexyl)benzylidene]piperidine;

N-(4-(l -(l-Cyclobutylpiperidin-4-ylidene)ethyl)benzyl)cyclopentanamine;

{4-[l-(l-Cyclobutylpiperidin-4-ylidene)ethyl]phenyl}methanol;

l-Cyclobutyl-4-{ l-[4-(3-methyl-l ,2,4-oxadiazol-5-yl)phenyl]ethylidene}piperidine; 4-{4-[(E)-(l -Cyclobutyl-3-methylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H- pyran-4-ol;

l-Cyclobutyl-4-[4-(tetrahydro-2H-pyran-4-ylsulfonyl)benzylidene]piperidine;

l -Cyclobutyl-4-{4-[(2-methoxyethyl)sulfonyl]benzylidene}piperidine;

l -Cyclobutyl-4-{4-[(3-methoxypropyl)sulfonyl]benzylidene}piperidine;

1 -Cyclobutyl-4-{4-[(tetrahydro-2H-pyran-4-ylmethyl)sulfonyl]benzylidene}piperidine; l-Cyclobutyl-4-{4-[(2-ethoxyethyl)sulfonyl]benzylidene}piperidine;

1 -Cyclobutyl-4-(4- { [(2-ethoxyethyl)sulfonyl]methyl } benzylidene)piperidine;

4-[(l-CyclobutyIpiperidin-4-ylidene)methyl]-N-methyl-N-(tetrahydro-2H-pyran-4- yl)benzenesulfonamide;

4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]-N-(tetrahydro-2H-pyran-4- yl)benzenesulfonamide;

-({4-[(l-Cyclobutyl iperidin-4-ylidene)methyl]phenyl}sulfonyl)mo holine;

l -Cyclobutyl-4-{4-[(3-methoxyazetidin-l -yl)sulfonyl]benzylidene}piperidine;

l -Cyclobutyl-4-{4-[(4-methoxypiperidin- l -yl)sulfonyl]benzylidene}piperidine;

1 -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyI]phenyl}-N-methyl-N-(tetrahydro-2H- pyran-4-yl)methanesulfonamide;

-({4-[(l -Cyclobut lpiperidin-4-y]idene)methyl]benz l}sulfonyl)mo holine;

1 -Cyclobutyl-4-(4- { [(3 -methoxy-3-methylazetidin- 1 - yl)sulfonyl]methyl}benzylidene)piperidine;

1 -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-N-(tetrahydro-2H-pyran-4- yl)methanesulfonamide;

l-Cyclobutyl-4-[4-(l,4-dimethoxycyclohexyl)benzylidene]piperidine;

l-Cyclobutyl-4-[4-(4-methoxytetrahydro-2H-pyran-2-yl)benzylidene]piperidine; 1 -Cyclobutyl-4- {4-[4-(methoxymethyl)tetrahydro-2H-pyran-4- yl]benzy(idene}piperidine;

Ethyl 4-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4- carboxylate;

2-(4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4- yl)propan-2-ol;

and pharmaceutically acceptable salts thereof.

Particularly useful compounds in accordance with the invention include each of the compounds described in the accompanying examples, and pharmaceutically acceptable salts thereof.

In accordance with a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect of the invention, together with one or more pharmaceutically acceptable excipients. Pharmaceutical compositions of this invention comprise any of the compounds of the first aspect of the present invention, or pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred. The pharmaceutical W compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection 5 or infusion techniques.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile

10 injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For

15 this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as that

20 described in Ph. Helv, or a similar alcohol.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the

25 case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening

30 and/or flavouring and/or colouring agents may be added.

The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.

The compounds of the present invention may be administered in a dose of around 1 to around 20,000 μg/kg per dose, depending on the condition to be treated or prevented, and the characteristics of the subject being administered with the compound. In many instances, the dose may be around 1 to around 1500 g/kg per dose. The dosing regimen for a given compound could readily be determined by the skilled person having access to this disclosure.

In one particular embodiment, the pharmaceutical composition of the invention additionally comprises one or more additional active pharmaceutical ingredients. These additional active ingredients may be agents known to the skilled person to be useful in the treatment or prevention of the diseases mentioned in the present disclosure, or comorbidities thereof.

In a third aspect, the present invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in therapy. In a fourth aspect, the invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity.

A number of conditions whose development or symptoms are linked to histamine H3 receptor activity are known to the skilled person. In a fifth aspect, the invention also provides a method of treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity, the method comprising the administration, to a subject in need of such treatment or prevention, of a therapeutically effective amount of a compound according to the first aspect of the invention, or a composition according to the second aspect.

In particular, there is provided a compound according to the fourth aspect, or a method according to the fifth aspect, wherein the condition is a disorder of the central nervous system.

In certain embodiments, the condition to be treated may be selected from sleep disorders (such as narcolepsy and hypersomnia), cognitive disorders (such as dementia and schizophrenia), attentional disorders (such as attention deficit hyperactivity disorder), neurodegenerative disorders (such as AD), schizophrenia, epilepsy, pain (such as neuropathic pain) and obesity.

In preferred embodiments the condition may be selected from schizophrenia, Alzheimer's Disease (AD) and dementia. In an alternative embodiment, the condition may be selected from narcolepsy, pain and obesity.

In particular embodiments, the condition may be selected from narcolepsy, neuropathic pain and obesity.

In a sixth aspect, the present invention provides the use of a compound according to the first aspect of the invention in the preparation of a medicament for the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity. Such conditions may be selected from those described above.

In the following process description, the symbols R|, R₂, R3, R4, R5, R^, R7, Rs_, R9, Rio, R1 1 , R12, i3, Ri4, Ri 5» Ri«. R17, Ri8, R19, R20, m, n, p, q, Qi , Q₂, Q3, Q4, Qs, Q₆, Χι, X2, X₃, X4, Ai and L| when used in the formulae depicted are to be understood to represent those groups as described above in relation to formula (1) unless otherwise indicated. During any of the synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. The methods of addition and removal of such protecting groups are those which would conventionally be used in relation to the particular molecule-type or group being protected, for example the methods described in standard works of reference in synthetic methodology, such as ocienski (2004) Protecting Groups. 4th Edn. Georg Thieme Verlag. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.

The following processes together with the intermediates are provided as further aspects of the invention.

Thus in another aspect of the invention, compounds according to formula (1), wherein Ri represents H, may be prepared by a process which comprises reacting a compound of formula (I) with a compound of formula (II):

(!)

wherein R₂, R₃₎ R4, R5, n, m, p, q, Ai, Li, X_\, X₂, X₃ and X₄ are as herein defined.

The reaction may be achieved by treatment with a suitable reducing agent, for example, sodium triacetoxyborohydride under acidic conditions e.g. in the presence of an organic acid such as acetic acid in a suitable solvent, such as a halogented hydrocarbon e.g. dichloromethane.

In a further process, compounds of formula (1), wherein Ri represents H, A] and Li each represent a covalent bond and R₅ represents an aryl or heteroaryl group, may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):

(III) Wherein R₂, R₃, R4, n, m, p, q, X|, X₂, X₃ and X4 are as herein defined, LGi represents a suitable leaving group, R_5a represents R₅ aryl or heteroaryl and -B(OZ)₂ represents boronic acid or a ester derivative thereof.

LGi typically represents halogen e.g. bromine. B(OZ)₂ typically represents boronic acid or boronic acid pinacol ester.

The reaction may conveniently be achieved by reaction in the presence of a suitable catalyst, such as palladium under basic conditions e.g. in the presence of an inorganic base such as sodium carbonate in an approriate solvent such as a cylic ether e.g. dioxane at elevated temperature. In another process, compounds of formula (1), where Li represents a covalent bond and-Ai- R₅ represents:

wherein R21 represents H or C1.3 alkyl, R₅ is as herein defined, Rs_b represents an optionally substituted C_3-g cycloalkyl or optionally substituted heterocyclyl ring and * represents the point of attachment, may be prepared by a process which comprises initial conversion of a compound of formula (III) to a Grignard reagent followed by reaction with R_5b=0 or (Rs)(R₂i)C=0 in a suitable solvent e.g. a cyclic ether such as

THF.

In a further process, compounds of formula (1), where L] represents a covalent bond and-Ai-R₅ represents:

wherein R₂i represents H or C1.3 alkyl, R₅ is as herein defined, R_5b represents an optionally substituted C3.8 cycloalkyl or optionally substituted heterocyclyl ring and * represents the point of attachment, may be prepared by a process which comprises reacting a compound of formula (III) with an epoxide of formula:

The reaction may conveniently be effected by initial reaction of a compound (III) with alkyllithium in the presence of an acid e.g. a Lewis acid such as borontrifluoride, followed by treatment with an epoxide in an appropriate solvent e.g. a cyclic ether such as THF.

In a further process, compounds of formula (1), where L₍ represents a covalent bond and R$ represents an oxadiazolyl group, may be prepared by conversion of an intermediate of formula (V):

(V) wherein R_\, R , R₃, R4, n, m, p, q, A\, X_t, X₂, X and X₄ are as herein defined.

Suitable conditions include treatment under basic conditions e.g. an inorganic base such as. sodium hydride, with acetamidoxime in an appropriate solvent e.g. THF. Alternative conditions include treatment with acetylhydrazide in the presence of trimethylaluminium, followed by treatment with POCI3 under reflux.

Alternatively, compounds of formula (1) wherein A] represents C 1.6 alkylene, L] represents -O- and R5 represents H, may be prepared by treating a compound of formula (V) with a suitable reducing agent e.g. lithium aluminium hydride in an appropriate solvent e.g. a cyclic ether such as THF.

In a further process, compounds of formula (1), wherein Li represents -NR₇CO- may be prepared by process which comprises reacting a compound of formula (V) with R₅R₇NH. Suitable conditions include reaction in the presence of trimethylaluminium or bis(trimethylaluminum)-l,4-diazabicyclo[2.2.2]octane adduct in a suitable solvent such as a cyclic ether e.g. THF. Compounds according to formula (1) wherein Li represents -CO- and R₅ represents N-linked heterocyclyl may be prepared in an analogous method. Alternatively an intermediate of formula (V) may be converted to the corresponding acid chloride using standard techniques such as reaction with LiOH followed by treatment with oxalyl chloride, which may then be reacted with R5R7NH in a suitable solvent e.g. a halogented hydrocarbon e.g. dichioromethane.

Intermediates of formula (I) may be prepared using methods known to those skilled in the art, or using the methods as described in the examples hereinafter. For example, an intermediate of formula (I) may be prepared by a process which comprises reacting a compound of formula (IA) or (IB) with a compound of formula (VI):

wherein R , R4, Rs, n, m, p, q, Ai, Lj, Xi, X₂, X3 and X4 are as herein -defined and Hali represents halogen.

Ha typically represents bromine.

The reaction is conventiently effected by the treatment under basic conditions e.g. an inorganic base such as potassium carbonate or sodium hydride in a suitable solvent such as a halogented hydrocarbon e.g. dichioromethane or an ether such as tetrahydrofuran. Reaction may be achieved at elevated temperature in the presence of catalyst such as a crown ether e.g. 18-crown-6 or 15-crown-5.

Intermediates of formula (IA) and (IB) may be prepared by using methods known to those skilled in the art, for example, using methods as described in the Examples hereinafter. Similarly, intermediates of formula (III), (V) and any other intermediates as used in the above processes, where not commercially available, may be prepared by using methods known to those skilled in the art, for example, using methods as described in the Examples hereinafter.

It will be understood that any compound of formula (1) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (1 ) by techniques known from the art. For example, suitable examples are provided in the examples hereinafter.

It will be further understood that a deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. The protecting groups may be removed using methods well known to those skilled in the ait.

The compounds of formula (1) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1 - hydroxy-2-napthoate (xinafoate), methanesulphonate or -toluenesulphonate salt.

Novel intermediates form a further aspect of the invention.

The invention will now be described in more detail by way of example only.

1. Synthetic Methodologies

The methods used for synthesis of the compounds of the invention are illustrated by the general schemes below and the preparative examples that follow. All compounds and intermediates were characterised at least by liquid chromatography-mass spectroscopy (LCMS). The starting materials and reagents used in preparing these compounds are available from commercial suppliers. These general schemes are merely illustrative of methods by which the compounds of this invention can be synthesised, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. Nuclear magnetic resonance (NMR) spectra were recorded at either 400 MHz or 300 MHz; the chemical shifts (δ) are reported in parts per million. Spectra were recorded using a Bruker 400 Avance instrument fitted with a 5 mm BBFO probe or DUL probe. Instrument control was by Bruker TopSpin 2, 1 software. Alternatively, spectra were recorded on a JEOL ECX 300 instrument. Purity was assessed using UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 nm, using a Waters Acquity UPLC system.

Compounds were purified using normal phase chromatography on silica or alumina, or by reverse phase chromatographic methods, using Biotage or Isolute KPNH Cartridge, SCX cartridge and SCX-2 solid phase extraction cartridges. Preparative HPLC was performed using an Agilent Technologies 1 100 Series system typically using Waters 19 mm id x 100 mm long CI 8 columns such as XBridge or SunFire 5μιτι materials at room temperature. Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0.1 % formic acid or 0.1 % ammonia. Room temperature in the following schemes means the temperature ranging from 20 °C to 25 °C.

Abbreviations:

Ac Acetyl

Ac₂0 Acetic anhydride

AcOH Acetic acid

Aq. Aqueous

Boc tert-Butoxy carbonyl

n-Bu n-butyl

cat Catalytic CDC1₃ Deuterated chloroform

CDI Carbonyl diimidazole

DAST Diethylaminosulfur trifluoride

dba Dibenzylideneacetone

dppf l, -Bis(dipheny[phosphino)ferrocene

DBU l,8-Diazabicycloundec-7-ene

DCM Dichloromethane

DIBAL-H Diisobutylaluminium hydride

DIPEA Diiospropylethylamine

DMAP Dimethylaminopyridine

DMSO Dimethyl sulfoxide

DMF Dimethyl formamide

EDC l -Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride

Et Ethyl

EtOAc Ethyl acetate

h Hours

HOAt 1 -Hydroxy-7-azabenzotriazole

KOAc Potassium acetate

HMDS Potassium bis(trimethylsilyl)amide

KOtBu Potassium tert-butoxide

LCMS Liquid Chromatography Mass Spectrum

mCPBA meta-Chloroperbenzoic acid

Me Methyl

min Minutes

MS Mass Spectrum

MW Microwave

NaHMDS Sodium bis(trimethylsilyl)amide

NBS N-Bromosuccinimide

NMM N-Methylmorpholine

NMR Nuclear Magnetic Resonance

PhMe Toluene

pTSA para-Toluenesulfonic acid

r.t. Room temperature sat. Saturated

TBAF Tetrabutylammonium fluoride

TBDMS tert-Butyldimethyl silyl

TFA Trifluoro cetic acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography

In the following experimental section the symbols Ri, R₂, R₃, R4, R5, Rs, R_?, R_8, R9, Rio, Ri i, R|_2> Ri 3, i , Ri5, Ri6, Ri 7, R(8, Ri , R20, rn, n, p, q, Q Q₂, Q₃, Q₄, Q₅, Q₆, X,, X₂, X₃, X4, A I and L| are as herein defined, unless otherwise specified.

1. INTERMEDIATES

Scheme 1

Q_A represents -C0₂Ci.₆ alkyl, CN, C_{1 -6} alkyl, halogen or -A_r

Hal represents halogen

Reagents and conditions: a) P(OEt)₃, 150 °C Intermediate 1

Diethyl 4-bromobenzylphosphonate

4-Bromoben2yl bromide (22.5g, 90mmol) and triethylphosphite (16.45g, 99mmol) were heated to 150°C for 3 h. The mixture was purifed by flash chromatography (1/4 EtOAc/hexane) to give diethyl 4-bromobenzylphosphonate (25.2g, 91%).

Ή NMR (300 MHz, CDCI3) δ ?7.45 (m, 2H), 7.15 (m, 2H), 4.00 (m, 4H), 3.05 (m, 2H), 1.25 (m, 6H)

Scheme 2

Q_A represents -CO2CL6 alkyl.CN, 0,.₆ alkyl, halogen or

Hal represents halogen

Reagents and conditions: a) PPh₃, toluene, reflux

Intermediate 2

(4^Bromobenzyl)(triphenyl)phosphonium bromide

To a stirred solution of 1 -bromo-4-(bromomethyl)benzene (8g, 32mmol) in toluene (160 ml) was added triphenylphosphine (8.4g, 32mmol). The reaction was stirred at 120°C under an atmoshpere of nitrogen for 17 hours after which time a white precipitate had formed. The reaction was then cooled to room temperature and the solid was collected by filtration, washing with a minimum amount of cold toluene to give (4- bromobenzyl)(triphenyl)phosphonium bromide as a white solid (15.4 g, 89 %) ^lH NMR (400 MHz, DMSO-c/₆) δ 7.85 - 8.01 (m, 2 H), 7.57 - 7.84 (m, 8 H), 7.33 - 7.55 (m, 1 H), 6.79 - 7.02 (m, 1 H), 5.04 - 5.28 (m, 2 H)

MS ES⁺ 433, 435

Scheme 3

Q_A= -C0₂C_1-6 alkyl, C_1-6 alkyl, CN, halogen or -A_rL_{r 5}

Q_B= H or R₃

Reagents and conditions: a) Potassium carbonate, 18-crown-6, DCM, reflux; b) NaH, 15-crown-5, 50 °C, 1 h

Intermediate 3

tert-Buty] 4-(4-bromobenzylidene)piperidine- 1 -carboxylate

Method A

To a suspension of (4-bromobenzyl)triphenylphosphonium bromide (Int 2) (49.3 g, 96 mmol) in DCM (300 ml) were added tert-butyl 4-oxopiperidine-l -carboxylate (19.2 g, 96 mmol), potassium carbonate (13.3 g, 96 mmol) and 18-crown-6 (2.5 g, 9.6 mmol). The reaction was stirred at 45°C under an atmosphere of nitrogen for 34 h. The reaction mixture was partitioned between DCM (300 ml) and water (200 ml). The aqueous layer was further extracted with DCM (200 ml). The combined organics were washed with brine (200 ml), dried over gSC _j, filtered and concentrated under reduced pressure to give an off white solid. Purification by column chromatography (Si0₂; 0-20 % EtOAc in petrol) gave (ert-buty\ 4-(4-bromobenzylidene)piperidine-l-carboxylate as a colourless oil (26.3 g, 74 %).

Method B

Diethyl 4-bromobenzylphosphonate (Int 1) (1.69 g, 5.5 mmol) in THF (3 ml) was added dropwise to a stirred suspension of sodium hydride (60 % dispersion in oil, 0.32 g, 8.0 mmol) in THF (20 ml) and 15-crown-5 (2 drops) at rt. The reaction was warmed to 65 C for 15 minutes and then cooled to rt. ieri-Butyl 4-oxopiperidine-l-carboxylate (1 g, 5 mmol) was added and the reaction was warmed to 50 °C for 1 h. The reaction mixture was poured onto ice water and extracted with ethyl acetate. The organic extract was washed with brine, dried over MgS0₄ and evaporated. Purification by column chromatography (Si0₂; 0-15 % EtOAc in petrol) gave te -butyl 4-(4- bromobenzylidene)piperidine-l-carboxylate as colourless oil (1.19 g, 69 %).

Ή NMR (400 MHz, MeOD) δ 7.41 - 7.50 (m, 2H), 7.05 - 7.17 (m, 2H), 6.35 (s, 1H), 3.45 - 3.56 (m, 2H), 3.37 - 3.45 (m, 2H), 2.39 - 2.48 (m, 2H), 2.29 - 2.38 (m, 2H), 1.39 - 1.54 (m, 9H)

MS ES⁺ 252

Scheme 4

Q_A = -C0₂C_1-6 alkyl, C,.₆ alkyl, CN, halogen or -A L R₅

Reagents and conditions: a) HC1, dioxane; b) Triethylamine, acetic acid, sodium triacetoxyborohydride, R₃C=0, DCM

Intermediate 4

4-(4-bromobenzylidene)piperidine hydrochloride

To a stirred solution of tert-butyl 4-(4-bromobenzylidene)piperidine-l -carboxylate (Int 3) (5 g, 14.2 mmol) in dioxane (14 ml) was added HC1 (4M in dioxane, 17.7 ml, 71 mmol). The reaction was stirred at r.t. under an atmosphere of nitrogen for 4 hours. The reaction mixture was concentrated under reduced pressure to give 4-(4- bromobenzylidene)piperidine hydrochloride as a white solid (4.1 g, 95 %).

Ή NMR (400 MHz, DMSO-d₆) δ 8.99 (br. s., 2H), 7.47 - 7.64 (m, 2H), 7.14 - 7.26 (m, 2H), 6.42 (s, 1H), 3.01 - 3.21 (m, 4H), 2.56 - 2.67 (m, 4H)

MS ES⁺ 252 and 254

Intermediate 5

4-(4-bromobenzylidene)- 1 -cyclobutylpiperidine

To a solution of 4-(4-bromobenzylidene)piperidine hydrochloride (Int 4) (8.4 g, 29 mmol), triethylamine (4.0 ml, 29.0 mmol) and cyclobutanone (6.1 g, 87 mmol), in DCM (100 ml) was added sodium triacetoxyborohydride (18.5 g, 87 mmol) and acetic acid (8.3 ml, 145 mmol). The mixture was stirred under nitrogen at r.t. for 4.5 h. The mixture was diluted with DCM (50 ml) and NaOH (2M aq., 150 ml) and the phases separated. The aqueous layer was further extracted with DCM (2 x 100 ml) and the organic extracts were combined, washed with brine (200 ml), dried (MgS0₄) and concentrated under reduced pressure. Purification by column chromatography (Si0₂; 0-15% (2% ammonium hydroxide in MeOH) in DCM) gave 4-(4-bromobenzylidene)-l - cyclobutylpiperidine as an off white solid (4.9 g, 16.2 mmol, 56% yield). W

Ή NMR (400 MHz, MeOD) δ 7.40 - 7.51 (m, 2 H), 7.05 - 7.16 (m, 2 H), 6.30 (s, 1 H), 2.69 - 2.87 (m, 1 H), 2.25 - 2.57 (m, 8 H), 2.03 - 2.16 (m, 2 H), 1.85 - 2.03 (m, 2 H), 1.66 - 1.82 (m, 2 H)

MS ES⁺ 306 and 308

5

Scheme 5

R_5a represents heteroaryl or aryl, each optionally substitued

Q_B = H or R₃

Reagents and conditions: a) PdCl₂(dppf), dioxane, 2M Na₂C0₃(aq), 120 °C, 10 microwave

2. Examples

2.1 Example 1

15 1 -Cyclobutyl-4-[4-( 1 -methyl- lH-pyrazol-4-yl)benzylidene]piperidine

Prepared according to Scheme 5

A mixture of 4-(4-brornobenzylidene)-l -cyclqbutylpiperidine (Int 5) (250 mg, 0.82 20 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (170 mg, 0.82 mmol) and PdCl₂(dppf) (59.7 mg, 0.08 mmol) in Na₂C0₃ aq. (2M, 2 ml) and dioxane (10 ml) was purged with nitrogen for 20 min. The reaction was then heated in the microwave for 2 h at 120°C. The reaction was filtered through a pad of celite and the filtrate concentrated. The residue was dissolved in DCM and washed with water and 25 brine, dried (MgS0 ) and evaporated. Purification by column chromatography (NH- silica 0-35% EtOAc ! petrol) gave l-cyclobutyl-4-(4-(l -methyl- lH-pyrazol-4- yl)benzylidene)piperidine as a pale brown solid (90 mg, 36%)

Ή NMR (400 MHz, CD₂CI₂) δ 7.71 (s, 1H), 7.62 (s, 1H), 7.38 - 7.45 (m, 2H), 7.16 - 7.23 (m, 2H), 6.26 (s, 1H), 3.86 - 3.94 (m, 3H), 2.63 - 2.75 (m, 1H), 2.47 - 2.54 (m, 2H), 2.36 (s, 4H), 2.22 - 2.30 (m, 2H), 1.96 - 2.07 (m, 2H), 1.79 - 1.92 (m, 2H), 1.60 - 1 .74 (m, 2H)

MS (ES⁺) 308. 2.2 Example 2

-Cyclobutyl-4-{4-[l-(2-methylpropyl)-lH-pyrazol-4-yl]benzylidene}piperidine

Prepared in an analogous manner to Example 1 via Scheme 5 starting with 4-(4- bromobenzyIidene)-l -cyclobutylpiperidine (Int 5) and using 1 -isobutylpyrazole-4- boronic acid pinacol ester.

Ή NMR (400 MHz, DMSO-c¾ δ 8.08 - 8.17 (m, 1 H), 7.80 - 7.89 (m, 1 H), 7.47 - 7.56 (m, 2 H), 7.12 - 7.22 (m, 2 H), 6.20 - 6.30 (m, 1 H), 3.84 - 3.98 (m, 2 H), 2.62 - 2.74 (m, 1 H), 2.41 - 2.47 (m, 2 H), 2.31 (m, 4 H), 2.19 - 2.26 (m, 2 H), 2.06 - 2.19 (m, 1 H), 1.91 - 2.02 (m, 2 H), 1.73 - 1.86 (m, 2 H), 1.55 - 1.68 (m, 2 H), 0.84 - 0.88 (m, 6 H) MS ES+ 350

2.3 Example 3

l-Cyclobutyl-4-[4-(3,5-dimethyl-l,2-oxazol-4-yl)benzylidene]piperidine

Prepared in an analogous manner to Example 1 via Scheme 5 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 3,5-dimethylisoxazole-4- boronic acid pinacol ester. Ή NMR (400 MHz, MeOD) δ 7.13 - 7.24 (m, 4 H), 6.27 (s, 1 H), 2.69 (quin, J = 7.96 Hz, 1 H), 2.42 - 2.52 (m, 2 H), 2.35 (d, J = 4.29 Hz, 2 H), 2.30 (s, 3 H), 2.21 - 2.29 (m, 2 H), 2.15 (s, 3 H), 1.93 - 2.05 (m, 2 H), 1.76 - 1.92 (m, 2 H), 1.56 - 1.69 (m, 2 H) MS ES+ 323

2.4 Example 4

l-Cyclobutyl-4-[4-(l-methyl-lH-pyrazol-5-yl)benzylidene]piperidine

Prepared in an analogous manner to Example 1 via Scheme 5 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using 1 -methyl- lH-pyrazol-5- yl)boronic acid.

Ή NMR (400 MHz, DMSC ₆) δ 7.43 - 7.54 (m, 3 H), 7.28 - 7.39 (m, 2 H), 6.36 - 6.43 (m, 1 H), 6.27 - 6.36 (m, 1 H), 3.86 (s, 3 H), 2.61 - 2.75 (m, 1 H), 2.46 (m, 2 H), 2.34 (s, 4 H), 2.21 - 2.28 (m, 2 H), 1.92 - 2.02 (m, 2 H), 1.73 - 1.86 (m, 2 H), 1.56 - 1.68 (m, 2

^H)

MS ES+ 308

2.5 Example 5

l -Cyclobutyl-4-[4-(2,4-dimethyl-l,3-thiazol-5-yl)benzylidene]piperidine

Prepared in an analogous manner to Example 1 via Scheme 5 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 2,4-dimethyl-5-(4,4,5,5- tetramethy]-l ,3,2-dioxaborolan-2-yl)-l,3-thiazole. Ή NMR (400 MHz, DMSO-d₆) δ 7.39 (s, 2 H), 7.24 - 7.32 (m, 2 H), 6.23 - 6.34 (m, 1 H), 2.64 - 2.74 (m, 1 H), 2.59 - 2.64 (m, 3 H), 2.42 - 2.48 (m, 2 H), 2.39 (s, 3 H), 2.29 - 2.35 (m, 4 H), 2.21 - 2.26 (m, 2 H), 1.92 - 2.02 (m, 2 H), 1.74 - 1.86 (m, 2 H), 1.61 (m, 2 H)

MS ES+ 339

2.6 Example 6

l -Cyclobutyl-4-[4-(l,5-dimethyl-lH-pyrazol-4-yl)benzylidene]piperidine

Prepared in an analogous manner to Example 1 via Scheme 5 starting with 4-(4- bromobenzylidene)-l-cycIobutylpiperidine (Int 5) and using 1,5-dimethyl-lH-pyrazole- 4-boronic acid pinacol ester.

Ή NMR (400 MHz, DMSO-4,) δ 7.55 (s, 1 H), 7.30 - 7.39 (m, 2 H), 7.15 - 7.28 (m, 2 H), 6.22 - 6.31 (m, 1 H), 3.78 (s, 3 H), 2.61 - 2.73 (m, 1 H), 2.41 - 2.48 (m, 2 H), 2.37 (s, 3 H), 2.32 (s, 4 H), 2.17 - 2.28 (m, 2 H), 1.88 - 2.03 (m, 2 H), 1.71 - 1.89 (m, 2 H), 1.53 - 1.71 (m, 2 H)

MS ES+ 322

2.7 Example 7

l-Cyclobutyl-4-[4-(l,2-oxazol-4-yl)benzylidene]piperidine

Prepared in an analogous manner to Example 1 via Scheme 5 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-y 1)- 1 ,2-oxazole. Ή NMR (400 MHz, MeOD) 69.06 (s, 1 H), 8.84 (s, 1 H), 7.59 (d, 2 H), 7.27 (d, 2 H), 6.37 (s, 1 H), 2.73 - 2.89 (m, 1 H), 2.57 (s, 2 H), 2.41 - 2.53 (m, 4 H), 2.32 - 2.42 (m, 2 H), 2.04 - 2.20 (m, 2 H), 1.88 - 2.04 (m, 2 H), 1.63 - 1.84 (m, 2 H)

MS ES+ 294 2.8 Example 8

l-Cyclobutyl-4-[4-(l ,3₎5-trimethyl-IH-pyrazol-4-yl)benzylidene]piperidine

Step a Intermediate 6

tert-butyl 4-[4-(l,3_>5-trimethyl- lH-pyrazol-4-yl)benzylidene]piperidine-l-carboxylate

Prepared in an analogous manner to Example 1 via Scheme 5 starting with ferf-butyl 4 (4-bromobenzylidene)piperidine-l-carboxylate (Int 3) and using l,3,5-trimethyl-4 (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole.

MS ES+ 382

Step b Example 8

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-[4-(l ,3,5-trimethyl-lH-pyrazol-4-yl)benzylidene]piperidine-l -carboxylate (Int 6) and using cyclobutanone in step b. Ή NMR (400 MHz, DMSO-afe) δ 7.12 - 7.29 (m, 4 H), 6.23 - 6.33 (m, 1 H), 3.69 (s, 3 H), 2.62 - 2.75 (m, 1 H), 2.42 - 2.48 (m, 2 H), 2.29 - 2.38 (m, 4 H), 2.22 (s, 5 H), 2.13 (s, 3 H), 1.90 - 2.05 (m, 2 H), 1.71 - 1.89 (m, 2 H), 1.62 (m, 2 H)

MS ES+ 336

2.9 Example 9

-[2-Chloro-4-( 1 -methyl- 1 H-pyrazol-4-yl)benzy lidene]- 1 -cyclobutylpiperidine

Step a Intermediate 7

Diethyl (4-bromo-2-chlorobenzyl)phosphonate

Prepared in an analogous manner to Intermediate 1 via Scheme 1 starting with 4- bromo-l -(bromomethyl)-2-chlorobenzene (CAS 89720-77-4).

Ή NMR (300MHz, CDC1₃) δ 7.53 (s, 1H), 7.31 (m, 2H), 4.04 (q, 4H), 3.26 (d, 2H), 1.25 (t, 6H).

Step b Intermediate 8

-(4-bromo-2-ch)orobenzylidene)-l -cyclobutylpiperidine

Prepared in an analogous manner to Intermediate 3 via Scheme 3, method B using diethyl (4-bromo-2-chlorobenzyl)phosphonate (Int 7) and l-cyclobutyl-4-piperidone

(CAS 359880-05-0). Step c Example 9

Prepared in an analogous fashion to Example 1 via Scheme 5 starting with 4-(4-bromo- 2-chlorobenzylidene)-l-cyclobutylpiperidine (Int 8) and using 1 -methyi-4-(4 ,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole.

Ή NMR (400 MHz, CD₂C1₂) δ 7.75 (s, 1 H), 7.65 (s, 1 H), 7.50 (s, 1 H), 7.21 - 7.37 (m, 2 H), 6.30 (s, 1 H), 3.90 (m, 3 H), 2.70 - 2.80 (m, 1 H), 2.38 - 2.43 (m, 6 H), 2.26 - 2.32 (m, 2 H), 2.00 - 2.10 (m, 2 H), 1.85 - 1.98 (m, 2 H), 1.65 - 1.77 (m, 2H)

MS (ES⁺) 342

2.10 Example 10

l-Cyclobutyl-4-[4-(3-methyl- l ,2,4-oxadiazol-5-yl)benzylidene]piperidine

Scheme 6

Reagents and conditions: a) Acetamidoxime, NaH, THF Step a Intermediate 9

Ethyl 4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzoate

Prepared in an analogous manner to Intermediate 5 via Scheme 5 starting with tert- butyl 4-(4-(ethoxycarbonyl)benzylidene)piperidine-l -carboxylate (CAS: 726185-65-5) and using cyclobutanone in step b. Ή NMR (400 MHz, DMSO-d₆) δ 7.84 - 7.96 (m, 2 H), 7.29 - 7.38 (m, 2 H), 6.34 (s, 1 H), 4.18 - 4.38 (m, 2 H), 2.61 - 2.75 (m, 1 H), 2.38 - 2.47 (m, 2 H), 2.28 - 2.36 (m, 4 H), 2.15 - 2.27 (m, 2 H), 1.89 - 2.03 (m, 2 H), 1.68 - 1.89 (m, 2 H), 1.52 - 1.68 (m, 2 H), 1.21 - 1.40 (m, 3 H)

MS ES⁺ 300

Step b Example 10

To a solution of acetamidoxime (74 mg, 1 mmol) in THF (10 ml) was added NaH (60% dispersion in oil, 42 mg, 1.1 mmol) and the mixture heated to reflux for 15 min. To this mixture was added a solution of ethyl 4-[(l -cyclobutylpiperidin-4- ylidene)methyl]benzoate (Int 9) (100 mg, 0.33 mmol) in THF (5 ml) and the reaction heated to reflux for 10 h. The reaction was allowed to cool to r.t. and was concentrated under reduced pressure. The residue was partitioned between DCM and water and the layers separated. The aqueous phase was further extracted with DCM and the combined organic extracts were dried (MgS0₄), concentrated under reduced pressure and purified by column chromatography (2% MeOH in DCM) to give l -cyclobutyl-4-[4-(3-methyl- l ,2,4-oxadiazol-5-yl)benzylidene]piperidine as yellow oil that crystallised on standing (60 mg, 58%). Ή NMR (400 MHz, MeOD) δ 7.99 - 8.13 (m, 2 H), 7.34 - 7.50 (m, 2 H), 6.43 (s, 1 H), 2.73 - 2.88 (m, 1 H), 2.53 - 2.64 (m, 2 H), 2.47 - 2.52 (m, 3 H), 2.45 (s, 3 H), 2.35 - 2.42 (m, 2 H), 2.04 - 2.16 (m, 2 H), 1.88 - 2.04 (m, 2 H), 1.64 - 1.85 (m, 2 H)

MS ES+ 310 2.11 Example 11

l -Cyclobutyl-4-[4-(5-methyl-l ,3,4-oxadiazol-2-yl)benzylidene]piperidine

Reagents and conditions: a) Acetylhydrazide, Me₃Al in PhMe, THF; b) POCI3, reflux

Step a Intermediate 10

'-Acetyl-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzohyd:

To a solution of ethyl 4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzoate (Int 9) (200 mg, 0.67 mmol) and acetyl hydrazide (50 mg, 0.67 mmol) in THF (10 ml) was added Me₃Al (2.0 M in toluene, 835 μΐ, 1.67 mmol) and the reaction stirred at r.t. for 72 h. The reaction was then heated to 60°C for 12 h. Further acetyl hydrazide (50 mg, 0.67 mmol) and Me₃Al (2.0 M in toluene, 835 μΐ, 1.67 mmol) were added and the reaction heated for 12 h. The reaction was allowed to cool to r.t. and Na₂SC>4.10H₂O was added. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was triturated from heptane/EtOAc to give N'-acetyl-4-[(l -cyclobutylpiperidin-4- ylidene)methy]]benzohydrazide (80 mg, 37%) which was used directly in the next step.

Step b Example 11 N'-Acetyl-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzohydrazide (Int 10) (67 mg, 0.2 mmol) was heated to reflux in POCl₃ (2 ml) for lh. The reaction was allowed to cool to r.t. and was then concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq. NaHC0₃ and the layers separated. The organic phase was dried (MgSC^), concentrated under reduced pressure and purified by column chromatography (Si0₂; DCM to 10% MeOH (NH₃)) to give l-cyclobutyl-4-[4-(5- methyl-l,3,4-oxadiazol-2-yl)benzylidene]piperidine as a cream solid (50 mg, 81 %).

Ή NMR (400MHz, CDCI3) δ ?7.97 (d, 2H, J = 8.0 Hz), 7.31 (d, 2H, J = 8.0 Hz), 6.35 (s, H), 2.96-2.19 (m, 7H), 2.61 (s, 3 H), 2.09 (m, 3H), 1.84-1.53 (m, 4H), 1.25 (m, IH) MS ES+ 310

2.12 Example 12

-Cyclobutyl-4-[4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)benzylidene]piperidine

Step a Intermediate 11

[4-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl (triphenyl)phosphonium bromide

Prepared in an analogous manner to Intermediate 2 via Scheme 2 starting from 3-(4- (bromomethyl)phenyl)-5-methyl-l,2,4-oxadiazole.

Ή NMR (400 MHz, DMSO-</₆) δ 2.65 (s, 3 H), 5.09 - 5.38 (m, 2 H), 7.10 - 7.21 (m, 3 H), 7.56 - 8.08 (m, 16 H)

Step b Example 12 Prepared in an analogous manner to Intermediate 5 via Scheme 3, method A and Scheme 4 starting with [4-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl](triphenyl) phosphonium bromide (Int 11) and using cyclobutanone in step b of Scheme 3. Ή NM (400 MHz, DMSO-<¼) δ 7.90 - 8.00 (m, 2 H), 7.33 - 7.43 (m, 2 H), 6.28 - 6.38 (m, 1 H), 2.66 (s, 4 H), 2.42 - 2.47 (m, 2 H), 2.34 (s, 4 H), 2.18 - 2.27 (m, 2 H), 1.89 - 2.04 (m, 2 H), 1.69 - 1.87 (m, 2 H), 1.54 - 1.68 (m, 2 H)

MS ES+ 310 2,13 Example 13

- [( 1 -Cyclopenty lpiperidm-4-ylidene)methyl]phenyl} methanol

Scheme 8

Reagents and conditions: a) LiAlH₄, THF

Step a Intermediate 12

-[( 1 -cyclopenty lpiperidin-4-ylidene)methyl]benzoate

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-(4-(ethoxycarbonyl)benzylidene)piperidine-l -carboxylate (CAS: 726185-65-5) and using cyclopentanone in step b.

Ή NMR (300 MHz, CDC1₃) δ 7.91 (d, 2H), 7.21 (d, 2H), 6.23 (s, 1 H), 4.29 (q, 2H), 2.44 (m, 8H), 2.08 (m, 1H), 1.9-1.3 (m, 10H), 1.30 (t, 3H)

Step b Example 13 To a solution of ethyl 4-[(l-cyclopentylpiperidin-4-ylidene)methyl]benzoate (Int 12) (3 g, 9,6 mmol) in THF (100 ml) at 0°C was added LiAlH₄ (1.1 g. 28 mmol) portionwise. The reaction was stirred for 72 h. NaSO₄.10H₂O was then added and the mixture stirred for 30 min. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The crude material was purified via column chromatography (Si0₂;EtOAc) to give {4-[(l -cyclopentylpiperidin-4-ylidene)methyl]phenyl} methanol as a white solid (1.1 g, 42 %).

Ή NMR (400 MHz, MeOD) δ 7.18 (d, J = 8.08 Hz, 2 H), 7.07 (d, J = 8.08 Hz, 2 H), 6.19 (s, 1 H), 4.47 (s, 2 H), 2.37 - 2.61 (m, 7 H), 2.26 - 2.36 (m, 2 H), 1.72 - 1.89 (m, 2 H), 1.55 - 1.69 (m, 2 H), 1.41 - 1.53 (m, 2 H), 1.25 - 1.40 (m, 2 H)

MS ES+ 272

2.14 Example 14

(4-{[l -(2-MethylpropyI)piperidin-4-ylidene]methyl}phenyl)methanol

Step a Intermediate 13

Ethyl 4-{[l -(2-methylpropyl)piperidin-4-ylidene]methyl}benzoate

Prepared in an analogous manner to Intermediate 3 via Scheme 3, method B using ethyl 4-[(diethoxyphosphoryl)methyl]benzoate (CAS 71441 -08-2) and l -(2- methylpropyl)piperidin-4-one (CAS 72544-16-2)

Ή NMR (300 MHz, CDCh) δ 7.96 (d, 2H), 7.25 (d, 2H), 6.25 (s, 1H), 4.33 (q, 2H), 2.48 (m, 4H), 2.36 (m, 4H), 2.06 (d, 2H), 1.75 (m, 1 H), )1.36 (q, 3H), 0.88 (d, 6H)

Step b Example 14 Prepared in an analogous manner to Example 13 via Scheme 8 starting with ethyl 4- {[l -(2-methylpropyl)piperidin-4-ylidene]methyl}benzoate (Int 13)

Ή NMR (400 MHz, MeOD) δ 7.18 (d, J = 8.08 Hz, 2 H), 7.05 (d, J = 8.08 Hz, 2 H), 6.18 (s, 1 H), 4.47 (s, 2 H), 2.36 - 2.47 (m, 4 H), 2.25 - 2.34 (m, 4 H), 2.03 (d, J = 7.33 Hz, 2 H), 1.64 - 1.81 (m, 1 H), 0.83 (d, J = 6.57 Hz, 6 H)

MS ES+ 260

2.15 Example IS

N- {4- [(1 -Cyclobuty lpiperidin-4-ylidene)methyl]benzy 1 } cyclopentanecarboxamide

Scheme 9

Reagents and conditions: a) LiAlH₄, THF; b) RC0₂H, EDC, NMM, DCM Step a Intermediate 14

/er/-But l 4-(4-cyanobenzylidene)piperidine-l-carboxylate

Prepared in an analogous manner to Intermediate 2 by method B, scheme 3, using diethyl (4-cyanobenzyl)phosphonate (CAS: 1552-41-6) and tert-butyl 4-oxopiperidine- 1 -carboxylate. Ή NMR (300 MHz, CDCI₃) δ 7.57 (m, 2H), 7.26 (m, 2H), 6.34 (s, 1H), 3.45 (m, 4H), 2.40 (m, 4H), 1.46 (s, 9H) Step b Intermediate 15

tert-Buty\ 4-[4-(arninomethyl)benzylidene]piperidine- 1 -carboxylate

ter Butyl 4-(4-cyanobenzylidene)piperidine-l -carboxylate (Int 14) (3 g, 0.01 mol) was added portionwise to a suspension of L1AIH4 (3 g, 0.08 mol) in THF (200 ml) at 0°C. The reaction was allowed to warm to r.t. and stirred for 18 h. The reaction was cooled to 0°C and excess Na₂SO₄.10H₂O was added. The mixture was stirred for 30 minutes and was then filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (Si0₂; 5% to 20% MeOH containing 2% NH₄OH, in DCM) gave tert-buty\ 4-[4-(aminomethyl)benzylidene]piperidine-l -carboxylate as a white solid (0.98 g, 32 %).

Ή NMR (300 MHz, CDCI3) δ ppm 7.26 (d, J = 8 Hz, 2H), 7.15 (d, J = 8 Hz, 2H), 6.33 (s, 1H), 3.84 (s, 2H), 3.49 (t, J = 5.5.Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H), 2.45 (t, J = 5.5 Hz, 2H), 2.32 (t, J = 5.5 Hz, 2H), 1.47 (s, 9H)

MS ES+ 230

Step c Intermediate 16

/er/-Butyl-4-(4-{[(cyclopentylcarbonyl)amino]methyl}benzylidene)piperidine-l- carboxylate

To a mixture of cyclopentanecarboxylic acid (120 μΐ, 1.1 mmol) and EDC (220 mg,

1.15 mmol) in DCM (5 ml) was added N-methyl morpholine (240 μΐ, 2.2 mmol) and the reaction stirred for 5 min. A solution of ierf-butyl 4-[4-(aminomethyl) benzylidene]piperidine-l -carboxylate (Int 15) (300 mg, 1. mmol) in DCM (5 ml) was then added and the reaction stirred for 18 h. The DCM was removed under reduced pressure and the residue partitioned between EtOAc and 10% aq. citric acid. The layers were separated and the aq. phase further extracted with EtOAc (><3). The combined organic extracts were washed with sat. aq. NaHC0₃, water then brine, dried (MgS0₄) and concentrated under reduced pressure to give tert-butyl 4-(4- {[(cyclopentylcarbonyl)amino]methyl}benzylidene)piperidine-l-carboxylate as an off- white solid (285 mg, 62 %). Ή NMR (300 MHz, CDClj) δ 7.22 (d, J = 8 Hz, 2H), 7.14 (d, J - 8 Hz, 2H), 6.32 (s, 1H), 5.73 (m, 1 H), 4.42 (d, J = 6 Hz, 2H), 3.50 (t, J = 6 Hz), 3.39 (t, J = 6 Hz, 2H), 2.54 (quintet, J = 8 Hz, 1H), 2.44 (t, J = 6 Hz, 2H), 2.32 (t, J = 6 Hz, 2H), 1.93-1.68 (m, 6H), 1.64-1.52 (m, 2H), 1.47 (s, 9H) Step d Example 15

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with Intermediate 16 and using cyclobutanone in step b.

Ή NMR (300 MHz, CDC1₃) δ 7.21 (d, J = 8 Hz, 2H), 7.15 (d, J = 8 Hz, 2H), 6.25 (s, 1H), 5.68 (m, 1H), 4.42 (d, J = 5.5 Hz, 2H), 2.71 (quin, J = 8 Hz, 1H), 2.54- 2.46 (m, 3H), 2.41 (s, 4H), 2.30 (m, 2H), 2.06- 1.56 (m, 14H)

MS ES+ 351 2,16 Example 16

N-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}tetrahydrofuran-3-carboxamide

Prepared in an analogous manner to Example 15 via Scheme 9 starting from Intermediate 16 using tetrahydrofuran-3-carboxylic acid in step b, and Scheme 4 using cyclobutanone in step b. Ή NMR (300 MHz, CDCb) δ 7.20 (d, J = 8 Hz, 2H), 7.15 (d, J = 8 Hz, 2H), 6.25 (s, 1H), 5.90 (m, 1 H), 4.42 (d, J = 8 Hz, 2H), 3.99- 3.87 (m, 3H), 3.81 (q, J = 7.5 Hz, 1H), 2.92 (quin, 5 = 6 Hz, 1H), 2.72 (quin, J = 7.5 Hz, 1H), 2.52 (t, J = 5.5 Hz, 2H), 2.41 (s, 4H), 2.30 (m, 2H), 2.24- 2.14 (m, 2H), 2.10- 2.00 (m, 2H), 2.00- 1.94 (m, 2H), 1.74- 1.64 (m, 2H)

MS ES⁺ 355

2.17 Example 17

2-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-N-cyclopentylacetamide

Scheme 10

wherein Qc represents R5R7NH or R₅ N-linked optionally substituted heterocyclyl.

Reagents and conditions: a) Bis(triraethylaluminum)-l ,4-diazabicyclo[2.2.2]octane adduct, R5R₇NH or R₅ N-linked optionally substituted heterocyclyl, THF, reflux -NR7-R5 or R_s N-linked optionally substituted heterocyclyl Step a Intermediate 17

M thyl {4-[( 1 -cyclobutylpiperidin-4- lidene)methyl]phenyl} acetate

Prepared in an analogous manner to Intermediate 5 via Scheme 3, method B starting with 2-(4-((diethoxyphosphoryI)methyl)phenyl)acetic acid (CAS 177712-50-4) and tert- butyl 4-oxopiperidine-l -carboxylate, and Scheme 4, using cyclobutanone in step b, followed by esterification with methanol using standard conditions.

Ή NMR (300 MHz, CDC1₃) δ 7.22 (d, J = 8 Hz, 2H), 7.10 (d, J = 8 Hz, 2H), 6.37 (s, 1H), 3.69 (s, 3H), 3.60 (s, 2H), 3.13 (quintet, J = 8 Hz, 1H), 2.94-2.54 (m, 10H), 2.18- 2.09 (m, 2H), 1.88 (q, J = 9 Hz, 1H), 1.76- 1.62 (m, 1H)

Step b Example 17

To bis(trimethylaluminum)-l ,4-diazabicyclo[2.2.2]octane adduct (154 mg, 0.6 mmol) in THF (5 ml) was added cyclopentylamine (60 μΐ, 0.6 mmol) and the mixture stirred at 40°C for 1 h. A solution of methyl {4-[(l-cycIobutyipiperidin-4-ylidene)methyl] phenyi}acetate (120 mg, 0.40 mmol) in THF (5 ml) was then added and the reaction heated at reflux for 18 h. The reaction was cooled, diluted with THF (5 ml) and quenched with Na₂SO4.10H₂O. The mixture was filtered, washing with EtOAc, and the filtrate concentrated under reduced pressure. Purification by column chromatography (Si0₂; 5% N¾/MeOH in DCM) gave 2-{4-[(l-cyclobutylpiperidin-4- yIidene)methyl]phenyl}-N-cyclopentylacetamide as a cream solid (47 mg, 33%). ^lH NMR (300 MHz, CDC1₃) δ 7.17 (s, 4H), 6.26 (s, 1H), 5.28 (br. s, 1H), 4.18 (sextet, J = 7 Hz, 1 H), 3.51 (s, 2H), 2.73 (m, 1H), 2.54 (m, 2H), 2.43 (m, 4H), 2.32 (m, 2H), 2.07- 2.01 (m, 3H), 1.98- 1.86 (m, 3H), 1.74- 1.60 ( , 3H), 1.58-1.51 (m, 3H), 1.24 (sextet, J = 6.5 Hz, 2H)

MS ES+ 353

2.18 Example 18

2-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyI}-N-(tetrahydrofuran-3- yl)acetamide

Prepared in an analogous manner to Example 17 via Scheme 10 starting with Intermediate 17 and using tetrahydrofuran-3-amine. Ή NMR (400 MHz, MeOD) δ 7.09 - 7.17 (m, 2H), 6.99 - 7.07 (m, 2H), 6.21 (s, 1H), 4.21 - 4.29 (m, 1H), 3.63 - 3.85 (m, 3H), 3.45 - 3.52 (m, 1H), 3.37 (s, 2H), 2.61 - 2.73 (m, 1H), 2.27 - 2.45 (m, 6H), 2.20 - 2.27 (m, 2H), 2.04 - 2.16 (m, 1H), 1.92 - 2.02 (m, 2H), 1.77 - 1.91 (m, 2H), 1.68 - 1.78 (m, 1H), 1.56 - 1.67 (m, 2H)

MS ES+ 355

2.19 Example 19

-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-l -(pyn-olidin-l -yl)ethanone

Prepared in an analogous manner to Example 17 via Scheme 10 starting with Intermediate 17 and using pyrrolidine.

1H NMR (400 MHz, MeOD) δ 7.13 (d, J = 8.08 Hz, 2 H), 7.05 (d, J = 8.08 Hz, 2 H), 6.21 (s, 1 H), 3.58 (s, 2 H), 3.42 (d, J = 6.57 Hz, 2 H), 3.33 (t, J = 6.82 Hz, 2 H), 2.59 - 2.82 (m, 1 H), 2.15 - 2.50 (m, 9 H), 1.91 - 2.06 (m, 2 H), 1.71 - 1.91 (m, 6 H), 1.54 - 1.71 (m, 2 H)

MS ES+ 339

2.20 Example 20

{4- [( 1 -Cyclobuty lpiperidin-4-ylidene)rnethyl]phenyl } (pyrrolidin- 1 -y l)methanone

Scheme 11

Wherein Qc represents R5R7NH or R5 N-Iinked optionally substituted heterocyclyl. Reagents and conditions: a) LiOH, EtOH, THF, H₂0; b)i) (COCl)₂, DMF, DCM ii) R5R7NH or R5 N-linked optionally substituted heterocyclyl, DCM

Step a Intermediate 18

4- l -cyclobutylpiperidin-4-ylidene)methyl]benzoic acid hydrochloride

Ethyl 4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzoate (Intermediate 9) (1.34 g, 4.5 mmol) was dissolved in ethanol (20 ml) and THF (20 ml) and lithium hydroxide (0.94 g, 22.4 mmol) in water (40 ml) was added. The reaction was stirred for 16 hours at rt. The reaction was concentrated and the resulting mixture was extracted with DCM and the aqueous phase acidified with 6M HC1 (aq.). The mixture was concentrated until a white solid precipitated; this was collected by filtration to yield 4-[(l- cyclobutylpiperidin-4-ylidene)methyl]benzoic acid hydrochloride (1.0 g, 73 %).

Ή NMR (300 MHz, DMSO-d₆) δ 12.90 (br s, 1 H), 1 1.24 (br s, 1H), 7.88 (d, J = 8 Hz, 2H), 7.32 (d, J = 8 Hz, 2H), 6.51 (s, 1H), 3.56 (quin, J = 7 Hz, 1H), 3.32 (br s, 4H), 2.84-2.64 (m, 2H), 2.47 (quin, J = 1.5 Hz, 2H), 2.36 (quin, J = 10 Hz, 2H), 2.11 (br m, 2H), 1.74-1.62 (m, 2H)

MS (ES⁺) 272

Step b Example 20

To a mixture of 4-((l -cyclobutylpiperidin-4-ylidene)methyl)benzoic acid (Int 18) (205 mg, 0.67 mmol) in DCM (5 ml) at 0 °C was added oxalyl chloride (64 μΐ, 0.73 mmol) followed by DMF (1 drop, catalytic). The reaction was allowed to warm to r.t. and was stirred for 2.5 h. The reaction was cooled to 0°C and pyrrolidine (195 μΐ, 2.33 mmol) was added. The reaction was stirred at 0°C for 30 min. The reaction was diluted with DCM and washed with water then brine. The organic phase was dried (MgS0₄) and concentrated under reduced pressure. The residue was dissolved in MeOH (2 ml) and loaded onto a 2 g SCX-2 column. The column was eluted with MeOH then 10 % 2M NH₃/MeOH in DCM and the appropriate fractions concentrated under reduced pressure. The residue was triturated from diethyl ether to give {4-[(l -cyclobutylpiperidin-4- ylidene)methyl]phenyl}(pyrrolidin-l-yl)methanone as an off-white solid (163 mg, 75%).

Ή NMR (300 MHz, CDC1₃) δ 7.46 (d, J = 8 Hz, 2H), 7.20 (d, J = 8 Hz, 2H), 6.28 (s, 1H), 3.64 (t, J = 7 Hz, 2H), 3.46 (t, J = 7 Hz, 2H), 2.71 (br. s, 1 H), 2.53 (br. s, 2H), 2.41 (br. s, 3H), 2.29 (br. s, 2H), 2.06- 1.85 (m, 8H), 1.74-1.61 (m, 3H)

MS ES+ 335

2.21 Example 21

- [( 1 -Cyclobuty lpiperidin-4-y lidene)methyl] -N-cyclopentylbenzamide

Prepared in an analogous manner to Example 20 via Scheme 11 starting with Intermediate 18 and using cyclopentylamine.

Ή NMR (300 MHz, CDC1₃) δ 7.68 (d, J = 8 Hz, 2H), 7.22 (d, J = 8Hz, 2H), 6.28 (s, 1H), 6.02 (d, J = 7 Hz, 1 H), 4.39 (sextet, J = 7Hz, 1H), 2.72 (quin, J = 7.5 Hz, 1H), 2.56- 2.47 (m, 2H), 2.46- 2.34 (s, 4H), 2.32- 2.24 (m, 2H), 2.17- 1.85 (m, 6H), 1.81- 1.58 (m, 6H), 1.55- 1.40 (m, 2H)

MS ES+ 339

2.22 Example 22

-[(l-Cyclobutylpiperidin-4-ylidene)methyl]-N-(tetrahydrofuran-3-yl)benzamide

Prepared in an analogous manner to Example 20 via Scheme 11 starting with Intermediate 18 and using 3-aminotetrahydrofuranyl. Ή NMR (300 MHz, CDC1₃) δ 7.69 (d, J = 8 Hz, 2H), 7.24 (d, J = 8 Hz, 2H), 6.28 (s, 1H), 6.24 (br. s, 1H), 4.76- 4.69 (m, 1H), 3.99 (q, J = 8 Hz, 1H), 3.90 (dd, J = 9.5, 5 Hz, 1H), 3.84 (dd, J = 8.5, 6 Hz, 1H), 3.81 - 3.76 (m, 1H), 2.51 (t, J = 5.5 Hz, 2H), 2.41 (s, 4H), 2.39- 2.34 (m, 1H), 2.71 (quin, J = 7.5 Hz, 1H), 2.30 (t, J = 5.5 Hz, 2H), 2.08- 1.89 (ra, 5H), 1.76- 1.60 (m, 2H).

MS ES+ 341

2.23 Example 23

-[(l -Cyclobutylpiperidin-4-ylidene)methyl]-N-(cyclopentylmethyl)benzaraide

Prepared in an analogous manner to Example 20 via Scheme 11 starting with Intermediate 18 and using 1-cyclopentylmethanamine.

Ή NMR (300 MHz, CDC1₃) δ 7.69 (d, J = 8 Hz, 2H), 7.24 (d, J = 8 Hz, 2H), 6.29 (s, 1H), 6.10 (m, 1H), 3.39 (dd, J = 7 Hz, 5 Hz, 2H), 2.72 (quin, J = 7.5 Hz, 1H), 2.54- 2.50 (m, 2H), 2.42 (br. s, 4H), 2.30 (br. s, 2H), 2.15 (septet, J = 7.5 Hz, 1H), 2.08- 2.05 (m, 2H), 2.03- 1.86 (m, 1H), 1.85- 1.50 (m, 8H), 1.33- 1.21 (m, 3H).

MS ES+ 353 2.24 Example 24

4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]-N-(tetrahydrofuran-3-ylmethyl)benzamide

Prepared in an analogous manner to Example 20 via Scheme 11 starting with Intermediate 18 and using l-(tetrahydrofuran-3-yl)methanamine. Ή NMR (300 MHz, CDC1₃) δ 7.69 (d, J = 8 Hz, 2H), 7.20 (d, J = 8 Hz, 2H), 6.61 (t, J = 5.5 Hz, 1H), 6.26 (s, 1H), 3.88 (td, J = 8 Hz, 5.5 Hz, 1H), 3.79 (dd, J = 8.5, 7 Hz, 1H), 3.71 (q, J = 8 Hz, lH), 3.60 (dd, J = 8.5, 5 Hz, 1H), 3.43 (td, J = 6.5, 2 Hz, 2H), 2.71 (quin, J = 7.5 Hz, 1H), 2.58 (septet, J = 7 Hz, 1H), 2.51 (t, J = 5.5 Hz, 2H), 2.42 (s, 4H), 2.30 (t, J = 5.5 Hz, 2H), 2.10- 1.90 (m, 5H), 1.73- 1.58 (m, 3H).

MS ES+ 355

2.25 Example 25

-[(l -Cyclobutylpiperidin-4-ylidene)methyl]-N-(pyridin-3-yl)benzamide

Prepared in an analogous manner to Example 15 via Scheme 9 starting with Intermediate 18 and using pyridin-3 -amine.

Ή NMR (300 MHz, CDCb) δ 8.66 (d, J = 2.5 Hz, 1H), 8.39 (d, J = 4.54 Hz, 1H), 8.31 (dd, J = 4.5 Hz, 2.5 Hz, IH), 7.92 (s, 1H), 7.83 (d, J = 8 Hz, 2H), 7.35 (s, 1H), 7.33 (d, J = 8 Hz, 2H), 6.32 (s, 1H), 2.71 (quin, J = 7.5 Hz, 1H), 2.53 (t, J = 6 Hz, 2H), 2.42 (s, 4H), 2.31 (t, J = 6 Hz, 2H), 2.10- 2.00 (m, 2H), 1.91 (quin, J = 9 Hz, 2H), 1.74- 1.62 (m, 2H).

MS ES+- 348

2.26 Example 26

N-{4-[(l -Cyclobutylpiperidin-4-y]idene)methyl]benzyl}pyridin-3-amine

Scheme 12

Reagents and conditions: a) L1AIH4, THF

To a solution of 4-[( l -cyclobutylpiperidin-4-yIidene)methyIJ-N-(pyridin-3-yl)benzamide (Example 25, 180 mg, 0.52 mmol) in THF (8 ml) at 0 °C was added L1AIH4 (1M solution on THF, 2.1 ml, 2.1 mmol) dropwise. The reaction was stirred for 2 h whilst allowing to warm to r.t. The reaction was cooled in ice/water, quenched via the addition of Na₂SO₄.10H₂O, diluted with THF ( 10 ml) and stirred for 30 min whilst allowing to warm to r.t. The mixture was filtered, washing with EtOAc, and the filtrate concentrated under reduced pressure. Purification by column chromatography (Si0₂; 5 % 2 NH₃/MeOH in DCM) gave N-{4-[(l - cyclobutylpiperidin-4-ylidene)methyl]benzyl}pyridin-3-amine as a white solid (88 mg, 51 %).

Ή NMR (300 MHz, CDCI3). δ 8.07 (d, J = 3 Hz, 1H), 7.97 (dd, J = 4.5, 1.5 Hz, 1H), 7.29 (d, J = 8 Hz, 2H), 7.18 (d, J = 8 Hz, 2H), 7.07 (dd, 3 = 8, 4.5 Hz, 1 H), 6.88 (ddd, J = 8, 3, 1.5 Hz, 1H), 6.26 (s, 1H), 4.32 (d, J = 5.5 Hz, 2H), 4.09 (t, J = 5.5 Hz, 1H), 2.70 (quin, J = 8Hz, 1H), 2.52 (t, J = 5.5 Hz, 2H), 2.40 (s, 4H), 2.29 (t, J = 5.5 Hz, 2H), 2.08- 2.00 (m, 2H), 1.95 (quin, J = 10 Hz, 2H), 1.86- 1.66 (m, 2H).

MS (ES⁺) 334 2.27 Example 27

{ 3 -Chloro-4- [( 1 -cyclobutylpiperidin-4-ylidene)methyl]phenyl } (pyrrolidin- 1 - yl)methanone

Scheme 13

Int 19 (nt 20

Reagents and conditions: a) PPh₃, CBr₄, DCM; b) NH₄Cl, Zn, MeOH, THF

Step a Intermediate 19

tert- ut ] 4-(dibromomethylidene)piperidine-l-carboxylate

A solution of tert-butyl 4-oxopiperidine-l -carboxylate (30 g, 151 mmol) and triphenylphosphme (79 g, 301 mmol) in DCM (300 ml) cooled to 0°C under nitrogen was treated portionwise with carbon tetrabromide (100 g, 301 mmol) and stirred at 0° C for 3 h before allowing to warm to r.t. and stining for 3 days. The reaction mixture was filtered and the filtrate evaporated to dryness. Et20 was added, the mixture stirred for 1 h and filtered. The filtrate was concentrated to give tert-butyl 4- (dibromomethylidene)piperidine-l-carboxylate contaminated with triphenylphosphine oxide as a white solid (53.9 g, quantitative).

Ή NMR (400 MHz, DMSO-<¾) δ 3.34 - 3.41 (m, 4 H), 2.37 - 2.45 (m, 4 H), 1.41 (s, 9

H)

MS ES⁺ 339, 341 , 343

Step b Intermediate 20

ierr-But l 4-(bromomethylidene)piperidine- 1 -carboxy late

To a stirred solution of tert-butyl 4-(dibromomethylene)piperidine-l -carboxylate (12 g, 33.8 mmol) in MeOH (80 ml) and THF (40 ml) at 0°C under an atmosphere of nitrogen was added ammonium chloride (14.46 g, 270 mmol). The reaction was stirred at 0°C for 30 minutes. After this time zinc dust (8.85 g, 135 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was then filtered, washing the solids with MeOH. The organics were concentrated under reduced pressure to give a white solid which was taken up in EtOAc/water. The layers were separated and the org phase dried (MgS0₄) and concentrated under reduced pressure to give tert-butyl 4-(bromomethylidene)piperidine-l -carboxylate (9 g, 96 %).

Ή NMR (400 MHz, DMSO-< ) δ 6.26 (s, 1 H), 3.19 - 3.43 (m, 4 H), 2.15 - 2.35 (m, 4 H), 1.41 (s, 9 H)

MS ES+ 220, 222 Scheme 14

Reagents and conditions: a) PdCl₂(dppf), sat, aq. Na₂C0_3, dioxane, 80 °C Step c Intermediate 21

tert-Butyl 4-[2-chloro-4-(methoxycarbonyl)benzylidene]piperidine- 1 -carboxylate

To a solution of ieri-butyl 4-(bromomethylidene)piperidine-l -carboxylate (Int 20) (1.0 g, 3.62 mmol) and [2-chloro-4-(methoxycarbonyl)phenyl]boronic acid (813 mg, 3.80 mmol) in dioxane (10 ml) was added sat. aq. Na₂C0₃ (1 ml) and the mixture degassed for 10 min. PdCl₂(dppf) (263 mg, 0.36 mmol) was added and reaction heated to 80°C for 18 h. The reaction was allowed to cool to r.t. and filtered through a pad of Celite, washing with EtOAc. The filtrate was concentrated under reduced pressure and purified by column chromatography (Si0₂; heptane to 5 % EtOAc in heptane) to give ½rr-butyl 4-[2-chloro-4-(methoxycarbonyl)benzylidene] pi eridine-l-carboxylate as a white solid (580 mg, 45%).

Ή NMR (300 MHz, CDC1₃) δ 8.03 (s, IH), 7.84 (d, J = 7.5 Hz, IH), 7.25 (d, J = 7.5 Hz, IH), 6.42 (s, IH), 3.90 (s, 3H). 3.52 (t, J = 6.0 Hz, 2H), 3.40 (t, J = 6.0 Hz, 2H). 2.37 (t, J = 6.0 Hz, 2H), 2.30 (t, J = 6.0 Hz, 2H), 1.46 (s, 9H)

MS ES+ 310

Scheme 15

Qc represents -NR7-R5 or R5 N-linked optionally substituted heterocyclyl

Reagents and conditions: a) Qc-H, Me Al in PhMe, THF

Step d Intermediate 22

Methyl 3-chloro-4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzoate

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-[2-chloro-4-(methoxycarbonyl)benzylidene]piperidine-l-carboxylate (Int 21) and using cyclobutanone in step b.

Ή NMR (300 MHz, CDCI3) δ 8.03 (s, IH), 7.83 (d, J = 8.3 Hz, IH), 7.27 (d, J = 8.3 Hz, IH), 6.29 (s, IH), 3.90 (s, 3H), 2.71 (m, IH), 2.43-2.30 (m, 6H), 2.30-2.20 (m, 2H), 2.04-2.02 (m, 2H), 1.89-1.85 (m, 2H), 1.69-1.67 (m, 2H)

MS ES+ 320 Step e Example 27

To Me₃AI (2M in toluene, 1.75 ml, 3.5 mmol) at 0 °C was added pyrrolidine (293 μΐ, 3.5 mmol) and the mixture stirred for 10 min. A solution of methyl 3-chloro-4-[(l- cyclobutylpiperidin-4-ylidene)methyl]benzoate (225 mg, 0.70 mmol) in THF (5 ml) was then added and the reaction allowed to warm to r.t. and stirred for 18 h. Further Me₃Al (2 M in toluene, 1.75 ml, 3.5 mmol) was added and the reaction stirred for 24 h. The reaction was poured onto sat. aq. Na₂S04 and EtOAc and the mixture stirred for 10 min. The layers were separated and the organic phase washed with water, dried (MgS0 ) and concentrated under reduced pressure. Purification by prep HPLC gave {3-chloro-4-[(l- cyclobutylpiperidin-4-ylidene)methyl]phenyl}(pyrrolidin-l-yl)methanone as an orange gum (101 mg, 40 %)

Ή NMR (400 MHz, MeOD) δ 7,40 (d, J = 1.52 Hz, 2 H), 7.25 (dd, J = 7.96, 1.39 Hz, 2 H), 7.16 (d, J = 8.08 Hz, 1 H), 6.17 (s, 1 H), 3.42 (t, J = 6.95 Hz, 2 H), 3.31 (t, J = 6.57 Hz, 2 H), 2.64 (quin, J = 7.89 Hz, 1 H), 2.26 - 2.38 (m, 4 H), 2.14 - 2.26 (m, 4 H), 1.86 - 1.99 (m, 2 H), 1.65 - 1.87 (m, 6 H), 1.46 - 1.64 (m, 2 H)

MS ES+ 385, 361 2.28 Example 28

{2-Chloro-4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}(pyrroHdin- l- yl)methanone

Step a Intermediate 23

Methyl 2-chloro-4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzoate

Prepared in an analogous manner to Intermediate 22 via Scheme 14 starting with [3- chloro-4-(methoxycarbonyl)phenyl]boronic acid and t-butyl 4-(bromomethylidene) piperidine-l -carboxylate (Int 20) and Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, MeOD) δ 7.69 (d, J = 8.08 Hz, 2 H), 7.22 (s, 2 H), 7.12 (d, J = 8.08 Hz, 2 H), 6.23 (s, 1 H), 3.80 (s, 3 H), 2.69 (quin, J = 7.96 Hz, 1 H), 2.15 - 2.49 (m, 8 H), 1.92 - 2.05 (m, 2 H), 1.75 - 1.91 (m, 2 H), 1.53 - 1.70 (m, 2 H)

MS ES+ 320 Step b Example 28

Prepared in an analogous manner to Example 27 via Scheme 15 starting with methyl 2- chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzoate (Int 23) and using pyrrolidine. Ή NMR (400 MHz, MeOD) 8 7.17 - 7.25 (m, 2 H), 7.13 (d, J = 8.59 Hz, 1 H), 6.23 (s, 1 H), 3.50 (t, J = 6.82 Hz, 2 H), 3.14 (t, J = 6.57 Hz, 2 H), 2.61 - 2.83 (m, 1 H), 2.19 - 2.50 (m, 8 H), 1.94 - 2.05 (m, 2 H), 1.75 - 1.94 (m, 6 H), 1.51 - 1.71 (m, 2 H)

MS ES+ 359, 361 2.29 Example 29

{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]-2-fluorophenyl}(pyrrolidin-l

y])methanone

Step a Intermediate 24

-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]-2-fluorobenzoate

Prepared in an analogous manner to Intermediate 22 via Scheme 14 starting with [3- fluoro-4-(methoxycarbonyl)phenyl]boronic acid and t-butyl 4-(bromomethylidene) piperidine-l-carboxylate (Int 20) and Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, DMSO-d₆) δ 7.69 - 7.81 (m, IH), 7.02 - 7.12 (m, 2H), 6.25 (s, IH), 4.18 - 4.29 (m, 2H), 2.56 - 2.66 (m, IH), 2.31 - 2.40 (m, 2H), 2.21 - 2.30 (m, 4H), 2.12 - 2.21 (m, 2H), 1.83 - 1.95 (m, 2H), 1.66 - 1.79 (m, 2H), 1.49 - 1.61 (m, 2H), 1.18 - 1.28 (m, 3H)

MS ES+ 318

Step b Example 29

Prepared in an analogous manner to Example 27 via Scheme 15 starting with ethyl 4- [(l -cyclobutylpiperidin-4-ylidene)methyl]-2-fluorobenzoate (Int 24) and using pyrrolidine.

Ή NMR (400 MHz, MeOD) δ 7.26 (t, J =7.45 Hz, 1 H), 7.01 (d, J = 7.83 Hz, 1 H), 6.94 (d, J =1 1.12 Hz, 1 H), 6.26 (s, 1 H), 3.49 (t, J - 6.82 Hz, 2 H), 3.25 (d, J = 6.82 Hz, 2 H), 2.64 - 2.86 (m, 1 H), 2.19 - 2.53 (m, 9 H), 1.95 - 2.08 (m, 2 H), 1.76 - 1.95 (m, 7 H)

MS ES+ 343

2.30 Example 30

{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]-3-fluorophenyl}(pyrro]idin- l- yl)methanone

Step a Intermediate 25

-[(l-cyclobutylpiperidin-4-ylidene)methyl]-3-fluorobenzoate

Prepared in an analogous manner to Intermediate 22 via Scheme 14 starting with [2- fluoro-4-(methoxycarbonyl)phenyl]boronic acid and t-butyl 4-(bromomethylidene) piperidine-l -carboxylate (Int 20) and Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, MeOD) δ 7.68 (dd, J = 7.96, 1.39 Hz, 3 H), 7.57 (dd, J = 10.48, 1.39 Hz, 3 H), 7.25 (t, J = 7.71 Hz, 3 H), 6.18 (s, 1 H), 3.81 (s, 3 H), 2.69 (quin, J = 7.96 Hz, 1 H), 2.14 - 2.47 (m, 8 H), 1.90 - 2.05 (m, 2 H), 1.74 - 1.91 (m, 2 H), 1.50 - 1.70 (m, 2 H)

MS ES+ 304

Step b Example 30

Prepared in an analogous manner to Example 27 via Scheme 15 starting with methyl 4- [(l -cyclobutylpiperidin-4-ylidene)memyl]-3-fluorobenzoate (Int 25) and using pyrrolidine.

Ή NMR (400 MHz, MeOD) δ 7.06 - 7.29 (m, 3 H), 6.17 (s, 1 H), 3.49 (t, J = 6.95 Hz, 2 H), 3.39 (t, J - 6.44 Hz, 2 H), 2.64 - 2.82 (m, 1 H), 2.19 - 2.53 (m, 8 H), 1.94 - 2.06 (m, 2 H), i.74 - 1.94 (m, 6 H), 1.56 - 1.70 (m, 2 H)

MS ES+ 343

2.31 Example 31

-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]-3 -fluorophenyl } methanol

Hal₂ represents CI or F

Reagents and conditions: a) L1AIH4, THF, 0 °C to r.t. To a stirred solution of methyl 4-((l-cyclobutylpiperidin-4-ylidene)methyl)-3- fluorobenzoate (Int 25) (78 mg, 0.257 mmol) in THF (1.2 ml) at 0°C under an atmosphere of nitrogen was added dropwise LiAlH₄ (1M in THF, 514 μΐ, 0.51 mmol). The reaction was then allowed to warm to room temperature and stirred under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to 0°C and quenched by the addition of Na2SC>4. 1 OH2O. The mixture was allowed to warm to room temperature and then filtered through a bed of celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (Si0₂; 0-10 % MeOH containing 2% NH₄OH, in DCM) to give {4-[(l-cyclobuty!p\peridin-4-ylidene)methyl]- 3-fluorophenyl}methanol as a clear oil (39 mg, 55 %).

Ή NMR (400 MHz, DMSO-d₆) δ 7.14 - 7.25 (m, 1H), 7.02 - 7.14 (m, 2H), 6.16 (s, 1H), 5.19 - 5.35 (m, 1H), 4.48 (d, J = 5.81 Hz, 2H), 2.58 - 2.75 (m, 1H), 2.15 - 2.38 (m, 8H), 1.88 - 2.05 (m, 2H), 1.71 - 1.87 (m, 2H), 1.49 - 1.69 (m, 2H)

MS ES+ 276

2.32 Example 32

-Chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}methanol

Prepared in an analogous manner to Example 31 via Scheme 16 starting with methyl 3- chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzoate (Int 22). Ή NMR (400 MHz, MeOD) δ 7.29 (s, 1 H), 7.01 - 7.17 (m, 2 H), 6.20 (s, 1 H), 4.47 (s, 2 H), 2.68 (quin, J = 7.96 Hz, 1 H), 2.13 - 2.46 (m, 7 H), 1.89 - 2.03 (m, 2 H), 1.75 - 1.90 (m, 2 H), 1.54 - 1.70 (m, 2 H)

MS ES+ 292, 294 2,33 Example 33

{6-[(l-Cyclobutylpiperidin-4-ylidene)methyl]pyridin-3-yl}(pyrrolidin-l-yl)methanone

Scheme 17

Reagents and conditions: a) Bis(pinacolato)diboron, KOAc, PPh₃, Pd₂dba3, dioxane, reflux

Step a Intermediate 26

/ert-Butyl 4-[(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)methylidene]piperidine-l - carbox late

tert-Butyl 4-(bromomethylidene)piperidine-l -carboxylate (3.00 g, 10.9 mmol), bis(pinacolato)diboron (4.1 g, 16 mmol), KOAc (1.9 g, 19.6 mmol), triphenylphosphine (185 mg, 0.65 mmol) and Pd₂dba₃ (300 mg, 0.33 mmol) were stirred in dioxane (50 ml) and degassed by bubbling Ar through the mixture for 20 min. The mixture was then heated at reflux overnight. The solution was cooled and the dioxane removed under reduced pressure. The residue was purified by column chromatography (Si0₂; 20; 1 heptane/ethyl acetate) to give tert-butyl 4-[(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)methylidene]piperidine-l -carboxylate as a white solid (1.45 g, 41 %).

^JH NM (300 MHz, CDC1₃) δ 5.14 (s, 1H), 3.43 (m, 4H), 2.59 (m, 2H), 1.41 (s, 9H), 1.25 (s, 18 H) cheme 18

Reagents and conditions: a) PdC idppf), sat. aq. Na₂C0 , dioxane, 80 °C

Step b Intermediate 27

MethyI-6-{[l-(tert-butoxycarbonyl)piperidin-4-ylidene]methyl}pyridine-3-carboxylate

A mixture of ferf-butyl 4-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)methylidene]piperidine-l -carboxylate (Int 26) (660 mg, 2.04 mmol) and methyl 6- bromopyridine-3-carboxylate (563mg, 2.14mmol) in dioxane (5 ml) and sat. aq. Na₂C0₃ (1 ml) was degassed for 10 min. PdCl₂(dppf) (149 mg, 0.02 mmol) was then added and the reaction heated to 80 °C for 18 h. The reaction mixture was allowed to cool to r.t. and was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated under reduced pressure and purified by column chromatography (Si0 ; 10 % diethyl ether in DCM) to give methyl 6-{[l-(tert-butoxycarbonyl)piperidin- 4-ylidene]methyl}pyridine-3-carboxylate as a pale yellow oil (223 mg, 33 %).

Ή NMR (300MHz, CDC1₃) δ 8.59 (s, 1 H), 8.09 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 6.8 Hz, 1H), 6.34 (s, 1H), 3.99 (s, 3H), 3.52 (t, J = 4.5 Hz, 2H), 3.41 (t, J = 4.5 Hz, 2H), 2.43 (t, J = 4.5 Hz, 2H), 2.36 (t, J = 4.5 Hz, 2H), 1.46 (s, 9H) Step c Intermediate 28

Methyl 6-[(l-cyclobutylpiperidin-4-ylidene)methyl]pyridine-3-carboxylate

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with methyl 6-{[l -(tert-butoxycarbonyl)piperidin-4-ylidene]methyl}pyridine-3-carboxylate (Int 27) using cyclobutanone in step b.

Ή NMR (300MHz, CDC1₃) δ 8.75 (s, 1H), 8.08 (d, 1H), 7.63 (d, 1H), 6.27 (s, 1H), 4.00 (s, 3H), 2.6-1.2 (m, 15H)

MS ES+ 287.5

Step d Example 33

Prepared in an analogous manner to Example 27 via Scheme 15 starting with methyl 6- [(l -cyclobutylpiperidin-4-ylidene)methyl]pyridine-3-carboxylate (Int 28) and using pyrrolidine.

'H MR (300MHz, CDCI3) 68.73 (s, 1H), 7.78 (d, 1H), 7.18 (d, 1H), 6.34 (s, 1H), 3.65 (t, 2H), 3.48 (t, 2H), 2.99 (t, 2H), 2.85 (m, 1H), 2.61 (m, 2H), 2.52 (s, 4H), 1.6-2.2 (m, 10H)

MS ES+ 326

2.34 Example 34

{6-[(l-Cyclobutylpiperidin-4-ylidene)methyl]pyridin-3-yl}methanol

Prepared in an analogous manner to Example 31 via Scheme 16 starting with methyl 6- [(l-cyclobutylpiperidin-4-ylidene)methyl]pyridine-3-carboxylate (Int 28).

Ή NMR (400 MHz, DMSO-d₆) δ 8.45 - 8.56 (m, 1 H), 7.62 - 7.77 (m, 1 H), 7.18 - 7.29 (m, 1 H), 6.31 (s, 1 H), 5.21 - 5.34 (m, 1 H), 4.44 - 4.63 (m, 2 H), 2.85 - 2.99 (m, 2 H), 2.67 - 2.82 (m, 1 H), 2.38 (d, J = 2.53 Hz, 5 H), 1.95 - 2.08 (m, 2 H), 1.78 - 1.94 (m, 2 H), 1.58 - 1.75 (m, 2 H)

MS ES+ 259 2.35 Example 35

{5-[(l-Cyclobutylpiperidin-4-yHdene)methyl]pyridin-2-yl}(pyrrolidiri- l-yl)methanone

Step a Intermediate 29

-[(l -cyclobutylpiperidin-4-ylidene)methyl]pyridine-2-carboxylate

Prepared in an analogous manner to Intermediate 28 via Scheme 18 starting with methyl 5-bromopyridine-2-carboxylate and tert-b iyl 4-[(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yI)methylidene]piperidine-l-carboxylate (Int 26) and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO- ₆) δ 8.48 - 8.58 (m, 1 H), 7.97 - 8.04 (m, 1 H), 7.75 - 7.85 (m, 1 H), 6.36 (s, 1 H), 3.87 (s, 3 H), 3.31 (s, 1 H), 2.41 - 2.46 (m, 2 H), 2.31 - 2.40 (m, 4 H), 2.23 - 2.31 (m, 2 H), 1.90 - 2.02 (m, 2 H), 1.70 - 1.88 (m, 2 H), 1.51 - 1.68 (m, 2 H)

Step b Example 35

Prepared in an analogous manner to Example 27 via Scheme 15 starting with methyl 5- [(l -cyc]obutylpiperidin-4-ylidene)methyl]pyridine-2-carboxylate (Int 29) and using pyrrolidine. Ή NMR (300MHz, CDC1₃) δ 8.40 (d, 1H, J = 2 Hz), 7.77 (d, 1H, J = 8 Hz), 7.57 (dd, 1H, J = 8, 2 Hz), 6.23 (s, 1H), 3.75 (m, 2H), 3.67 (m, 2H), 2.70 (m, 1H), 2.35-2.58 (m, 6H), 2.30 (m, 2H), 1.80-2.10 (m, 8H), 1.69 (m, 2H)

MS ES+ 326

2.36 Example 36

Pyrrolidin- 1 -yl(4- { [ I -(tetrahydrofuran-3 l)piperidin-4-ylidene]methyl } phenyl) methanone

Step a Intermediate 30

Ethyl 4- { [ 1 -(tetrahydrofuran-3-yl)piperidin-4-ylidene]methyl } benzoate

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-(4 (ethoxycarbonyl)benzylidene)piperidine-l-carboxylate (CAS: 726185-65-5) and using dihydrofuran-3(2H)-one in step b.

Ή NMR (300MHz, CDCI3) δ 7.98 (m, 2H), 7.25 (m, 2H), 6.31 (s, 1H), 4.37 (q, 2H), 3.99-3.67 (m, 2H), 3.79 (m, 1H), 3.67 (m, 1H), 3.01_. (quin, 1H), 2.62 (m, 1H), 2.53 (m, 4H), 2.43 (m, 3H), 2.06 (m, 1H0, 1.89 (m, 1H), 1.39 (t, 3H).

Step b Example 36

Prepared in an analogous manner to Example 27 via Scheme 15 starting with ethyl 4- {[l-(tetrahydrofuran-3-yl)piperidin-4-ylidene]methyl} benzoate (Int 30) and using pyrrolidine.

Ή NMR (400 MHz, MeOD) δ 7.39 (d, J = 8.08 Hz, 2 H), 7.19 (d, J = 8.08 Hz, 2 H), 6.26 (s, 1 H), 3.84 (td, J = 8.59, 4.04 Hz, 1 H), 3.74 - 3.81 (m, 1 H), 3.65 (q, J = 8.34 Hz, 1 H), 3.56 (dd, J = 8.72, 6.95 Hz, 1 H), 3.49 (t, J = 6.95 Hz, 2 H), 3.39 (t, J = 6.69 Hz, 2 H), 2.93 (quin, J = 7.26 Hz, 1 H), 2.50 - 2.62 (m, 1 H), 2.40 - 2.50 (m, 4 H), 2.27 - 2.39 (m, 3 H), 1.95 - 2.08 (m, 1 H), 1.64 - 1.95 (m, 6 H)

MS (ES⁺) 341

2.37 Example 37

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methy[]benzyl}pyridin

Reagents and conditions: a) LiAIH₄, THF, 0 °C to r.t. Step a Intermediate 31

rerf-Buty 1 4-(4-(hydroxymethyl)benzylidene)piperidine- 1 -carboxylate

A solution of ethyl 4-[(l-cyclobutylpiperidin-4-ylidene)methyI]benzoate (Int 9) (3.45 g, 10 mmol) in THF (30 ml) was stirred at 0°C under argon. L1AIH4 (0.76 g, 20 mmol) was added in portions and the mixture was stirred overnight, allowing it to warm to room temperature. It was then cooled back to 0^°C before finely ground Na₂S( H₂0 (2 g) was added potionwise while stirring vigorously. After 1 hour the mixture was filtered, rinsing the solid well with THF (100 ml). Evaporation of the solvents afforded tert-butyl 4-(4-(hydroxymethyl)benzylidene)piperidine-l -carboxylate (2.5 g, 83 %) which was used without further purification. Ή NMR (400 MHz, MeOD-d₄) δ 7.28 - 7.37 (m, 2H), 7.14 - 7.24 (m, 2H), 6.42 (s, 1H), 4.55 - 4.65 (m, 2H), 3.48 - 3.56 (m, 2H), 3.38 - 3.48 (m, 2H), 2.41 - 2.55 (m, 2H), 2.31 - 2.41 (m, 2H), 1.42 - 1.54 (m, 9H)

MS (ES)⁺ 326 (M + Na⁺)

Scheme 20

Reagents and conditions: a) CBr₄, PPh₃, DCM

Step b Intermediate 32

/er/-Butyl 4-(4-(bromomethyl)benzylidene)piperidine- 1 -carboxylate

/£? /-Butyl 4-(4-(hydroxymethyl)benzylidene)piperidine-l -carboxylate (Int 31) (4.1 g, 13.5 mmol) and triphenylphosphine (4.3 g, 16.2 mmol) were dissolved in DCM (50 ml) to give a colourless solution. Carbon tetrabromide (5.4 g, 16.2 mmol) was added in portions and the reaction mixture was stirred at r.t. for 20 h. The reaction was concentrated and purified by column chromatography (Si0₂; 0-15 % EtOAc / petrol) to give rert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate as a clear oil which solidified on standing (2.7 g, 53 %).

Ή NMR (400 MHz, DMSO-d₆) 67.36 - 7.48 (m, 2H), 7.17 - 7.26 (m, 2H), 6.36 (s, 1H), 4.70 (s, 2H), 3.36 - 3.48 (m, 2H), 3.27 - 3.37 (m, 2H), 2.36 - 2.43 (m, 2H), 2.25 - 2.34 (m, 2H), 1.41 (s, 9H)

MS ES+ 310, 312

Scheme 21

Li_b represents a covalent bond or -O-

Reagents and conditions: a) NaH, D F, R₅-L|_b-H; or a); Cs₂C0₃, DMF, R₅-L_{l b}-H; or a) K₂C0₃, THF, R₅-L|_b-H; or a) LiHMDS, DMF R₅-L_{t b}-H or a) KHMDS, DMF, R₅- L_lb-H

Step c Intermediate 33

-Butyl 4- {4-[(2-oxopyridin- 1 (2H)-yl)methy l]benzylidene}piperidine- 1 - carboxylate

To a solution of 2-hydroxypyridine (93 mg, 0.98 mmol) in THF (5 ml) at 0°C was added sodium hydride (60% dispersion in oil, 50 mg, 1.23 mmol) and the mixture was stirred for 30 min. iert-Butyl-4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate (Int 32) (300 mg, 0.82 mmol) was added and the ice bath removed and the mixture was diluted with DMF (0.5 ml) and stirred for 2.5 days. The mixture was then poured into water (10 ml) and extracted with diethyl ether (3 x 0 ml). The combined extracts were washed with water (2 x 10 ml) and brine (10 ml) and dried over MgS0 . After evaporation of the solvents the residue was purified by column chromatography (Si0₂, 3% 2M NH₃/MeOH in DCM) to afford the desired material as a pale yellow-brown solid (260 mg, 83 %).

Ή NMR (300 MHz, CDC1₃) δ 7.33 - 7.25 (2H, m), 7.24 (2H, d, J = 8 Hz), 7.14 (2H, d, J = 8 Hz), 7.00 (1H, d, J = 9 Hz), 6.30 (1H, s), 6.14 (1H, td, J = 6.5 Hz, 1.5 Hz), 5.33 (2H, s), 3.48 (2H, t, J = 5.5 Hz), 3.37 (2H, t, J = 5.5 Hz), 2.42 (2H, t, J = 5.5 Hz), 2.31 (2H, t, J = 5.5 Hz), 1.46 (9H, s).

Step d Example 37

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4- {4-[(2-oxopyridin-l(2H)-yl)methyl]benzylidene}piperidine-l -carboxylate (Int 33) using cyclobutanone in step b. Ή NMR (300 MHz, CDCI3) δ 7.34- 7.26 (m, 2H), 7.23 (d, J = 8 Hz, 2H), 7.16 (d, J = 8 Hz, 2H), 6.61 (d, J = 9 Hz, 1H), 6.24 (s, 1H), 6.14 (td, J = 6.5 Hz, 1 Hz, 1H), 5.12 (s, 2H), 2.70 (quin, J = 7.5 Hz, 1H), 2.50 (t, J = 5.5 Hz, 2H), 2.40 (s, 4H), 2.28 (m, 2H), 2.06- 1.99 (m, 2H), 1.96- 1.90 (m, 1H), 1.74- 1.63 (m, 3H)

MS ES+ 335

2.38 Example 38

-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}pyridazin-3(2H)-one

Step a Intermediate 34

tert-Butyl 4-{4-[(6-oxopyridazin-l(6H)-yl)methyl]benzylidene}piperidine-l- carboxylate

Intennediate 34 was prepared in an analogous manner to Intermediate 33 starting with reri-butyl 4-(4-(bromomethyl)benzylidene)piperi dine- 1 -carboxyl ate (Int 32) and using pyridazin-3(2H)-one. Used as isolated in next step. Step b Example 38

-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}pyridazin-3(2H)-one

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-{4-[(6-oxopyridazin-l (6H)-yl)methyl]benzylidene}piperidine-l -carboxylate (Int 34) and using cyclobutanone in step b.

Ή NMR (300 MHz, CDC1₃) δ 7.76 (dd, J = 4 Hz, 1.5 Hz, 1H), 7.36 (d, J = 8 Hz, 2H), 7.15 (dd, J = 6 Hz, 4 Hz, 1H), 7.14 (d, J = 8 Hz, 2H), 6.93 (dd, J = 9 Hz, 1.5 Hz, 1H), 6.24 (s, 1 H), 5.30 (s, 2H), 2.71 (quin, J = 7 Hz, 1H), 2.51 (m, 2H), 2.39 (s, 4H), 2.28 (m, 2H), 2.08- 1.99 (m, 2H), 1.74- 1.60 (m, 4H).

MS (ES⁺) 336 2.39 Example 39

-({4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl } oxy)pyridazine

Step a Intermediate 35

tert-Butyl 4-{4-[(pyridazin-3-yloxy)methyl]benzylidene}piperidine-l -carboxylate

Intermediate 35 was prepared in an analogous manner to Intermediate 33 starting with terf-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using pyridazin-3-ol. Used as isolated in next step.

Step b Example 39

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-{4-[(pyridazin-3-yloxy)methyl]benzylidene}piperidine-l-carboxylate (Int 35) and using cyclobutanone in step b.

Ή NMR (300 MHz, CDC1₃) δ 7.75 (d, J = 5 Hz, 1H), 7.38 (d, J = 8 Hz, 2H), 7.25 (dd, J = 9, 5 Hz, 1H), 7.22 (d, J = 8 Hz, 2H), 6.95 (d, J = 9 Hz, 1H), 6.25 (s, 1H), 5.32 (s, 2H), 2.71 (quin, J = 8 Hz, 1H), 2.50 (t, J =5.5 Hz, 2H), 2.41 (s, 4H), 2.29 (t, J = 5.5 Hz, 2H), 2.06-1.98 (m, 2H), 1.96-1.89 (m, 2H), 1.73-1.63 (m, 2H).

MS (ES⁺) 336

2.40 Example 40

l -{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-methoxypyridin-2(lH)-one

Step a Intermediate 36

tert-Butyl 4-{4-[(3-methoxy-2-oxopyridin-l(2H)-yl)methyl]benzylidene}piperidine-l-

To a solution of 3-methoxypyridin-2(lH)-one (123 mg, 0.98 mmol) in DMF (3 ml) was added cesium carbonate (534 mg, 1.64 mmol) at 0 °C and the reaction stirred for 45 min. Tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate (300 mg, 0.82 mmol) was added and the reaction allowed to warm to r.t and stirred for 16 h. The reaction was quenched with brine and extracted with EtOAc (x 3). The combined organics were washed with brine (x 5), dried over MgSO^ and evaporated to dryness.

Purification by column chromatography (Si0₂ 0-100 % EtOAc/petrol then 0-10 % MeOH/EtOAc) gave tert-butyl 4-(4-((3-methoxy-2-oxopyridin-l(2H)- yl)methyl)benzylidene)piperidine- l -carboxylate as a white gum (271 mg, 81 %).

Ή NMR (400 MHz, DMSO-<¼) δ 7_:26 - 7.42 (m, 1 H), 7.05 - 7.28 (m, 4 H), 6.74 - 6.85 (m, 1 H), 6.34 (s, 1 H), 6.08 - 6.22 (m, 1 H), 5.09 (s, 2 H), 3.70 (s, 3 H), 3.37 - 3.46 (m, 2 H), 2.31 - 2.41 (m, 2 H), 2.24 - 2.31 (m, 2 H), 1.41 (s, 9 H)

MS ES+ 41 1

Step b Example 40

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-{4-[(3-methoxy-2-oxopyridin-l(2H)-yl)methyl]benzylidene}piperidine-l- carboxylate (Int 36) and using cyclobutanone in step b. Ή NMR (400 MHz, MeOD) δ 7.07 - 7.17 (m, 3H), 6.97 - 7.06 (m, 2H), 6.72 - 6.79 (m, 1H), 6.12 - 6.22 (m, 2H), 5.05 (s, 2H), 3.67 (s, 3H), 2.55 - 2.69 (m, 1H), 2.21 - 2.37 (m, 6H), 2.10 - 2.21 (m, 2H), 1.86 - 1 .97 (m, 2H), 1.71 - 1.84 (m, 2H), 1.51 - 1.62 (m, 2H) MS (ES⁺) 365

2.41 Example 41

Methyl l-{4-[(l -cycIobutylpiperidin-4-ylidene)methyl]benzyl}-6-oxo-l ,6- dihydropyridine-3-carboxyIate

Prepared in an analogous manner to Example 40 (using CS2CO3 as base) via Scheme 21 starting with tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate (Int 32) and using methyl 6-oxo-l ,6-dihydropyridine-3-carboxylate and Scheme 4 using cyclobutanone in step b. 'H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 7.76 - 7.86 (m, 1H), 7.22 - 7.32 (m, 2H), 7.12 - 7.21 (m, 2H), 6.43 - 6.54 (m, 1 H), 6.23 (s, 1H), 5.17 (s, 2H), 3.79 (s, 3H), 2.60 - 2.72 (m, 1H), 2.24 - 2.42 (m, 6H), 2.13 - 2.24 (m, 2H), 1.90 - 2.00 (m, 2H), 1.71 - 1.85 (m, 2H), 1.54 - 1.67 (m, 2H)

MS (ES⁺) 393

2.42 Example 42

-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-methylpyridin-2(lH)-one

Prepared in an analogous manner to Example 40 (using Cs₂C0₃ as base) via Scheme 21 starting with teri-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using 3-methylpyridin-2(lH)-one and Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, MeOD) δ 7.52 - 7.60 (m, 1H), 7.37 - 7.45 (m, 1H), 7.23 - 7.31 (m, 2H), 7.14 - 7.22 (m, 2H), 6.28 - 6.35 (m, 2H), 5.19 (s, 2H), 2.75 - 2.86 (m, 1H), 2.31 - 2.55 (m, 8H), 2.03 - 2.18 (m, 5H), 1.87 - 2.01 (m, 2H), 1.66 - 1.81 (m, 2H)

MS (ES⁺) 348

2.43 Example 43

l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-6-methyl-3- (trifluoromethy l)pyridin-2( 1 H)-one

Prepared in an analogous manner to Example 40 (using Cs₂C0₃ as base) via Scheme 21 starting with /Y-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using 6-methyl-3-(trifluoromethyI)pyridin-2(lH)-one and Scheme 4 using cyclobutanone in step b.

1H NMR (400 MHz, MeOD) δ 7.16 - 7.25 (m, 2H), 7.10 - 7.16 (m, 2H), 6.77 - 6.83 (m, lH), 6.48 - 6.54 (m, 1H), 6.29 - 6.35 (m, 1H), 5.43 (s, 2H), 2.73 - 2.84 (m, 1H), 2.38 - 2.55 (m, 9H), 2.29 - 2.38 (m, 2H), 2.02 - 2.13 (m, 2H), 1.89 - 2.01 (m, 2H), 1.65 - 1.80 (m, 2H)

MS (ES⁺) 417

2.44 Example 44

l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-(trifluoromethyl)pyridin- -one

Prepared in an analogous manner to Example 40 (using CS2CO3 as base) via Scheme 21 starting with ter/-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using 3-(trifluoromethyl)pyridin-2(lH)-one and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.91 - 8.03 (m, 2H), 7.28 - 7.36 (m, 2H), 7.16 - 7.24 (m, 2H), 6.43 - 6.50 (m, 1H), 6.32 (s, 1H), 5.22 (s, 2H), 2.74 - 2.86 (m, 1H), 2.39 - 2.57 (m, 6H), 2.30 - 2.39 (m, 2H), 2.03 - 2.16 (m, 2H), 1.88 - 2.00 (m, 2H), 1.65 - 1.82 (m, 2H) MS (ES⁺) 403

2.45 Example 45

- { 4- [( 1 -cyclobuty lpiperidin-4-y lidene)methy 1] benzyl } piperidin-2-

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with iert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using piperidin-2-one and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.14 - 7.27 (m, 4H), 6.33 (s, 1 H), 4.59 (s, 2H), 3.25 - 3.31 (m, 2H), 2.75 - 2.88 (m, 1H), 2.32 - 2.58 (m, 10H), 2.05 - 2.14 (m, 2H), 1.90 - 2.01 (m, 2H), 1.69 - 1.87 (m, 6H)

MS (ES⁺) 339

2.46 Example 46

-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}mo^holin-3-one

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with tert-b tyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using morpholin-3-one and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, CDC1₃) δ 7.15 - 7.26 (m, 4H), 6.25 - 6.32 (m, 1H), 4.63 (s, 2H), 4.27 (s, 2H), 3.80 - 3.91 (m, 2H), 3.25 - 3.34 (m, 2H), 2.67 - 2.79 (m, 1H), 2.48 - 2.59 (m, 2H), 2.37 - 2.47 (m, 4H), 2.26 - 2.37 (m, 2H), 2.01 - 2.11 (m, 2H), 1.85 - 2.00 (m, 2H), 1.65 - 1.79 (m, 2H)

MS (ES⁺) 341

2,47 Example 47

-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}pyrrolidin

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with ferf-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using pyrrotidin-2-one and Scheme 4 using cyclobutanqne in step b.

Ή NMR (400 MHz, DMSO-d₆) δ 7.14 - 7.20 (m, 4H), 6.26 (s, 1H), 4.34 (s, 2H), 3.19 - 3.28 (m, 2H), 2.61 - 2.71 (m, 1H), 2.36 - 2.43 (m, 2H), 2.25 - 2.36 (m, 6H), 2.15 - 2.25 (m, 2H), 1.88 - 2.01 (m, 4H), 1.72 - 1 ,85 (m, 2H), 1.56 - 1 .69 (m, 2H)

MS (ES⁺) 325

2.48 Example 48

l -{4-[(l-cyclobutylpiperidin-4-ylidene)rnethyl]benzyl}-5-(methoxyrnethyl)pyridin- -one

Scheme 22

Reagents and conditions: a) DIBAL-H, THF, -78 °C; b) NaH, Mel, DMF Step a Intermediate 37

tert-butyl 4-{4-[(5-formyl-2-oxopyridin-l(2H)-yl)methy!]benzylidene}piperidine-l- carboxylate

Prepared in an analogous manner to Example 40 (Cs₂C0₃) via Scheme 21 starting with ierf-butyl 4-(4-(bromomethyl)benzylidene)piperidine- l -carboxylate (Int 32) and using 6-oxo- 1 ,6-dihydropyrid e-3-carbaldehyde.

Ή NM (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.70 - 8.79 (m, IH), 7.75 - 7.84 (m, 1H), 7.26 - 7.38 (m, 2H), 7.19 - 7.26 (m, 2H), 6.48 - 6.59 (m, 1H), 6.35 (s, 1H), 5.18 (s, 2H), 3.37 - 3.44 (m, 2H), 3.30 - 3.35 (m, 2H), 2.32 - 2.40 (m, 2H), 2.22 - 2.31 (m, 2H), 1.41 (s, 9H)

MS (ES⁺) 353

Step b Intermediate 38

tert-butyl 4-(4- { [5 -(hydroxymethyl)-2-oxopyridin- 1 (2H)-yl]methyl jbenzylidene) piperidine-1 -carboxylate

To a solution of tert-butyl 4-(4-((5-formyl-2-oxopyridin-l (2H)- yl)methyl)benzylidene)piperidine-l -carboxylate (Int 37) (500 mg, 1.22 mmol) in THF (8 ml) at -78°C was added DIBAL-H (3.67 ml, 1 M solution in hexanes, 3.67 mmol) and the reaction stirred at this temperature for 1 h. The reaction was quenched with a sat. aq. solution of sodium potassium tartrate, diluted with EtOAc and filtered through a pad of celite washing with EtOAc. The filtrate was concentrated under reduced pressure to give tert-butyl 4-(4-((5-(hydroxymethyl)-2-oxopyridin-l (2H)- yl)methyl)benzylidene)piperidine-l -carboxylate as an orange gum (501 mg, quantitative). Ή NMR (400 MHz, DMSO-d₆) 5 7.54 - 7.61 (m, 1H), 7.27 - 7.36 (m, 1H), 7.14 - 7.21 (m, 2H), 7.06 - 7.14 (m, 2H), 6.30 - 6.37 (m, 1 H), 6.25 (s, 1H), 4.93 - 5.03 (m, 3H), 4.09 - 4.15 (m, 2H), 3.27 - 3.37 (m, 2H), 3.20 - 3.25 (m, 2H), 2.24 - 2.31 (m, 2H), 2.14 - 2.21 (m, 2H), 1.32 (s, 9H)

MS (ES⁺) 41 1

Step c Intermediate 39

tert-butyl 4-(4-{[5-(methoxymethyl)-2-oxopyridin-l(2H)-yl]methyl}benzylidene) piperidine- 1 -carboxylate

To a solution of tert-butyl 4-(4-((5-(hydroxymethyl)-2-oxopyridin- l(2H)- yl)methyl)benzylidene)piperidine-l -carboxylate (Int 38) (585 mg, 1.42 mmol) in DMF (5 ml) at 0°C was added sodium hydride (1 14 mg, 60 % dispersion in oil, 2.85 mmol). The reaction was stirred at this temperature for 1 hour. Methyl iodide (0.1 1 ml, 1.7 mmol) was added and the reaction allowed to warm to r.t. and stirred for 16 h. The reaction was cooled to 0°C and quenched with brine and extracted with EtOAc (x 2). The organics were combined and washed with brine (x 5), dried over MgS and evaporated to dryness. The residue was purified by column chromatography (Si0₂; 50- 100 % EtO Ac/petrol) to give tert-butyl 4-(4-((5-(methoxymethyl)-2-oxopyridin-l(2H)- yl)methyl)benzylidene)piperidine-l -carboxylate (223 mg, 37%).

Ή NMR (400 MHz, MeOD) δ 7.67 - 7.73 (m, 1 H), 7.51 - 7.59 (m, 1H), 7.25 - 7.33 (m, 2H), 7.15 - 7.24 (m, 2H), 6.57 - 6.63 (m, 1H), 6.40 (s, 1H), 5.19 (s, 2H), 4.25 (s, 2H), 3.46 - 3.58 (m, 2H), 3.37 - 3.45 (m, 2H), 3.35 (s, 3H), 2.40 - 2.49 (m, 2H), 2.29 - 2.39 (m, 2H), 1.48 (s, 9H)

MS (ES⁺) 425

Step d Example 48

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- but l 4-(4- { [5 -(methoxymethy l)-2-oxopyridin- 1 (2H)-yl]methyl }benzylidene) piperidine- 1 -carboxylate (Int 39) and using cyclobutanone in step b. Ή NMR (400 MHz, DMSO-d₆) δ 7.78 (s, IH), 7.37 - 7.46 (m, IH), 7.21 - 7.30 (m, 2H), 7.12 - 7.20 (m, 2H), 6.39 - 6.47 (m, IH), 6.24 (s, IH), 5.06 (s, 2H), 4.13 (s, 2H), 3.23 (s, 3H), 2.59 - 2.72 (m, IH), 2.25 - 2.42 (m, 6H), 2.15 - 2.24 (m, 2H), 1.90 - 2.00 (m, 2H), 1.71 - 1.84 (m, 2H), 1.53 - 1.67 (m, 2H)

MS (ES⁺) 380

2.49 Example 49

(3S)-l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]ben2yl}-3-methoxypyiTolidin-2- one

Reagents and conditions: a) TBAF, THF; b) NaH, Mel, DMF or NaHMDS, Mel, DMF

Step a Intermediate 40

tert-butyl 4-(4- { [(3 S)-3 - { [tert-butyl (dimethyl)silyl] oxy } -2-oxopyrrolidin- 1 - yl]methyl } benzylidene)piperidine- 1 -carboxylate

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting from /er/-butyl 4-(4-(bromomethyl)ben2ylidene)piperidine-l-carboxylate (Int 32) and using (3S)-3-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-one. Ή NMR (400 MHz, MeOD) δ 6.97 - 7.10 (m, 4H), 6.23 (s, 1H), 4.16 - 4.36 (m, 3H), 3.29 - 3.39 (m, 2H), 3.19 - 3.28 (m, 2H), 3.09 - 3.13 (m, 1H), 2.99 - 3.08 (m, 1H), 2.24 - 2.32 (m, 2H), 2.1 1 - 2.23 (m, 3H), 1.62 - 1.75 (m, 1H), 1.31 (s, 9H), 0.77 (s, 9H), 0.01 (br. s., 6H)

MS (ES⁺) 445

Step b Intermediate 41

tert-butyl 4-(4-{[(3S)-3-hydroxy-2-oxopyrrolidin-l-yl methyl}benzylidene) piperidine- -carboxylate

To a solution of (S)-tert-butyl 4-(4-((3-(tert-butyldimethylsilyloxy)-2-oxopyrrolidin-l- yl)methyl)benzylidene)piperidine-l -carboxylate (Int 40) (1.65 g, 3.29 mmol) in THF (10 ml) at 0°C was added TBAF (1.0 M in THF, 6.58 ml, 6.58 mmol) and the reaction allowed to warm to r.t. Water and EtOAc were added and the layers separated. The organic phase was washed with brine, dried over MgSO^ and concentrated under reduced pressure. The residue was purified by column chromatography (Si0₂; 80-100 % EtO Ac/petrol to 0-10 % MeOH/EtOAc to give (S)-tert-butyl 4-(4-((3-hydroxy-2- oxopyrrolidin-l -yl)methyl)benzylidene)piperidine-l -carboxylate (0.90 g, 71 %). Ή NMR (400 MHz, MeOD) δ 7.17 - 7.28 (m, 4H), 6.41 (s, 1H), 4.32 - 4.54 (m, 3H), 3.48 - 3.56 (m, 2H), 3.37 - 3.46 (m, 2H), 3.18 - 3.29 (m, 2H), 2.32 - 2.50 (m, 5H), 1.79 - 1.92 (m, 1H), 1.43 - 1.53 (m, 9H)

MS (ES⁺) 331

Step c Intermediate 42 tert-butyl 4-(4-{[(3S)-3-methoxy-2-oxopyrrolidin-l -yl]methyl}benzylidene) piperidine- -carboxylate

To a solution of (S)-tert-butyl 4-(4-((3 -hydroxy -2-oxopyrrolidin- 1 - yl)methyl)benzylidene)piperidine-l -carboxylate (Int 41) (904 mg, 2.339 mmol) in DMF (7mL) at 0 °C was added NaH (60% dispersion on oil, 187 mg, 4.68 mmol). The reaction was stirred at this temperature for 1 h. To this suspension was added methyl iodide (0.176 ml, 2.81 mmol) and the reaction allowed to warm slowly to r.t. and stirred overnight. The reaction was cooled to 0°C and quenched with brine and extracted with EtOAc (x 2). The organics were combined and washed with brine (x 5), dried over MgSC>4 and concentrated under reduced pressure to give an orange oil which solidified on standing (~l g). Purification by column chromatography (Si0₂; 80-100 % EtGAc/petrol) gave tert-butyl 4-(4-{[(3S)-3-methoxy-2-oxopyrrolidin-l- yl]methyl}benzylidene)piperidine- l-carboxylate which solidified on standing to give a pale yellow solid (659 mg, 70 %).

Ή NMR (400 MHz, MeOD) δ 7.05 - 7.31 (m, 4 H), 6.41 (s, 1 H), 4.30 - 4.57 (m, 2 H), 3.95 - 4.19 (m, I H), 3.48 - 3.57 (m, 5 H), 3.38 - 3.46 (m, 2 H), 3.29 - 3.37 (m, 1 H), 3.17 - 3.29 (m, 1 H), 2.27 - 2.50 (m, 5 H), 1.82 - 1.97 (m, 1 H), 1.49 (s, 9 H)

MS ES+ 345

Step d Example 49

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-(4- { [(3 S)-3-methoxy-2-oxopyrrolidin- 1 -yl]methyl } benzylidene)piperidine- 1 - carboxylate (Int 42) using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.13 - 7.26 (m, 4H), 6.33 (s, 1H), 4.36 - 4.55 (m, 2H), 4.03 - 4.14 (m, 1H), 3.53 (s, 3H), 3.18 - 3.29 (m, 1 H), 2.74 - 2.88 (m, 1H), 2.31 - 2.56 (m, 10H), 2.04 - 2.14 (m, 2H), 1.85 - 2.01 (m, 3H), 1.68 - 1.82 (m, 2H)

MS (ES⁺) 355 2.50 Example 50

(4R)-l -{4-[(1 -cyclobutylpiperidin'4-ylidene)methyl]benzyl}-4-methoxypyrrolidin-2- one

Step a Intermediate 43

tert-Butyl 4-(4-{[(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-oxopyrrol

oxylate

To a solution of (R)-4-(tert-butyldimethylsiIyloxy)pyrrolidin-2-one (0.71 g, 3.28 mmol) in DMF (5 ml) was added NaHMDS (1 M solution in THF, 4.10 ml, 4.10 mmol) at 0 °C and the reaction stirred at this temperature for 10 min and then allowed to warm to r.t. for 1 h. tert-Butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) (1.0 g, 2.73 mmol) was added at 0 °C and the reaction allowed to warm to r.t. slowly in the ice bath and stirred for 3 h. The reaction was quenched by the careful drop-wise addition of brine at 0 °C and extracted with EtOAc (x 2) and washed combined organics with brine (x 5), dried over MgSC^ and evaporated under reduced pressure to give a brown oil. Purification by column chromatography (Si0₂; 30-70% EtOAc/petrol) gave the tert-buty] 4-(4-{[(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-oxopyrrolidin-l - yl]methyl}benzylidene)piperidine-l-carboxylate as a bright yellow oil which solidified on standing.

Ή NMR (400 MHz, MeOD) δ 7.20 - 7.26 (m, 2 H), 7.13 - 7.20 (m, 2 H), 6.39 (s, 1 H), 4.62 - 4.74 (m, 1 H), 4.43 - 4.54 (m, 1 H), 4.17 - 4.27 (m, 1 H), 3.54 - 3.64 (m, 1 H), 3.44 - 3.54 (m, 2 H), 3.35 - 3.44 (m, 2 H), 3.07 - 3.18 (m, 1 H), 2.69 - 2.83 (m, 1 H), 2.39 - 2.48 (m, 2 H), 2.22 - 2.39 (m, 3 H), 1.47 (s, 10 H), 0.86 (s, 10 H), 0.08 (s, 3 H), 0.02 (s, 3 H)

MS (ES+) 445 Step b Example 50

Prepared in an analogous manner to Example 49 via Scheme 23 starting with tert-butyl 4-(4-{[(4R)-4-{[tert-buty](dirnethyl)silyl]oxy}-2-oxopyrrolidin-l-yl]methyl} benzylidene)piperidine-l-carboxylate (Int 43) and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 6.97 - 7.09 (m, 4H), 6.17 (s, 1H), 4.20 - 4.38 (m, 2H), 3.81 - 3.94 (m, 1H), 3.32 - 3.44 (m, 1H), 3.12 (s, 3H), 2.52 - 2.67 (m, 3H), 2.11 - 2.40 (m, 9H), 1.86 - 1.96 (m, 2H), 1.71 - 1.84 (m, 2H), 1.50 - 1.62 (m, 2H)

MS (ES⁺) 355

2.51 Example 51

-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-l ,4-oxazepan-5-one

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with feri-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate (Int 32) and using 1.4-oxazepan-5-one and via Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.22 - 7.30 (m, 2H), 7.15 - 7.23 (m, 2H), 6.33 (s, 1H), 4.60 (s, 2H), 3.74 - 3.82 (m, 2H), 3.56 - 3.63 (m, 2H), 3.49 - 3.57 (m, 2H), 2.75 - 2.86 (m, 3H), 2.31 - 2.57 (m, 8H), 2.04 - 2.14 (m, 2H), 1.88 - 2.01 (m, 2H), 1.70 - 1.83 (m, 2H)

MS (ES⁺) 355

2.52 Example 52

-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-methylimidazolidin-2-

Step a Intermediate 44 tert-Butyl 4-{4-[(3-methyl-2-oxoimidazolidin-l-yl)methyl]benzylidene}piperidine-l- carboxylate

A suspension of tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine- l-carboxylate (Int 32) (0.25 g, 0.68 mmol), potassium carbonate (0.47 g, 3.41 mmol) and 1 - methylimidazolidin-2-one (68 mg, 0.68 mmol) in acetonitrile (5 ml) was stirred at r.t. overnight. The reaction mixture was then heated to reflux for 24 h. The reaction mixture was quenched with water and partitioned between EtOAc and brine. The organic phase was dried over MgS0₄, concentrated in vacuo and the residue purified by dry flash column chromatography (Si0 ; 10-70 % EtOAc/petrol) to give tert-butyl 4-{4- [(3-methyl-2-oxoimidazolidin- l-yl)methyl]benzyiidene}piperidine- 1-carboxylate as a colourless gum (0.104 g, 40 % yield). Ή NMR (400 MHz, MeOD) 6 7.19 (m, 4 H) 6.39 (s, 1 H) 4.31 (s, 2 H) 3.50 (t, J = 5.56 Hz, 2 H) 3.41 (t, J =5.56 Hz, 2 H) 3.32 - 3.36 (m, 2 H) 3.19 - 3.25 (m, 2 H) 2.80 (s, 3 H) 2.45 (t, J = 5.68 Hz, 2 H) 2.34 (t, J = 5.68 Hz, 2 H) 1.47 (s, 9 H)

MS ES+ 330 Step b Example 52

Prepared in an analogous manner to Intermediate 5 via Scheme 4 stalling with tert- butyl 4-{4-[(3-methyl-2-oxoimidazolidin-l-yl)methyl]benzylidene}piperidine-l - carboxylate (Int 44) and using cyclobutanone in step b. Ή NMR (400 MHz, MeOD) δ 7.23 (d, 2 H), 7.18 (d, 2 H), 6.34 (s, 1 H), 4.34 (s, 2 H), 3.34 - 3.39 (m, 3 H), 3.20 - 3.27 (m, 2 H), 2.81 (s, 3 H), 2.31 - 2.59 (m, 8 H), 2.03 - 2.15 (m, 2 H), 1.96 (t, J =9.47 Hz, 2 H), 1.67 - 1.81 (m, 2 H)

MS (ES⁺) 340 2.53 Example 53

3-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-l,3-oxazolidin-2-one

Prepared in an analogous manner to Example 52 via Scheme 21 starting with tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate (Int 32) and using 1,3- oxazolidin-2-one and via Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO-d₆) δ 7.12 - 7.27 (m, 4 H), 6.26 (s, 1 H), 4.32 (s, 2 H), 4.22 - 4.29 (m, 2 H), 3.37 - 3.45 (m, 2 H), 2.61 - 2.72 (m, 1 H), 2.37 - 2.43 (m, 2 H), 2.26 - 2.35 (m, 4 H), 2.16 - 2.24 (m, 2 H), 1.90 - 2.00 (m, 2 H), 1.71 - 1.84 (m, 2 H), 1.54 - 1.67 (m, 2 H)

MS (ES⁺) 327

2.54 Example 54

-Cyclobutyl-4-{4-[(cyclopentyloxy)methyl]benzylidene}piperidine

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using cyclopentanol and via Scheme 4 using cyclobutanone in step b. Ή NMR (300 MHz, CDC1₃) δ 7.27 (d, J = 8 Hz, 2H), 7.19 (d, J = 8 Hz, 2H), 6.27 (s, 1H), 4.44 (s, 2H), 4.02- 3.97 (m, 1H), 2.72 (quin, J = 7.5 Hz, 1H), 2.54 (t, J = 5.5 Hz, 2H), 2.42 (br. s, 4H), 2.31 (t, J = 5.5 Hz, 2H), 2.09- 1.90 (m, 4H), 1.78- 1.66 (m, 8H), 1.57- 1.48 (m, 2H).

MS (ES⁺) 326

2.55 Example 55

-cyclobutyl-4-{4-[(tetrahydrofuran-3-ylmethoxy)methyl]benzylidene}piperidine

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with tert-buty\ 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using tetrahydrofuran-3-ylmethanol and via Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.17 (d, J = 8.08 Hz, 2 H), 7.08 (d, J = 8.08 Hz, 2 H), 6.23 (s, 1 H), 4.39 (s, 2 H), 3.66 - 3.76 (m, 2 H), 3.55 - 3.65 (m, 1 H), 3.42 - 3.51 (m, 1 H), 3.25 - 3.41 (m, 2 H), 2.63 - 2.81 (m, 1 H), 2.17 - 2.53 (m, 9 H), 1.75 - 2.05 (m, 5 H), 1.45 - 1.71 (m, 3 H)

MS (ES⁺) 342

2.56 Example 56

-cyclobutyl-4-{4-[(cyclopentylmethoxy)methyl]benzylidene}piperidine

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with tert-b tyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using cyclopentylmethanol, and via Scheme 4 using cyclobutanone in step b.

1H NMR (300 MHz, CDC1₃) δ 7.27 (d, J = 8 Hz, 2H), 7.16 (d, J = 8 Hz, 2H), 6.27 (s, 1H), 4.48 (s, 2H), 3.33 (d, J = 7 Hz, 2H), 2.72 (quin, J = 6.5 Hz, 1H), 2.55 (br. s, 2H), 2.42 (br. s, 4H), 2.31 (br. s, 2H), 2.20 (septet, J = 7.5 Hz, 1H), 2.06- 1.88 (m, 4H), 1.79- 1.50 (m, 8H), 1.27- 1.21 (m, 2H).

MS (ES⁺) 340 2.57 Example 57

-cyclobutyl-4-{4-[(tetrahydro-2H-pyran-4-yloxy)methyl]benzylidene}piperidine

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with ferf-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using tetrahydro-2H-pyran-4-ol, and via Scheme 4 using cyclobutanone in step b. Ή NMR (300 MHz, CDC1₃) 6 7.28 (d, J = 8 Hz, 2H), 7.16 (d, J = 8 Hz, 2H), 6.27 (s, 1 H), 4.53 (s, 2H), 3.96 (dt, J = 12 Hz, 4 Hz, 2H), 3.59 (tt, J = 9, 4 Hz, 1 H), 3.43 (ddd, J = 12, 9, 3 Hz, 2H), 2.73 (quin, J = 8 Hz, 1 H), 2.55 (t, J = 5.5 Hz, 2H), 2.43 (s, 4H), 2.32 (t, J = 5.5 Hz, 2H), 2.06- 1.90 (m, 6H), 1 .75- 1.59 (m, 4H).

MS (ES⁺) 342

2.S8 Example S8

l-Cyclobutyl-4-(4-{[(2-methyl-l,3-oxazol-4-yl)methoxy]methyl}benzylidene) piperidine

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with reri-butyl 4-(4-(bromomethyl)benzylidene)piperidine- l -carbox late (Int 32) and using (2-methyl-l ,3-oxazol-4-yl)methanol, and via Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 7.28 (d, 2H), 7.18 (d, 2H), 6.27 (s, 1 H), 4.49 (s, 2H), 4.35 (s, 2H), 2.62-2.74 (m, 1 H), 2.36-2.45 (m, 5H), 2.26-2.35 (m, 4H), 2.17-2.26 (m, 2H), 1.90-2.01 (m, 2H), 1 .72-1.85 (m, 2H), 1.52- 1.68 (m, 2H).

MS (ES⁺) 353

2.59 Example 59

1 -Cyclobuty)-4-(4- { [(5-methyl- 1 ,2-oxazol-3-yl)methoxy]methyl } benzylidene)

Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting with tert-buiyl 4-(4-(bromomethyl)benzy)idene)piperidine- l -carboxylate (Int 32) and using (S-methyl-l ^-oxazol-S-y methanol, and via Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, DMSO) δ 7.29 (d, 2H), 7.18 (d, 2H), 6.28 (s, 2H), 4.53 (s, 2H), 4.50 (s, 2H), 2.61-2.72 (m, IH), 2.36-2.44 (m, 5H), 2.27-2.35 (m, 4H), 2.18-2.25 (m, 2H), 1.86-2.01 (m, 2H), 1 .71-1.86 (m, 2H), 1.52-1.70 (m, 2H).

MS (ES⁺) 353

2.60 Example 60

-({4-[(l-cyclobutylpiperidin-4-ylidene)methyI]benzyl}oxy)pyridine

Prepared in an analogous mariner to Example 37 ( aH) via Scheme 21 starting with tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using pyridin-3-ol, and via Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO) δ 8.36 (d, IH), 8.18 (d, IH), 7.46 (dd, IH), 7.42 (d, 2H), 7.30-7.37 (m, IH), 7.23 (d, 2H), 6.29 (s, IH), 5.16 (s, 2H), 2.60-2.76 (m, IH), 2.38-2.46 (m, 2H), 2.27-2.37 (m, 4H), 2.17-2.27 (m, 2H), 1.89-2.02 (m, 2H), 1.72-1.87 (m, 2H), 1.53-1.68 (m, 2H).

MS (ES⁺) 335

2.61 Example 61

-Cyclobutyl-4-(4-{[(5-methyl-l,2-oxazol-3-yl)oxy]methyl}benzylidene)piperidine

Prepared in an analogous manner to Example 52 ( .₂C0₃ in DMF instead of MeCN) via Scheme 21 starting with tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l - carboxylate (Int 32) and using 5-methyl-l ,2-oxazol-3-ol, and Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, DMSO) δ 7.40 (d, 2H), 7.22 (d, 2H), 6.29 (s, 1H), 6.00 (s, 1H), 5.17 (s, 2H), 2.58-2.77 (m, 1H), 2.37-2.45 (m, 2H), 2.27-2.37 (m, 7H), 2.1 1 -2.27 (m, 2H), 1.90-2.02 (m, 2H), 1.71 -1 .87 (m, 2H), 1.53-1.69 (m, 2H).

MS (ES⁺) 339

2.62 Example 62

1 -cyclobutyl-4-[4-({ [1 -methyl-5-(trifluoromethyl)- 1 H-pyrazol-3- yl]oxy}methyI)benzyIidene]piperidine

Prepared in an analogous manner to Example 40 (Cs₂C0₃ in DMF) via Scheme 21 starting with tert-butyl 4-(4-(bromomethyi)benzylidene)piperidme-l-carboxylate (Int 32) and using l -methyl-5-(trifluoromethyl)-lH-pyrazol-3-ol, and via Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, DMSO) δ 7.38 (d, 2H), 7.21 (d, 2H), 6.42 (s, 1H), 6.28 (s, 1H), 5.14 (s, 2H), 3.81 (s, 3H), 2.62-2.73 (m, 1H), 2.37-2.45 (m, 2H), 2.26-2.37 (m, 4H), 2.17-2.26 (m, 2H), 1.89-2.02 (m, 2H), 1.71- 1.86 (m, 2H), 1.53-1 ,69 (m, 2H).

MS (ES⁺) 406 2.63 Example 63

l-Cyclobutyl-4-[4-({[l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl]oxy}methyl) benzylidene]piperidine

Step a Intermediate 45

tert-butyl 4-[4-( { [ 1 -methyl-3-(trifluoromethy!)- 1 H-pyrazoI-5- yl]oxy}methyl)benzylidene]piperidine-l -carboxylate

To a solution of l -methyl-3-(trifluoromethyl)-l H-pyrazol-5-ol (350 mg, 2.107 mmol) in dry DMF (3 ml) cooled to 0° C under nitrogen was added HMDS (0.5M in toluene, 4.23 ml, 2.12 mmol) and the reaction mixture stirred at 0 °C for 1 h. ieri-Butyl 4-(4- (bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) (500 mg, 1.37 mmol) was added and the reaction mixture stirred at 0°C for 1 h, then at r.t. for 20 h. Water (20 ml) was added and the organics extracted with EtOAc (3 x 20 ml). The combined organics were washed with brine (2 x 15 ml), dried (H frit) and evaporated to dryness. The crude product was purified by column chromatography (Si0₂ ; 0-35 % EtOAc / petrol) to give tert-butyl 4-[4-({[l -methyl-3-(trifluoromethyl)-lH-pyrazol-5- yl]oxy}methyl)benzylidene]piperidine-l-carboxylate (97 mg, 16 %).

Ή NMR (400 MHz, CDC1₃) δ 7.32 - 7.40 (m, 2 H), 7.19 - 7.27 (m, 2 H), 6.37 (s, 1 H), 5.84 (s, 1 H), 5.09 (s, 2 H), 3.70 (s, 3 H), 3.32 - 3.61 (m, 4 H), 2.41 - 2.53 (m, 2 H), 2.28 - 2.41 (m, 2 H), 1.49 (s, 9 H)

MS ES+ 452

Step b Example 63

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting from tert- butyl 4-[4-( { [ 1 -methyl-3-(trifluoromethyl)- 1 H-pyrazol-5-yl]oxy } methyl)benzy tidene] piperidine-l -carboxylate (Int 45) and using cyclobutanone in step b. ^lH NMR (400 MHz, DMSO) δ 7.44 (d, 2H), 7.24 (d, 2H), 6.29 (s, 2H), 5.21 (s, 2H), 3.64 (s, 3H), 2.62-2.73 (m, 1 H), 2.37-2.45 (m, 2H), 2.27-2.36 (m, 4H), 2.18-2.26 (m, 2H), 1.90-2.02 (m, 2H), 1.73-1.86 (m, 2H), 1.51 -1.69 (m, 2H).

MS (ES⁺) 406

2.64 Example 64

3-({4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]benzyl}oxy)-N,N-dimethyl-l,2- oxazole-5-carboxamide

Reagents and conditions: a) LiOH, THF, MeOH, H₂0; b) Me₂NH.HCl, EDC.HCl, HOAt, DIPEA, DCM

Step a Intermediate 46

tert-Butyl 4-[4-({[5-(methoxycarbonyl)-l ,2-oxazol-3-yl]oxy}methyl)benzylidene]

Prepared in an analogous manner to Example 40 (Cs₂C0₃ in DMF) via Scheme 21 starting with /Y-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate (Int 32) and using methyl 3-hydroxy- l,2-oxazole-5-carboxylate.

'H NMR (400 MHz, DMSO-d₆) 8 7.41 - 7.49 (m, 2H), 7.22 - 7.30 (m, 2H), 7.13 (s, 1H), 6.39 (s, 1 H), 5.30 (s, 2H), 3.89 (s, 3H), 3.39 - 3.48 (m, 2H), 3.32 - 3.37 (m_; 2H), 2.35 - 2.44 (m, 2H), 2.25 - 2.33 (m, 2H), 1.42 (s, 9H)

Step b Intermediate 47

3-[(4-{[l-(tert-Butoxycarbonyl)piperidin-4-ylidene]methyl}benzyl)oxy]-l ,2-oxazole-5-

01

A mixture of methyl 3-(4-((l-(tert-butoxycarbonyl)piperidin-4- ylidene)methyl)benzyloxy)isoxazole-5-carboxylate (Int 46) (258 mg, 0.60 mmol) and Li OH (2.0 ml, 4.00 mmol) in THF (1 ml) and MeOH (2 ml) was stirred at r.t. for 5 h. The reaction mixture was evaporated to dryness and 2M HC1 (5 ml) was added. The organics were extracted with DCM (3 x 20 ml), dried (H frit) and evaporated to dryness to give 3-[(4-{[l-(tert-butoxycarbonyl)piperidin-4-ylidene]methyl} benzyl)oxy]-l ,2- oxazole-5-carboxylic acid (246 mg, 99 %).

MS (ES-) 413

Step c Intermediate 48

tert-Butyl 4-[4-({[5-(dimethylcarbamoyl)-l,2-oxazol-3-yl]oxy}methyl)benzylidene] piperidine- 1 -carboxylate

A mixture of 3-(4-((l -(tert-butoxycarbonyl)piperidin-4-ylidene)methyl) benzyloxy)isoxazole-5-carboxylic acid (Int 47) (246 mg, 0.59 mmol), dimethylamine hydrochloride (145 mg, 1.78 mmol), EDC (171 mg, 0.89 mmol) and HOAt (121 mg, 0.89 mmol) in DCM (10 ml) was treated with DIPEA (0.31 ml, 1.78 mmol) and the solution stirred at r.t. for 20 h. Sodium bicarbonate solution (20 ml) was added and extracted with DCM (3 x 20 ml), dried (H frit) and evaporated to dryness. The residue was purified by column chromatography (Si0₂; 0-60 % EtOAc/petrol) to give tert-butyl 4-[4-( { [5 -(dimethylcarbamoyl)- 1 ,2 -oxazol-3 -yl]oxy } methyl)benzylidene] piperidine- 1 - carboxylate (270 mg, quantitative).

MS (ES⁺) 442

Step d Example 64

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting from tert- butyl 4-[4-({[5-(dimethylcarbamoyl)-l,2-oxazol-3-yl]oxy}methyl)benzylidene] piperidine- 1 -carboxylate (Int 48) and using cyclobutanone in step b. Ή NMR (400 MHz, DMSO) δ 7.43 (d, 2H), 7.23 (d, 2H), 6.75 (s, 1H), 6.29 (s, 1H), 5.27 (s, 2H), 3.09 (s, 3H), 2.99 (s, 3H), 2.62-2.74 (m, 1H), 2.37-2.46 (m, 2H), 2.27-2.36 (m, 4H), 2.17-2.27 (m, 2H), 1.89-2.02 (m, 2H), 1.71-1.86 (m, 2H), 1.52-1.69 (m, 2H). MS (ES⁺) 396

2.65 Example 65

-Cyclobutyl-4-[4-(piperidin- 1 -ylmethyl)benzylidene]piperidine

Step a Intermediate 49

(Scheme 21)

ethy l)benzylidene]piperidine- 1 -carboxylate

A mixture of tert-butyl 4-[4-(bromomethyl)benzylidene]piperidine-l -carboxylate (Int 32) (350 mg, 0.96 mmol), piperidine (1 15 μΐ, 1.15 mmol) and potassium carbonate (400 mg, 2.9 mmol) in THF (10 ml) was stirred at r.t. for 72 h. The reaction was diluted with EtOAc and washed with water. The organic phase was washed further with water (x 2) and brine then dried (MgS0 ) and concentrated under reduced pressure to give tert- butyl 4-[4-(piperidin-l-ylmethyl)benzylidene]piperidine-l -carboxylate as a white solid (297 mg, 83 %).

Ή NMR (300 MHz, CDC1₃) δ 7.26 (d, J = 8 Hz, 2H), 7.13 (d, J = 8 Hz, 2H), 6.33 (s, 1H), 3.50 (t, J = 6 Hz, 2H), 3.46 (s, 2H), 3.40 (t, J = 6 Hz, 2H), 2.47 (t, J = 5.5 Hz, 2H), 2.38 (m, 4H), 2.32 (t, J = 5.5 Hz, 2H), 1.62-1.52 (m, 6H), 1.47 (s, 9H)

MS ES⁺ 371

Step b Example 65

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting from tert- butyl 4-[4-(piperidin-l -ylmethyl)benzylidene]piperidine-l -carboxylate (Int 49) and using cyclobutanone in step b. Ή NMR (400 MHz, eOD) δ 7.17 (d, J = 7.83 Hz, 4H), 7.05 (d, J = 8.08 Hz, 4H), 6.22 (s, 1H), 3.38 (s, 2H), 2.67 (quin, J = 7.96 Hz, 1H), 2.1 1 - 2.49 (m, 25H), 1.91 - 2.05 (m, 2H), 1.74 - 1.90 (m, 5H), 1.55 - 1.70 (m, 5H), 1.42 - 1.56 (m, 1 1H), 1.33 - 1.42 (m, 5H) MS ES⁺ 325

2.66 Example 66

- {4-[( 1 -cyclobutylpiperidin-4-yl idene)raethyl]benzyl } morpho 1 ine

Prepared in an analogous manner to Example 65 via Scheme 21 startng with tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate (Int 32) and using morpholine, and Scheme 4 using cyclobutanone in step b.

Ή NMR (300 MHz, CDC1₃) δ 7.25 (d, J = 8 Hz, 2H), 7.14 (d, J = 8 Hz, 2H), 6.26 (s, 1H), 3.70 (t, J = 5 Hz, 4H), 3.47 (s, 2H), 2.71 (quin, J = 8 Hz, 1H), 2.54 (t, J = 5 Hz, 2H), 2.46-2.38 (m, 6H), 2.30 (t, J = 5 Hz, 2H), 2.07- 1.98 (m, 2H), 1.98- 1.88 (m, 2H), 1.74- 1.61 (m, 4H).

MS ES⁺ 327 2.67 Example 67

- {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]benzyl } -4,4-difluoropiperidine

Prepared in an analogous manner to Example 65 via Scheme 21 startng with tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate (Int 32) and using 4,4- difluoropiperidine, and Scheme 4 using cyclobutanone in step b.

Ή NMR (300 MHz, CDC1₃) δ 7.24 (d, J = 8 Hz, 2H), 7.14 (d, J = 8 Hz, 2H), 6.26 (s, 1H), 3.52 (s, 2H), 2.71 (quin, J = 8 Hz, 1H), 2.54 (t, J = 5.5 Hz, 6H), 2.41 (s, 4H), 2.30 (t, J = 5.5 Hz, 2H), 2.05- 1.90 (m, 6H), 1.74- 1.62 (m, 4H).

MS ES⁺ 361 2.68 Example 68

-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]benzyl}-2,6-dimethylrnorpholine

Prepared in an analogous manner to Example 65 via Scheme 21 startng with rert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using 2,6- dimethylmorpholine, and Scheme 4 using cyclobutanone in step b.

Ή NMR (300 MHz, CDC1₃) δ 7.24 (d, J = 8 Hz, 2H), 7.1 (d, J = 8 Hz, 2H), 6.27 (s, 1H), 3.74- 3.64 (m, 2 H), 3.44 (s, 2H), 2.78- 2.69 (m, 1H), 2.70 (d, J = 10.5 Hz, 2H), 2.56 (t, J = 5.5 Hz, 2H), 2.43 (s, 4H), 2.33 (t, J = 5.5 Hz, 2H), 2.06- 1.93 (m, 4H), 1.74 (t, J = 10.5 Hz, 2H), 1.75- 1.64 (m, 2H), 1.13 (d, J = 6 Hz, 6H).

MS ES⁺ 355 2.69 Example 69

l -Cyclobutyl-4-{4-[(4-methoxypiperidin-l -yl)methyl]benzylidene}piperidine

Prepared in an analogous manner to Example 65 via Scheme 21 startng with tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l -carboxylate (Int 32) and using 4- methoxypiperidine, and Scheme 4 using cyclobutanone in step b.

Ή NMR (300 MHz, CDCI3) δ 7.24 (d, J = 8 Hz, 2H), 7.13 (d, J = 8 Hz, 2H), 6.25 (s, 1H), 3.46 (s, 2H), 3.33 (s, 3H), 3.21 (tt, J = 8.5, 5 Hz, 1H), 2.76- 2.66 (m, 3H), 2.53 (t, J = 5.5 Hz, 2H), 2.39 (s, 4H), 2.29 (t, J = 5.5 Hz, 2H), 2.18- 2.09 (m, 2H), 2.08- 1.99 (m, 2H), 1.95- 1.84 (m, 4H), 1.77- 1.59 (m, 4H)

MS ES⁺ 355

2.70 Example 70 N-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]benzyl}-2-methoxy-N- methylethanamine

Prepared in an analogous manner to Example 65 via Scheme 21 staring with tert-butyl 4-(4-(bromomethyl)benzylidene)piperidine-l-carboxylate (Int 32) and using 2- methoxy-N-methylethanamine, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.17 (d, J =7.83 Hz, 2H), 7.05 (d, J =8.08 Hz, 2H), 6.22 (s, 1H), 3.35 - 3.49 (m, 4H), 3.22 (s, 3H), 2.68 (quin, J =7.96 Hz, 1H), 2.50 (t, J =5.68 Hz, 2H), 2.19 - 2.47 (m, 8H), 2.15 (s, 3H), 1.90 - 2.03 (m, 2H), 1 .76 - 1.89 (m, 2H), 1.55 - 1.69 (m, 2H)

MS ES⁺ 329

2.71 Example 71

N-(4-( -ethylpiperidin-4-ylidene)methyl)benzyl)cyclopentanamine dihydrochloride

2HCI

Scheme 25

Reagents and conditions: a) DIBAL, DCM, 0 °C; b)i) cyclopentylamine, AcOH, THF ii) HC1, MeOH

Intermediate 50

-[(l-ethylpiperidin-4-ylidene)rnethyl]benzonitrile

Prepared in an analogous manner to Intermediate 3 via Scheme 3, method B using diethyl (4-cyanobenzyl)phosphonate (CAS: 1552-41-6) and l-ethylpiperidin-4-one. Step a Intermediate 51

-[(l -ethylpiperidin-4-ylidene)methyl]benzaldehyde

To a solution of 4-[(l -ethylpiperidin-4-ylidene)methyl]benzonitrile (Int 50) (6.0 g, 26.5 mmol) in DCM (60 ml) at 0 °C was added DIBAL (21.2 ml, 1.25 M, 26.5 mmol). The reaction was stirred at this temperature for 1 h. Further DIBAL (1 1 ml, 1.25 M, 7.3 mmol) was added and the reaction stirred for 1 h. Saturated aq. sodium potassium tartrate was added and the mixture stirred at r.t. for 1 h. The layers were separated. 10 % aq. HCl was added to the organic phase and the mixture stirred for 1 h. The mixture was then basified by the addition of 2 M NaOH (aq.) and extracted into DCM. The organic phase was dried (Na₂S0₄) and concentrated under reduced pressure. Purification by column chromatography gave 4-[(l-ethylpiperidin-4-ylidene)methyl]benzaldehyde (520 mg, 9 %).

Ή NMR (300 MHz, CDC1₃) δ 9.96 (s, 1H), 7,82 (d, J = 7.2 Hz, 2H), 7.33 (d, J = 7.2 Hz, 2H), 6.32 (s, 1H), 2.57 (m, 4H), 2.47 (m, 6H), 1.12 (t, J = 7.2, Hz, 3H)

Step b Example 71

To a solution of 4-[(l-ethylpiperidin-4-ylidene)methyl]benzaldehyde (Int 51) (416 mg, 1.81 mmol) in THF (5 ml) at r.t. was added cyclopentylamine (0.18 ml, 1.81 mmol) and the reaction stirred for 18 h. The mixture was concentrated under reduced pressure and the residue taken up into MeOH. NaBH (137 mg, 3.63 mmol) and AcOH (2 drops) were added and the reaction stirred at r.t. for 72 h. Saturated aq. NaHC0₃ (10 ml) was added and the mixture extracted with DCM. The organic phase was dried (Na₂S0₄), concentrated under reduced pressure and purified by column chromatography (Si0₂, 1/20 saturated NH₃ in MeOH/DCM) to give N-(4-((l -ethylpiperidin-4- ylidene)methyl)benzyl)cyclopentanamine as a clear oil. This was dissolved in MeOH (5 ml) and a solution of HCl in MeOH (5 ml) was added. The mixture was stirred at r.t. for 2 h then concentrated under reduced pressure to give N-(4-((l-ethylpiperidin-4- ylidene)methyl)benzyl)cyclopentanamine dihydrochloride as a white solid (220 mg, 36 Ή NMR (400 MHz, DMSO-4s) δ 10.68 (br. s., 1 H), 9.22 (br. s., 2 H), 7.45 - 7.57 (m, H), 7.19 - 7.32 (m, 2 H), 6.43 (s, 1 H), 3.95 - 4.1 (m, 2 H), 3.3 1 - 3.62 (m, 3 H), 2.94 3.1 1 (m, 2 H), 2.63 - 2.94 (m, 4 H), 2.46 - 2.62 (m, 2 H), 1.77 - 2.01 (m, 2 H), 1.55 1.77 (m, 4 H), 1.36 - 1.55 (m, 2 H), 1.09 - 1.30 (m, 3 H)

MS ES⁺ 299

2.72 Example 72

-(4-(( 1 -Cyclobutylpiperidin-4-ylidene)methyl)phenyl)ethanol

R_5b represents R₅ cycloalkyl or heterocyclyl, each of which may be optionally substituted, R_2! represents H or C 1 -3 alkyl.

Reagents and conditions: a) n-Butyllithium, THF, -78 °C; or Mg, reflux, THF; b) R_5b=0 or R₅R₂,C=0

Step a Intermediate 52

Bromo{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}magnesium

Into a dry flask fitted with condensor and dropping funnel was added Mg (397 mg, 16.3 mmol) and iodine (2 crystals). A solution of 4-(4-bromobenzylidene)- 1 - cyclobutylpiperidine (5 g, 16.3 mmol) in THF (20 ml) was added dropwise to the magensium and iodine with heating to give a THF solution of bromo{4-[(l - cyclobuty lpiperidin-4-y lidene)methyl]phenyl } magnesium. Step b Example 72

To a solution of acetaldehyde (108 mg, 2.46 mmol) in THF (5 ml) at r.t. was added a THF solution of bromo{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl} magnesium (Int 52) (4.25 ml, 2.05 mmol). The mixture became warm (~ 30 °C). The reaction was stirred for 30 min. The reaction mixture was evaporated, treated with 2 M HC1 (5 ml) and EtOAc (20 ml). The layers were separated and the aqueous layer basified and extracted with EtOAc. The combined organic extracts were dried (Na₂S0₄), concentrated under reduced pressure and purified by column chromatography (Si0₂, 5% MeOH in DCM with 1% NH₄OH) to give l -(4-((l -cyclobutylpiperidin-4- ylidene)methyl)phenyl)ethanoI (132 mg, 24 %).

Ή NMR (300MHz, CDC1₃) δ 7.29 (d, J = 8.26 Hz, 2H), 7.14 (d, J = 8.26 Hz, 2H), 6.23 (s, 1H), 4.85 (q, J = 6.16 Hz, 1H), 2.67 (br s, 1H), 2.66 (quin, J - 7.91 Hz, 1H), 2.45 (t, J = 5.85 Hz, 2H), 2.35 (m, 4H), 2.23 (t, J = 5.85 Hz, 2H), 1.98 (m, 2H), 1.86 (m, 2H), 1.63 (m, 2H), 1.46 (d, J = 6.54 Hz, 3H)

MS ES⁺ 272

2.73 Example 73

-((l -cyclobutylpiperidin-4-ylidene)methyl)phenyl)(cyclopentyl)methanol

Prepared in an analogous manner to Example 72 via Scheme 26 using bromo{4-[(l - cyclobutylpiperidin-4-ylidene)methyl]phenyl} magnesium (Int 52) and cyclopentane carbaldehyde.

Ή NMR (400 MHz, DMSO-d₆) δ 7.21 - 7.30 (m, 2H), 7.07 - 7.17 (m, 2H), 6.25 (s, 1H), 5.00 - 5.07 (m, 1 H), 4.20 - 4.28 (m, 1 H), 2 62 - 2.74 (m, 1H), 2.37 - 2.45 (m, 2H), 2.18 - 2.36 (m, 6H), 2.01 - 2.12 (m, 1 H), 1.89 - 2.00 (m, 2H), 1.72 - 1.86 (m, 2H), 1.35 - 1.70 (m, 8H), 1.23 - 1.33 (m, 1H), 1.11 - 1.22 (m, 1H)

MS ES⁺ 326 2.74 Example 74

-(4-(( 1 -Cyclobutylpiperidin-4-ylidene)methyl)phenyl)-3 -methylbutan- 1 -ol

Prepared in an analogous manner to Example 72 via Scheme 26 starting with bromo{4- [(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl} magnesium (Int 52) and using 3- methylbutana).

Ή NMR (300MHz, CDC1₃) δ 7.29 (d, J = 8.26 Hz, 2H), 7.14 (d, J = 8.26 Hz, 2H), 6.23 (S-, 1H), 4.85 (q, J = 6.16 Hz, 1 H), 2.67 (br s, 1H), 2.66 (quin, J = 7.91 Hz, 1 H), 2.45 (t, J = 5.85 Hz, 2H), 2.35 (m, 4H), 2.23 (t, J = 5.85 Hz, 2H), 1.98 (m, 2H), 1.86 (m, 2H), 1.63 (m, 2H), 1.46 (d, J = 6.54 Hz, 3H)

MS ES+ 314

2.75 Example 75

-(( 1 -Cyclobutylpiperidin-4-ylidene)methyl)phenyl)methanol

To DMF (0.19 ml, 2.45 mmol) under argon was added a solution of bromo{4-[(l- cycIobutylpiperidin-4-ylidene)methyl]phenyl} magnesium (Int 52) (0.674 g, 2.04 mmol) in THF (4.4 ml). The reaction was stirred for 10 min and was then concentrated under reduced pressure. The residue was taken up in MeOH (5 ml) and NaBH₄ (1 16 mg, 3.06 mmol) was added. The reaction was concentrated under reduced pressure and 2 M HCI (aq.) was added. The mixture was basified and EtOAc was added. The mixture was filtered through Celite and the layers separated. The organic phase was dried (Na₂S0₄), concentrated under reduced pressure and purified by column chromatography (Si0₂ ; 5- 10 % MeOH (NH₃) in DCM) to give (4-((l-cyclobutyIpiperidin-4- ylidene)methyl)phenyl)methanol (53 mg, 10 %).

Ή NMR (400 MHz, DMSO-i/₆) δ 7.27 - 7.36 (m, 2H), 7.12 - 7.25 (m, 2H), 6.32 (s, 1H), 5.09 - 5.23 (m, 1H), 4.44 - 4.61 (m, 2H), 2.64 - 2.81 (m, 1H), 2.19 - 2.50 (m, 8H), 1.94 - 2.09 (m, 2H), 1.75 - 1.94 (m, 2H), 1.54 - 1.75 (m, 2H)

MS ES⁺ 258

2.76 Example 76

2-(4-(( 1 -cyclobuty lpiperidin-4-y lidene)methyl)phenyl)propan-2-ol

Prepared in an analogous manner to Example 72 via Scheme 26 starting with bromo{4- [(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}magnesium (Int 52) and using acetone.

Ή NMR (400 MHz, MeOD) δ 7.39 - 7.48 (m, 2H), 7.1 1 - 7.19 (m, 2H), 6.33 (s, 1H), 2.73 - 2.86 (m, 1H), 2.31 - 2.61 (m, 8H), 2.04 - 2.15 (m, 2H), 1.87 - 2.02 (m, 2H), 1.67 - 1.83 (m, 2H), 1.46 - 1.60 (m, 6H)

MS ES⁺ 286

2.77 Example 77

-(4-((l -Cyclobuty lpiperidin-4-ylidene)methyl)phenyl)-2-methylpropan-l -ol

Prepared in an analogous manner to Example 72 via Scheme 26 starting with bromo{4- [(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}magnesium (Int 52) and using 2- methylpropanal.

Ή NMR (400 MHz, DMSO-c¾ δ 7.17 - 7.26 (m, 2H), 7.08 - 7.16 (m, 2H), 6.19 - 6.27 (m, 1H), 4.97 - 5.06 (m, 1H), 4.15 - 4.25 (m, 1H), 2.61 - 2.73 (m, 1H), 2.36 - 2.46 (m, 2H), 2.25 - 2.36 (m, 4H), 2.16 - 2.25 (m, 2H), 1.89 - 2.02 (m, 2H), 1.70 - 1.86 (m, 3H), 1.52 - 1.68 (m, 2H), 0.81 - 0.91 (m, 3H), 0.73 (m, 3H)

MS ES⁺ 300 2.78 Example 78

-Chloro-4-((l -cyclobutylpiperidin-4-ylidene)methyl)phenyl)(cyclopentyl)methanol

Prepared in an analogous manner to Example 72 via Scheme 26 starting with 4-(4- bromo-2-chlorpbenzylidene)-l -cyclobutylpiperidine in step a and using cyclopentanecarbaldehyde in step b.

Ή NMR (400 MHz, DMSO-4 S 7.37 (s, 1H), 7.13 - 7.28 (m, 2H), 6.23 (s, 1H), 5.24 (m, 1H), 4.24 - 4.32 (m, 1 H), 2.63 - 2.76 (m, 1H), 2.18 . 2.40 (m, 7H), 1.92 (m, 3H), 1.73 - 1.87 (m, 2H), 1.36 - 1.68 (m, 8H), 1.15 - 1.36 (m, 3H) - MS ES⁺ 360

2.79 Example 79

-(4-((l-Cyclobutylpiperidin-4-ylidene)methyl)phenyl)-2-cyclopentylethanol

Prepared in an analogous manner to Example 72 via Scheme 26 starting with bromo{4- [(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}magnesium (Int 52) and using cyclopentylacetaldehyde.

Ή NMR (300MHz, CDC1₃) δ 7.27 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.24 (s, 1H), 4.65 (t, J = 5.5 Hz, 1H), 2.67 (m, 1H), 2.49 (m, 2H), 2.40 (m, 6H), 2.27 (m, 2H), 1.99-1.40 (m, 16H)

MS ES⁺ 340

2.8Q Example 80

1 -(4-((l -Cyclobutylpiperidin-4-ylidene)methyl)phenyl)-2-cyclopropylethanol

Prepared in an analogous manner to Example 72 via Scheme 26 starting with bromo{4- [(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl} magnesium (Int 52) and using cyclopropylacetaldehyde.

Ή NMR (400 MHz, DMSO-i¾ δ 7.24 - 7.31 (m, 2H), 7.10 - 7.17 (m, 2H), 6.27 (br. s., 1H), 5.06 - 5.12 (m, 1H), 4.51 - 4.58 (m, 1H), 3.32 (s, 1H), 2.68 (br. s, 1H), 2.41 (br. s., 2H), 2.31 (br. s., 4H), 2.19 - 2.27 (m, 1H), 1.97 (br. s., 2H), 1.72 - 1.89 (m, 2H), 1.55 - 1.70 (m, 3H), 1.27 - 1.37 (m, 1H), 0.63 - 0.75 (m, 1H), 0.28 - 0.43 (m, 2H), -0.07 - 0.08 (m, 2H)

MS ES⁺ 312

2.81 Example 81

Reagents and conditions: a) Ac₂0, DMAP, pyridine; b) TFA, DCM

Step a Intermediate 53

ieri-Buty I 4-{4-[cyclopentyl(hydroxy)methyl]benzylidene}piperidine- 1 -carboxylate

To a solution of tert-butyl 4-(4-bromobenzylidene)piperidine- l-carboxylate (Int 3) (5 g,

14.2 mmol) in THF (200 ml) at -78 °C was added n-BuLi (9.3 ml, 2.3 M in hexanes,

21.3 mmol) and the reaction stirred at this temperature for 10 min. A solution of cyclopentanecarbaldehyde (1.7 g, 17 mmol) in THF (10 ml) was added and the reaction stirred for 3 h whilst allowing to warm to r.t. The reaction was quenched via the addition of 20 % aq. citric acid and extracted twice with EtOAc. The combined organic extracts were dried (MgS0₄), concentrated under reduced pressure and purified by column chromatography (Si0₂; 5/1 hexane/EtOAc) to give tert-butyl 4-{4- [cyclopentyl(hydroxy)methyl]benzylidene}piperidine-l -carboxylate as a clear oil (3.78 g, 59 %).

Ή NMR (300MHz, CDC ) δ 7.29 (d, 2H), 7.15 (d, 2H), 6.33 (s, 1H), 4.39 (d, 1H), 3.50 (t, 2H), 3.40 (t, 2H), 2.48 (t, 2H), 2.32 (t, 2H), 2.20 (m, 1H), 1.90 (m, 2H), 1.60-1.40 (m, 16H).

MS ES⁺ 339

Step b Intermediate 54

tert-Butyl 4-{4-[(acetyloxy)(cyclopentyl)methyl]benzylidene}piperidine-l-carboxylate

To a solution of tert-butyl 4-{4-[cyclopentyl(hydroxy)methyl]benzylidene}piperidine-l- carboxylate (Int 53) (500 mg, 1.35 mmol) in pyridine (7 ml) at r.t. was added acetic anhydride (0.14 ml, 1.48 ml) and DMAP (2 mg, cat.). The reaction was stirred at r.t. for 3 h and was then concentrated under reduced pressure. The residue was taken up in EtOAc, washed with water (x 3), dried (MgSC ) and concentrated under reduced pressure to give tert-butyl 4-{4-[(acetyloxy)(cyclopentyl)methyl]benzylidene} piperidine-l -carboxylate (535 mg, 96 %).

Ή NMR (300MHz, CDC1₃) 5 7.27 (d, 2H), 7.13 (d, 2H), 6.31 (s, 1H), 5.51 (d, 1H), 3.49 (t, 4H), 3.39 (t, 4H), 2.45 (t, 4H), 2.32 (t, 4H), 2.05 (s, 3H), 1.8 (m, 1H), 1.57 (m, 8H), 1.46 (s, 9H).

I l l MS ES⁺ 354

Step c Intermediate 55

Cyclopentyl[4-(piperidin-4-ylidenemethyl)phenyl]methanol

To a solution of (ert-butyl 4-{4-[(acetyloxy)(cyclopentyl)methyl] benzylidene}piperidine- l-carboxylate (Int 55) (535 mg, 1.30 ramol) in DCM (10 ml) was added TFA (2 ml) and the reaction stirred at r.t. for 1.5 h. The reaction was quenched via the addition of aq. Na₂C0₃ and the layers were separated. The organic phase was dried (MgS0₄) and concentrated under reduced pressure. The residue was taken up in MeOH (2 ml) and 1 M NaOH (aq., 2 ml) and the reaction stirred at r.t. for 1 h. The solvent was removed under reduced pressure and the resultant residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organics dried (MgS0₄) and concentrated under reduced pressure to give cyclopentyl[4-(piperidin-4-ylidenemethyl)phenyl]methanol as a yellow solid (256 mg, 73 %).

'H MR (300MHz, CDC ) δ 7.28 (d, 2H), 7.16. (d, 2H), 6.26 (s, 1 H), 4.38 (d, 1H), 2.95 (t, 2H), 2.83 (t, 2H), 2.45 (t, 2H), 2.32 (t, 2H), 2.22 (m, 1H).

MS ES⁺ 272

Step d Example 81

Prepared in an analogous manner to Intermediate 5 via step b of Scheme 4 starting with cyclopentyl[4-(piperidin-4-ylidenemethyl)phenyl]methanol (Int 55) and using isobutyraldehyde.

Ή NMR (300MHz, CDCI₃) 67.29 (d, 2H), 7.14 (d, 2H), 6.34 (d, 1H), 4.38 (d, 1H), 2.4 - 2.84 (m, 4H), 2.19 (m, 1H), 1.88 (m, 7H), 1.4 - 1.68 (m, 6H), 1.02 - 1.25 (m, 8H) MS ES⁺ 328 2.82 Example 82

Cyclopentyl(4-((l -ethylpiperidin-4-ylidene)methyl)phenyl)methanol

Prepared in an analogous manner to Intermediate 5 via step b of Scheme 4 starting with cyclopentyl[4-(piperidin-4-ylidenemethyl)phenyl]methanol (Int 55) and using acetaldehyde.

' H NMR (300MHZ, CDCI3) 57.28 (d, 2H), 7.16 (d, 2H), 6.26 (s, 1 H), 4.38 (d, 1H), 2.53 (m, 4H), 2.42 (m, 6H), 2.22 (m, 1 H), 1.88 (m, 2H), 1 .37 - 1.7 (m, 6H), 1 .10 (t, 3H) MS ES⁺ 300

2.83 Example 83

Cyclopentyl(4-((l-(cyclopropylmethyl)piperidin-4-ylidene)methyl)phenyl)methanol

Prepared in an analogous manner to Intermediate 5 via step b of Scheme 4 starting with cyclopentyl[4-(piperidin-4-ylidenemethyl)phenyl]methanol (Int 55) and using cyclopropanecarbaldehyde.

^LH NMR (300MHz, CDC1₃) δ 7.28 (d, 2H), 7.17 (d, 2H), 6.26 (s, 1H), 4.38 (d, 1H), 2.40-2.64 (m, 8H), 2.17-2.29 (m, 3H), 1.91 (s, 2H), 1.37- 1.70 (m, 6H), 0.89 (m, 1H), 0.51 (q, 2H), 0.4 (q, 2H)

MS ES⁺ 326

2.84 Example 84

-(4-((l -Cyclobutylpiperidin-4-ylidene)methyl)phenyl)cyclopentanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using cyclopentanone. (BuLi method).

Ή NMR (300MHz, CDC1₃) 67.44 (d, 2H), 7.17 (d, 2H), 6.30 (s, 1H), 2.68 (m, 1H), 2.58 (m, 2H), 2.38 (s, 4H), 2.28 (m, 2H), 1.6-2.1 (m, 14H)

MS ES⁺ 312

2.85 Example 85

1 - {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]pheny 1 } cyclohexanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using cyclohexanone. (BuLi method).

Ή NMR (400 MHz, MeOD) δ 7.29 - 7.37 (m, 2H), 7.00 - 7.07 (m, 2H), 6.22 (s, 1H), 2.60 - 2.79 (m, 1H), 2.14 - 2.54 (m, 9H), 1.90 - 2.06 (m, 2H), 1.77 - 1.91 (m, 2H), 1.55 - 1.77 (m, 9H), 1.37 - 1.55 (m, 2H)

MS ES⁺ 326

2.86 Example 86

-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydrofuran-3-ol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using dihydrofuran-3(2H)-one. (BuLi method).

Ή NMR (400MHz, CDC1₃) 57.43 (d, J = 8Hz, 2H), 7.21 (d, J = 8 Hz, 2H), 6.26 (s, 1H), 4.19 (m, 2H), 3.97 (dd, J = 9.1, 1.4 Hz, 1H), 3.90 (d, J = 9.6 Hz, 1H), 2.70 (m, 1H), 1.50-2.50 (m, 16H) MS ES⁺ 314 2.87 Example 87

-{4-[(l-Cyclobuiylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol

Prepared in an analogous maimer to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using tetrahydro-4H-pyran-4- one. (BuLi method). Ή NMR (400 MHz, DMSO-cfc) δ 7.34 - 7.51 (m, 2H), 7.08 - 7.25 (m, 2H), 6.25 (s, 1H), 4.97 (br. s., 1H), 3.59 - 3.89 (m, 4H), 2.58 - 2.78 (m, 1H), 2.37 - 2.46 (m, 2H), 2.13 - 2.38 (m, 6H), 1.87 - 2.04 (m, 4H), 1.71 - 1.87 (m, 2H), 1.44 - 1.70 (m, 4H)

MS ES⁺ 328 2,88 Example 88

l-(4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-hydroxypiperidin-l- yl)ethanone

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using 1 -acetylpiperidine-4-one. (BuLi method).

Ή NMR (400 MHz, DMSO-<¾ δ 7.34 - 7.51 (m, 2H), 7.07 - 7.28 (m, 2H), 6.26 (br. s., 1 H), 5.07 (br. s., 1H), 4.21 - 4.39 (m, 1 H), 3.58 - 3.78 (m, 1H), 3.37 - 3.53 (m, 1H), 2.81 - 2.99 (m, 1H), 2.57 - 2.79 (m, 1 H), 2.37 - 2.47 (m, 2H), 2.26 - 2.38 (m, 4H), 2.14 - 2.27 (m, 2H), 2.03 (s, 3H), 1.93 - 1.99 (m, 2H), 1.54 - 1.93 (m, 8H)

MS ES⁺ 369 2.89 Example 89

N-(4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-

Prepared in an analogous manner to Intermediate 53 via Scheme 26 stalling with 4-(4- bromobenzylidene)- l-cyclobutylpiperidine (Int 5) and using N-(4- oxocycIohexyl)acetamide. (BuLi method). A mixture of ring isomers was obtained.

Ή NMR (400 MHz, MeOD) δ 7.40 - 7.57 (m, 2H), 7.1 1 - 7.25 (m, 2H), 6.34 (s, 1H), 3.64 - 4.05 (m, 1H), 2.74 - 2.90 (m, 1H), 2.32 - 2.62 (m, 8H), 2.01 - 2.33 (m, 3H), 1.88 - 2.02 (m, 8H), 1.66 - 1.88 (m, 8H)

MS ES⁺ 383

2.90 Example 90

Ethyl 4-{4-[(l-cyclobutylpiperidin-4-yiidene)methyl]ph< hydroxycyclohexanecarboxylate

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cycIobutyIpiperidine (Int 5) and using ethyl 4- oxocyclohexanecarboxylate. (BuLi method). A mixture of ring isomers was obtained.

Ή NMR (400 MHz, CDCb) δ 7.39 - 7.51 (m, 2H), 7.15 - 7.26 (m, 2H), 6.28 (s, 1H), 4.10 - 4.26 (m, 2H), 2.60 - 2.84 (m, 1H), 2.48 - 2.61 (m, 2H), 2.15 - 2.48 (m, 7H), 1.80 - 2.13 (m, 1 1H), 1.57 - 1.80 (m, 3H), 1.22 - 1.38 (m, 3H)

MS ES⁺ 398

2.91 Example 91

l-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methoxycyclohexanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylptperidine (Int 5) and using 4-methoxycyclohexanone. (BuLi method). One ring isomer was isolated.

Ή NMR (400 MHz, CDC1₃) δ 7.45 (d, J = 8.08 Hz, 2H), 7.21 (d, J = 8.08 Hz, 2H), 6.28 (s, 1 H), 3.42 (s, 3H), 3.21 - 3.33 (m, 1 H), 2.65 - 2.79 (m, IH), 2.50 - 2.62 (m, 2H), 2.35 - 2.47 (m, 4H), 2.24 - 2.35 (m, 2H), 1.52 - 2.14 (m, 15H)

MS ES⁺ 357

2.92 Example 92

4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-l -(pyrimidin-2-yl)piperidin-4-

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)- l-cyclobutylpiperidine (Int 5) and using l-(pyrimidin-2- yl)piperidin-4-one. (BuLi method).

Ή NMR (400 MHz, DMSO-t¾ δ 8.35 (d, J = 4.55 Hz, 2H), 7.42 (d, J = 8.34 Hz, 2H), 7.14 (d, J = 8.34 Hz, 2H), 6.58 (t, J = 4.67 Hz, 1H), 6.24 (s, 1H), 5.09 (br. s., 1H), 4.48 - 4.65 (m, 2H), 3.16 - 3.39 (m, 2H), 2.60 - 2.76 (m, 1H), 2.36 - 2.45 (m, 2H), 2.24 - 2.37 (m, 4H), 2.13 - 2.25 (m, 2H), 1.90 - 2.04 (m, 2H), 1.72 - 1.90 (m, 4H), 1.52 - 1.72 (m, 4H)

MS ES⁺ 405

2.93 Example 93 1 -{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-

(hydroxymethyl)cyclohexanol

Scheme 28

Reagents and conditions: a) UAIH4, THF, 0 °C to r.t.

To a stirred solution of ethyl 4-(4-(( l -cyclobutylpiperidin-4-ylidene)methyl)phenyl)-4- hydroxycyclohexanecarboxylate (Ex 90) (81 mg, 0.204 mmol) in dry THF (10 ml) at 0 °C under an atmosphere of nitrogen was added dropwise L1AIH4 ( 1M in THF, 407 μΐ,, 0.407 mmol). The reaction was stirred at 0 °C for 30 minutes, then allowed to warm to room temperature and stirred for I h. The reaction mixture was quenched with water ( 10 ml). The organics were extracted using EtOAc (2 x 50 ml). The combined organics were washed with brine (25 ml), dried over M SO^ filtered and concentrated to give a colourless oil. Purification via column chromatography (NH silica, 0-100 % EtOAc in petrol) afforded ] -{4-[( l -cyclobutylpiperidin-4- ylidene)methyl]phen l }-4-(hydroxymethyl)cyclohexanol as a white solid (39 mg, 51 %).

Ή NMR (400 MHz, DMSO-i¾) δ 7.33 - 7.52 (m, 2H), 7.03 - 7.21 (m, 2H), 6.24 (s, 1H), 4.53 - 4.73 (m, 1 H), 4.27 - 4.46 (m, 1 H), 3.21 - 3.28 (m, 2H), 2.60 - 2.75 (m, 1 H), 2.36 - 2.46 (m, 2H), 2.25 - 2.36 (m, 4H), 2.16 - 2.27 (m, 2H), 1.73 - 2.10 (m, 5H), 1.13 - 1.73 (m, 10H)

MS ES⁺ 356 2.94 Example 94

1 -[4-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4- hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl]ethanone

Reagents and conditions: a) AcCl, Na₂C0₃ (aq.), DCM Step a Intermediate 56

2-Acetylhexahydrocyclopenta[c]pyrrol-4(lH)-one

To a solution of hexahydrocyclopenta[c]pyrrol-4(5H)-one hydrochloride (2.9 g, 17.8 mmol) in sodium carbonate (aq.) (35.5 ml, 71.0 mmol) at 0 °C under an atmosphere of nitrogen was added dropwise a solution of acetyl chloride (1.22 ml, 17.8 mmol) in dry DCM (36 ml). The reaction was then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was separated and the organic layer was washed with brine (50 ml), dried over MgSO^ and concentrated to give an orange oil (1.83 g, 62 %).

Ή NMR (400 MHz, CDC1₃) δ 3.56 - 3.87 (m, 3H), 3.18 - 3.27 (m, 1H), 3.01 - 3.17 (m, 1H), 2.75 - 2.86 (m, 1H), 2.30 - 2.48 (m, 2H), 2.13 - 2.30 (m, 1H), 2.01 - 2.07 (m, 3H), 1.79 - 1.96 (m, 1H)

Step b Example 94

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclpbutylpiperidine (Int 5) and using 2- acetylhexahydrocyclopenta[c]pyrro 1-4(1 H)-one (Int 56). (BuLi method). ^' Ή NMR (400 MHz, CDC1₃) δ 7.34 - 7.47 (m, 2H), 7.17 - 7.27 (m, 2H), 6.17 - 6.37 (m, . 1H), 3.68 - 3.88 (m, 2H), 3.28 - 3.60 (m, 2H), 2.86 - 3.16 (m, 2H), 2.64 - 2.82 (m, 1 H), 2.48 - 2.61 (m, 2H), 2.37 - 2.49 (m, 4H), 2.27 - 2.39 (m, 2H), 2.1 1 - 2.26 (m, 2H), 2.01 - 2.12 (m, 6H), 1.80 - 2.00 (m, 3H), 1.64 - 1.79 (m, 2H)

MS ES⁺ 395

2.95 Example 95

l -{4-[(l-Cyclobutylpiperidin-4-ylidene)methy]]phenyl}-4-(3-methyl-l ,2,4-oxadiazol-5-

Reagents and conditions: a) Acetamidoxime, NaH, THF

Prepared in an analogous manner to Example 10 starting with ethyl 4-{4-[(l- cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-hydroxycyclohexanecarboxylate

(Example 90). Ή NMR (400 MHz, CDC1₃) δ 7.37 - 7.53 (m, 2H), 7.14 - 7.25 (m, 2H), 6.19 - 6.35 (m, 1H), 2.90 - 3.37 (m, lH), 2.64 - 2.84 (m, 1H), 2.49 - 2.63 (m, 2H), 2.37 - 2.51 (m, 6H), 2.16 - 2.38 (m, 5H), 1.88 - 2.16 (m, 7H), 1.78 - 1.88 (m, 1H), 1.57 - 1.78 (m, 5H) MS ES⁺ 408

2.96 Example 96

1 -(4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-hydroxyazepan- 1 - y])ethanone

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-] -cyclobutylpiperidine (Int 5) and using l-acetylazepan-4-one (CAS 50492-23-4).

Ή NMR (400 MHz, CDC1₃) δ 7.35 - 7.45 (m, 2H), 7.16 - 7.24 (m, 2H), 6.23 - 6.34 (m, 1H), 3.85 - 4.21 (m, 1H), 3.48 - 3.74 (m, 2H), 3.25 - 3.47 (m, 1H), 2.65 - 2.81 (m, 1H), 2.48 - 2.62 (m, 2H), 2.37 - 2.47 (m, 4H), 2.26 - 2.35 (m, 2H), 2.12 - 2.18 (m, 3H), 1.80 - 2.13 (m, 9H), 1.47 - 1.78 (m, 4H)

MS ES⁺ 383

2.97 Example 97

1 -(3 - { 4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } -3 -hydroxy-8- azabicyclo[3.2.1]oct-8-yl)ethanone

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 8-acetyl-8- azabicyclo[3.2.1]octan-3-one (CAS 56880-02-5). Ή NMR (400 MHz, CDC1₃) δ 7.31 - 7.40 (m, 2H), 7.14 - 7.23 (m, 2H), 6.18 - 6.33 (m, 1H), 4.80 - 4.89 (m, 1H), 4.19 - 4.31 (m, 1H), 2.66 - 2.80 (m, 1H), 2.49 - 2.58 (m, 3H), 2.36 - 2.48 (m, 5H), 2.26 - 2.38 (m, 3H), 2.15 - 2.26 (m, 1H), 2.13 (s, 3H), 2.00 - 2.10 (m, 4H), 1.84 - 1.99 (m, 4H), 1.63 - 1.81 (m, 2H), 1.56 - 1.62 (m, 1H)

MS ES⁺ 395

2.98 Example 98 Ethyl 3-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}-3- hydroxycyclobutanecarboxylate

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using ethyl 3- oxocyclobutanecarboxylate (CAS 87121-89-9). A mixture of ring isomers was obtained.

Ή NMR (400 MHz, MeOD) δ 7.35 - 7.42 (m, 2H), 7.06 - 7.16 (m, 2H), 6.20 - 6.30 (m, 1H), 3.98 - 4.1 1 (m, 2H), 2.61 - 2.82 (m, 4H), 2.21 - 2.58 (m, 10H), 1.94 - 2.06 (m, 2H), 1.77 - 1.94 (m, 2H), 1.56 - 1.71 (m, 2H), 1.16 (m, 3H)

MS ES⁺ 370

2.99 Example 99

{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}(tetrahydro-2H-pyran-4- yl)methanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using tetrahydro-2H-pyran-4- carbaldehyde.

Ή NMR (400 MHz, MeOD) δ 7.27 (s, 2H), 7.19 (s, 2H), 6.29 - 6.38 (m, 1H), 4.24 - 4.35 (m, 1H), 3.93 - 4.06 (m, 1H), 3.81 - 3.94 (m, 1H), 3.36 - 3.44 (m, 1H), 3.34 - 3.36 (m, 1H), 2.71 - 2.85 (m, 1H), 2.49 - 2.56 (m, 2H), 2.39 - 2.50 (m, 4H), 2.30 - 2.39 (m, 2H), 2.03 - 2.15 (m, 2H), 1.78 - 2.02 (m, 4H), 1.67 - 1.78 (m, 2H), 1.25 - 1.48 (m, 2H), 1.13 - 1.24 (m, 1H)

MS ES⁺ 342 2.100 Example 100

4- {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } -4-hydroxy-N,N- dimethylcyclohexanecarboxamide

Scheme 31

Reagents and conditions: a) Me₂NH.HCl, EDC, HOAt, DIPEA, DCM

Step a Intermediate 57

-dimethyl-4-oxocyclohexanecarboxamide

To a stirred solution of 4-oxocyclohexanecarboxylic acid (1 g, 7.03 mmol) in dry DCM (24 ml) was added dimethylamine hydrochloride (1.72 g, 21.1 mmol), HOAt (1.436 g, 10.6 mmol), EDC (2.02 g, 10.6 mmol) and DIPEA (3.69 ml, 21.1 mmol). The solution was stirred at r.t. for 17 h. The reaction mxiture was partitioned between DCM (50 ml) and water (25 ml). The organics were further extracted with DCM (50 ml) and the combined organics washed with brine (25 ml), dried (MgS0₄) and concentrated under reduced pressure. The crude material was purified by SCX ion-exchange chromatography, eiuting with MeOH and concentrated under reduced pressure to give a colourless oil. The crude oil was further purified by column chromatography (Si0₂, 0- 100% EtOAc in petrol then 0-15% MeOH in EtOAc) to give N,N-dimethyl-4- oxocyclohexanecarboxamide as a colourless oil (0.693 g, 55%).

Ή NMR (400 MHz, CDC1₃) δ ppm 3.14 (s, 3H), 3.00 (s, 3H), 2.92 - 2.98 (m, 1H), 2.53

- 2.63 (m, 2H), 2.30 - 2.45 (m, 2H), 2.01 - 2.15 (m, 4H) Step b Example 100

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using N,N-dimethyl-4- oxocyclohexanecarboxamide (Int 57)

Ή NMR (400 MHz, CDC1₃) δ 7.40 - 7.53 (m, 2H), 7.12 - 7.25 (m, 2H), 6.15 - 6.34 (m, 1H), 3.1 1 (s, 3H), 2.99 (s, 3H), 2.66 - 2.78 (m, 1H), 2.50 - 2.66 (m, 3H), 2.37 - 2.47 (m, 4H), 2.25 - 2.36 (m, 2H), 2.00 - 2.19 (m, 4H), 1.82 - 2.00 (m, 6H), 1.63 - 1.81 (m, 5H) MS ES⁺ 398

2.101 Example 101

1 - { 4-[( 1 -cyclobutyIpiperidin-4-y lidene)methyl]pheny 1 } - 1 -( 1 -methyl- 1 H-pyrazol-4- yl)ethanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using 1-(1 -methyl- lH-pyrazol-4- yl)ethanone.

Ή NMR (400 MHz, CDCI₃) δ 7.37 - 7.47 (m, 3H), 7.15 - 7.26 (m, 3H), 6.20 - 6.36 (m, lH), 3.87 (s, 3H), 2.65 - 2.79 (m, 1H), 2.48 - 2.63 (m, 2H), 2.36 - 2.48 (m, 4H), 2.25 - 2.36 (m, 2H), 2.01 - 2.16 (m, 3H), 1.86 - 2.00 (m, 5H), 1.55 - 1.85 (m, 2H)

MS ES⁺ 352

2.102 and 2.103 Examples 102 and 103

4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-2,6-dimethyltetrahydro-2H- pyran-4-ol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using 2,6-dimethyltetrahydro- 4H-pyran-4-one. Two isomers were isolated, isomer A and isomer B: ISOMER A

Ή NMR (400 MHz, CDC1₃) δ 7.36 - 7.50 (m, 2H), 7.15 - 7.26 (m, 2H), 6.21 - 6.32 (m, 1H), 3.38 - 3.58 (m, 2H), 2.63 - 2.80 (m, 1H), 2.50 - 2.60 (m, 2H), 2.37 - 2.50 (m, 6H), 2.25 - 2.36 (m, 2H), 2.01 - 2.13 (m, 2H), 1.85 - 2.01 (m, 2H), 1.53 - 1.85 (m, 5H), 1.16 - 1.33 (m, 6H)

MS ES⁺ 357

ISOMER B Ή NMR (400 MHz, CDC1₃) δ?7.38 - 7.51 (m, 2H), 7.17 - 7.25 (m, 2H), 6.15 - 6.34 (m, 1H), 3.96 - 4.1 1 (m, 2H), 2.66 - 2.82 (m, 1H), 2.48 - 2.63 (m, 2H), 2.36 - 2.48 (m, 4H), 2.22 - 2.36 (m, 2H), 2.00 - 2.14 (m, 2H), 1.84 - 2.00 (in, 2H), 1.63 - 1.81 (m, 5H), 1.48 - 1.63 (m, 2H), 1.18 - 1.33 (m, 6H)

MS ES⁺ 357

■

2.104 Example 104

4-{3-Chloro-4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran- -ol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromo-2-chlorobenzylidene)-l -cyclobutylpiperidine (Int 8) and using tetrahydro-4H- pyran-4-one.

Ή NMR (400 MHz, MeOD) δ 7.55 (d, J =1.52 Hz, 1H), 7.39 (dd, J =8.08, 1.52 Hz, 1 H), 7.22 (d, J =8.08 Hz, 1H), 6.33 (s, 1H), 3.89 - 4.01 (m, 2H), 3.77 - 3.88 (m, 2H), 2.67 - 2.98 (m, 1H), 2.44 - 2.63 (m, 4H), 2.29 - 2.44 (m, 4H), 2.04 - 2.19 (m, 4H), 1.88 - 2.04 (m, 2H), 1.70 - 1.83 (m, 2H), 1.59 - 1.68 (m, 2H)

MS ES⁺ 363 2.105 Example 105

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methoxy-4- methy lcyclohexano 1

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 4-methoxy-4- methylcyclohexanone (CAS 23438- 15-5).

Ή NMR (400 MHz, CDC1₃) 6 7.42 - 7.53 (m, 2H), 7.13 - 7.25 (m, 2H), 6.19 - 6.32 (m, 1H), 3.30 (s, 3H), 2.64 - 2.79 (m, 1H), 2.50 - 2.60 (m, 2H), 2.37 - 2.46 (m, 4H), 2.27 - 2.37 (m, 2H), 1.85 - 2.12 (m, 10H), 1.62 - 1.82 (m, 2H), 1.47 - 1.62 (m, 5H)

MS ES⁺ 370

2.106 Example 106

-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methylcyclohexane-l ,4-diol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4 bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 4-hydroxy-4 methy lcyclohexanone . Ή NMR (400 MHz, CDC1₃) δ 7.30 - 7.42 (m, 2H), 7.09 - 7.16 (m, 2H), 6.06 - 6.24 (m, 1H), 2.55 - 2.74 (m, 1H), 2.40 - 2.53 (m, 2H), 2.27 - 2.38 (m, 4H), 2.16 - 2.27 (m, 2H), 1.74 - 2.06 (m, 10H), 1.40 - 1.74 (m, 8H), 1.24 - 1.34 (m, 1H)

MS ES⁺ 356 2.107 and 2.108 Examples 107 and 108

l -{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4- (methoxymethyl)cyclohexanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)- l-cyclobutylpiperidine (Int 5) and using 4- (methoxymethyl)cyclohexanone (CAS 17159-84-1). Two isomers were separated, Isomer A and Isomer B: ISOMER A

Ή NMR (400 MHz, DMSO-<¾) δ 7.32 - 7.50 (m, 2H), 7.05 - 7.26 (m, 2H), 6.05 - 6.31 (m, 1H), 4.70 (s, 1H), 3.31 (s, 3H), 3.26 (d, J= 6.32 Hz, 2H), 2.61 - 2.77 (m, 1H), 2.37 - 2.46 (m, 2H), 2.25 - 2.36 (m, 4H), 2.14 - 2.25 (m, 2H), 1.89 - 2.1 1 (m, 4H), 1.70 - 1.88 (m, 5H), 1.55 - 1.70 (m, 2H), 1.40 - 1.55 (m, 2H), 1.12 - 1.34 (m, 2H)

MS ES⁺ 370

ISOMER B Ή NMR (400 MHz, DMSO-i¾ δ 7.33 - 7.50 (m, 2H), 6.92 - 7.18 (m, 2H), 6.16 - 6.31 (m, 1H), 4.62 (s, 1H), 3.25 (s, 3H), 3.19 (d, J = 6.32 Hz, 2H), 2.59 - 2.74 (m, 1H), 2.37 - 2.45 (m, 2H), 2.26 - 2.37 (m, 4H), 2.11 - 2.26 (m, 2H), 1.88 - 2.03 (m, 2H), 1.36 - 1.88 (m, 13H)

MS ES⁺ 370

2.109 Example 109

-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-ethoxycyclohexanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 4-ethoxycyclohexanone.

Ή NMR (400 MHz, CDC1₃) δ 7.38 - 7.51 (m, 2H), 7.14 - 7.24 (m, 2H), 6.19 - 6.35 (m, 1H), 3.59 (q, J = 7.07 Hz, 2H), 3.27 - 3.42 (m, 1H), 2.63 - 2.81 (m, 1H), 2.48 - 2.62 (m, 2H), 2.36 - 2.47 (m, 4H), 2.23 - 2.36 (m, 2H), 1.62 - 2.12 (m, 14H), 1.26 (t, J = 6.95 Hz, 3H)

MS ES⁺ 370

2.110 Example 110

- {4- [( 1 -Cyclobutylpiperidin-4-ylidene)methyl]pheny 1 } - 1 -oxaspiro[4.5]de<

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using l-oxaspiro[4.5]decan-8- one

Ή NMR (400 MHz, DMSO-^) δ 7.35 - 7.49 (m, 2H), 7.00 - 7.20 (m, 2H), 6.16 - 6.31 (m, 1H), 4.74 (br. s., 1 H), 3.71 (t, J = 6.57 Hz, 2H), 2.56 - 2.79 (m, 1H), 2.36 - 2.45 (m, 2H), 2.24 - 2.36 (m, 4H), 2.14 - 2.26 (m, 2H), 1.73 - 2.06 (m, 12H), 1 _:52 - 1.71 (m, 4H), 1.32 - 1.45 (m, 2H)

MS ES⁺ 383

2.111 and 2.112 Examples 111 and 112

1 - { 3-Chloro-4-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]phenyl } -4- methoxycyclohexanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4 bromo-2-chlorobenzy]idene)-l-cyclobutylpiperidine (Int 8) and using 4 methoxycyclohexanone. Two isomers were separated, Isomer A and Isomer B: ISOMER A

Ή NMR (400 MHz, DMSO-tf₆) δ 7.53 (d, J =1.52 Hz, 2 H), 7.36 (dd, J = 8.08, 1.26 Hz, 1 H), 7.19 (d, J = 8.08 Hz, 1 H), 6.21 (s, 1 H), 4.93 (s, 1 H), 3.26 (s, 3 H), 3.15 - 3.24 (m, 1 H), 2.60 - 2.75 (m, 1 H), 2.30 - 2.39 (m, 4 H), 2.16 - 2.29 (m, 4 H), 1.88 - 2.02 (m, 2 H), 1.69 - 1.88 (m, 6 H), 1.48 - 1.69 (m, 6 H)

MS ES⁺ 390, 392 ISOMER B

Ή NMR (400 MHz, MeOD) δ 7.52 (d, J =1.52 Hz, 1 H), 7.34 (dd, J = 8.08, 1.77 Hz, 1 H), 7.19 (d, J = 8.08 Hz, 1 H), 6.31 (s, 1 H), 3.50 - 3.59 (m, 1 H), 3.38 (s, 3 H), 2.78 (d, J = 8.59 Hz, 1 H), 2.42 - 2.53 (m, 4 H), 2.30 - 2.42 (m, 4 H), 2.03 - 2.16 (m, 4 H), 1.88 - 2.03 (m, 4 H), 1.79 - 1.88 (m, 2 H), 1.66 - 1.79 (m, 2 H), 1.47 - 1.60 (m, 2 H)

MS ES⁺ 390, 392

2.113 and 2.114 Examples 113 and 114

l -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-(propan-2- yloxy)cyclohexanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 4-(propan-2- yloxy)cyclohexanone (CAS 69697-46-7). The 2 ring isomers were separated and isolated.

ISOMER A Ή NMR (400 MHz, DMSO-i¾) δ 7.28 - 7.48 (m, 2H), 7.03 - 7.19 (m, 2H), 6.10 - 6.30 (m, 1H), 4.71 (br. s., 1H), 3.64 - 3.85 (m, 1H), 3.33 - 3.46 (m, 1H), 2.59 - 2.78 (m, 1H), 2.36 - 2.46 (m, 2H), 2.25 - 2.36 (m, 4H), 2.13 - 2.25 (m, 2H), 1.88 - 2.05 (m, 2H), 1.54 -

1.86 (m, 12H), 1.08 (d, J = 6.06 Hz, 6H)

MS ES⁺ 385 ISOMER B

^]H NMR (400 MHz, DMSO-c¾ δ 7.29 - 7.49 (m, 2H), 7.06 - 7.18 (m, 2H), 6.12 - 6.34 (m, 1H), 4.62 - 4.75 (m, 1H), 3.53 - 3.80 (m, 1H), 3.36 - 3.46 (m, 1H), 2.58 - 2.76 (m, 1H), 2.37 - 2.45 (m, 2H), 2.26 - 2.36 (m, 4H), 2.13 - 2.26 (m, 2H), 1.88 - 2.05 (m, 2H), 1.50 - 1.88 (m, 12H), 0.92 - 1.19 (m, 6H)

■ MS ES⁺ 385

2.115 Example 115

-{4-[(l-Cyclobutylpiperidin-4-yiidene)methyl]phenyl}-4-methoxybutan-2-ol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutyipiperidine (Int.5) and using 4-raethoxybutan-2-one. . Ή NMR (400MHz, CD₂C1₂) δ 7.39 (d, 2H), 7.21 (d, 2H), 6.30 (s, 1H), 3.98 (s, 1H), 3.53 (quint, 1H), 3.20-3.33 (m, 4H), 2.66-2.80 (m, 1H), 2.48-2,60 (m, 2H), 2.35-2.46 (m, 4H), 2.22-2.35 (m, 2H), 1.99-2.18 (m, 4H), 1.81-1.97 (m, 2H), 1.57-1.81 (m, 2H), 1.51 (s, 3H).

MS ES⁺ 330

2.116 Example 116

1 - {4-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]phenyl} -3- (methoxymethyl)cyclobutanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using 3- (methoxymethyl)cyclobutanone (CAS 1068160-23-5). A mixture of ring isomers was obtained.

Ή NMR (400 MHz, DMSO-d₆) 87.31 - 7.49 (m, 2H), 7.10 - 7.22 (m, 2H), 6.22 - 6.28 (m, 1H), 5.43 (s, 1H), 3.37 - 3.46 (m, 2H), 3.25 (s, 3H), 2.60 - 2.82 (m, 2H), 2.3.7 - 2.47 (m, 3H), 2.31 (s, 4H), 2.09 - 2.27 (m, 4H), 1.88 - 2.08 (m, 3H), 1.71 - 1.86 (m, 2H), 1.62 (m, 2H)

MS ES⁺ 342

2.117 and 2.118 Examples 117 and 118

- { 4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } -3 -methoxycyclohexanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 3-methoxycyclohexanone. The 2 ring isomers were separated and isolated.

ISOMER A Ή NMR (400 MHz, DMSO- ¾ δ 7.33 - 7.51 (m, 2H), 7.07 - 7.23 (m, 2H), 6.16 - 6.30 (m, 1H), 4.78 (s, 1H), 3.37 - 3.46 (m, 1H), 3.27 (s, 3H), 2.61 - 2.77 (m, 1H), 2.38 - 2.47 (m, 2H), 2.26 - 2.38 (m, 4H), 2.12 - 2.26 (m, 3H), 1.88 - 2.10 (m, 3H), 1.48 - 1.89 (m, 9H), 1.18 - 1.40 (m, 1H)

MS ES⁺ 357

ISOMER B

Ή NMR (400 MHz, DMSO-c¾ δ 7.31 - 7.54 (m, 2H), 7.07 - 7.21 (m, 2H), 6.09 - 6.34 (m, 1H), 4.79 (s, 1H), 3.43 - 3.63 (m, 1H), 3.23 (s, 3H), 2.60 - 2.74 (m, 1H), 2.36 - 2.46 (m, 2H), 2.25 - 2.36 (m, 4H), 2.14 - 2.25 (m, 2H), 1.89 - 2.12 (m, 4H), 1.50 - 1.87 (m, 8H), 1.35 - 1.50 (m, 1H), 0.99 - Ί .22 (m, 1 H)

MS ES⁺ 357 2.119 Example 119

1 - {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } -4-( 1 H-pyrazol- 1 - yl)cyclohexanol

Scheme 32

Reagents and conditions: a) TsCl, pyridine; b) NaH, lH-pyrazole, DMF, 60 °C; c) HC1, THF

Step a Intermediate 58

-Dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate

A solution of l ,4-dioxaspiro[4.5]decan-8-oI (1.00 g, 6.32 mmol) in pyridine (10 ml) was treated with 4-methylbenzenesulfonyl chloride (1.45 g, 7.59 mmol) and the reaction mixture stirred at r.t. under nitrogen for 18 h. The reaction mixture was quenched with brine and extracted with EtOAc (x2). The combined organics were washed with 0.5 M HC1, sat. sodium bicarbonate and brine (20 ml), dried (hydrophobic frit) and concentrated under reduced pressure to give a clear liquid. The crude product was purified by column chromatography (KPNH, 0-50 % EtOAc in petrol) to give the desired product as a clear liquid, which crystallised upon standing to give a white solid (1.85 g, 94 %). Ή NMR (400 MHz, DMSO-<_¾) δ 7.74 - 7.86 (m, 2H), 7.41 - 7.53 (m, 2H), 4.56 - 4.67 (m, 1H), 3.76 - 3.88 (m, 4H), 2.42 (s, 3H), 1.45 - 1.75 (m, 8H)

Step b Intermediate 59

-(l,4-Dioxaspiro[4.5]dec-8-yl)- lH-pyrazote

To a mixture of sodium hydride (60% dispersion in mineral oil, 70 mg, 1.76 mmol) in DMF (5 ml) at 0° C was added IH-pyrazole (109 mg, 1.60 mmol) and the reaction mixture stirred under nitrogen for 30 min. l,4-Dioxaspiro[4.5]decan-8-yl 4- methylbenzenesulfonate (Int 58) (500 mg, 1.60 mmol) was added and the reaction mixture stirred at 0° C for 10 min then heated to 60° C for 5 h. The reaction mixture was cooled, quenched with water and partitioned between EtOAc and water. The organic layer separated, washed with brine, dried (hydrophobic frit) and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO-2, 0- 100 % EtOAc in petrol) to give l-(l,4-dioxaspiro[4.5]dec-8-yl)-l H-pyrazole as a white solid (1 12 mg, 34 %).

Ή NMR (400 MHz, DMSO-c¾) δ 7.69 - 7.77 (m, 1H), 7-35 - 7.45 (m, 1H), 6.13 - 6.27 (m, 1H), 4.17 - 4.33 (m, 1H), 3.80 - 3.94 (m, 4H), 1.89 - 2.05 (m, 4H), 1.59 - 1.85 (m, 4H)

Step c Intermediate 60

-(lH-Pyrazol-l -yl)cyclohexanone

A solution of l -(l,4-dioxaspiro[4.5]decan-8-yl)-lH-pyrazole (Int 59) (1 10 mg, 0.528 mmol), HC1 (5 M, 0.5 ml, 2.50 mmol) and THF (2 ml) was stirred at room temperature for 20 h. The mixture was quenched with water, extracted with EtOAc (x 3), and the combined organics dried (hydrophobic frit) and concentrated under reduced pressure to give 4-(lH-pyrazol-l-yl)cyclohexanone (82 mg, 95 %). Ή NMR (400 MHz, CDCI₃) δ 7.37 - 7.51 (m, 2H), 6.17 - 6.27 (m, IH), 4.52 - 4.65 (m, IH), 2.45 - 2.58 (m, 3H), 233 - 2.45 (m, 2H), 2.19 - 2.33 (m, 2H), 1.96 - 2.14 (m, IH) Step d Example 119

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using 4-(lH-pyrazol- l- yl)cyclohexanone (Int 60). Ή NMR (400MHz, DMSO-afe) δ 7.75 (d, IH), 7.48 (d, 2H), 7.44 (s, IH), 7.15 (d, 2H), 6.25 (d, 2H), 4.92 (s, IH), 4.22 - 4.35 (m, I H), 2.60 - 2.73 (m, IH), 2.38 - 2.46 (m, 2H), 2.27-2.36 (m, 4H), 2.13 - 2.27 (m, 4H), 1.70 - 2.05 (m, 10H), 1.53 - 1.68 (m, 2H).

MS ES⁺ 392 2.120 Example 120

- { 4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } -2-methoxycyclohexanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 2-methoxycycIohexanone.

Ή NMR (400 MHz, MeOD) δ 7.50 (d, J = 8.34 Hz, 2H), 7.14 (d, J = 8.34 Hz, 2H), 6.33 (s, I H), 3.25 - 3.29 (m, IH) 2.99 (s, 3H), 2.73 - 2.87 (m, IH), 2.23 - 2.61 (m, 9H), 1.36 - 2.02 (m, 1 1H)

MS ES⁺ 356

2.121 and 2.120 Examples 121 and 122

4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}oxepan-4-ol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using oxepan-4-one (CAS 62643- 1.9-0). The 2 ring isomers were separated and isolated ISOMER A:

Ή NMR (400 MHz, MeOD) δ 7.45 (d, J = 8.08 Hz, 2H), 7.16 (d, J = 8.08 Hz, 2H), 6.32 (s, 1H), 3.85 - 3.97 (m, 2H), 3.75 - 3.85 (m, 1H), 3.66 - 3.75 (m, 1H), 2.69 - 2.89 (m, 1H), 2.27 - 2.62 (ra, 9H), 2.14 - 2.27 (m, 2H), 2.02 - 2.15 (m, 2H), 1.60 - 2.02 (m, 7H) MS ES⁺ 342

ISOMER B:

Ή NMR (400 MHz, MeOD) δ 7.47 (d, J = 8.34 Hz, 2H), 7.14 (d, J = 8.08 Hz, 2H), 6.33 (s, 1H), 3.55 (dd, J =10.86, 4.29 Hz, 1H), 2.69 - 2.88 (m, 1H), 2.51 - 2.61 (m, 2H), 2.39 - 2.50 (m, 4H), 2.28 - 2.39 (m, 2H), 2.03 - 2.16 (m, 2H), 1.89 - 2.03 (m, 3H), 1.74 (d, J = 2.27 Hz, 7H), 1.35 - 1.56 (m, 2H)

MS ES⁺ 342

2.123 and 2.124 Examples 123 and 124

- (4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl} -3-methoxycycloheptanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 3-methoxycycloheptanone (CAS 17159-70-5)._. The 2 ring isomers were separated and isolated ISOMER A:

Ή NMR (400 MHz, DMSO-<¼) δ 7.31 - 7.51 (m,^'2H), 7.04 - 7.21 (m, 2H), 6.14 - 6.34 (m, 1H), 4.91. (s, 1 H), 3.50 - 3.69 (m, 1H), 3,18 (s, 3H), 2.57 - 2.79 (m, 1H), 2.36 - 2.46 (m, 2H), 2.25 - 2.36 (m, 4H), 2.16 - 2.26 (m, 2H), 1.86 - 2.09 (m, 6H), 1.73 - 1.86 (m, 2H), 1.48 - 1.73 (m, 7H), 1.38 - 1.48 (m, 1H)

MS ES⁺ 370 ISOMER B:

Ή NMR (400 MHz, DMSO-ctf) δ 7.34 - 7.51 (m, 2H), 6.99 - 7.26 (m, 2H), 6.16 - 6.32 (m, 1H), 4.85 (s, 1H), 3.25 - 3.29 (m, 1H), 3.10 (s, 3H), 2.58 - 2.79 (m, 1H), 2.37 - 2.46 (m, 2H), 2.15 - 2.36 (m, 7H), 1.87 - 2.09 (m, 4H), 1.57 - 1.87 (m, 8H), 1.25 - 1.58 (m, 3H)

MS ES⁺ + 1 371

2.125 Example 125

-{4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl} - 1 -(tetrahydrofuran-3-yl)ethanol

Reagents and conditions: a) MeMgBr, THF

Step a Intermediate 61

-(Tetrahydrofuran-3-yl)ethanone

To a solution of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (CAS 766539-67- 7, 1 g, 6.28 mmol) in THF (10 ml) at -78 °C was added methylmagnesium bromide (3 M in THF, 2.51 ml, 7.54 mmol) dropwise. The reaction was then stirred at -78 °C for 1.5 h. The mixture was quenched with water and extracted with EtOAc. The organic phase was dried (MgS0 ) and concentrated under reduced pressure to give 1- (tetrahydrofuran-3-yl)ethanone as a pale yellow oil (320 mg, 45 %). Used crude in the next step.

Step b Example 125 Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzyIidene)-l -cycIobutylpiperidine (Int 5) and using l -(tetrahydrofuran-3- yl)ethanone (Int 61) Ή NMR (400 MHz, MeOD) δ 7.39 - 7.49 (m, 2H), 7.09 - 7.22 (m, 2H), 6.32 (s, 1 H), 3.60 - 3.95 (m, 3H), 3.40 - 3.58 (m, 1H), 2.65 - 2.89 (m, 2H), 2.25 - 2.62 (m, 8H), 1.84 - 2.18 (m, 5H), 1.57 - 1.83 (m, 3H), 1.52 (d, J =13.14 Hz, 3H)

MS ES⁺ 342 2.126 Example 126

l-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-2- (methoxymethyl)cyclopentanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 2- (methoxymethyl)cyclopentanone (CAS 35457-02-4).

'H NMR (400 MHz, DMSO--4) δ 7.31 - 7.50 (m, 2H), 7.05 - 7.22 (m, 2H), 6.25 (s, 1H), 4.67 (s, 1H), 3.13 - 3.26 (m, 2H), 3.08 (s, 3H), 2.59 - 2.75 (m, 1H), 2.39 - 2.44 (m, 2H), 2.08 - 2.35 (m, 8H), 1.50 - 2.08 (m, 12H)

MS ES⁺ 356

2.127 and 2.128 Examples 127 and 128

-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyI}-4-methoxycycloheptanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 4-methoxycycloheptanone (CAS 17429-01-5). The 2 ring isomers were separated and isolated ISOMER A:

Ή NMR (400 MHz, CDC1₃) δ 7.38 - 7.52 (m, 2H), 7.12 - 7.23 (m, 2H), 6.15 - 6.37 (m, 1 H), 3.43 - 3.62 (m, 1H), 3.35 (s, 3H), 2.66 - 2.83 (m, 1H), 2.48 - 2.61 (m, 2H), 2.24 - 2.45 (m, 7H), 1.85 - 2.20 (m, 8H), 1.49 - 1.85 (m, 8H)

MS ES⁺ 370

ISOMER B:

Ή NMR (400 MHz, CDC1₃) δ 7.36 - 7.50 (m, 2H), 7.09 - 7.23 (m, 2H), 6.19 - 6.36 (m, 1H), 3.51 - 3.67 (m, 1H), 3.39 (s, 3H), 2.96 - 3.10 (m, 1H), 2.62 - 2.81 (m, 1H), 2.49 - 2.62 (m, 2H), 2.35 - 2.47 (m, 4H), 2.21 - 2.35 (m, 2H), 1.82 - 2.16 (m, 12H), 1.63 - 1.83 (m, 3H), 1.47 - 1.63 (m, 1H)

MS ES⁺ 370 2.129 Example 129

- {4-[( 1 -cyclopentylpiperidin-4-yIidene)methyl]phenyl } -4-methoxycyclohexanol

Step a Intermediate 62

-(4-Bromobenzy lidene)- 1 -cyclopentylpiperidine

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-(4-bromobenzylidene)piperidine-l-carboxylate (Int 3) and using cyclopentanone in step b.

Ή NMR (400 MHz, DMSO-c/₆) δ 7.51 (d, J =8.34 Hz, 2H), 7.16 (d, J = 8.34 Hz, 2H), 6.22 (s, 1H), 2.45 - 2.50 (m, 3H), 2.42 (s, 4H), 2.26 - 2.35 (m, 2H), 1.77 (d, J = 6.32 Hz, 2H), 1.54 - 1.66 (m, 2H), 1.49 (dd, 2H), 1.26 - 1.41 (m, 2H) MS ES⁺ 320, 322 Step b Example 129

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclopentylpiperidine (Int 62) and using 4- methoxycyclohexanone.

Ή NMR (400 MHz, CDC1₃) δ 7.40 - 7.51 (m, 2H), 7.16 - 7.25 (m, 2H), 6.16 - 6.34 (m, 1H), 3.42 (s, 3H), 3.12 - 3.35 (m, 1H), 2.34 - 2.70 (m, 9H), 1.95 - 2.09 (m, 2H), 1.65 - 1.95 (m, 1 OH), 1.35 - 1.64 (m, 5H)

MS ES⁺ 371

2.130 Example 130

-{4-[(l-Cyclopentylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-cyclopentylpiperidine (Int 62) and using tetrahydro-4H-pyran-4- one. Ή NMR (400 MHz, DMSO-tf₆) δ 7.34 - 7.49 (m, 2H), 7.05 - 7.21 (m, 2H), 6.24 (s, 1H), 4.97 (s, 1H), 3.78 (s, 4H), 2.45 - 2.49 (m, 3H), 2.35 - 2.45 (m, 4H), 2.25 - 2.35 (m, 2H), 1.86 - 2.05 (m, 2H), 1.70 - 1.85 (m, 2H), 1.41 - 1.70 (m, 6H), 1.22 - 1.40 (m, 2H) MS ES⁺ 342 2.131 Example 131

-Methoxy-l-(4-{[l -(propan-2-yl)piperidin-4-yIidene]methyl}phenyl)cyclohexanol

Step a Intermediate 63

-(4-Bromobenzylidene)-l -(propan-2-yl)piperidine

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-(4-bromobenzylidene)piperidine-l -carboxylate (Int 3) and using acetone in step

Ή NMR (400 MHz, CDC1₃) 5 7.39 - 7.46 (m, 2H), 7.03 - 7.1 1 (m, 2H), 6.19 (s, 1H), 2.72 - 2.82 (m, 1H), 2.56 - 2.64 (m, 2H), 2.49 (s, 4H), 2.34 - 2.42 (m, 2H), 1.05 (d, J =6.57 Hz, 6H)

MS ES⁺ 294, 296

Ste b Example 131

-Methoxy-l -(4-{ [l -(propan-2-yl)piperidin-4-ylidene]methyl}phenyl)cyclohexanol

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l -(propan-2-yl)piperidine (Int 63) and using 4- methoxycyclohexanone. Ή NMR (400 MHz, DMSO-i ₆) δ 7.34 - 7.49 (m, 2H), 7.04 - 7.20 (m, 2H), 6.1 1 - 6.32 (m, 1H), 4.74 (s, 1 H), 3.31 (s, 3H), 3.15 - 3.24 (m, 1 H), 2.63 - 2.80 (m, 1H), 2.34 - 2.46 (m, 4H), 2.21 - 2.36 (m, 2H), 1.50 - 1.88 (m, 8H), 0.96 (d, 6H)

MS ES⁺ 345

2.132 Example 132

-(4-{[l-(propan-2-yl)piperidin-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4-

Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-(propan-2-yl)piperidine (Int 63) and using tetrahydro-4H-pyran- 4-one. Ή NMR (400 MHz, MeOD) δ 7.43 - 7.51 (m, 2H), 7.15 - 7.25 (m, 2H), 6.33 (s, 1H), 3.91 - 4.02 (m, 2H), 3.78 - 3.87 (m, 2H), 2.78 - 2.88 (m, 1H), 2.64 - 2.74 (m, 2H), 2.53 - 2.64 (m, 4H), 2.42 - 2.49 (m, 2H), 2.09 - 2.21 (m, 2H), 1.65 - 1.73 (m, 2H), 1.06 - 1.15 (m, 6H)

MS ES⁺ 316

2.133 Example 133

1 -(4- { [ 1 -(Cyclopropylmethyl)piperidin-4-ylidene]methyl }phenyl)-4- methoxycyclohexanol

Step a Intermediate 64

-(4-Bromobenzylidene)- 1 -(cyclopropylmethyl)piperidine

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-(4-bromobenzylidene)piperidine-l-carboxylate (Int 3) and using cyclopropanecarbaldehyde in step b.

Ή NMR (400 MHz, CDC1₃) δ 7.37 - 7.47 (m, 2H), 6.99 - 7.14 (m, 2H), 6.21 (s, 1H), 2.60 - 2.70 (m, 2H), 2.52 (s, 4H), 2.36 - 2.47 (m, 2H), 2.20 - 2.33 (m, 2H), 0.82 - 0.97 (m, 1H), 0.41 - 0.57 (m, 2H), 0.00 - 0.16 (m, 2H)

MS ES⁺ 306, 308

Step b Example 133 Prepared in an analogous manner to Intermediate 53 via Scheme 26 starting with 4-(4- bromobenzylidene)-l-(cyclopropylmethyl)piperidine (Int 64) and using 4- methoxycyclohexanone. Ή NMR (400 MHz, DMSO-cfc) δ 7.22 - 7.43 (m, 2H), 6.99 - 7.18 (m, 2H), 6.06 - 6.25 (m, 1H), 4.67 (s, 1H), 3.20 (s, 3H), 3.09 - 3.17 (m, 1H), 2.43 - 2.51 (m, 2H), 2.31 - 2.39 (m, 4H), 2.17 - 2.30 (m, 2H), 2.01 - 2.18 (m, 2H), 1.45 - 1.80 (m, 8H), 0.64 - 0.87 (m, H), 0.30 - 0.48 (m, 2H), -0.13 - 0.07 (m, 2H)

MS ES⁺ 356

2.134 Example 134

-(4-(( 1 -Cyclobuty lpiperidin-4-ylidene)methyl)phenyl)propan-2-ol

Reagents and conditions: a) CDI, dimethyl Ν,Ο-hydroxylamine HC1, Et₃N, DCM; b) TFA, DCM; c) cyclobutanone, triethylamine, acetic acid, sodium triacetoxyborohydride, DCM; d) MeMgBr, Et₂0, THF; e) NaBH₄, MeOH

Intermediate 65

(4-{[l -(tert-butoxycarbonyl)piperidin-4-ylidene]methyl}phenyl)acetic acid

Prepared in an analogous manner to Intermediate 3 via Scheme 3, method B, starting from 2-(4-((diethoxyphosphoryl)methyl)phenyl)acetic acid (CAS 177712-50-4) and using tert-butyl 4-oxopiperidine- 1 -carboxy late.

1H NMR (300MHz, CDC1₃) δ 10.5 (br s, 1H), 7.22 (d, 2H), 7.15 (d, 2H), 6.32 (s, 1H), 3.62 (s, 2H), 3.49 (m, 2H), 3.38 (m, 2H), 2.44 (m, 2H), 2.30 (m, 2H), 1.44 (s, 9H).

No LCMS

Step a Intermediate 66

tert-Butyl 4-(4-{2-[methoxy(methyl)amino]-2-oxoethyl}benzylidene)piperidine-l - carboxylate

To a solution of (4-{[l-(tert-butoxycarbonyl)piperidin-4-yiidene]methyl}phenyl)acetic acid (Int 65) (2.5 g, 7.5 mmol) in DCM (50 ml) was added CDI (1.3 g, 8.3 mmol) and the reaction stirred for 20 min. Dimethyl N,0-hydroxylamine hydrochloride (0.9 g, 9.1 mmol) and Et₃N (3 ml) were added and the reaction stirred for 1 h. The reaction was diluted with DCM and washed with 2 % citric acid (aq.) then brine, dried (Na₂S0₄) and concentrated under reduced pressure to give tert-butyl 4-(4-{2- [methoxy(methyl)amino]-2-oxoefhyl}benzylidene)piperidine-l-carboxylate as a brown oil (2.46 g, 87 %).

Ή NMR (300MHz, CDC1₃) δ 7.24 (d, 2H), 7.13 (d, 2H), 6.31 (s, 1H), 3.75 (s, 2H), 3.65 (s, 3H), 3.48 (t, 2H), 3.38 (t, 2H), 3.18 (s, 3H), 2.45 (t, 2H), 2.31 (t, 2H), 1.43 (s, 9H).

Step b Intermediate 67

N-Methoxy-N-methyl-2-[4-(piperidin-4-ylidenemethyl)phenyl]acetamide

trifluoroacetate

To a solution of tert-butyl 4-(4-{2-[methoxy(methyl)amino]-2- oxoethyl}benzylidene)piperidine-l -carboxylate (Int 66) (2.46 g, 6.6 mmol) in DCM (10 ml) at r.t. was added TFA (5 ml, 66 mmol) and the reaction stirred for 1 h. The reaction was then concentrated under reduced pressure and azeotroped with toluene to give N- methoxy-N-methyl-2-[4-(piperidin-4-ylidenemethyl)phenyl]acetamide trifluoroacetate (4.78 g, 100 %) Ή NMR (300MHz, CDC ) δ 7.17-7.30 (m, 4H), 6.50 (s, 1H), 3.76 (s, 2H), 3.68 (s, 3H), 3.30 (s, 3H), 3.10 - 3.30 (m, 4H), 2.72 (t, 2H), 2.62 (t, 2H).

Step c Intermediate 68

2-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-N-methoxy-N- methylacetam i de

Prepared in an analogous manner to Intermediate 5 via Scheme 4, step b, starting from N-methoxy-N-methyl-2-[4-(piperidin-4-ylidenemethyl)phenyl]acetamide

trifluoroacetate (Int 67) and using cyclobutanone.

Ή NMR (300MHz, CDC1₃) 57.17 (d, 2H), 7.08 (d, 2H), 6.19 (s, 1 H), 3.68 (s, 2H), 3.58 (s, 3H), 3.12 (s, 3H), 2.65 (quin, 1H), 2.47 (t, 2H), 2.34 (s, 4H), 2.23 (t, 2H), 1.95 (m, 2H), 1.85 (m, 2H), 1.65 (m, 2H).

MS ES⁺ 329

Step d Intermediate 69

-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}propan-2-one

To a solution of 2-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}-N-methoxy-N- methylacetamide (Int 68) (180 mg, 0.54 mmol) in THF (4 ml) at r.t. was added methyl magnesium bromide (2 ml, 3 M solution in Et₂0, 6.0 mmol) and the reaction stined for 1 h. The reaction was poured onto 2 M HC1 (aq.) (10 ml), basified and then extracted ■ into EtOAc (2 x 20 ml). The combined organics were dried (Na₂S0 ) and concentrated under reduced pressure to give l-{4-[(l-cyclobutylpiperidin-4- ylidene)methyl]phenyl}propan-2-one (120 mg, 78 %). Ή NMR (300MHz, CDC1₃) 57.13 (m, 4H), 6.22 (s, 1H), 3.66 (s, 2H), 2.68 (q, 1H), 2.50 (t, 2H), 2.38 (s, 4H), 2.27 (t, 2H), 2.13 (s, 3H), 2.0 (m, 2H), 1.88 (m, 2H), 1.66 (m, 2H).

Step e Example 134

To a solution of l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}propan-2-one (Int 69) (120 mg, 0.42 mmol) in MeOH (3 ml) at r.t. was added NaBH (40 mg, 1.05 mmol) and the reaction stirred for 1 h. The reaction was concentrated under reduced pressure then treated with 20 % citric acid (aq.) then basified with 2.5 M NaOH (aq and extracted with EtOAc (x 2). The combined organics were dried (MgS0₄), concentrated under reduced pressure and purified by column chromatography (Si0₂ ; 10 % MeOH in DCM) to give l-(4-((l-cyclobutylpiperidin-4- ylidene)methyl)phenyl)propan-2-ol as a clear oil (100 mg, 83 %).

Ή NMR (300MHz, CDC1₃) δ 7.12 (m, 4H), 6.25 (s, 1H), 3.98 (m, 1H), 2.80-2.35 (m, l lH), 2.04 (m, 4H), 1.69 (m, 2H), 1.23 (m, 3H)

MS ES⁺ 286

2.135 Example 135

-(4-((l-Cyclobutylpiperidin-4-ylidene)methyl)phenyl)-l -cyclopentylethanol

Prepared in an analogous manner to Example 134 via Scheme 34, using cyclopentyl magnesium bromide in step d.

Ή NMR (300MHz, CDC1₃) 6 7.15 (m, 4H), 6.25 (s, IH), 3.61 (m, IH), 2.90- 1.20 (m, 26H)

MS ES⁺ 340

2.136 Example 136

1 -(4-(4-(( 1 -Cyclobutylpiperidin-4-ylidene)methyl)benzyl)-4-hydroxypiperidin- 1 - yl)ethanone

R_5b represents R₅ cycloalkyl or heterocyclyl, each of which may be optionally substituted.

Reagents and conditions: a) n-Butyllithium, THF, -78 °C; or Mg, reflux, THF; b) BF₃.Et₂0, -78 °C to r.t. Step a Intermediate 170

½r/-Butyl-4-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-4-hydroxypiperidine- -carboxylate

To a solution of 4-(4-bromobenzylidene)-l-cyclobutylpiperidine (Int 5) (500 mg, 1.63 mmol) in THF (10 ml) at - 78 °C was added «-BuLi (0.81 ml, 2 in hexanes, 1.63 mmol). The reaction was stirred for 10 min then BF₃.OEt2 (200 ΐ,, 1.63 mmol) was added and the reaction stirred for a further 5 min. A solution of ierf-butyl l-oxa-6- azaspiro[2.5]octane-6-carboxylate (348 mg, 1.63 mmol) in THF (2 ml) was added dropwise and the reaction stirred for 1 h. The reaction was quenched via the addition of sat. aq. NH₄C1 and basified with K₂C0₃. The mixture was extracted with EtOAc (x 3), dried (MgS0₄), concentrated under reduced pressure and purified by column chromatography (Si0₂; 0 to 5 % MeOH in DCM) to give /ert-butyl 4-{4-[(l - cyclobutylpiperidin-4-ylidene)methyl]benzyl}-4-hydroxypiperidine-l -carboxylate (300 mg, 42 %) as a yellow gum.

Ή NMR (300MHz, CDC1₃) S 7.13 (s, 4H), 6.32 (s, 1H), 3.87 (s, 2H), 3.08 (t, 2H), 2.96 (s, 1H), 2.60 - 2.76 (m, 6H), 2.12 (m, 2H), 1.50 - 1.90 (m, 8H), 1.45 (s, 9H).

MS ES⁺ 441.5

Scheme 36

Reagents and conditions: a) TFA, DCM; b) Ac₂0, Et₃N, DCM

Step b Intermediate 171

4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]benzyl}piperidin-4-ol

Prepared in an analogous manner to Intermediate 67 starting from Intermediate 170 (TFA dep). The free base was obtained via loading the TFA salt onto an SCX column and eluting with NH₃ in MeOH. The filtrate was concentrated under reduced pressure to give 4-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}piperidin-4-ol.

Ή NMR (300MHz, CDC1₃): δ 7.13 (s, 4H), 6.24 (s, 1 H), 2.91 (m, 5H), 2.67 - 2.73 (m, 3H), 2.52 (t, 2H), 2.39 (s, 4H), 2.28 (t, 1H), 1.82 - 2.08 (m, 4H), 1.67 (m, 6H), 1.52 (m, 2H).

Step c Example 136

To a solution of 4-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}piperidin-4-ol (Int 171) (100 mg, 0.29 mmol) and Et₃N (82 μΐ, 0.59 mmol) in DCM (2 ml) at 0 °C was added AC2O (33 μΐ, 0.35 mmol). The reaction was allowed to warm to r.t. and stirred for 2 h. The reaction was diluted with DCM, washed with sat. aq. NaHC0₃, dried (MgS0₄), concentrated under reduced pressure and purified by column chromatography (Si0₂ ; 0 to 5 % MeOH in DCM) to give l -(4-(4-((l -cyclobutylpiperidin-4- ylidene)methyl)benzy])-4-hydroxypiperidin-l-yI)ethanone as a beige solid (1 10 mg, 99 %).

Ή NMR (300MHz, CDC1₃) S 7.13 (m, 4H), 6.27 (s, 1H), 4.38 (d, 1H), 3.59 (d, 1H), 3.39 (m, 1H), 2.93 (t, 1 H), 2.77 (s, 3H), 2.4 - 2.6 (m, 10H), 2.0 - 2.1 (m, 6H), 1.5 - 1.73 (m, 5H)

MS ES⁺ 383

2.137 Example 137

-(4-(( 1 -Cyclobutylpiperidin-4-ylidene)methyl)benzyl)cyclopentanol

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using l-oxaspiro[2.4]heptane (CAS 185-60-4). Ή NMR (300MHz, CDC1₃) δ 7.24 (d, 2H), 7.09 (d, 2H), 6.46 (s, 1H), 3.38 (m, 1H), 2.68 - 3.00 (m, 6H), 2.56 (m, 2H), 2.26 (m, 2H), 1.99 (m, 2H), 1.48 - 1.88 (m, 12H) MS ES⁺ 326

2.138 Example 138

l-Cyclopentyl-2-(4-((l-ethylpiperidin-4-ylidene)methyl)phenyl)ethanol

Step a Intermediate 172

-(4-Bromobenzy lidene)- 1 -ethylpiperidine

Prepared in an analogous manner to Intermediate 3 via Scheme 3, method B using diethyl 4-bromobenzylphosphonate and l-ethylpiperidin-4-one.

Ή NMR (300MHz, CDCI3) δ 7.41 (d, 2H), 7.05 (d, 2H), 6.17 (s, 1H), 2.48 (m, 4H), 2.38 (m, 6H), 1.10 (t, 3H).

MS ES⁺ 309.

Step b Example 138

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromobenzylidene)-l -ethylpiperidine (Int 172) and using l-oxaspiro[2.4]heptane (CAS 185-60-4).

^!H NMR (400 MHz, DMSO-<¾ δ 7.13 - 7.19 (m, 2H), 7.03 - 7.12 (m, 2H), 6.18 - 6.28 (m, 1H), 4.36 - 4.45 (m, 1H), 3.42 - 3.51 (m, 1H), 2.63 - 2.74 (m, 1H), 2.40 - 2.48 (m, 4H), 2.24 - 2.40 (m, 6H), 1.72 - 1.86 (m, 1H), 1.35 - 1.70 (m, 8H), 1.20 - 1.36 (m, 1H),

1.01 (m, 3H)

MS ES⁺ 314 2.139 Example 139

-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-l -(tetrahydrofuran-3-yl)ethanol

Scheme 37

Reagents and conditions: a) Trimethylsulfoxonium iodide, OtBu, DME

Step a Intermediate 173

-(oxiran-2-yl)tetrahydrofuran

To a suspension of trimethylsulfoxonium iodide (2.1 g, 9.4 mmol) in DME (20 ml) was added O'Bu (1.15 g, 9.4 mmol). The reaction was stirred for 30 min at r.t. and was then cooled to 0 °C. A solution of tetrahydrofuran-3-carbaldehyde (858 mg, 8.6 mmol) in DME was added dropwise and the reaction stirred for 1 h. The reaction was quenched via the addition of sat. aq. NH₄C1 and extracted with EtOAc. The organics were washed with sat. aq. NaHC0₃ and brine then dried (MgS0₄) and concentrated under reduced pressure to give 3-(oxiran-2-yl)tetrahydrofuran (140 mg, 14 %).

Ή NMR (300MHz, CDC1₃) δ 3.70 (m, 4H), 2.92 (m, 1H), 2.80 (q, 1H), 2.53 (m, 1H), 1.80 (m, 3H) Step b Example 139

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 3-(oxiran-2- yl)tetrahydrofuran (Int 173).

Ή NMR (300MHz, CDCI₃) 67.15 (s, 4H), 6.24 (s, 1 H), 3.59 - 3.97 (m, 5H), 1.53 - 2.92 (m, 20H)

MS ES⁺ 342

2.140 Example 140

4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]benzyl}tetrahydro-2H-pyran-4-ol

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 1 ,6- dioxaspir o [2.5 Joctane .

Ή NMR (400 MHz, MeOD) δ 7.08 (d, 2H, J = 8.08 Hz), 7.07 (m, 2H), 7.01 (d, 2H, J = 8.08 Hz), 6.21 (s, 1H), 3.51 - 3.71 (m, 4H), 2.61 - 2.73 (m, 1H), 2.64 (s, 2H), 2.38 - 2.47 (m, 2H), 2.26 - 2.38 (m, 4H), 2.17 - 2.26 (m, 2H), 1.90 - 2.02 (m, 2H), 1.74 - 1.90 (m, 2H), 1.52 - 1.69 (m, 4H), 1.26 - 1.38 (m, 2H)

MS ES⁺ 342 2.141 Example 141

4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]-3-fluorobenzyl}tetrahydro-2H-pyran-

4-ol

Step a Intermediate 174

-(4-Bromo-2-fluorobenzy lidene)- 1 -cyclobutylpiperidine

Prepared in an analogous manner to Intermediate 5 via Scheme 3, method A, starting from (4-bromo-2-fluorobenzyl)(triphenyl)phosphonium bromide and tert-butyl 4- oxopiperidine-1 -carboxylate, and Scheme 4 using cyclobutanone in step b.

Step b Example 144

4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]-3-fluorobenzyl}tetrahydro-2H-pyran- -ol

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromo*2»fluorobenzylidene)-l -cyclobutylpiperidine (Int 174) and using 1 ,6- dioxaspiro[2.5]octane.

Ή NMR (400 MHz, MeOD) 5 7.08 - 7.21 (m, 1H), 6.91 - 7.07 (m, 2H), 6.24 (s, 1 H), 3.67 - 3.81 (m, 4H), 2.78 - 2.89 (m, 1H), 2.77 (s, 2H), 2.25 - 2.55 (m, 8H), 2.03 - 2.19 (m_; 2H), 1.85 - 2.03 (m, 2H), 1.61 - 1.83 (m, 4H), 1.43 (m, 2H), 1.36 - 1.50 (m, 2H) MS ES⁺ 360

2.142 Example 142

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]benzyl}-4-methoxycyclohexanol

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using 6-methoxy-l- oxaspiro[2.5]octane. A mixture of ring isomers was obtained. ' H NMR (400 MHZ, D SO-t¾ δ 7.1 1 - 7.21 (m, 2H), 7.00 - 7.11 (m, 2H), 6.23 (s, 1H), 4.08 (br. s., 1 H), 3.19 (s, 3H), 2.92 - 3.09 (m, 1 H), 2.63 - 2.76 (m, 1 H), 2.55 - 2.64 (m, 2H), 2.36 - 2.47 (m, 2H), 2.26 - 2.35 (m, 4H), 2. 15 - 2.26 (m, 2H), 1 .89 - 2.03 (m, 2H), 1 .72 - 1 .88 (m, 2H), 1 .56 - 1 .72 (m, 4H), 1.38 - 1.51 (m, 4H), 1 .17 - 1 .33 (m, 2H) MS ES⁺ 370

2.143 Example 143

4-(4- { [ 1 -(Tetrahydro uran-3-yl)piperidin-4-ylidene]methyl }benzyl)tetrahydro-2H- pyran-4-ol

Step a Intermediate 175

-(4-Bromobenzylidene)-l-(tetrahydrofuran-3-yl)piperidine

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-(4-bromobenzylidene)piperidine-l -carboxylate (Intermediate 3) and using dihydrofuran-3(2H)-one in step b.

1H NMR (300MHz, CDC1₃) δ 7.42 (m, 2H), 7.05 (m, 2H), 6.21 (s, 1H), 3.62 - 3.99 (m, 4H), 2.98 - 3.03 (m, 1 H), 2.40 - 2.60 (m, 8H), 1 .81 - 2.12 (m, 2H)

Step b Example 143

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromobenzylidene)-l -(tetrahydrofuran-3-yl)piperidine (Int 175) and using 1,6- dioxaspiro[2.5]octane.

Ή NMR (400 MHz, MeOD) 8 7.17 - 7.24 (m, 2H), 7.08 - 7.16 (m, 2H), 6.33 (s, 1H), 3.84 - 4.01 (m, 2H), 3.62 - 3.84 (m, 6H), 3.00 - 3.13 (m, 1 H), 2.76 (s, 2H), 2.62 - 2.74 (m, 1H), 2.52 - 2.62 (m, 4H), 2.39 - 2.52 (m, 3H), 2.03 - 2.22 (m, 1H), 1.81 - 1.99 (m, 1 H), 1.60 - 1.80 (m, 2H), 1.39 - 1.52 (m, 2H)

MS ES⁺ 358 2.144 Example 144

4-(4-{[l-(3-Fluorocyclobutyl)piperidin-4-ylidene]raethyl}benzyl)tetrahydro-2H-pyran- 4-ol

Reagents and conditions: a) TBAF, THF; b)i) BH₃.THF, THF ii) C₄F₉S0₂F, DBU, PhMe

Step a Intermediate 176

4-(4-Bromobenzylidene)-l -(3-{[i^,err-butyl(dimethyl)silyl]oxy}cyclobutyl)piperidine

OTBDMS Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-(4-bromobenzylidene)piperidine-l -carboxylate (Intermediate 3) and using 3- {[rerf-butyl(dimethyl)silyl]oxy}cyclobutanone (CAS 929913-18-8) in step b. Ή NMR (300MHz, CDC1₃): 6 7.42 (m, 2H), 7.05 (m, 2H), 6.20 (s, 1H), 3.97 (m, 1H), 2.20 - 2.45 (m, 9H), 2.04 (m, 2H), 1.27 (m, 2H), 0.85 (s, 9H), 0.02 (s, 6H)

Step b Intermediate 177

3-[4-(4-Bromobenzylidene)piperidin-l-yl]cyclobutanol

To a solution of 4-(4-bromobenzylidene)-l -(3-{[/ert-butyl(dimethyl)silyl] oxy}cyclobutyl)piperidine (Int 176) (0.88 g, 2.0 mmol) in THF (10 ml) was added TBAF (2.0 ml, 1 M solution in THF, 2.0 mmol) and the reaction stirred at r.t. for 18 h. Sat. aq. NaHC0₃ was added and the mixture extracted into DCM (x 3). The organics were washed with brine, dried (MgSO^), concentrated under reduced pressure and purified by column chromatography (Si0₂ ; 50 % EtOAc in petrol) to yield 3-[4-(4- bromobenzylidene)piperidin-l-yl]cyclobutanol as a white solid (612 mg, 94 %).

Ή NMR (300MHz, CDC1₃): 67.42 (m, 2H), 7.05 (m, 2H), 6.23 (s, 1H), 4.01 (m, 1H), 2.30 - 2.64 (m, l lH), 2.10 (m, 1H), 1.91 - 2.00 (m, 2H)

Step c Intermediate 178

4-(4-bromobenzylidene)- 1 -(3-fluorocyclobutyl)piperidine

To a solution of 3-[4-(4-bromobenzylidene)piperidin- l-yl]cyclobutanol (Int 177) (355 mg, 1.1 mmol) in THF (10 ml) at -78 °C was added borane.THF (1.1 ml, 1 M solution in THF, 1.1 mmol). The reaction was stirred at this temperature for 2 h and was then allowed to warm to r.t. The solvent was removed under reduced pressure to give a white foam (405 mg). This dissolved in toluene (10 ml) and DBU (0.54 ml, 2.6 mmol) and nonafluorobutanesulfonyl fluoride (0.31 ml, 1.8 mmol) were added. The reaction was stirred for 18 h. Sat. aq. NaHC0₃ was added and the mixture extracted into EtOAc (x 3). The organics were washed with brine, dried (MgS0₄), concentrated under reduced pressure and purified by column chromatography (Si0₂; 5 % MeOH in DCM) to give 4- (4-bromobenzylidene)-l-(3-fluorocyclobutyl)piperidine (120 mg, 31 %).

Ή NMR (300MHz, CDC1₃): δ 7.42 (m, 2H), 7.05 (m, 2H), 6.21 (s, 1H), 5.15 (m, 1H), 3.05 (m, 1H), 2.24 - 2.47 (m, 8H), 1.55 - 1.70 (m, 4H) Step d Example 144

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromobenzylidcnc)-l-(3-fluorocyclobutyl)pipcridinc (Int 178) and using 1 ,6- di oxaspiro [2.5 ] octane . Ή NMR (400 MHz, DMSO-<¾) δ 6.93 - 7.25 (m, 4 H), 6.26 (s, 1 H), 4.93 - 5.30 (m, 1 H), 4.32 (s, 1 H), 3.45 - 3.67 (m, 4 H), 2.81 - 3.08 (m, 1 H), 2.66 (s, 2 H), 2.44 (br. s., 2 H), 2.07 - 2.40 (m, 9 H), 1.37 - 1.61 (m, 2 H), 1.09 - 1.37 (m, 3 H)

MS ES⁺ 360 2.145 Example 145

2-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}- l-(tetrahydro-2H-pyran-4- yl)ethanol

Scheme 39

Reagents and conditions: a) Trimethylsulfoxonium iodide, NaH, DMSO Step a Intermediate 179

-(Oxiran-2-yl)tetrahydro-2H-pyran

To a suspension of trimethylsulfoxonium iodide (1.778 g, 8.08 mmol) and NaH (0.308 g, 7.71 mmol) in DMSO (14 ml) was added dropwise tetrahydro-2H-pyran-4- carbaldehyde (0.8 g, 7.01 mmol). The resultant solution was stirred at r.t. for 20 min and then heated for 30 min at 60 °C. The mixture was poured into water and extracted with DCM (x 3). The organics were dried (MgSO^), filtered and concentrated under reduced pressure to yield a colourless oil. The oil was dissolved into diethyl ether and washed with half saturated brine (x 5),The organics were dried (MgSC^), filtered and concentrated under reduced pressure to yield 4-(oxiran-2-yl)tetrahydro-2H-pyran as a colourless oil (236 mg, 26 %). Used without further purification in next step.

Step b Example 145

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromobenzylidene)-l-cyclobutylpiperidine (Int 5) and using 4-(oxiran-2- yl)tetrahydro-2H-pyran (Int 179).

Ή NMR (400 MHz, MeOD) 67.16 - 7.25 (m, 2H), 7.09 - 7.16 (m, 2H), 6.28 - 6.35 (m, 1H), 3.92 - 4.04 (m, 2H), 3.52 - 3.61 (m, 1H), 3.35 - 3.42 (m, 2H), 2.71 - 2.92 (m, 2H), 2.58 - 2.68 (m, 1 H), 2.29 - 2.58 (m, 8H), 2.03 - 2.16 (m, 2H), 1.89 - 2.03 (m, 2H), 1.68 - 1.84 (m, 3H), 1.39 - 1.67 (m, 4H)

MS ES⁺ 356 2.146 Example 146 3-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]benzyi}tetrahydrofuran-3-ol

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting (4-bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using dioxaspiro[2.4]heptane (CAS 185-61-5).

Ή NMR (400 MHz, CDC1₃) δ 7.14 - 7.25 (m, 4H), 6.23 - 6.33 (m, 1H), 3.89 - 4.13 (m, 2H), 3.72 - 3.80 (m, lH), 3.59 - 3.72 (m, 1H), 2.97 (s, 2H), 2.65 - 2.80 (m, 1H), 2.47 - 2.61 (m, 2H), 2.38 - 2.47 (m, 4H), 2.23 - 2.38 (m, 2H), 2.00 - 2.15 (m, 3H), 1.84 - 2.00 (m, 3H), 1.62 - 1.84 (m, 3H)

MS ES⁺ 328

2.147 Example 147

4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydrofuran-3-ol

Prepared in an analogous manner to Intermediate 170 via Scheme 35 starting with 4- (4-bromobenzylidene)-l -cyclobutylpiperidine (Int 5) and using 3,6- dioxabicyclo[3.1.0]hexane. ^lH NMR (400MHz, DMSO-<¾) δ 7.21 (m, 2H), 7.14 (m, 2H), 6.24 (s, 1 H), 5.24 (m, 1H), 4.21 (m, 1H), 4.14 (m, 1H), 3.94 (m, 1 H), 3.70 (m, 1H), 3.56 (m, 1H), 3.12 - 3.19 (m, 1H), 2.67 (m, 1H), 2.36 - 2.44 (m, 2H), 2.25 - 2.35 (m, 4H), 2.17 - 2.25 (m, 2H), 1.90 - 2.02 (m, 2H), 1.72 - 1.85 (m, 2H), 1.49 - 1.68 (m, 2H)

MS ES⁺ 314

2.148 and 2.149 Examples 148 and 149 Example 148

l -{4-[(E)-(l -Cyclobutylazepan-4-ylidene)methyl]phenyl} -4-methoxycyclohexanol

Examples 148 and 149 were prepared as a mixture of alkene isomers and separated at the end of the synthesis.

Scheme 40

R_5b represents R_s cycloalkyl or heterocyclyl, each of which may be optionally substituted, R₂i represents H or C 1.3 alkyl.

Reagents and conditions: a) NaH, EtOH, THF 75 °C, 3 h; b) HCl, dioxane; c) triethylamine, acetic acid, sodium triacetoxyborohydride, R₃=0, DCM; d) n- Butyllithium, THF, -78 °C, R_5b=0 or R₅R₂₁C=0 Step a Intermediate 180

-4-(4-Bromobenzylidene)-l -cyclobutylazepane

Prepared in an analogous manner to Intermediate 5 via Scheme 3, method B, starting from ri-butyl 4-oxoazepane-l-carboxylate and diethyl (4-bromobenzyl)phosphonate, and Scheme 4 using cyclobutanpne in step b. Ή NMR (400 MHz, CDC1₃) δ 7.24 - 7.36 (m, 2 H), 6.90 - 7.07 (m, 2 H), 6.12 (s, 1 H), 2.66 - 2.91 (m, 1 H), 2.23 - 2.58 (m, 8 H), 1.84 - 2.05 (m, 2 H), 1.41 - 1.84 (m, 6 H) MS (ES⁺) 320.5, 322.5

Step b Examples 148 and 149

Prepared in an analogous manner to Intermediate 53 via Scheme 40 starting with (4E/Z)-4-(4-bromobenzylidene)-l-cyclobutylazepane (Int 180) and using 4- methoxycyclohexanone. The crude material was purified by column chromatography (NH Si0₂; 20 - 100 % EtOAc in petrol) and then by reverse phase HPLC to give the separate alkene isomers.

'

Example 148

Ή NMR (400 MHz, CDC1₃) δ 7.40 - 7.50 (m, 2H), 7.19 - 7.27 (m, 2H), 6.28 (s, 1H), 3.42 (s, 3H), 3.19 - 3.36 (m, 1H), 2.78 - 2.93 (m, 1H), 2.59 - 2.68 (m, 2H), 2.48 - 2.59 (m, 4H), 2.40 - 2.48 (m, 2H), 1.58 - 2.13 (m, 16H)

MS ES⁺ 371 _t Example 149 Ή NMR (400 MHz, CDC1₃) δ 7,39 - 7.50 (m, 2H), 7.18 - 7.26 (m, 2H), 6.29 (s, 1 H), 3.42 (s, 3H), 3.21 - 3.33 (m, 1H), 2.82 - 3.01 (m, 1H), 2.61 - 2.74 (m, 2H), 2.39 - 2.61 (m, 6H), 1.95 - 2.12 (m, 4H), 1.60 - 1.95 (m, 12H) MS ES⁺ 371

2,150 Example 150

-{4-[(E)-(l-CyclobutyIazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol

2.151 Example 151

-{4-[(Z)-(l -Cyclobutylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol

Examples 150 and 151 were prepared in an analogous manner to Examples 148 and 149 via Scheme 40 starting from (4E/Z)-4-(4-bromobenzylidene)-l-cyclobutylazepane (Int 180) and using tetrahydro-4H-pyran-4-one. Example 150

Ή NMR (400 MHz, CDC1₃) δ 7.38 - 7.52 (m, 2H), 7.22 - 7.28 (m, 2H), 6.19 - 6.38 (m, 1H), 3.80 - 4.04 (m, 4H), 2.79 - 2.94 (m, 1H), 2.37 - 2.68 (ra, 8H), 2.14 - 2.27 (m, 2H), 1.99 - 2.12 (m, 2H), 1.77 - 1.96 (m, 4H), 1.49 - 1.77 (m, 5H)

MS ES⁺ 343

Example 151

Ή NMR (400 MHz, CDCI₃) δ 7.40 - 7.50 (m, 2 H), 7.22 - 7.28 (m, 2 H), 6.29 (s, 1 H), 3.83 - 4.02 (m, 4 H), 2.84 - 2.97 (m, 1 H), 2.62 - 2.71 (m, 2 H), 2.44 - 2.61 (m, 6 H), 2.13 - 2.25 (m, 2 H), 1.98 - 2.12 (m, 2 H), 1.51 - 1.93 (m, 10 H)

MS ES⁺ 343

2.152 Example 152 -(4- {(E)-[ 1 -(Propan-2-yl)azepan-4-ylidene]methy 1 } phenyl)tetrahydro-2H-pyran-4-ol

2.153 Example 153

-(4-{(Z)-[l -(Propan-2-yl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4-

Examples 152 and 153 were prepared as a mixture of alkene isomers and separated at the end of the synthesis.

Step a Intermediate 181

-4-(4-bromobenzylidene)- 1 -(propan-2-yl)azepane

Prepared in an analogous manner to Intermediate 5 via Scheme 3, method B, starting from tert-butyl 4-oxoazepane-l-carboxylate and diethyl (4-bromobenzyl)phosphonate, and Scheme 4 using acetone in step b.

Ή NMR (400 MHz, MeOD) δ 7.39 - 7.52 (m, 2H), 7.07 - 7.22 (m, 2H), 6.24 - 6.33 (m, 1H), 2.84 - 3.03 (m, lH), 2.41 - 2.84 (m, 8H), 1.70 - 1.88 (m, 2H), 1.07 (m, 6H)

MS ES⁺ 308/310

Step b Examples 152 and 153

Examples 152 and 153 were prepared in an analogous manner to Examples 148 and 149 via Scheme 40 starting from (4E/Z)-4-(4-bromobenzylidene)-l-(propan-2- yl)azepane (Int 181) and using tetrahydro-4H-pyran-4-one. Example 152

'H NMR (400 MHZ, MeOD) δ 7.41 - 7.51 (m, 2H), 7.18 - 7.28 (m, 2H), 6.30 - 6.39 (m, 1 H), 3.90 - 4.01 (m, 2H), 3.75 - 3.89 (m, 2H), 2.97 - 3.13 (m, 1H), 2.69 - 2.94 (m, 4H), 2.47 - 2.69 (m, 4H), 2.06 - 2.22 (m, 2H), 1.78 - 1.92 (m, 2H), 1.60 - 1.74 (m, 2H), 1.12 (m, 6H)

MS ES⁺ 330

Example 153

¹ H NMR (400 MHz, MeOD) 67.42 - 7.51 (m, 2H), 7.18 - 7.29 (m, 2H), 6.26 - 6.37 (m, 1H), 3.89 - 4.03 (m, 2H), 3.76 - 3.88 (m, 2H), 2.87 - 2.99 (m, 1H), 2.72 - 2.85 (m, 4H), 2.63 - 2.73 (m, 2H), 2.46 - 2.55 (m, 2H), 2.07 - 2.23 (m, 2H), 1.77 - 1.88 (m, 2H), 1.58 - 1.73 (m, 2H), 1.05 (m, 6H)

MS ES⁺ 330

2.154 Example 154

-{4-[(E)-(l-Cyclobutylazepan-4-ylidene)methyl]benzyl}tetrahydro-2H-pyran-4-ol

Prepared in an analogous manner to Intermediate 170 via Scheme 40 starting with (4E/Z)-4-(4-bromobenzylidene)-l-cyclobutylazepane (Int 180) and using 1,6- dioxaspiro [2.5]octane . Ή NMR (400 MHz, CDC1₃) δ 7.14 - 7.25 (m, 4H), 6.24 - 6.32 (m, 1H), 3.70 - 3.84 (m, 4H), 2.83 - 2.91 (m, 1 H), 2.77 (s, 2H), 2.49 - 2.67 (m, 6H), 2.39 - 2.49 (m, 2H), 2.00 - 2.13 (m, 2H), 1.74 - 1.94 (m, 6H), 1.61 - 1.73 (m, 2H), 1.40 - 1.52 (m, 2H), 1.26 (s, 1H) MS ES⁺ 356 2.155 Example 155

4-{4-[(E)-(l -Cyclopentylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol

2.156 Example 156

-{4-[(Z)-(l-cyclopentylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol

Examples 155 and 156 were prepared as a mixture of alkene isomers and separated at the end of the synthesis.

Step a Intermediate 182

-4-(4-Bromobenzylidene)-l -cyclopentylazepane

Prepared in an analogous manner to Intermediate 5 via Scheme 3, method B, starting from tert-butyl 4-oxoazepane-l -carboxylate and diethyl (4-bromobenzyl)phosphonate, and Scheme 4 using cyclopentanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.39 - 7.51 (m, 2H), 7.10 - 7.22 (m, 2H), 6.24 - 6.32 (m, 1H), 2.71 - 3.01 (m, 5H), 2.47 - 2.70 (m, 4H), 1.68 (m, 12H)

MS ES⁺ 334/336

Step b Examples 155 and 156

Examples 155 and 156 were prepared in an analogous manner to Examples 148 and 149 via Scheme 40 starting from (4E/Z)-4-(4-bromobenzylidene)-l-cyclopentylazepane (Int 182) and using tetrahydro-4H-pyran-4-one.

Example 155 Ή NMR (400 MHz, MeOD) δ 7.43 - 7.51 (m, 2H), 7.21 - 7.28 (m, 2H), 6.32 - 6.38 (m, 1H), 3.91 - 4.02 (m, 2H), 3.77 - 3.87 (m, 2H), 2.90 - 3.03 (m, 1H), 2.82 - 2.91 (m, 2H), 2.71 - 2.81 (m, 2H), 2.56 - 2.64 (m, 4H), 2.08 - 2.22 (m, 2H), 1.80 - 1.97 (m, 4H), 1.54 - 1.79 (m, 6H), 1.46 (m, 2H)

MS ES⁺ 356

Example 156 1H NMR (400 MHz, MeOD) 57.42 - 7.50 (m, 2H), 7 20 - 7.29 (m, 2H), 6.29 - 6.39 (m, 1H), 3.89 - 4.04 (m, 2H), 3.75 - 3.89 (m, 2H), 2.94 - 3.04 (m, 1H), 2.86 - 2.94 (m, 2H), 2.77 - 2.86 (m_; 2H), 2.65 - 2.76 (m, 2H), 2.47 - 2.59 (m, 2H), 2.07 - 2.20 (m, 2H), 1.79 - 1.94 (m, 4H), 1.62 - 1.77 (m, 4H), 1.49 - 1.62 (m, 2H), 1.42 (m, 2H)

MS ES⁺ 356

2.157 Example 157

4-(4-{(E)-[l-(Cyclopropylmethyl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H-

2.158 Example 158

4-(4-{(Z)-[l-(Cyclopropylmethyl)azepan-4-ylidene]niethyl}phenyl)tetrahydro-2H- pyran-4-ol

Examples 157 and 158 were prepared as a mixture of alkene isomers and separated at the end of the synthesis.

Step a Intermediate 183 -4-(4-Bromobenzylidene)-l -(cyclopropylmethyl)azepane

Prepared in an analogous manner to Intermediate 5 via Scheme 3, method B, starting from tert-butyl 4-oxoazepane-l-carboxylate and diethyl (4-bromobenzyl)phosphonate, and Scheme 4 using cyclopropanecarboxaldehyde in step b.

Ή NMR (400 MHz, MeOD) 67.44 (m, 2H), 7.06 - 7.21 (m, 2H), 6.21 - 6.35 (m, 1H), 2.70 - 2.91 (m, 4H), 2.46 - 2.70 (m, 4H), 2.39 (s, 2H), 1.73 - 1.91 (m, 2H), 0.80 - 0.96 (m, 1 H), 0.46 - 0.62 (m, 2H), 0.04 - 0.21 (m, 2H)

MS ES⁺ 320/322

Step b Examples 157 and 158

Examples 157 and 158 were prepared in an analogous manner to Examples 148 and 149 via Scheme 40 starting from (4E/Z)-4-(4-bromobenzylidene)-l- (cyclopropyJmethyl)azepane (Int 183) and using tetrahydro-4H-pyran-4-one.

Example 157

Ή NMR (400 MHz, MeOD) δ 7.39 - 7.49 (m, 2H), 7.17 - 7.26 (m, 2H), 6.27 - 6.36 (m, 1H), 3.87 - 4.00 (m, 2H), 3.74 - 3.87 (m, 2H), 2.83 - 2.92 (m, 2H), 2.73 - 2.83 (m, 2H), 2.55 - 2.67 (m, 4H), 2.39 - 2.48 (m, 2H), 2.04 - 2.20 (m, 2H), 1.79 - 1.93 (m, 2H), 1.60 - 1.73 (m, 2H), 0.84 - 1.00 (m, 1H), 0.50 - 0.60 (m, 2H), 0.08 - 0.21 (m, 2H)

MS ES⁺ 342 Example 158

Ή NMR (400 MHz, MeOD) δ 7.42 - 7.48 (m, 2H), 7.19 - 7.28 (m, 2H), 6.30 - 6.35 (m, 1H), 3.89 - 3.99 (m, 2H), 3.76 - 3.86 (m, 2H), 2.86 - 2.94 (m, 2H), 2.78 - 2.86 (m, 2H), 2.66 - 2.73 (m, 2H), 2.50 - 2.58 (m, 2H), 2.37 - 2.46 (m, 2H), 2.07 - 2.20 (m, 2H), 1.79 - 1.87 (m, 2H), 1.61 - 1.71 (m, 2H), 0.84 - 0.94 (m, 1H), 0.49 - 0.57 (m, 2H), 0.12 (m, 2H) MS ES⁺ 342

2.159 Example 159

4-(4-{(E)-[l-(2-Methylpropyl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4-

2.160 Example 160

4-(4-{(Z)-[l-(2-Methylpropyl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4-

Examples 159 and 160 were prepared as a mixture of alkene isomers and separated at the end of the synthesis. Step a Intermediate 184

-4-(4-Bromobenzylidene)- 1 -(2-methylpropyl)azepane

Prepared in an analogous manner to Intermediate 5 via Scheme 3, method B, starting from tert-butyl 4-oxoazepane-l-carboxylate and diethyl (4-bromobenzyl)phosphonate, and Scheme 4 using isobutyraldehyde in step b.

Ή NMR (400 MHz, MeOD) 5 7.45 (m, 2H), 7.07 - 7.22 (m, 2H), 6.19 - 6.32 (m, 1H), 2.41 - 2.82 (m, 8H), 2.13 - 2.34 (m, 2H), 1.65 - 1.87 (m, 3H), 0.92 (m, 6H)

MS ES⁺ 322/324

Step b Examples 159 and 160 Examples 159 and 160 were prepared in an analogous manner to Examples 148 and 149 via Scheme 40 starting from (4E/Z)-4-(4-Bromobenzylidene)-l- (cyclopropylmethyl)azepane (Int 184) and using tetrahydro-4H-pyran-4-one. Example 159

Ή NMR (400 MHz, MeOD) δ 7.43 - 7.51. (m, 2H), 7.16 - 7.30 (m, 2H), 6.27 - 6.34 (m, 1H), 3.91 - 4.00 (m, 2H), 3.74 - 3.88 (m, 2H), 2.71 - 2.81 (m, 2H), 2.63 - 2.71 (m, 2H), 2.53 - 2.63 (m, 4H), 2.22 - 2.35 (m, 2H), 2.08 - 2.21 (m, 2H), 1.76 - 1.89 (m, 3H), 1.61 - 1.73 (m, 2H), 0.95 (m, 6H)

MS ES⁺ 344

Example 160 Ή NMR (400 MHz, MeOD) 67.43 - 7.49 (m, 2H), 7. 8 - 7.28 (m, 2H), 6.29 - 6.35 (m, 1H), 3.89 - 4.01 (m, 2H), 3.77 - 3.88 (m, 2H), 2.77 - 2.87 (m, 2H), 2.69 - 2.77 (m, 2H), 2.61 - 2.69 (m, 2H), 2.46 - 2.55 (m, 2H), 2.22 - 2.34 (m, 2H), 2.06 - 2.22 (m, 2H), 1.63 - 1.86 (m, 5H), 0.90 (m, 6H)

MS ES⁺ 344

2,161 Example 161

4-{4-[(E)-(l-Ethylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol

Scheme 41

Reagents and conditions: a) Etl, K₂C0₃, DMF Step a Intermediate 185

-4-(4-Bromobenzylidene)-l -ethylazepane

To a stirred suspension of 4-(4-bromobenzylidene)azepane hydrochloride (2.23 g, 7.36 mmol) in DMF (25 ml) was added K₂C0₃ (2.54 g, 18.40 mmol) and iodoethane (0.589 ml, 7.36 mmol) and mixture stirred at r.t. for 18 h.

Sat. NH4CI and EtOAc were added and phases separated and aqueous was further extracted with EtOAc (x 3). The organics were washed with brine (x 4), dried (MgS0₄), filtered and concentrated under reduced pressure. The residue was purified via column chromatography (NH Si0₂, 0 - 60 % EtOAc in petrol) to yield (4E/Z)-4-(4- bromobenzylidene)-l-ethylazepane as a yellow oil (1.86 g, 86 %).

Ή NMR (400 MHz, MeOD) δ 7.40 - 7.53 (m, 2H), 7.10 - 7.24 (m, 2H), 6.22 - 6.36 (m, 1H), 2.42 - 2.86 (m, 10H), 1.75 - 1.94 (m, 2H), 1.13 (m, 3H)

MS ES ' 294/296

Step b Example 161

Example 161 was prepared in an analogous manner to Examples 148 and 149 via Scheme 40 starting from (4E/Z)-4-(4-bromobenzylidene)-l-ethylazepane (Int 185) and using tetrahydro-4H-pyran-4-one.

Ή NMR (400 MHz, MeOD) δ 7.43 - 7.51 (m, 2H), 7.21 - 7.28 (m, 2H), 6.32 - 6.38 (m, 1H), 3.90 - 4.01 (m, 2H), 3.78 - 3.88 (m, 2H), 2.75 - 2.85 (m, 2H), 2.68 - 2.75 (m, 2H), 2.55 - 2.68 (m, 6H), 2.09 - 2.21 (m, 2H), 1.81 - 1.92 (m, 2H), 1.62 - 1.73 (m, 2H), 1.15 (s, 3H)

MS ES⁺ 316

2.162 Example 162

l-{6-[(l-Cyclobutylpiperidin-4-ylidene)methyl]pyridin-3-yl}-4-methoxycyclohexanol

Reagents and conditions: a) Int 26, K3PO4, PdCl₂(dppf), dioxane, water, 100 °C MW

Step a Intermediate 186

tert-Butyl 4-[(5-bromopyridin-2-yl)methylidene]piperidine-l-carboxylate

A mixture of 2,5-dibromopyridine (1.61 g, 6.81 mmol), tert-butyl 4-((4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)methylene)piperidine-l-carboxylate (Int 26) (2.20 g, 6.81 mmol), potassium phosphate (1.45 g, 6.81 mmol) and PdCl₂(dppf) (0.498 g, 0.681 mmol) in 1 , 4-dioxane (7 ml) and water (7 ml) was heated in the microwave at 100 °C for 20 min. Water was added and the mixture extracted with EtOAc, dried (MgS0₄), concentrated under reduced pressure and purified by column chromatography (Si0₂; 0 - 20 % EtOAc in petrol) to give tert-butyl 4-[(5-bromopyridin-2- yl)methylidene]piperidine-l-carboxylate as a yellow solid (645 mg, 27 %).

Ή NMR (400 MHz, DMSCW₆) δ 8.64 (m, 1H), 7.98 (m, 1H), 7.26 (m, 1H), 6.35 (s, 1H), 3.44 (m, 2H), 3.37 (m, 2H), 2.87 (m, 2H), 2.31 (m, 2H), 1.42 (s, 9H)

■ MS ES⁺ 253/255 Step b Example 162

Prepared via Scheme 4 starting from tert-butyl 4-[(5-bromopyridin-2- yl)methylidene]piperidine-l -carboxylate (Int 186) using cyclobutanone and Scheme 26 using nBuLi starting from 5-bromo-2-[(l -cyclobutylpiperidin-4- ylidene)methyl]pyridine and using 4-methoxycyclohexanone. Ή NMR (400 MHz, DMSO-i¾ δ 8.56 - 8.67 (m, 1H), 7.67 - 7.79 (m, 1H), 7.07 - 7.20 (m, 1H), 6.24 (s, 1H), 4.93 (s, 1H), 3.13 - 3.28 (m, 4H), 2.81 - 2.93 (m, 2H), 2.57 - 2.72 (m, 1H), 2.27 - 2.38 (m, 5H), 2.17 - 2.27 (m, 2H), 1.91 - 2.02 (m, 2H), 1.69 (m, 12H) MS ES⁺ 357

2.163 Example 163

4-({5-[(l -Cyclobutylpiperidin-4-ylidene)methyl]pyridin-2-yl}methyl)tetrahydro-2H- pyran-4-ol

Scheme 43

Reagents and conditions: a) n-BuLi, THF, -20 °C, tetrahydro-4H-pyran-4-one Step a Intermediate 187

5-[(l -Cyclobutylpiperidin-4-ylidene)methyl]-2-methylpyridine

Prepared in an analogous manner to Intermediate 3 via Scheme 3 method B starting from 5-(bromomethyl)-2-methylpyridine hydrobromide and using tert-butyl 4- oxopiperidine-l-carboxylate then Scheme 4 using cyclobutanone in step b. Ή NMR (300MHz, CDC1₃) 58.34 (d, 1H, J = 2.0 Hz), 7.39 (dd, 1H, J - 8.0, 2.0 Hz), 7.09 (d, 1 H, J = 8.0 Hz), 6.19 (s, 1H), 2.73 (quin, 1H, J = 8.0 Hz), 2.53 (br. s., 2H), 2.49 (m, 2H), 2.43 (br. s., 2H), 2.31 (m, 2H), 2.08 - 1.89 (m, 4H), 1.77 - 1.59 (m, 2H)

Step b Example 163 To a solution of 5-[(l -cyclobutylpiperidin-4-ylidene)methyl]-2-methyIpyridine (Int 187) (80 mg, 0.33 mmol) in THF (5 ml) at -20 °C was added n-BuLi (155 μΐ, 2.35 M in hexanes, 0.36 mmol). Tetrahydro-4H-pyran-4-one (34 μΐ, 0.36 mmol) was added immediately and the reaction allowed to warm to r.t. and stirred for 72 h. The reaction was quenched via the addition of AcOH and was then concentrated under reduced pressure. The residue was purified by column chromatography (Si0₂; 0 to 10 % MeOH (1 % NH₃) in DCM then 10 % MeOH in toluene) to give 4-({5-[(l-cyclobutylpiperidin- 4-ylidene)methyl]pyridin-2-yl}methyl)tetrahydro-2H-pyran-4-ol (38 mg, 34 %). · Ή NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 7.41 - 7.55 (m, 1 H), 7.13 - 7.27 (m, 1H), 6.21 (s, 1 H), 3.52 - 3.74 (m, 4H), 2.83 (s, 2H), 2.63 - 2.78 (m, 1H), 2.14 - 2.47 (m, 8H), 1 .92 - 2.07 (m, 2H), 1.75 - 1.91 (m, 2H), 1.53 - 1.74 (m, 4H), 1.30 - 1.43 (m, 2H) MS ES⁺ 343 2.164 and 2.165 Examples 164 and 165

-{5-[(l -Cyclobutylpiperidin-4-ylidene)methyl]pyridin-2-yl} -4-methoxycyclohexanol

Prepared via Scheme 2 starting from 2-bromo-5-(bromomethyl)pyridine to give [(6- bromopyridin-3-yl)methyl](triphenyl)phosphonium bromide then Scheme 3 method A to give tert-butyl 4-[(6-bromopyridin-3-yl)methylidene]piperidine-l -carboxylate then Scheme 4 using cyclobutanone in step b to give 2-bromo-5-[(l -cyclobutylpiperidin-4- ylidene)methyl]pyridine then Scheme 26 using nBuLi and 4-methoxycyclohexanone. The 2 ring isomers were separated and isolated.

Example 164 ISOMER 1

Ή NMR (400 MHz, DMSO-a¾) δ 8.32 (s, 1H), 7.50 - 7.67 (m, 2H), 6.24 (s, 1H), 5.00 (s, 1 H), 3.26 (s, 3H), 3.10 - 3.24 (m, 1H), 2.60 - 2.75 (m, 1H), 2.35 - 2.43 (m, 2H), 2.28 - 2.36 (m, 4H), 2.17 - 2.26 (m, 2H), 1.87 - 2.02 (m, 4H), 1.69 - 1.87 (m, 4H), 1.48 - 1.69 (m, 6H) MS ES⁺ 357

Example 165 ISOMER 2 1H NMR (400 MHz, DMSO-£¾) δ 8.33 (s, 1H), 7.48 - 7.65 (m, 2H), 6.24 (s, 1H), 4.94 (s, 1 H), 3.37 - 3.47 (m, 1H), 3.23 (s, 3H), 2.59 - 2.76 (m, 1H), 2.36 - 2.43 (m, 2H), 2.33 (s, 4H), 2.08 - 2.29 (m, 4H), 1.91 - 2.06 (m, 2H), 1.48 - 1.91 (m, 8H), 1.25 - 1.39 (m, 2H)

MS ES⁺ 357

2.166 Example 166

-Cyclobutyl-4-{4-[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]benzylidene}piperidine

R_5b is as defined in Scheme 35

Reagents and conditions: a) DAST, DCM, -78 °C

To a solution of 4-(4-((l-cyclobutylpiperidin-4-ylidene)methyl)benzyl)tetrahydro-2H- pyran-4-ol (Example 143) (226 mg, 0.66 mmol) in DCM (3.31 ml) at -78 °C was added DAST (437 μΐ, 3.31 mmol). The reaction was stirred at this temperature for 5 h. Water was added and reaction allowed to warm to r.t. Sat. aq. NaHC0₃ and DCM were added and the layers separated. The organics were dried (MgS0₄), concentrated under reduced pressure and purified by column chromatography (NH silica; 0 - 40 % EtOAc in petrol). The residue was purified by prep. HPLC to give l-cyclobutyl-4-{4-[(4-fluorotetrahydro- 2H-pyran-4-yl)methyl]benzylidene}piperidine as a white solid (26 mg, 1 1 %). Ή NMR (400 MHz, DMSC .) δ 7.17 (m, 2H, J = 8.08 Hz), 7.13 (d, 2H, J =8.08 Hz), 6.25 (s, 1H), 3.61 - 3.79 (m, 2H), 3.40 - 3.57 (m, 2H), 2.91 (d, 2H, J = 22.99 Hz), 2.57 - 2.75 (m, 1H), 2.41 (t, 2H, J = 5.43 Hz), 2.25 - 2.36 (m, 4H), 2.22 (t, 2H, J = 5.68 Hz), 1.90 - 2.04 (m, 2H), 1.69 - 1.90 (m, 3H), 1.44 - 1.69 (m, 5H)

MS ES⁺ 344

2.167 Example 167

-Cyclobutyl-4-[4-(4-fluorotetrahydro-2H-pyran-4-yl)benzylidene]piperidine

Prepared in an analogous manner to Example 166 via Scheme 44 starting from 4-{4- [( I -cyclobuty lpiperidin-4-y lidene)methy ljphenyl } tetrahydro-2H-pyran-4-ol (Exam pie 88).

Ή NMR (400 MHz, CDC1₃) δ 7.32 - 7.41 (m, 2H), 7.18 - 7.27 (m, 2H), 6.21 - 6.37 (m, 1H), 3.82 - 4.03 (m, 4H), 2.64 - 2.81 (m, 1H), 2.50 - 2.62 (m, 2H), 2.37 - 2.50 (m, 4H), 2.28 - 2.37 (m, 2H), 2.00 - 2.27 (m, 4H), 1.84 - 2.01 (m, 4H), 1.63 - 1.82 (m, 2H) MS ES⁺ 331

2.168 Example 168

-Cyclobutyl-4-[4-(l ^fluoro-4-methoxycyclohexyl)benzylidene]piperidine

Prepared in an analogous manner to Example 166 via Scheme 44 starting from l-{4- [(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-met oxycyclohexanol (Example 91).

Ή NMR (400 MHz, CDC1₃) 5 7.30 - 7.38 (m, 2H), 7.14 - 7.24 (m, 2H), 6.22 - 6.32 (m, 1 H), 3.43 (s, 3H), 3.23 - 3.37 (m, 1 H), 2.66 - 2.80 (m, 1 H), 2.48 - 2.61 (m, 2H), 2.37 - 2.46 (m, 4H), 2.27 - 2.37 (m, 2H), 2.00 - 2.23 (m, 6H), 1.84 - 1.99 (m, 3H), 1.62 - 1.84 (m, 5H) MS ES⁺ 358

2.169 Example 169

-(4-( 1 -( 1 -Cyclobutylpiperidin-4-ylidene)ethyl)benzyl)cyclopentanamine

Reagents and conditions: a) cyclobutanone, sodium triacetoxyborohydride, DCM; b) (C0C1)₂, DMSO, Et₃N, DCM, -78 °C to r.t.; c) tnmethylorthoformate, pTSA, MeOH; d)i) Mg, I₂, THF, reflux then Int 189, THF, 0 °C to r.t. then HC1 (aq.); e) cyclopentylamine,^' THF then NaBH₄, MeOH; f) (COCl)₂₎ DMSO, Et₃N, DCM, -78 °C to r.t.; g) MeMgBr, THF; h) 2N H₂S0₄ Step a Intermediate 188

-Cy clobuty lpiperidin-4-yl)methanol

To a stirring solution of piperidin-4-ylmethanol (5.42 g, 47.6 mmol) in DCM was added cyclobutanone (5 g, 71.3 mmol) at r.t. Sodium triacetoxyborohydride (15.1 g, 71.3 mmol) was added portionwise. The resulting suspension was allowed to stir for 40 min. NaOH (10 g, 250 mmol) was then added to brine (100 ml) and added to the reaction mixture. The layers were separated and the aqueous layer back extracted with EtOAc (x 2). The organics were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to yield l-cycIobutyIpiperidin-4-yl)methanoI as a crude yellow oil (7.98 g, 100 %).

^VH NMR (300MHz, CDC1₃) 63.50 (m, 2H), 2.85 (m, 2H), 2.70 - 2.50 (m, 2H), 2.00 (m, 2H), 1.90 - 1.60 (m, 7H), 1.40 (m, 1H), 1.20 (m, 2H)

MS ES⁺ 170

Step b Intermediate 189

l -Cyclobutylpiperidine-4-carbaldehyde

Oxalyl chloride (7.19 g, 47.2 mmol) was dissolved in DCM and cooled to -78 °C. DMSO (8.85 g, 113.3 mmol) was added dropwise and the mixture stirred for 5 min before a solution of (l-cyclobutylpiperidin-4-yl)methanol (Int 188) (7.98 g, 47.2 mmol) was added dropwise and mixture stirred at -78 °C for 15 min. Triethylamine (23.84 g, 236 mmol) was added dropwise. The resulting off-white suspension was allowed to warm to r.t. for 1 h. The reaction mixture was filtered through celite, dried (sodium sulfate), filtered, concentrated under reduced pressure and azeotroped with toluene to yield l-cyclobutylpiperidine-4-carbaldehyde as an orange oil (7.02 g, 88 %). Ή N R (300MHz, CDC1₃) δ 9.60 (s, 1H), 2.75 (m, 2H), 2.25 (m, 1H), 2.10 - 1.80 (m, 9H), 1 .70 (m, 4H)

MS ES⁺ 168

Step c Intermediate 190

-Bromo-4-(dimethoxymethyl)benzene

4-Bromobenzaldehyde (30 g, 162 mmol) trimethylorthoformate (51.62 g, 486 mmol) and para-toluenesulfonic acid (3.0 g, 16.2 mmol) were stirred in MeOH (300 ml) at r.t. for 20 h. A further portion of trimethylorthoformate (25.81 g, 243 mmol) was added and the water azeotroped with toluene under reduced pressure. The residue was diluted with toluene and washed with 15 % aqueous sodium hydroxide, dried (sodium sulfate), filtered and concentrated under reduced pressure. It was purified by vacuum distillation to give l-bromo-4-(dimethoxymethyl)benzene as a colourless liquid (23.92 g, 64 %).

Ή NMR (300MHz, CDCI3) δ 7.48 (m, 2H), 7.35 (m, 2H), 5.35 (s, 1H), 3.30 (s, 6H) MS ES⁺ 168

Step d i) Intermediate 191

Bromo[4-(dimethoxymethyl)phenyl]magnesium

Magnesium turnings (1.22 g, 50.2 mmol) were charged to dried glassware in anhydrous THF (20 ml) with an iodine crystal. A solution of l-bromo-4- (dimethoxymethyl)benzene (Int 190) (1 1.57 g, 50.3 mmol) in anhydrous THF was added dropwise with heating. The bromo[4-(dimethoxymethyl)phenyl]magnesium solution was used directly in the subsequent reactions.

Step d ii) Intermediate 192

4-((l -Cyclobutylpiperidin-4-yl)(hydroxy)methyl)benzaldehyde

A solution of l-cyclobutylpiperidine-4-carbaldehyde (Int 189) (6.54 g, 0.39 mmol) in anhydrous THF was added dropwise to a suspension of bromo[4- (dimethoxymethyl)phenyl]magnesium (Int 191) (50.3 mmol) in anhydrous THF at 0 °C with stirring and the mixture was allowed to warm to r.t. After stirring for 1 h the reaction mixture was concentrated under reduced pressure and treated with 2N aqueous HC1 (30 ml) and stirred for 5 min before washing with DCM (x 2). The aqueous layer was then basified with 50 % aqueous NaOH and extracted with EtOAc (x 2). The organics were combined and dried (sodium sulfate) and concentrated under reduced pressure to yield 4-((l-cyclobutylpiperidin-4-yl)(hydroxy)methyl)benzaldehyde as an off-white solid (9.31 g, 75 %).

Ή NMR (300MHz, CDC1₃) δ 9.99 (s, 1H), 7.85 (m, 2H), 7.45 (m, 2H), 4.50 (m, 1H), 2.85 (m, 2H), 2.60 (m, 1H), 2.00 - 1.20 (m, 13H)

MS ES⁺ 274

Step e Intermediate 193

(l -Cyclobutylpiperidin-4-yl)(4-((cyclopentylamino)methyl)phenyl)methanol

To a solution of 4-((l-cyclobutylpiperidin-4-yl)(hydroxy)methyl)benzaldehyde (Int 192) (4.67 g, 17.18 mmol) in anhydrous THF (50 ml) was added cyclopentylamine (2.19 g, 25.8 mmol) and mixture was stirred at r.t. for 1 h. Further cyclopentylamine (0.73 g, 8.59 mmol) was added and stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure and diluted with MeOH (50 ml). Sodium borohydride (1.94 g, 51.5 mmol) was added portionwise and stirred at r.t. for 1 h. The reaction mixture was concentrated under reduced pressure and treated with 2 N aqueous HCi, basified with 2.5 N aqueous NaOH and extracted into EtOAc (x 2). The organics were dried (sodium sulfate) and concentrated under reduced pressure to yield (1- cyclobutylpiperidin-4-yl)(4-((cyclopentylamino)methyl)phenyl)methanol as a crude yellow oil (5.54 g, 95 %).

Ή NMR (300MHz, CDC1₃) 67.25 (m, 4H), 4.30 (m, 1H), 3.70 (s, 2H), 3.10 (m, 1H), 2.90 (m, 1H), 2.75 (m, 1H), 2.60 (m, 1H), 2.00 - 1.20 (m, 22H)

MS ES⁺ 343 Step f Intermediate 194

(l-Cyclobutylpiperidin-4-yl){4-[(cyclopentylamino)methyl]phenyl}methanone

To a solution of oxalyl chloride (2.47 g, 19.4 mmol) in DCM (30 ml) at -78 °C was added dropwise DMSO (3 g, 38.9 mmol). The resultant mixture was stirred at -78. °C for 5 min then (l-cyclobutyIpiperidin-4-yl)(4-((cyclopentylamino)methyl) phenyl)methanol (Int 193) (5.54 g, 16.2 mmol) in DCM was added dropwise. The mixture was stirred for 15 min then NEt₃ (8.2 g, 81 mmol) was added dropwise and the mixture allowed to warm to r.t. The reaction mixture was poured into sat. aq. NaHC0₃ and the aqueous was extracted with DCM (x 2). The organics were dried (sodium sulfate) and concentrated under reduced pressure to yield (l-cyclobutylpiperidin-4- yl)(4-((cyclopentylamino)methyl)phenyl)methanone as a yellow waxy solid (4.3 g, 78

%). Ή NMR (300MHz, CDCI3) 6 7.89 (m, 2H), 7.40 (m, 2H), 3.81 (s, 2H), 3.20 (m, 1H),

3.10 (m, 1H), 2.90 (m, 2H), 2.70 (m, 1H), 2.10 -1.10 (m, 21H) MS ES⁺ 341

Step g Intermediate 195

-(l-Cyclobutylpiperidin-4-yl)-l-{4-[(cyclopentylamino)methyl]phenyl}ethanoI

To a solution of (l-cyclobutylpiperidin-4-yl)(4-((cyclopentylamino)methyl)phenyl) methanone (Int 194) (1.0 g, 2.94 mmol) in anhydrous THF (15 ml) was added methylmagnesium bromide (4.9 ml, 14.71 mmol) dropwise and stirred at r.t. for 1 h. The reaction mixture was concentrated under reduced pressure and treated with 2N aqueous HCl (10 ml) then basified with 50 % aqueous NaOH and extracted with EtOAc. The organics were dried, (sodium sulfate) and concentrated under reduced pressure. The crude material was purified by column chromatography (Si0₂; 5 % eOH (1% NH₃)/ DCM) to yield l-(l-cyclobutylpiperidin-4-yl)-l-{4- [(cyclopentylamino)methyl]phenyl}ethanol (530 mg, 43 %).

Ή NMR (300MHz, CDC1₃) §7.30 (m, 2H), 7.20 (m, 2H), 3.70 (s, 2H), 3.10 (m, 1H),

2.85 (d, 2H), 2.55 (m, 1H), 2.00 - 1.20 (m, 24H)

MS ES⁺ 357

Step h Example 169

1 -( 1 -cyclobutylpiperidin-4-yl)- 1 - { 4-[(cyclopentylamino)methyl]phenyl} ethanol (Int 195) (450 mg, 1.26 mmol) was treated with 2N aqueous sulfuric acid (1 ml) and heated to 80 °C for 18 h. The reaction was basified using brine .NaOH and extracted into EtOAc, dried (sodium sulphate) and concentrated under reduced pressure. The crude material was purified by column chromatography (Si0₂; 5 % MeOH (1 % NH₃) / DCM) to yield N-{4-[l -(l-cyclobutylpiperidin-4-ylidene)ethyl]benzyl} cyclopentanamine (109 mg, 26 %). 1H NMR (300MHz, CDC1₃?)57.25 (m, 2H), 7.05 (m,? 2H), 3.70 (s, 2H), 3.10 (m, 1H), 2.65 (m, 1H), 2.45 - 2.30 (m, 4H), 2.15 (m, 4H), 1.95 (m, 2H), 1.90 (s, 3H), 1.85 (m, 4H), 1.70 (m, 4H), 2.50 (m, 2H), 1.35 (m, 2H)

MS ES⁺ 339

2.170 Example 170

-[ 1 -( 1 -Cyclobutylpiperidin-4-ylidene)ethyl]phenyl } methanol

Reagents and conditions: a) Br₂, K₂C0₃₎ DCM; b) DBU, DCM; c) MeB(OH)₂, 3P0 , PdC (dppf), THF, H₂0, 60 °C MW Step a Intermediate 196

tert-Butyl 4-bromo-4-{bromo[4-(ethoxycarbonyl)phenyl]methyl}piperidine-l- carboxylate

Potassium carbonate (1 g, 7 mmol) was added to a solution of ethyl 4-[(l- cyclobutylpiperidin-4-ylidene)methyl]benzoate (Int 9) (5.53 g, 16 mmol) in DCM (250 ml) and the suspension was stirred at r.t. A solution of bromine (2.9 g, 18 mmol) in DCM (50 ml) was added over 5 min and the mixture was then stirred for 2 h. The mixture was filtered and the solvent evaporated to afford a white solid which was triturated with heptane and dried to yield tert-butyl 4-bromo-4-{bromo[4- (ethoxycarbonyl)phenyl]methyl}piperidine-l -carboxylate (6.2 g, 76 %). Ή NMR (300 MHz, CDC1₃) δ 8.00 (m, 2H), 7.58 (m, 2H), 5.12 (s, 1H), 4.39 (m, 2H), 4.10 (m, 2H), 3.10 (m, 2H), 2.13 (m, 2H), 1.90 - 1.70 (m, 2H), 1.41 (s, 9H), 1.38 (m, 3H)

Step b Intermediate 197

tert-Butyl 4-{bromo[4-(ethoxycarbonyl)phenyl]methylidene}piperidine-l -carboxylate

A solution of iert-butyl . 4-bromo-4-{bromo[4-

(ethoxycarbonyl)phenyl]methyl}piperidine-l-carboxylate (Int 196) (2.52 g, 5 mmol) in DCM (75 ml) was stirred at r.t. and DBU (0.91 g, 6 mmol) in DCM (25 ml) was added over 5 min. The solution was allowed to stand overnight before a further aliquot of DBU (0.40 g, 2.5 mmol) was added and the solution warmed to 40 °C for 1 h. After cooling to r.t., the mixture was washed with water (x 3), dried (MgSC^) and concentrated under reduced pressure. This was stirred with cold diethyl ether and the supernatant decanted. Evaporation of the ether yielded tert-butyl 4-{bromo[4- (ethoxycarbonyl)phenyl]methylidene}piperidine-l-carboxylate as a yellow solid (1.7 g, 80 %).

Ή NMR (300 MHz, CDC1₃) 58.02 (m, 2H), 7.32 (m, 2H), 4.37 (m, 2H), 3.54 (m, 2H), 3.32 (m, 2H), 2.64 (m, 2H), 2.22 (m, 2H), 1.41 (s, 9H), 1.38 (m, 3H)

Step c Intermediate 198

tert-Butyl 4-{ l-[4-(ethoxycarbonyl)phenyl]ethylidene}piperidine-l-carboxylate

To a stirred solution of the ter/-butyl 4-{bromo[4- (ethoxycarbonyl)phenyl]methylidene}piperidine- l -carboxylate (Inr 197) (1.5 g, 3.5 mmol) and methylboronic acid (630 mg, 10.5 mmol) in THF (15 ml) was added 3PO4 (2.23 g, 10.5 mmol) in water (3 ml). The mixture was degassed by bubbling argon through it for 10 min and then Pd(dppf)Cl2 (292 mg, 0.4 mmol) was added and it was irradiated at 60^°C in a microwave for 2 h. The mixture was filtered through celite and silica and concentrated under reduced pressure then purified by column chromatography (Si0₂; 5 % EtOAc in heptane) to yield /er/-but l 4-{ l -[4- (ethoxycarbonyl)phenyl]ethylidene}piperidine-l-carboxylate

as a colourless oil (990 mg, 79 %).

Ή NMR (300 MHz, CDC ) 67.99 (d, 2H, J - 6.8 Hz), 7.14 (d, 2H, J = 6.8 Hz), 4.37 (q, 2H, J = 7.4 Hz), 3.48 (t, 2H, J = 6 Hz), 3.29 (t, 2H, J = 6 Hz), 2.39 (t, 2H, J = 6 Hz), 2.09 (t, 2H, J = 6 Hz), 1.97 (s, 3H), 1.46 (s, 9H), 1.40 (t, 3H, J = 7.4 Hz)

Step d Intermediate 199

-[l -0 -cyclobutylpiperidin-4-ylidene)ethyl]benzoate

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting with tert- butyl 4-{ l-[4-(ethoxycarbonyl)phenyl ethylidene}piperidine-l-carboxylate (Int 198) and using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.88 (d, 2H, J = 8.08 Hz), 7.13 (d, 2H, J = 8.08 Hz), 4.26 (q, 2H, J = 7.07 Hz), 2.84 - 3.00 (m, 1H), 2.51 - 2.63 (m, 2H), 2.43 - 2.51 (m, 2H), 2.31 - 2.42 (m, 2H), 1.98 - 2.16 (m, 4H), 1.84 - 1.98 (m, 5H), 1.58 - 1.73 (m, 2H), 1.29 (t, 3H, J = 7.07 Hz)

MS ES⁺ 314 Step e Example 170 Prepared in analogous manner to Intermediate 31 via Scheme 16 starting from ethyl 4- [l -(l -cyclobutylpiperidin-4-ylidene)ethyl]benzoate (Int 199).

Ή NMR (300 MHz, CDC1₃) δ 7.24 (d, 2H, J = 8 Hz), 7.13 (d, 2H, J = 8 Hz), 6.25 (s, 1H), 3.46 (s, 2H), 3.33 (s, 3H), 3.21 (tt, 1H, J = 8.5 Hz, 5 Hz), 2.76- 2.66 (m, 3H), 2.53 (t, 2H, J = 5.5 Hz), 2.39 (s, 4H), 2.29 (t, 2H, J = 5.5 Hz), 2.18 - 2.09 (m, 2H), 2.08 - 1.99 (m, 2H), 1.95 - 1.84 (m, 4H), 1.77 - 1.59 (m, 4H)

MS ES⁺ 272 2.171 Example 171

-Cyclobutyl-4-{ l -[4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl]ethylidene}piperidine

Prepared in analogous manner to Example 10 via Scheme 6 starting from ethyl 4-[l-(l - cyclobutylpiperidin-4-ylidene)ethyl]benzoate (Example 199).

Ή NMR (400 MHz, CDC1₃) δ 7.98 (d, 2H, J = 8.34 Hz), 7.19 (m, 2H), 2.57 - 2.71 (m, 1H), 2.37 - 2.45 (m, 5H), 2.28 - 2.37 (m, 2H), 2.06 - 2.22 (m, 4H), 1.77 - 2.02 (m, 7H), 1.52 - 1.72 (m, 2H)

MS ES⁺ 324

2.172 Example 172

4-{4-[(E)-(l-Cyclobutyl-3-methylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H- pyran-4-ol (racemic)

Prepared via Scheme 3 Method A starting from /<?r/-butyl 3-methyl-4-oxopiperidine-l- carboxylate and (4-bromobenzyl)(tripheny])phosphonium bromide then Scheme 4 using cyclobutanone in step b then Scheme 26 starting from (4E)-4-(4-bromobenzyIidene)-l- cyclobutyl-3-methylpiperidine and using BuLi and tetrahydro-4H-pyran-4-one.

Ή NMR (400 MHz, MeOD) δ 7.44 (d, 2H, J = 8.08 Hz) 7.17 (d, 2H, J = 8.08 Hz) 6.31 (s, 1H) 3.89 - 4.01 (m, 2H) 3.77 - 3.88 (m, 2H) 2.69 - 2.93 (m, 4H) 2.42 - 2.56 (m, 1H) 2.01 - 2.30 (m, 5H) 1.83 - 2.01 (m, 3H) 1.71 - 1.81 (m, 3H) 1.64 - 1.82 (m, 6H) 1.68 (d, 3H, J = 12.88 Hz) 1.18 (d, 3H, J = 6.82 Hz)

MS ES⁺ 342 2.173 Example 173

-Cyclobutyl-4-[4-(tetrahydro-2H-pyran-4-ylsulfonyl)benzylidene]piperidine

Scheme 47

Reagents and conditions: a) NaH, R₅Br, DMF; b) mCPBA, DCM; c) Int 26, Pd(PPh₃)₄, K₂C0₃, dioxane, H₂0, 100 °C MW or Int 26, PdCl₂(dppf), sat. aq. Na₂C0₃, dioxane, 80 °C MW

Step a) Intermediate 200

-[(4-Bromophenyl)sulfanyl]tetrahydro-2H-pyran

To a solution of 4-bromobenzenethiol (2 g, 10.58 mmol) in DMF (20 ml) was added NaH (0.635 g, 15.87 mmol) at 0 °C and the reaction stirred for 1 h. To this was added 4-bromotetrahydro-2H-pyran (1.92 g, 1 1.64 mmol) in DMF and the reaction allowed to warm to r.t. and stirred for 67 h. Reaction was quenched by addition of water and extracted with EtOAc (x 2). The organics were washed with brine (x 5), dried (MgSC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (Si0₂; 0 -100 % DCM in petrol) to yield 4-[(4- bromophenyl)sulfanyl]tetrahydro-2H-pyran (2.18 g, 75 %). Ή NMR (400 MHz, DMSO- ) 87.52 (ra, 2H), 7.35 (m, 2H), 3.73 - 3.88 (m, 2H), 3.44 - 3.56 (m, 1H), 3.39 (m, 2H), 1.84 (m, 2H), 1.49 (m, 2H)

Step b) Intermediate 201

-[(4-Bromophenyl)sulfonyl]tetrahydro-2H-pyran

To a solution of 4-[(4-bromophenyl)sulfanyl]tetrahydro-2H-pyran (Int 200) (2.18 g, 8 mmol) in DCM (25 ml) was added 3-chlorobenzoperoxoic acid (4.13 g, 37 mmol). Mixture was quenched by addition of sodium hydrogen carbonate and extracted with DCM (x 2). The organics were dried (MgSC^) and concentrated under reduced pressure to yield 4-(4-bromophenylsulfonyl)tetrahydro-2H-pyran (2.66 g, 100 %). Taken on as crude material in the next step.

MS ES⁺ 309 Step c Intermediate 202

tert-Buryl 4-[4-(tetrahydro-2H-pyran-4-ylsulfonyl)benzylidene]piperidine-l -carboxylate

A microwave vial was charged with 4-(4-bromophenylsulfonyl)tetrahydro-2H-pyran (Int 201) (598 mg, 2.0 mmol), reri-butyl 4-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)methylene)piperidine- l-carboxylate (Int 26) (950 mg, 2.9 mmol), and potassium carbonate (1.083 g, 7.84 mmol) in 1 ,4-Dioxane : ¾0 (4 ml : 4 ml). The vial was sealed and purged with nitrogen then Pd(PPh₃)₄ (226 mg, 0.2 mmol) was added and mixture irradiated in the microwave for 45 min at 100 °C. Mixture was quenched by the addition of sat. aq. NaHC0₃ and extracted with EtOAc (x 2). The organics were washed with brine, dried (MgSO_i) and concentrated under reduced pressure. Residue was purified by column chromatography (Si0_2; 0 - 50 % EtOAc in petrol) to yield tert-butyl 4-[4-(tetrahydro-2H-pyran-4-ylsulfonyl)benzylidene]piperidine-l -carboxylate as a white solid.

MS ES⁺ 422

Ste d Example 173

Prepared in an analogous manner to Intermediate 5 via Scheme 4 starting from tert- butyl 4-[4-(tetrahydro-2H-pyran-4-ylsulfonyl)benzylidene]piperidine-l-carboxyiate (Int 202) using cyclobutanone in step b

Ή NMR (400 MHz, DMSO-d₆) δ 7.74 - 7.85 (m, 2H), 7.46 - 7.55 (m, 2H), 6.40 (s, 1 H), 3.84 - 3.95 (m, 2H), 3.45 - 3.60 (m, 1 H), 3.22 - 3.30 (m, 2H), 2.65 - 2.76 (m, 1H), 2.40 - 2.47 (m, 2H), 2.31 - 2.40 (m, 4H), 2.20 - 2.29 (m, 2H), 1.92 - 2.05 (m, 2H), 1.67 - 1.85 (m, 4H), 1 .45 - 1.67 (m, 4H)

MS ES⁺ 376

2.174 Example 174

l -cyclobutyl-4-{4-[(2-methoxyethyl)sulfonyl]benzylidene}piperidine

Prepared in an analogous manner to Example 173 via Scheme 47 starting from 4- bromobenzenethiol and 2-methoxyethanethiol using PdCl₂dppf and Na₂C0₃ in step c, and Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, DMSO-rf₆) δ 7.72 - 7.88 (m, 2H), 7.32 - 7.51 (m, 2H), 6.37 (s, 1H), 3.51 - 3.68 (m, 4H), 3.10 (s, 3H), 2.59 - 2.76 (m, 1H), 2.40 - 2.46 (m, 2H), 2.34 (s, 4H), 2.19 - 2.30 (m, 2H), 1.91 - 2.03 (m, 2H), 1.71 - 1.91 (m, 2H), 1.50 - 1.71 (m, 2H) MS ES⁺ 350

2.175 Example 175

-Cyclobutyl-4-{4-[(3-methoxypropyl)sulfonyl]benzylidene}piperidine

Prepared in an analogous manner to Example 173 via Scheme 47 starting from 4- bromobenzenethiol and 3-methoxypropane-l -thiol using PdCl₂dppf and Na₂C0₃ in step c, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO-de) δ 7.73 - 7.88 (m, 2H), 7.39 - 7.53 (m, 2H), 6.38 (s, 1H), 3.22 - 3.42 (m, 7H), 2.59 - 2.78 (m, 1H), 2.40 - 2.47 (m, 2H), 2.34 (s, 4H), 2.17 - 2.29 (m, 2H), 1.88 - 2 4 (m, 2H), 1.70 - 1.88 (m, 4H), 1.51 - 1.70 (m, 2H)

MS ES⁺ 364

2.176 Example 176

-Cyclobutyl-4-{4-[(tetrahydro-2H-pyran-4-ylmethyl)sulfonyl]benzylidene} piperidine

Prepared in an analogous manner to Example 173 via Scheme 47 starting from 4- bromobenzenethiol and tetrahydro-2H-pyran-4-ylmethanethiol using Pd(PPh₃)₄ and K₂C0₃ in step c, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.87 (m, 2H, J = 8.34 Hz), 7.46 (m, 2H, J = 8.34 Hz), 6.42 (s, 1H), 3.78 - 3.91 (m, 2H), 3.39 (td, 2H, J = 1 1.81 , 1.89 Hz), 3.18 (d, 2H, J = 6.32 Hz), 2.74 - 2.84 (m, 1H), 2.51 - 2.57 (m, 2H), 2.46 (s, 4H), 2.36 (t, 2H, J = 5.56 Hz), 2.02 - 2.21 (m, 3H), 1.87 - 2.00 (m, 2H), 1.68 - 1.82 (m, 4H), 1.34 - 1.49 (m, 2H) MS ES⁺ 390 2,177 Example 177

-Cyclobutyl-4-{4-[(2-ethoxyethyl)sulfonyl]benzylidene}piperidine

Prepared in an analogous manner to Example 173 via Scheme 47 starting from 4- bromobenzenethiol and 2-ethoxyethanethiol using PdCl₂dppf and Na₂C0₃ in step c, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO-< ) δ 7.74 - 7.92 (m, 2H), 7.34 - 7.59 (m, 2H), 6.59 (s, 1H), 3.52 - 3.71 (m, 5H), 3,43 - 3.52 (m, IH), 3.34 - 3.43 (m, 1H), 3.21 - 3.29 (m, 2H), 2.66 - 2.91 (m, 4H), 2.54 - 2.66 (m, 2H), 2.26 - 2.46 (m, 2H), 2.04 - 2.26 (m, 2H), 1.53 - 1.86 (m, 2H), 0.77 - 0.92 (m, 3H)

MS ES⁺ 364 2,178 Example 178

-Cyclobutyl-4-(4-{[(2-ethoxyethyl)sulfonyl]methyl}benzylidene)piperidine

Prepared in an analogous manner to Example 173 via Scheme 47 using appropriate starting materials and using PdCl₂dppf and Na₂C0 in step c, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, CDC1₃) δ 7.34 - 7.48 (m, 2H), 7.18 - 7.26 (m, 2H), 6.29 (s, IH), 4.36 (s, 2H), 3.76 - 3.96 (m, 2H), 3.51 - 3.68 (m, 2H), 3.02 - 3.13 (m, 2H), 2.66 - 2.84 (m, IH), 2.48 - 2.62 (m, 2H), 2.43 (m, 4H), 2.20 - 2.36_. (m, 2H), 2.01 - 2.13 (m, 2H), 1.81 - 2.01 (m, 2H), 1.49 - 1.81 (m, 2H), 1.13 - 1.44 (m, 3H)

MS ES⁺ 378

2.179 Example 179

4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]-N-methyl-N-(tetrahydro-2H-pyran-4- yl)benzenesulfonamide

Scheme 48

Reagents and conditions: a) R_{5 8}NH, Et₃N, DCM or R₅RgNH, Na₂C0₃, MeCN; b) Int 26, Pd(PPh₃)₄, K₂C0₃, dioxane, H₂0, 100 °C MW or Int 26, PdCl₂(dppf), sat. aq. Na₂C0₃, dioxane, 80 °C MW or Int 26, Pd(PPh₃)₄, Na₂C0₃, dioxane, H₂0, 100 °C MW

Step a Intermediate 203

-Bromo-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonaniide

To a solution of N-methyltetrahydro-2H-pyran-4-amine (0.710 g, 6.16 mmol) and Et₃N (1.227 ml, 8.81 mmol) in DCM (10 ml) cooled to 0 °C was added dropwise a solution of 4-bromobenzene-l-sulfonyl chloride (1.5 g, 5.87 mmol) in DCM (10 ml). The reaction was allowed to warm to r.t. and stirred for 20 h. The reaction was concentrated under reduced pressure and the resultant white solid dissolved in EtOAc and filtered. The filtrate was concentrated under reduced pressure and the resulting solid dried under high vacuum to yield 4-bromo-N-methyl-N-(tetrahydro-2H-pyran-4- yl)benzenesulfonamide as an off-white solid (1.94 g, 99 %).

Ή NMR (400 MHz, DMSO- 57.79 (m, 4H), 3.87 - 4.01 (m, 1 H), 3.73 - 3.86 (m, 2H), 3.33 - 3.37 (m, 1H), 3.29 (m, 1H), 2.70 (s, 3H), 1.54 - 1 .70 (m, 2H), 1.11 - 1.27 (m, 2H)

Ste b Example 179 Prepared in an analogous manner to Example 173 via Scheme 48 starting from 4- bromo-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (Int 203) in step b and using PdCl dppf and Na₂C0₃, and Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, DMSO- δ 7,70 - 7.79 (m, 2H), 7.34 - 7.46 (m, 2H), 6.34 (s, 1H), 3.87 - 4.00 (m, 1H), 3.75 - 3.87 (m, 2H), 3.31 (m, 2H), 2.61 - 2.74 (m, 4H), 2.38 - 2.45 (m, 2H), 2.30 - 2.38 (m, 4H), 2.21 - 2.29 (m, 2H), 1.88 - 2.05 (m, 2H), 1.72 - 1.88 (m, 2H), 1.54 - 1.72 (m, 4H), 1.14 - 1.26 (m, 2H)

MS ES⁺ 405

2.180 Example 180

4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]-N-(tetrahydro-2H-pyran-4- yl)benzenesulfonamide

Prepared in an analogous manner to Example 179 via Scheme 48 starting with 4- bromobenzene- l-sulfonyl chloride and tetrahydro-2H-pyran-4-amine and using Pd(PPh3)₄ and Na₂C0₃ in step b, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO-ifc) δ 7.69 - 7.78 (m, 2H), 7.29 - 7.48 (m, 2H), 6.34 (br. s., 1H), 3.65 - 3.81 (m, 2H), 3.09 - 3.27 (m, 3H), 2.61 - 2.75 (m, 1H), 2.33 (br. s., 9H), 1.87 - 2.05 (m, 2H), 1.70 - 1.87 (m, 2H), 1.56 - 1.70 (m, 2H), 1.41 - 1.56 (m, 2H), 1.32 (m, 2H)

MS ES⁺ 391 2.181 Example 181

-({4-[(l-CycIobutylpiperidin-4-ylidene)methyl]phenyl}sulfonyl)morpholine

Prepared in an analogous manner to Example 179 via Scheme 48 starting with 4- bromobenzene- l-sulfonyl chloride and morpholine and using PdCl₂dppf and Na₂C0₃ in step b, and Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, DMSO-fl¾) δ 7.62 - 7.72 (m, 2H), 7.41 - 7.51 (m, 2H), 6.38 (s, 1H), 3.55 - 3.68 (m, 4H), 2.79 - 2.93 (m, 4H), 2.63 - 2.78 (m, 1H), 2.40 - 2.47 (m, 2H), 2.34 (s, 4H), 2.17 - 2.29 (m, 2H), 1.90 - 2.03 (m, 2H), 1.71 - 1.90 (m, 2H), 1.53 - 1.71 (m, 2H)

MS ES⁺ 377

2.182 Example 182

-Cyclobutyl-4-{4-[(3-methoxyazetidin-l-yl)sulfonyl]benzylidene}piperidine

Prepared in an analogous manner to Example 179 via Scheme 48 starting with 4- bromobenzene- l-sulfonyl chloride and 3-methoxyazetidine hydrochloride and using PdCl₂dppf and Na₂C0₃ in step b, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO-i¾ δ 7.67 - 7.80 (m, 2H), 7.40 - 7.57 (m, 2H), 6.39 (s, 1H), 3.97 - 4.08 (m, 1H), 3.86 - 3.97 (m, 2H), 3.39 - 3.51 (m, 2H), 3.05 (s, 3H), 2.62 - 2.76 (m, 1H), 2.41 - 2.48 (m, 2H), 2.35 (s, 3H), 2.19 - 2.32 (m, 2H), 1.89 - 2.04 (m, 2H), 1.71 - 1.89 (m, 2H), 1,51 - 1.71 (m, 2H)

MS ES⁺ 377

2.183 Example 183

-Cyc[obutyI-4-{4-[(4-methoxypiperidin- l-yl)sulfonyl]benzylidene}piperidine

Prepared in an analogous manner to Example 179 via Scheme 48 starting with 4- bromobenzene-l -sulfonyl chloride and 4-methoxypiperidine and using PdCl₂dppf and

Na₂C0₃ in step b, and Scheme 4 using cyclobutanone. in step b. Ή NMR (400 MHz, DMSO-c¾ δ 7.58 - 7.74 (m, 2H), 7.36 - 7.51 (ra, 2H), 6.36 (s, 1H), 3.19 - 3.27 (m, 1H), 3.15 (s, 3H), 2.99 - 3.1 1 (m, 2H), 2.73 - 2.83 (m, 2H), 2.63 - 2.73 (m, 1H), 2.41 - 2.48 (m, 2H), 2.34 (s, 4H), 2.20 - 2.29 (m, 2H), 1.89 - 2.04 (m, 2H), 1.70 - 1.89 (m, 4H), 1.45 - 1.70 (m, 4H)

MS ES⁺ 405

2.184 Example 184

1 - {4- [( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } -N-methyl-N-(tetrahydi pyran-4-yl)methanesulfonamide

Step a) Intermediate 204

l-(4-Bromophenyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)methanesulfonamide

To a suspension of N-methyltetrahydro-2H-pyran-4-amine (0.507 g, 4.40 mmol) and sodium carbonate (0.467 g, 4.40 mmol) in MeCN (10 ml) was added (4- bromophenyl)methanesulfonyl chloride (0.593 g, 2.201 mmol) and the reaction mixture was stirred at r.t. for 1.5 h. The mixture was quenched with water and extracted with EtOAc (x 2). The organics were dried (MgS0₄) and concentrated under reduced pressure to yield l-(4-bromophenyl)-N-methyl-N-(tetrahydro-2H-pyran-4- yl)methanesulfonamide as a white solid (0.634 g, 83 %).

Ή NMR (400 MHz, MeOD) δ 7.56 (m, 2H, J = 8.34 Hz), 7.38 (m, 2H, J = 8.34 Hz), 4.34 (s, 2H), 3.95 (dd, 2H, J = 1 1.62, 4.55 Hz), 3.69 - 3.82 (m, 1H), 3.35 - 3.43 (m, 2H), 2.72 (s, 3H), 1.74 - 1.87 (m, 2H), 1.45 - 1.53 (m, 2H)

Step b Example 187 Prepared in an analogous manner to Example 179 via Scheme 48, step b starting with l -(4-bromophenyl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)methanesulfonamide (Int 204) and using Pd(PPh₃)4 and K₂C0₃, and Scheme 4 using cyclobutanone in step b. Ή NMR (400 MHz, CDClj) δ 7.34 (m, 2H J = 7.83 Hz), 7.20 (m, 2H, J = 8.08 Hz), 6.27 (s, 1H), 4.20 (s, 2H), 3.92 (dd, 2H, J = 1 1.37, 4.29 Hz), 3.60 - 3.75 (m, 1H), 3.29 (t, 2H, J = 1 1.37 Hz), 2.59 - 2.76 (m, 4H), 2.44 - 2.54 (m, 2H), 2.41 (s, 4H), 2.20 - 2.32 (m, 2H), 1.99 - 2.10 (m, 2H), 1.81 - 1.99 (m, 2H), 1.62 - 1.79 (m, 4H), 1.29 - 1.41 (m, 2H) MS ES⁺ 419

2.185 Example 185

4-({4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]benzyl}sulfonyl)morpholine

Prepared in an analogous manner to Example 184 via Scheme 48 starting with (4- bromophenyl)methanesulfonyl chloride and morpholine and using Pd(PPh₃)₄ and K₂C0₃ in step b, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) δ 7.42 (m, 2H, J = 8.08 Hz), 7.24 (m, 2H, J = 8.08 Hz), 6.36 (s, 1H), 4.36 (s, 2H), 3.59 - 3.70 (m, 4H), 3.10 - 312 l (m, 4H), 2.73 - 2.87 (m, 1H), 2.51 - 2.59 (m, 2H), 2.41 - 2.51 (m, 4H), 2.36 (t, 2H, J = 5.43 Hz), 2.02 - 2.16 (m, 2H), 1.89 - 2.02 (m, 2H), 1.65 - 1.84 (m, 2H)

MS ES⁺ 391 2.186 Example 186

l-Cyclobutyl-4-(4-{[(3-methoxy-3-methylazetidin-l -yl)sulfonyl]methyl}

benzylidene)piperidine

Prepared in an analogous manner to Example 184 via Scheme 48 starting with (4- bromophenyl)methanesulfonyl chloride and 3-methoxy-3-methylazetidine hydrochloride and using Pd(PPh )₄ and K₂C0₃ in step b, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO-<¾) δ 7.36 (d, 2H, J = 8.08 Hz), 7.20 (d, 2H, J = 8.08 Hz), 6.27 (s, 1H), 4.48 (s, 2H), 3.85 (d, 2H, J = 8.34 Hz), 3.56 (d, 2H, J = 8.34 Hz), 3.13 (s, 3H), 2,62 - 2.74 (m, 1H), 2.35 - 2.45 (m, 2H), 2.31 (s, 4H), 2.22 (t, 2H, J = 5.56 Hz), 1.86 - 2.06 (m, 2H), 1.69 - 1.83 (m, 2H), 1.53 - 1.67 (m, 2H), 1.39 (s, 3H)

MS ES⁺ 405

2.187 Example l87

l -{4-[(l -Cyclobuty]piperidin-4-ylidene)methyl]phenyl}-N.-(tetrahydro-2H-pyran-4- yl)methanesulfonamide

Prepared in an analogous manner to Example 184 via Scheme 48 starting with (4- bromophenyl)methanesulfonyl chloride and tetrahydro-2H-pyran-4-amine and using Pd(PPh )₄ and K₂C0₃ in step b, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, DMSO- 0 δ 7,33 (d, 2H, J = 8.08 Hz), 7.13 - 7.25 (m, 3H), 6.27 (s, 1H), 4.30 (s, 2H), 3.67 - 3.83 (m, 2H), 3.14 - 3.27 (m, 3H), 2.60 - 2.73 (m, 1H), 2.40 (t, 2H, J = 5.31 Hz), 2.31 (br. s., 4H), 2.13 - 2.25 (m, 2H), 1.87 - 2.00 (m, 2H), 1.66 - 1.87 (m, 4H), 1.49 - 1.66 (m, 2H), 1.28 - 1.48 (m, 2H)

MS ES⁺ 405

2.188 Example 188

l -Cyclobutyl-4-[4-(l ,4-dimethoxycyclohexyl)benzylidene]piperidine

cheme 49

Reagents and conditions: a)i) BH₃.THF, THF, -78 °C ii) NaHMDS, Mel, THF iii) 2M NaOH (aq.)

To a stirred solution of l-(4-((l-cyclobutylpiperidin-4-ylidene)methyl)phenyl)-4- methoxycyclohexanol (Example 91) (700 mg, 1.969 mmol) in dry THF (19.7 ml) at -78 °C, under an atmosphere of nitrogen, was added dropwise borane.THF complex (2.166 ml, 2.166 mmol) and the reaction was stirred at -78 °C for 2 h. The reaction was then allowed to warm to r.t. and then concentrated under reduced pressure. To a solution of the resultant oil dissolved in dry THF (10 ml), cooled to 0 °C under nitrogen, was added dropwise NaHMDS in THF (2.166 ml, 2.166 mmol). The reaction was stirred at 0 °C for 15 min. lodomethane was then added dropwise (148 μΐ, 2.363 mmol) and the reaction was stirred at 0 °C for 1 h and then allowed to warm to r.t. and stirred for 17 h. 2M sodium hydroxide (10 ml) was added and the reaction was stirred at r.t. for 5 days. The mixture was extracted with EtOAc (x 2). The organics were washed with water and brine, dried (MgSC^), filtered and concentrated under reduced pressure. The crude oil was purified by column chromatography (NH silica; 0 - 30 % EtOAc in petrol) to yield a colourless oil which was dried in the high vacuum oven at 60 °C for 3 h to yield 1- cyclobutyl-4-[4-(l ,4-dimethoxycyclohexyl)benzylidene]piperidine as a yellow solid (274 mg, 36 %).

Ή NMR (400 MHz, DMSO-cfc) δ 7.26 - 7.39 (m, 2H), 7.07 - 7.26 (m, 2H), 6.18 - 6.31 (m, 1 H), 3.26 (s, 3H), 3.10 - 3.23 (m, 1H), 2.87 (s, 3H), 2.61 - 2.73 (m, 1H), 2.38 - 2.46 (m, 2H), 2.26 - 2.36 (m, 4H), 2.16 - 2.26 (m, 2H), 1.89 - 2.04 (m, 4H), 1.72 - 1.89 (m, 4H), 1.56 - 1.72 (m, 4H), 1.39 - 1.55 (m, 2H)

MS ES⁺ 370 2.189 Example 189

l-Cyclobutyl-4-[4-(4-methoxytetrahydro-2H-pyran-2-yl)benzylidene]piperidine

Reagents and conditions: a) But-3-en-l -ol, H₂S0₄; b) NaH, Mel, THF; c) Int 26, Pd(PPh₃) , ₂C0₃, dioxane/water, 100 °C, MW

Step a Intermediate 205

-(4-Bromophenyl)tetrahydro-2H-pyran-4-

To a mixture of 4-bromobenzaldehyde (5 g, 27.0 mmol) and but-3-en- l-ol (5.85 g, 81 mmol) was added dropwise sulfuric acid (4.32 ml, 81 mmol) and the reaction mixture was stirred at r.t. for 18 h. The reaction was poured onto ice water, basified to pH 8 with 1M NaOH, extracted with EtOAc and dried (MgS0₄), and concentrated under reduced pressure. The crude oil was purified by column chromatography (Si0₂; 0 - 55 % EtOAc in petrol) and concentrated under reduced pressure to yield 2-(4- bromophenyl)tetrahydro-2H-pyran-4-ol as a white solid (2.5 g, 36 %). Ή NMR (400 MHz,MeOD) δ7.49 (m, 2H), 7.30 (s, 2H), 4.28 - 4.40 (m, 1H), 4.04 - 4.18 (m, 1H), 3.81 - 3.96 (m, 1H), 3.54 - 3.71 (m, 1H), 2.07 - 2.18 (m, 1H), 1.85 - 2.00 (m, 1 H), 1.49 - 1.66 (m, 1 H), 1.39 (m, 1 II) Ste b Intermediate 206

2-(4-bromophenyl)-4-methoxytetrahydro-2H-pyran

To a solution of 2-(4-bromophenyl)tetrahydro-2H-pyran-4-ol (Int 205) (2.5 g, 9.72 mmol) in THF, under a nitrogen atmosphere, was added sodium hydride (0.506 g, 12.64 mmol) at 0 °C and the resultant slurry stirred for 1 h at 0 °C. Iodomethane (0.790 ml, 12.64 mmol) was added dropwise and the reaction mixture allowed to warm to r.t. and stirred for 18 h. The reaction was quenched with sat. NH₄C1 and extracted with Et₂0 (x 3). The organics were dried (MgS0₄), filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (Si0₂; 5 - 40 % EtOAc in petrol) to yield the 2-(4-bromophenyl)-4-methoxytetrahydro-2H-pyran as a clear, colourless oil (1.2 g, 46 %).

Ή NMR (400 MHz, CD₂C1₂) 61.39 (m, 1H), 1.48 - 1.60 (m, 1H), 2.00 - 2.09 (m, 1H), 2.24 (dt, 1H, J = 12.57, 2.05 Hz), 3.38 (s, 3H), 3.45 - 3.62 (m, 2H), 4.12 - 4.25 (m, 1H), 4.31 (dd, 1H, J = 1 1.49, 1.39 Hz); 7.28 (d, 2H, J = 8.34 Hz), 7.51 (d, 2H, J = 8.59 Hz)

Step c Example 189

Prepared in an analogous manner to Example 179 via Scheme 48, step b starting with 2-(4-bromophenyl)-4-methoxytetrahydro-2H-pyran (Int 206) and using Pd(PPh₃)₄ and 2C0₃, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, MeOD) 5 7.25 - 7.41 (m, 2H), 7.12 - 7.23 (m, 2H), 6.34 (s, 1H), 4.28 - 4.41 (m, 1H), 4.08 - 4.20 (m, 1H), 3.51 - 3.68 (m, 2H), 3.40 (s, 3H), 2.70 - 2.87 (m, 1H), 2.29 - 2.60 (m, 8H), 2.17 - 2.29 (m, 1H), 2.02 - 2.16 (m, 3H), 1.84 - 2.02 (m, 2H), 1.63 - 1.84 (m, 2H), 1.29 - 1.59 (m, 2H)

MS ES⁺ 342 2.190 Example 190

1 -Cyclobutyl-4- {4-[4-(methoxymethyl)tetrahydro-2H-pyran-4- yl]benzyltdene} piperidine

Scheme 51

Reagents and conditions: a) NaH, l -bromo-2-(2-bromoethoxy)ethane, DMF, Et₂0; b) LiAlH₄, THF; c) NaH, Mel, DMF; d) Int 26, Pd(PPh₃)₄, K₂C0₃, dioxane, H₂0, 100 °C MW

Step a Intermediate 207

-Bromophenyl 2-ethyltetrahydro-2H-pyran-4-carboxylate

A mixture of NaH (60% in mineral oil) (2.057 g, 51.4 mmol) in DMF (67 ml) stirred at 0 °C was treated dropwise with a mixture of ethyl 2-(4-bromophenyl)acetate (5 g, 20.57 mmol) and 1 -bromo-2-(2-bromoethoxy)ethane (2.59 ml, 20.57 mmol) in 3 ml of diethyl ether. The mixture was allowed to warm to r.t. and stirred for 17 h. Mixture was quenched with water and sat. NH4CI. The mixture was extracted with EtOAc (x 3) and then organics washed with brine (x 3) and dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si0₂; 0 - 100 % EtOAc in petrol) to yield 4-bromophenyl 2-ethyltetrahydro-2H-pyran-4- carboxylate as a pale yellow oil (2.88 g, 45 %).

Ή NMR (400 MHz, CD₂C1₂) 57.46 - 7.56 (m, 2H), 7.32 (m, 2H), 4.15 (m, 2H), 3.84 - 3.98 (m, 2H), 3.50 - 3.63 (m, 2H), 2.38 - 2.56 (m, 2H), 1.95 (m, 2H), 1.21 (m, 3H)

Step b Intermediate 208

-(4-Bromophenyl)tetrahydro-2H-pyran-4-yl]methanol

To a solution of ethyl 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carboxylate (2.88 g, 9.19 mmol) in THF (30 ml) at 0°C was added LiAlH₄ (1 M solution on THF, 9.19 ml,

9.19 mmol) dropwise. The reaction was left to stir at 0°C for an hour and was then quenched via the dropwise addition of sat. sodium sulphate and the mixture stirred for 1 hour. The mixture was then filtered through celite washing with THF and EtOAc and the filtrate was concentrated.

Purification via column chrmoatography (Si0₂ 0-100 % EtO Ac/petrol,). Gave (4-(4- bromophenyl)tetrahydro-2H-pyran-4-yl)methanol (2.5838 g, 9.53 mmol, 104 % yield) as a colourless oil (2.5 g, quantitative).

Ή NMR (400 MHz, CD₂C1₂) 67.50 - 7.59 (m, 2H), 7.28 (m, 2H), 3.77 (m, 2H), 3.61 (s, 2H), 3.47 - 3.58 (m, 2H), 2.06 - 2.15 (m, 2H), 1.91 (m, 2H)

Step c Intermediate 209

4-(4-Bromophenyl)-4-(methoxymethyl)tetrahydro-2H-pyran

A round-bottomed flask was charged with (4-(4-bromophenyl)tetrahydro-2H-pyran-4- yI)methanol (2.5838 g, 9.53 mmol) in DMF (32 ml) and cooled to 0°C in an ice bath. Sodium hydride (0.419 g, 10.48 mmol) was added and mixture stirred under nitrogen for 10 mins. Mel (0.715 ml, 1 1.43 mmol) was added dropwise and mixture was allowed to warm to RT and stirred overnight under nitrogen.

Water (50 ml) was added to quench reaction.The aqueous layer was backextracted with EtOAc (3 x 100 ml). Combined the organic layers and wash with brine (3 x 100 ml). The organic was dried MgS0₄, filtered and concentrated. The residue was purified via Biotage (0-100% EtO Ac/Petrol, 100G silica SNAP column), yielding 4-(4- bromophenyl)-4-(methoxymethyl)tetrahydro-2H-pyran (1 ,745 g, 6.12 mmol, 64.2 % yield) as a colourless oil. Ή NMR (400 MHz, CD₂C1₂) δ 7.44 - 7.54 (m, 2H), 7.22 - 7. 1 (m, 2H), 3.69 - 3.83 (m, 2H), 3.47 - 3.59 (m, 2H), 3.39 (m, 2H), 3.22 (m, 3H), 2.01 - 2.13 (m, 2H), 1.93 (m, 2H) MS ES⁺ 285/287

Step d Example 190

Prepared in an analogous manner to Example 179 via Scheme 51, step c starting with 4-(4-bromophenyl)-4-(methoxymethyl)tetrahydro-2H-pyran (Int 209) and using Pd(PPh₃)₄ and K₂C0₃, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, CD₂C1₂) δ 7.29 - 7.40 (m, 2H), 7.17 - 7.27 (m, 2H), 6.44 - 6.54 (m, 1H), 3.69 - 3.82 (m, 2H), 3.44 - 3.64 (m, 4H), 3.41 (s, 2H), 3.24 (s, 5H), 2.97 - 3.10 (m, 2H), 2.75 - 2.90 (m, 2H), 2.35 - 2.64 (m, 3H), 2.18 - 2.31 (m, 2H), 2.05 - 2: 14 (m, 2H), 1.90 - 2.03 (m, 3H), 1.72 - 1.86 (m, 1H)

MS ES⁺ 356 2.191 Example 191 Ethyl 4-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyI}tetrahydro-2H-pyran-4- carboxylate

Scheme 52

Reagents and conditions: a) Int 26, Pd(PPh₃)₄, K₃P0₄, THF, H₂0, 100 °C MW Prepared in an analogous manner to Example 179 via Scheme 52 starting with ethyl 4- (4-bromophenyl)tetrahydro-2H-pyran-4-carboxylate (Int 207) and using Pd(PPh₃)₄ and Κ₃ ϋ₄, and Scheme 4 using cyclobutanone in step b.

Ή NMR (400 MHz, CDC1₃) δ 7.30 - 7.38 (m, 2H), 7.13 - 7.23 (m, 2H), 6.26 (s, 1H), 4.06 - 4.24 (m, 2H), 3.89 - 4.06 (m, 2H), 3.51 - 3.64 (m, 2H), 2.64 - 2.81 (m, 1H), 2.48 - 2.60 (m, 4H), 2.41 (s, 4H), 2.22 - 2.36 (m, 2H), 1.81 - 2.13 (m, 6H), 1.66 - 1.81 (m, 2H), 1.1 1 - 1.26 (m, 3H)

MS ES⁺ 384 2.192 Example 192

2-(4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4- yl)propan-2-ol

Scheme 53

Reagents and conditions: a) MeMgBr, Et₂0, THF To a stirred solution of ethyl 4-(4-(( 1 -cyclobutylpiperidin-4- ylidene)methyl)phenyl)tetrahydro-2H-pyran-4-carboxylate (Example 191) (91 mg, 0.237 mmol) in dry THF (791 μΐ) at 0 °C, under an atmosphere of nitrogen, was added dropwise methylmagnesium bromide in diethyl ether (174 μΐ, 0.522 mmol) and the reaction was stirred at 0 °C for 30 min. Reaction was allowed to warm to r.t. for 2 h. Further methylmagnesium bromide in diethyl ether (174 μΐ, 0.522 mmol) was added at r.t. The reaction was stirred under nitrogen for 2 h. To this mixture was added methylmagnesium bromide in diethyl ether (174 μΐ, 0.522 mmol) and the reaction was stirred at r.t. for 17 h. The reaction mixture was quenched with water (10 ml). The organics were extracted with EtOAc (x 2). The organics were washed with brine, dried (MgS04), filtered and concentrated under reduced pressure. The crude oil was purified by column chromatography (NH silica; 10 - 100 % DCM in petrol), oil was dried in a high vacuum oven at 50 °C for 17 h to yield 2-(4-{4-[(l-cyclobutylpiperidin-4- ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-yl)propan-2-ol as a colouless oil (18 mg, 20 %).

Ή NMR (400 MHz, DMSO-cfe) δ 7.24 - 7.34 (ra, 2H), 7.08 - 7.22 (m, 2H), 6.25 (s, 1H), 4.25 (s, 1H), 3.59 - 3.78 (m, 2H), 2.99 - 3.16 (m, 2H), 2.60 - 2.74 (m, 1H), 2.41 - 2.47 (m, 2H), 2.27 - 2.36 (m, 4H), 2.23 - 2.27 (m, 2H), 2.1 1 - 2.21 (m, 2H), 1.88 - 2.08 (m, 4H), 1.73 - 1.87 (m, 2H), 1.55 - 1.69 (m, 2H), 0.92 (s, 6H)

M.S ES⁺ 370

3. Biological efficacy of compounds of the invention 3.1 In Vitro H3 Binding Assay The ability of compounds to bind to the H3 receptor was determined by measuring the reduction in tritiated N- -methyl-histamine (³H-NctMH) binding in a competition binding assay. Changes in the levels of bound radio-label were monitored by scintillation counting with a Triiux Microbeta (Perkin Elmer). Membranes were prepared from CHO-K1 cells stably expressing human H3 receptor; routinely grown as monolayers in Ham's F12 medium (Invitrogen) supplemented with 10% Foetal Clone III (Hyclone), 50(^g/ml G418 (Invitrogen), 5 μ^ηιΐ blasticidine S (Invivogen) and 50 g ml Gentamicin (Sigma) in 5% CO₂ at 37°C. Cells were grown to 80-95% confluency, rinsed once with lx PBS (Invitrogen) and detached by incubating with lx PBS containing 0.02% EDTA (Sigma) for 10 minutes at room temperature. Cells were collected by centrifugation at 900 xg, 4°C for 1 minutes. Cells were rinsed once with lx PBS and re-suspended in ice cold homogenisation buffer (50mM Tris-HCl (pH 7.4), 2.5mM EDTA, 5mM MgCl₂, 200mM Sucrose). at lxlO⁷ cells/ml and kept on ice. Cells were homogenised on ice and debris removed by centrifugation at 500 x g, 4°C for 5 minutes. The resulting supernatant was centrifuged at 75,600 xg, 4°C for 60 minutes. Membranes were suspended in homogenisation buffer, protein concentration was determined (BCA Protein Assay kit (Pierce)), diluted to 2.2 mg/ml, dispensed into lml aliquots and stored at -80 °C.

Membranes were thawed on ice, sonicated with 4 cycles of 20 pulses (50% amplitude, 0.5 pulse) (UP200S Hielscher) on ice, diluted in assay buffer (50mM Tris-HCl (pH7.4), 5mM MgCl ) to 62.5 μg ml. Compound was serially diluted in DMSO before being diluted 1 :10 with assay buffer. 5 g of membrane in 80 μΐ of assay buffer was added per well of a 96 well polystyrene plate (Corning). 10 μΐ of compound was added per well. The assay was initiated by the addition of 10 μΐ of 20nM ³H-NaMH per well and incubated for one hour at room temperature with shaking. Total binding was determined in the presence of 1% DMSO and non-specific binding was determined by the inclusion of 1 μΜ R- -methyl-histamine (RaMH). Incubations were then filtered through filtermat A (Perkin Elmer) and washed three times with assay buffer. Filtermats were dried at 42°C for two hours, scintillant added and the level of bound radioactivity determined. 1C50 values for compounds were determined from seven point log scale dose-response studies and represent the concentration of compound required to inhibit 50% of the specific binding of 2nM ³H-NaMH (difference between total and non-specific binding). Curves were generated using the average of duplicate wells for each data point and analyzed using nonlinear regression of sigmoidal dose response (variable slope).

3.2 In Vitro H3 Functional Assay

The functional activity of compounds at the H3 receptor was determined by measuring changes in the level of intracellular cAMP using a cAMP response element driven luciferase reporter assay. The changes in luciferase expression were monitored by a luminescence plate reader, Analyst HT (MDS Analytical). Increases in intracellular cAMP were readily detected upon activation of protein kinase A by forskolin (Sigma) and suppression of this response observed with the application of the H3 receptor agonist RctMH (Sigma).

CHO(dhfr⁺)-cre-luc cells stably expressing human H3 receptor were routinely grown as monolayers in Minimal Essential Medium a (MEMa) (Invitrogen) supplemented with 10% dialysed FBS (Hyclone), in 5% C0 at 37°C. 48 hours prior to assay, cells were seeded in clear-base' white walled 384-well plates (Corning) at a density of 5000 cells/well. On the day of assay, growth media was removed and replaced with 15 μΐ of assay buffer (MEMa, 5 mg/ml fatty acid free BSA (Sigma)) per well. Cells were then incubated for 30 minutes at 37°C, 5% C0₂. Compound was serially diluted in DMSO before being diluted 1 : 10 with assay buffer. 2.5 μΐ of compound diluted in assay buffer was added and cells incubated for 5 minutes at 37°C, 5% C0₂. 2.5 μΐ of each reagent was then added in the following order: RaMH (10 nM), isobutylmethylxanthine (1- methyl-3-(2-methylpropyl)-7H-purine-2,6-dione; IBMX) (500 μΜ) (Sigma) and forskolin (1 μΜ). Cells were then incubated for 90 minutes at 37°C, 5% C0₂, followed by 30 minutes at room temperature. At the end of incubation 25 μΐ of Steadylite reagent (Perkin Elmer) was added, plates were sealed and placed on a shaker for 5 minutes. The level of light output to determine the level of luciferase expression was then measured.

IC50 values for compounds were determined from ten point half log scale dose- response studies and represent the concentration of compound required to prevent 50% inhibition of forskolin stimulated cells in the presence of RaMH alone. Curves were generated using the average of duplicate wells for each data point and analyzed using nonlinear regression of four parameter dose response.

3.3 Results

Example 1 0

16 5

Example 142

37 5

Example 148

3 2

Example 150

21 2

Example 155

4 1

Example 159

35

Example 162

56

Example 167

12

Example 168

29 6

Example 173

37 3

Example 175

320 14

Example 1 9

160 8

Example 185

150 3

Example 191

85

These results indicate that compounds of the invention have potent antagonist or inverse agonist activity at the H3 receptor, both in terms of binding and, where tested, in terms of inhibition of the functional response caused by receptor activation. The compounds tested above exhibit IC50 values significantly less than 1 μΜ, with the compounds showing low nanomolar affinity at the H3 receptor. Accordingly, the compounds of the invention are expected to have usefulness in the prevention or treatment of conditions, such as those discussed above, in which H3 receptor activity is implicated.

In addition, the compounds of the present invention may possess variously advantageous pharmacological and/or toxicological profiles, when tested in a variety of standard tests for such parameters. For example, the compounds of the invention may exhibit one or more potentially useful properties for in vivo use, when characterised by pharmacological and/or toxicological tests including: HERG interaction (which is an indication of potential cardiotoxicity, and measures the effects of the compounds on the human ether -a-go-go-related gene, using for example the PatchXpress 7000A platform); Cy P 5o interactions (which may be measured in accordance with the FDA draft guidelines for drug interaction studies (study design, data analysis and implications for dosing and labeling) (Sep. 2006), see www.fda.gov); phototoxicity (for example using a protocol in accordance with assay details outlined in the OECD guidelines for testing of chemicals: 432 In Vitro 3T3 Neutral Red Uptake phototoxicity test, April 2004); determination of pharmacokinetic parameters (for example following in vivo dosing via multiple routes, with plasma concentrations of compounds being determined from venous blood samples using an LC-MS/MS protocol); and in vivo receptor occupancy (determined, for example, using protocols based on Medhurst et al, Journal of Pharmacology and Experimental Therapeutics, 2007, 321, 1032). These standard tests for the characterisation of drug molecules are well known to the skilled person.

REFERENCES 1. J.-M. Arrang, M. Garbarg and J.-C. Schwartz. Nature, 1983, 302, 832

2. T. W. Lovenberg, B. L. Roland, S. J. Wilson, X. Jiang, J. Pyati, A. Huvar, M. R. Jackson and M. G. Erlander, Mol. Pharmacol, 1999, 55, 1101.

3. S. J. Hill, C. Ganellin, H. Timmermans, J. C. Schwartz, N. Shankley, J. M. Young, W. Schunack, R. Levi and and H. L. Haas. Pharmacol. Rev., 1997, 49, 253. 4. Passani MB, Lin J-S, Hancock A, Crochet S, Blandina P. The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends Pharmacol. Sci. 2004;25:618-25.

5. Witkin JM, Nelson DL. Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system. Pharmacol. Ther. 2004;103:1-20

6. Monti J.M et al. Effect of Selective activation or blockade of the hitamine H3 receptor on sleep and wakefulness. 1991 Eur. J. Pharmacol.205, 283-287.

7. Esbenshade T.A. et al. Biochemical Pharmacology 68 (2004) 933-945.

8. Morimoto T, Yamamoto Y, Yamatodani A. Leptin facilitates histamine release from the hypothalamus in rats. Brain Res. 2000; 868:367-9

9. A. A. Hancock. Biochem. Pharmacol., 2006, 71, 1 103.

10. A. A. Hancock and M. E. Brune. Expert Opin. Investig. Drugs, 2005, 14, 223 11. D. Farzin, L. Asghari and M. Nowrouzi. Pharmacol. Biochem. Behav., 2002, 72, 751.

12. WO 04/089410

13. Medhurst A.D. et al. Biochemical Pharmacology 73 (2007) 1 182-94

14. Esbenshade T.A et al. J. Pharmacol. Exp. Ther. 2005 313(1) 165-75

Claims

C L A I M S

1. A compound of formula ( 1 ):

wherein:

Ri represents H or C|.₆ alkyl;

R₂ represents C|.<5 alkyl, wherein each R2 iriay be the same or different;

p represents 0, 1, 2, 3 or 4;

m represents 1 or 2;

n represents 1 or 2; provided that both and m and n do not represent 2;

R₃ represents Ci-6 alkyl, -Qi-C3,r> cycloalkyl or -Q₂-3-6 membered monocyclic heterocyclyl, wherein each may be optionally substituted by one or more substituents, independently selected from halogen, Ci_-(s alkyl or Cue alkoxy;

Q[ and Q₂ independently represent a covalent bond or C 1 -3 alkylene;

Xi, X₂, X3 and X₄ independently represent CH or N; wherein no more than 2 of i, X₂, X₃ and X4 represent N;

R4, independently represents halogen, Ci-β alkyl, haloCi.₆ alkyl, Ci.₆ alkoxy or haloC| -6 alkoxy;

q represents 0, 1 or 2;

A I represents a covalent bond or Ci- alkylene optionally substituted by one or more hydroxy or C|.₆ alkoxy;

L, represents a covalent bond or -NRe-, -0-, ^b-NR₇CO-^a, ^b-CONR₈-^a, -C(O)-, - NR₇S0₂-^a, ^b-S0₂NR₈-^a, -S(0)₂-, in which ^a represents the point of attachment to A| and ^b represents the point of attachment to R5;

R₆, R₇ and Rg independently represent H or Ci_-6 alkyl;

R₅ represents -(CH₂)i.₃0C|.6 alkyl, or -Q3-C3.8 cycloalkyl, -Q₄-heteroaryl, -Q5- heterocyclyl, -Q₆-aryl; in which the C₃.g cycloalkyl, heteroaryl, heterocyclyl and aryl are optionally substituted with one or more R9; wherein each R9 may be the same or different;

when Ai represents optionally substituted Ci_-6 alkylene, R₅ also represents H or C 1.6 alky 1;

Q3, Q₄, Q5 and Q₆ independently represent a covalent bond or C 1-3 alkylene;

R₉ represents halogen, -CN, -N0₂, =0, -OR₁₀, -NR, ,Ri₂, -CORn, -C0₂Ri₂, - CONRi₃Ri₄, -S0₂NR,₃Ri₄, -NR_{) 5}CORi₆, -NR,₅S0₂R₁₆, -OCONR_{) 3}Ri₄, -NRi₃C0₂Ri₄, - NR|₃CONRi₃Ri4_; -SR|4, -SOR_H, -S0₂Ri₄, -OS0₂Ri₄, -C₃-₆cycloalkyl, -aryl, -heteroaryl, -heterocyclyl, or C|.₆ alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -ORi₀, -NRnRi₂, -CORn , -C0₂Ri₂, - CONR,₃R, 4, -S0₂NR,₃R,₄, -NR,₅COR,₆, -NR₎₅S0₂R,₆, -OCONR,₃R₁₄, -NR,₃C0₂R,_4; - NR|₃CONR|₃R|_4! -SR|4, -SOR,₄, -S0₂R,₄, -OS0₂Ri₄, -C_3-6cycloalkyl, -aryl, -heteroaryl or -heterocyclyl; in which each Ci_-6 alkyl, C_3-6Cycloalkyl, aryl, heteroaryl or heterocyclyl present as or as part of R9 is optionally substituted with one or more Rp, wherein each Ri 7 may be the same or different;

Rio represents H, C_t.₃ alkyl or haloCi_-3 alkyl;

Ri i , R|2, R13, R14, Ri5 and R₎₆ independently represent H or Ci- alkyl;

Ri_? represents halogen, Ci_-6 alkyl, haloC].₆ alkyl, - CN, -N0₂, =0, -ORig_, C0₂R, 9, -COR19, -NR,₉R₂₀, -CONR,₉R₂₀, -NR,₉COR₂₀, -NR,₉SO₂R₂₀ or -SO₂NR,₉R₂₀;

Rig represents H, Ci.₆alkyl or -haloCi.₆ alkyl;

Ri9 and R₂₀ independently represent H or C).₆alkyl;

excluding 4,4'-(l ,4-phenylenedimethylidyne)bis[l ,2,2,6,6-pentamethyl]- piperidine;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein R| represents H.

3. A compound according to claim 1 or claim 2, wherein p represents 0.

4. A compound according to any of claims 1 to 3, wherein m represents 1 represents 1 or 2.

5. A compound according to any of claims 1 to 4, wherein R₃ represents optionally substituted C3_-6 cycloalkyl.

6. A compound according to any one of claims 1 to 5, wherein Xi, X₂, X₃ and X4 each represent CH.

7. A compound according to any one of claims 1 to 6, wherein -LJ-AI- represents a covalent bond, Ci.₆ alkylene, -NR₆-Ci-6 alkylene-, -0-Ci_-6 alkylene-, -NR7CO-, - NR₇CO-C,_-5alkylene-, -CONR₈-C,.₆ alkylene-, -C(0>, -NR₇S0₂-₅ -NR₇S0₂-C,. ₆alkylene-, -S0₂NRg-, -S(0)₂-C |.₆alkylene-and -S(0)₂, wherein C|.₆ alkylene, when present, is optionally substituted .

8. A compound according to any one of claims 1 to 7, wherein R5 represents - Q3-C3.8 cycloalkyl, -Q₄-heteroaryl or -Q₅-heterocyclyl; in which the C_3-g cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with one or more R9, each of which may be the same or different.

9. A compound according to claim 8, wherein R₅ C3_-8cycIoalkyl, heteroaryl and heterocyclyl groups present when R₅ represents -Q3-C3.₈ cycloalkyl, -Q₄-heteroaryl or -

Q₅-heterocyclyl respectively are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyridazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, imidazolidinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, oxepanyl, octahydrocyclopenta[c]pyrrolyl, azabicyclo[3.2.1]octanyl or oxaspiro[4.5]decanyl, each of which may be optionally substituted with one or more R_9> each of which may be the same or different.

10. A compound according to any preseding claim, wherein R9 represents halogen, C e alkyl, haloC|,₆ alkyl, =0, -C₀-₆ alkyl-ORio, -C₀-₆ alkyl-CORi 1 , -C₀.₆ alkyl-.C0₂R₎₂, -

C_0-6 alkyl-CONR|3Ri4, -Co-6 alkyl-NR|₅COR[6, or -Co_-6alkyl-heteroaryl, wherein said Ci-6 alkyl or -C₀-6alkyl-heteroaryl is optionally substituted with one or more R17, each of which may be the same or different.

1 1. A compound of formula (1) as defined in claim 1 selected from the group consisting of:

l-cyclobutyl-4-[4-(l -methyl- lH-pyrazol-4-yl)benzylidene]piperidine;

l-cyclobutyl-4-{4-[l -(2-methylpropyl)-lH-pyrazol-4-yl]benzylidene}piperidine;

l-cyclobutyl-4-[4-(3,5-dimethyl-l ,2-oxazol-4-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(l -methyl- lH-pyrazol-5-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(2,4-dimethyl-l,3-thiazol-5-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(l ,5-dimethyl-lH-pyrazol-4-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(l ,2-oxazol-4-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(l,3,5-trimethyl-l H-pyrazol-4-yl)benzylidene]piperidine;

4-[2-chloro-4-(l -methyl-lH-pyrazol-4-yl)benzylidene]-l -cyclobutylpiperidine;

l-cyclobutyl-4-[4-(3 -methyl- l ,2,4-oxadiazol-5-yl)benzylidene]piperidine;

l-cyclobutyl-4-[4-(5-methyl- l,3,4-oxadiazol-2-yl)benzylidene]piperidine;

1- cyclobutyl-4-[4-(5-methyl-l _i2,4-oxadiazol-3-yl)benzylidene]piperidine;

{4- [( 1 -cyclopentylpiperidin-4-ylidene)methyl]phenyl } methanol;

(4- { [ 1 -(2-methylpropy l)piperidin-4-ylidene]methyl } phenyl)methanol;

N-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}cyclopentanecarboxamide;

N-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}tetrahydrofuran-3-carboxamide;

2- {4- [( 1 -cyclobutylpiperidin-4-ylidene)methyl]phenyl } -N-cyclopentylacetamide;

2-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}-N-(tetrahydrofuran-3- yl)acetamide;

2- {4- [( 1 -cyclobutylpiperidin-4-ylidene)methyl]phenyl } - 1 -(pyrrolidin- 1 -yl)ethanone;

{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}(pyrrolidin- l-yl)methanone;

4-[(l-cyclobutylpiperidin-4-ylidene)methyl]-N-cyclopentylbenzamide;

4-[(l -cyclobutylpiperidin-4-ylidene)methyl]-N-(tetrahydrofuran-3-yl)benzamide;

4-[(l-cyclobutylpiperidin-4-ylidene)methyI]-N-(cyclopentylmethyl)benzamide;

4-[(l -cyclobutylpiperidin-4-yIidene)methyl]-N-(tetrahydrofuran-3-yImethyI)benzamide;

4-[(l -cyclobutylpiperidin-4-ylidene)methyl]-N-(pyridin-3-yl)benzamide;

N- {4-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]benzyl } pyridin-3 -amine;

{3-chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl} (pyrrolidin- 1- yl)methanone; {2-chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}(pyrrolidin-l - yl)methanone;

{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]-2-iluorophenyl}(pyrrolidin-l- yl)methanone;

{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]-3-fluorophenyl}(pyrrolidin-l - yl)methanone;

{ 4- [( 1 -cyclobuty lpiperidin-4-y lidene)methy 1] -3 -fluorophenyl } methanol ;

{3-chloro-4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}methanol;

{6-[(l-cyclobutylpiperidin-4-ylidene)methyl]pyridin-3-yl}(pyrrolidin- l -yl)methanone; {6-[(l-cyclobutylpiperidin-4-ylidene)methyl]pyridin-3-yl}methanoI;

{5-[(l -cyc]obutylpiperidin-4-ylidene)methyl]pyridin-2-yl}(pyrrolidin-l -yl)methanone; pyrrolidin-l-yl(4-{[l -(tetrahydrofuran-3-yl)piperidin-4-ylidene]methyl}phenyl) methanone;

l -{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}pyridin-2(lH)-one;

2-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}pyridazin-3(2H)-one;

3- ({4-[(l-cycIobutylpiperidin-4-ylidene)methyl]benzyl}oxy)pyridazine;

1 - { 4-[( 1 -cy clobutylpiperidin-4-ylidene)methyl]benzy 1 } -3 -methoxypyridin-2( 1 H)-one; methyl l -{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-6-oxo-l,6- dihydropyridine-3-carboxylate;

l -{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-methylpyridin-2(lH)-one; l -{4-[(l -cyclobuty]piperidin-4-ylidene)methyl]benzyl}-6-methyl-3- (trifluoromethyl)pyridin-2(lH)-one;

l -{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-(trifluoromethyl)pyridin- 2(lH)-one;

l -{4-[(] -cyclobuty]piperidin-4-ylidene)methyl]benzyl}piperidin-2-one;

4- {4-[( 1 -cyclobutylpiperidin-4-ylidene)methyl]benzyl } morpholin-3-one;

l -{4-[(l -cyclobuty lpiperidin-4-ylidene)methyl]benzyl}pyrrolidin-2-one;

l -{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-5-(methoxymethyl)pyridin- 2(lH)-one;

(3S)-l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-methoxypyrrolidin-2- one;

(4R)-l -{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-4-methoxypyrrolidin-2- one; 4- {4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-l ,4-oxazepan-5-one;

l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-3-methylimidazolidin-2-one; 3-{4-[(l -cyclobutylpiperidm-4-ylidene)methyl]benzyl}-l ,3-oxazolidin-2-one;

l-cyclobutyl-4-{4-[(cyclopentyloxy)methyl]benzylidene}piperidine;

l-cyclobutyl-4-{4-[(tetrahydrofuran-3-ylmethoxy)methyl]benzylidene}piperidine; l-cyclob tyl-4-{4-[(cyclopentylmethoxy)methyl]benzylidene}piperidine;

l-cyclobutyl-4-{4-[(tetrahydro-2H-pyran-4-yloxy)methyl]benzylidene}piperidine; l-cyclobutyl-4-(4-{[(2-methyl-l ,3-oxazol-4-yl)methoxy]methyl}benzylidene) piperidine;

l -cyclobutyl-4-(4-{[(5-methyl-l ,2-oxazol-3-yl)methoxy]methyl}benzylidene) piperidine;

3-({4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}oxy)pyridine;

l -cyclobutyl-4-(4-{[(5-methyl-l,2-oxazol-3-yl)oxy]methyl}benzylidene)piperidine; l-cyclobutyl-4-[4-({[l -methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl oxy}methyl)benzylidene]piperidine;

l-cyclobutyl-4-[4-({[l -methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl]oxy}methyl) benzyl i denejpiperi dine;

3- ({4-[(l -cyclobutylpiperidin-4-ylidene)methyl benzyl}oxy)-N,N-diniethyl-l ,2- oxazole- 5 -carboxamide;

1 -cyclobutyl-4-[4-(piperidin- 1 -ylmethyl)benzy lidenejpiperidine;

4- {4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}morpholine;

l-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]benzyl}-4,4-difluoropiperidine; -{4-[(l-cyclobutyl iperidin- -ylidene)methyl]benzyl}-2,6-dimethylmoφholine; l -cyclobutyl-4-{4-[(4-methoxypiperidin-l -yl)methyl]benzylidene}piperidine;

N-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzyl}-2-methoxy-N- methylethan amine;

N-(4-((l-ethylpiperidin-4-ylidene)methyl)benzyl)cyclopentanamine dihydrochloride;

1- (4-((l-cyclobutylpiperidin-4-ylidene)methyl)phenyl)ethanol;

(4-((l-cyclobutylpiperidin-4-ylidene)methyl)phenyl)(cyclopentyl)methanol;

l -(4-((l-cyclobutylpiperidin-4-ylidene)methyl)phenyl)-3-methylbutan-l-ol;

(4-((l -cyclobutylpiperidin-4-ylidene)methyl)phenyl)methanol;

2- (4-((l-cyclobutylpiperidin-4-ylidene)methyl)phenyl)propan-2-ol;

l-(4-((l-Cyclobutylpiperidin-4-ylidene)methyl)phenyl)-2-methylpropan-l-ol; (3-Chloro-4-((l-cyclobutylpiperidin-4-ylidene)methyl)phenyl)(cyclopentyl)methanol; l-(4-((l-Cyclobutylpiperidin-4-ylidene)methyl)phenyl)-2-cyclopentylethanol;

l-(4-((l-Cyclobutylpiperidin-4-ylidene)methyl)phenyl)-2-cyclopropylethanol;

Cyclopentyl(4-{[l -(2-methylpropyl)piperidin-4-ylidene]methyl}phenyl)methanol;

Cyclopentyl(4-((l-ethylpiperidin-4-ylidene)methyl)phenyl)methanol;

Cyclopentyl(4-((l -(cyclopropylmethyl)piperidin-4-ylidene)methyI)phenyl)methanol; l-(4-((l-Cyclobutylpiperidin-4-ylidene)methyl)phenyl)cyclopentanol;

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}cyclohexanol;

3- {4-[( 1 -Cyclobuty lpiperidin-4-y lidene)methyl]phenyl } tetrahydrofuran-3 -ol;

4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol; l-(4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-hydroxypiperidin-l - yl)ethanone;

N-(4-{4-[(l-Cyclobutylpiperidin-4-yIidene)methyl]phenyI}-4- hydroxycyclohexyl)acetamide;

Ethyl 4-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4- hydroxycyclohexanecarboxylate;

l -{4- (l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-melhuxycy lohexaiiol;

4- {4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-l -(pyrimidin-2-yl)piperidin-4- ol;

1 - { 4-[(l -cyclpbutylpiperidin-4-ylidene)methy l pheny I } -4- (hydroxymethyl)cyclohexanol;

l-[4-{4-[(l-cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4- hydroxyhexahydrocyclopenta[c]pyrrol-2(l H)-yl]ethanone;

l -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-(3-methyl-l,2,4-oxadiazol-5- yl)cyclohexanol;

1 -(4- {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methy l]phenyl } -4-hydroxyazepan- 1 - yl)ethanone;

l-(3-{4-[(l-Cyclobutylpiperidin-4rylidene)methyl]phenyl}-3-hydroxy-8- azabicyclo[3.2.1 ]oct-8-yl)ethanone;

Ethyl 3-{4-[(l -cyclobutyIpiperidin-4-ylidene)methyl]phenyl}-3- hydroxycyclobutanecarboxylate;

{4-[(l-CycIobutylpiperidin-4-ylidene)methyl]phenyl}(tetrahydro-2H-pyran-4- yl)methanol; 4- {4- [( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } -4-hydroxy-N,N- dimethylcyclohexanecarboxamide;

l -{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}-l-(l-methyl-lH-pyrazol-4- yl)ethanol;

4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-2,6-dimethyltetrahydro-2H- pyran-4-ol;

4-{3-Chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran- 4-ol;

l -{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methoxy-4- methylcyclohexanol ;

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methylcyclohexane-l,4-diol; 1 - {4-[( 1 -Cyclobutylpiperidin-4-y lidene)methyl]phenyl } -4- (methoxymethyl)cyclohexanol;

l -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-ethoxycyclohexanol;

8- {4- [( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } - 1 -oxaspiro [4.5]decan-8 -ol; l-{3-Chloro-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4- methoxy cyclohexanoi ;

l -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-(propan-2- y loxy )cyc lohexano 1 ;

2-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methoxybutan-2-ol;

l-{4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}-3- (methoxymethyl)cyclobutanol;

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-3-methoxycyclohexanol; l -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-(lH-pyrazol-l - yl)cyclohexanol;

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-2-methoxycyclohexanol;

4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}oxepan-4-ol;

1 - {4- [( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl} -3 -methoxycycloheptanol;

{4-[(l-Cyclobutylpiperidin-4-ylidene)raethyl]phenyl}-l-(tetrahydrofuran-3-yl)ethanol; 1 -{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-2-

(methoxymethyl)cyclopentanol ;

l-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}-4-methoxycycloheptanol; l-{4-[(l -cyclopentylpiperidin-4-ylidene)methyl]phenyl}-4-methoxycyclohexanol; 4-{4-[(l-Cyclopentylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol; 4-Methoxy-l -(4-{[l -(propan-2-yl)piperidin-4-ylidene]methyl}phenyl)cyclohexanol; 4"(4-{[l-(propan-2ryl)piperidin-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4-ol; l-(4-{[l-(Cyclopropylmethyl)piperidin-4-ylidene]methyl}phenyl)-4- methoxycyclohexanol;

1 - (4-((l -Cyclobutylpiperidin-4-ylidene)methyl)phenyl)propan-2-ol;

2- (4-((l-Cyclobutylpiperidin-4-ylidene)methyI)phenyl)-l-cyclopentylethanol;

1- (4-(4-((l-Cyclobutylpiperidin-4-ylidene)methyl)benzyl)-4-hydroxypiperidin-l- yl)ethanone;

l-(4-((l-Cyclobutylpiperidin-4-ylidene)methyl)benzyl)cyclopentanol;

1 -Cyclopenty l-2-(4-(( 1 -ethy lpiperidin-4-y lidene)methyl)phenyl)ethanol;

2- {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } - 1 -(tetrahydrofliran-3- yl)ethanol;

4-{4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]benzyl}tetrahydro-2H-pyran-4-ol; 4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]-3-fluorobenzyl}tetrahydro-2H-pyran- 4-ol;

1- {4-[(l-Cyclobutylpiperidin-4-ylidene)methyl]bcnzyl}-4-mcthoxycyclohexanoI; 4-(4-{[l-(Tetrahydrofuran-3-yl)piperidin-4-ylidene]methyl}benzyl)tetrahydro-2H- pyran-4-ol

4-(4- { [ 1 -(3-Fluorocyclobutyl)piperidin-4-:y lidene]methyl } benzyl)tetrahydro-2H-pyran- 4-ol;

2- { 4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } - 1 -(tetrahydro-2H-pyran-4- yl)ethanol;

3- {4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]benzyl}tetrahydrofuran-3-ol;

4- { 4-[( 1 -Cyclobuty lpiperidin-4-ylidene)methy l]pheny 1 }tetrahydrofuran-3 -ol ;

l -{4-[(E)-(l -Cyclobutylazepan-4-y]idene)methyl]phenyl}-4-methoxycyclohexanol; 1 - {4- [(Z)-( 1 -Cyclobutylazepan-4-ylidene)methy l]phenyl } -4-methoxycyclohexanol;

4- {4-[(E)-(l-CycIobutylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol; 4-{4-[(Z)-(l -Cyclobutylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol; 4-(4-{(E)-[l -(Propan-2-yl)azepan-4-ylidene]methyl}phenyl)tetrahydio-2H-pyran-4-ol; 4-(4-{(Z)-[l -(Propan-2-yl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4-ol; 4-{4-[(E)-(l -Cyclobutylazepan-4-ylidene)methyl]benzyl}tetrahydro-2H-pyran-4-ol; 4-{4-[(E)-(l -Cyclopentylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol; 4-{4-[(Z)-(l-cyclopentylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol;

4-(4-{(E)-[l -(Cyclopropylmethyl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H- pyran-4-ol;

4-(4-{(Z)-[l -(Cyclopropylmethyl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H- pyran-4-ol;

4-(4-{(E)-[l -(2-Methylpropyl)azepan-4-ylidene]methyl}phenyl)tetrahydro-2H-pyran-4- ol;

4-(4-{(Z)~[l -(2-Methylpropyl)azepan-4'ylidene]methyl}phenyl)tetrahydro-2H-pyran-4- ol;

4-{4-[(E)-(l-Ethylazepan-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4-ol;

l -{6-[(l-Cyclobutylpiperidin-4-ylidene)methyl]pyridin"3-yl}-4-methoxycyclohexanol;

4-({5-[(l-Cyclobutylpiperidin-4-ylidene)methyl]pyridin-2-yl}methyl)tetrahydro-2H- pyran-4-ol;

l -{5-[(l-Cyclobutylpiperidin-4-ylidene)methyl]pyridin-2-yl}-4-methoxycyclohexanol; 1 -Cyclobutyl-4-{4-[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]benzylidene}piperidine; l -Cyclobutyl-4-[4-(4-fluorotetrahydro-2H-pyran-4-yl)benzylidene]piperidine;

1 -Cyclobutyl-4-[4-(l -fluoro-4-methoxycyclohexyl)benzylidene]piperidine;

N-(4-(l -(l -Cyclobutylpiperidin-4-ylidene)ethyl)benzyl)cyclopentanamine;

{4-[l -(l-Cyclobutylpiperidin-4-ylidene)ethyl]phenyl}methanol;

1 -Cyclobutyl-4-{ 1 -[4-(3-methyl-l ,2,4-oxadiazol-5-yl)phenyl]ethylidene}piperidine;

4-{4-[(E)-(l -Cyclobutyl-3-methylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H- pyran-4-ol;

l -Cyc]obutyl-4-[4-(tetrahydro-2H-pyran-4-y]sulfonyl)benzylidene]piperidine;

l -Cyclobutyl-4-{4-[(2-methoxyethyl)sulfonyl]benzylidene}piperidine;

1 -Cyclobutyl-4- { 4-[(3 -methoxypropyl)sulfony] Jbenzylidene} piperidine;

1 -Cyclobutyl-4- (4-[(tetrahydro-2H-pyran-4-ylmethyl)sulfonyl] benzylidenejpiperidine;

1 -Cyclobutyl-4- {4-[(2-ethoxyethyl)sulfonyl]benzylidene}piperidine;

l -Cyclobutyl-4-(4-{[(2-ethoxyethyl)sulfonyl]methyl}benzylidene)piperidine;

4-[(l-Cyclobutylpiperidin-4-yIidene)methyl]-N-methyI-N-(tetrahydro-2H-pyran-4- yl)benzenesulfonamide;

4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]-N-(tetrabydro-2H-pyran-4- yl)benzenesulfonamide;

4-({4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}sulfonyl)morpholine; l-Cyclobutyl-4-{4-[(3-methoxyazetidin-l-yl)sulfonyl]benzylidene}piperidine;

l -Cyclobutyl-4-{4-[(4-methoxypiperidin-l -yl)sulfonyl]benzylidene}piperidine;

l-{4-[(l -Cyclobut)'lpiperidin-4-ylidene)methyl]phenyl}-N-methyl-N-(tetrahydro-2II- pyran-4-yl)methanesulfonamide;

4-({4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]benzyl}sulfonyl)morpholine;

1 -Cyclobutyl-4-(4- { [(3 -methoxy-3 -methylazetidin- 1 -yl)sulfonyl]methyl }

benzy 1 idene)piperidine ;

1 - {4-[( 1 -Cyclobutylpiperidin-4-ylidene)methyl]phenyl } -N-(tetrahydro-2H-pyran-4- yl)methanesulfonamide;

1 -Cyclobutyl-4-[4-( 1 ,4-dimethoxycyclohexyl)benzy lidene]piperidine;

l-Cyclobutyl-4-[4-(4-methoxytetrahydro-2H-pyran-2-yl)benzylidene]piperidine;

1 - Cyclobutyl-4-{4-[4-(methoxymethyl)tetrahydro-2H-pyran-4- yl]benzylidene}piperidine;

Ethyl 4- {4-[(l -cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4- carboxylate;

2- (4-{4-[(l -Cyclobutylpiperidin-4-ylidene)methyl]phenyl}tetrahydro-2H-pyran-4- yl)propan-2-ol;

and pharmaceutically acceptable salts thereof.

12. A process for the preparation of a compound of formula (1) or a pharmaceutically acceptable salt thereof as defined in claim 1 which comprises:

(i) when R| represents H, reacting a compound of formula (I) with a compound of formula (II):

wherein R₂, R₃, R4, R5, n, m, p, q, Ai, L|, Xj, X₂, X₃ and X4 are as herein defined; or (ii) when Ri represents H, Ai and Lj each represent a covalent bond and R5 represents an aryl or heteroaryl group, reacting a compound of formula (III) with a compound of formula (IV):

wherein R₂, R3, R4, n, m, p, q, X_is X₂, X₃ and X₄ are as herein defined, LG| represents a suitable leaving group, R_5a represents R₅ aryl or heteroaryl and -B(OZ)₂ represents boronic acid or a ester derivative thereof; or

(iii) when Ri represents H, Lj represents a covalent bond and -Ai - R5 represents:

conversion of a compound of formula (III) to a Grignard reagent followed by reaction with

wherein R₂i represents H or C|.₃ alkyl, R₅ is as herein defined, R₅b represents an optionally substituted C₃.₈ eycloalkyi or optionally substituted heterocyclyl ring and * represents the point of attachment; or

(iv) when Ri represents H, Li represents a covalent bond and -A1 -R5 represents:

reacting a compound of formula (III) with an epoxide of formula:

wherein R₂ i represents H or C1-3 alkyl, R₅ is as herein defined, Rsb represents an optionally substituted C_3-8 cycloalkyl or optionally substituted heterocyclyl ring and * represents the point of attachment; or

(v) when L| represents a covalent bond and R5 represents an oxadiazolyl group, conversion of an intermediate of formula (V):

wherein Ri , R₂, R3, R4, n, m, p, q, A] , Xi , X₂, X3 and X₄ are as herein defined; or

(vi) when Ri represents H, Ai represents C).₆ alkylene, Li represents -O- and R₅ represents H, reacting a compound of formula (V) with a suitable reducing agent; or

(vii) when R_\ represents H, Li represents -NR₇CO-, reacting a compound of formula (V) with R5R₇NH; or

(viii) when Ri represents H, Li represents -CO- and R₅ represents N-linked heterocyclyl; reacting a compound of formula (V) with a N containing heterocyclyl; and optionally thereafter carrying out one or more of the following procedures:

•converting a compound of formula (1) into another compound of formula (1) • removing any protecting groups

· forming a pharmaceutically acceptable salt.

13. A pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 1 1, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

14. A composition according to claim 13, comprising one or more additional, pharmaceutically active ingredients.

15. A compound according to any of claims 1 to 1 1 , or a composition according to claim 13 or 14, for use in therapy.

16. A compound according to any of claims 1 to 1 1, or a composition according to claim 13 or 14, for use in the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity.

17. A method of treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity, the method comprising the administration, to a subject in need of such treatment or prevention, of a therapeutically effective amount of a compound according to any of claims 1 to I I .

18. A compound for use according to claim 16, or a method according to claim 17, wherein the condition is a disorder of the central nervous system.

19. A compound for use or a method according to any of claims 16 to 18, wherein the disorder is selected from schizophrenia, neurodegenerative disorders (such as Alzheimer's Disease), cognitive disorders (such as dementia and schizophrenia), sleep disorders (such as narcolepsy and hypersomnia), pain, obesity, attentional disorders and epilepsy.