Flavour compositions

Abstract

The invention relates to flavour compositions containing a mixture of coolant compounds comprising at least one menthane carboxamide selected from N-(4-cyanomethylphenyl) p- menthanecarboxamide, 2-isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide, or mixtures thereof and at least one TRPM8 modulator, in a specific ratio. The invention further relates to a flavour composition comprising the coolant compounds and the use of such flavour compositions in consumer products.

Description

[0001] ORGANIC COMPOUNDS

[0002] The present invention is concerned with flavour compositions comprising and menthane carboxamides and transient receptor potential melastatin member 8 (TRPM8) modulator, and in particular, with such compositions containing either low levels of menthol or no menthol. The invention is also concerned with consumable products, in particular oral care products, containing said flavour compositions.

[0003] BACKGROUND

[0004] A large number of coolant compounds of natural or synthetic origin have been described in the art. However, the most well-known compound is menthol, particularly l-menthol, which is found naturally in peppermint oil, notably of Mentha arvensis L and Mentha viridis L. Of the isomers of menthol, the l-isomer occurs most widely in nature and is typically what is referred by the name menthol having coolant properties. L-menthol has the characteristic peppermint odor, has a clean fresh taste and exerts a cooling sensation when applied to the skin and mucosal surfaces.

[0005] In order to deliver a strong consumer perception of freshness and cooling, flavours, in particular peppermint flavours, can exceed 50% by weight of menthol and it is not uncommon to find 60% or more. However, despite it having gained very wide acceptance and use, menthol, when used alone, has an initial high flavour impact, but the flavour impact drops sharply within a few minutes after use and it tends to distort flavour notes and render the products containing it bitter. Furthermore, as well as bitterness problems, very high levels of menthol can restrict flavour creation and cause additional processing constraints.

[0006] In order to address some of the drawbacks of menthol use, it has become increasingly common to use it in admixture with other coolant compounds, most notably the N-substituted-p- menthane carboxamides. For example, GB233873 discloses such mixtures in order to provide different cooling profiles and even longer lasting coolant effects. On the other hand, WO 2012 / 113873 discloses combinations of low levels of menthol and menthane carboxamides.

[0007] A challenge faced by the flavours industry today, is the drive from the consumer products companies to reduce the levels of non-active materials contained in their compositions. This is related, obviously to cost, but also to the need for sustainability, and the need to deliver greener products to the marketplace. Accordingly, it is desirable to reduce the level of menthol without the loss of sensorial attributes and consumer liking attendant with its use. If one can reduce or compact the amount of a major component used in a flavour composition, one can, in turn, compact the amount of flavour composition used in consumer products, or alternatively one can exploit the use of lower levels of menthol to permit the use of more flavour ingredients thereby increasing a flavorist’s latitude to create new and interesting flavour profiles and drive consumer preference. None of this would be possible, of course, if by reducing menthol one simply replaces it with other coolant materials in like amounts. In another aspect, it is also advantageous for a flavorist’s arsenal, if different combinations of coolant compounds can be available so as to address different consumer perspectives in different geographies or to provide alternative coolant mixtures, which still maintain, if not enhance, desired sensorial attributes. It is also desirable for a flavorist to have

[0008] 31511 PCT coolant mixtures in their palette, which may provide either similar of better consumer performance than known coolant mixtures in the art, especially menthol.

[0009] SUMMARY

[0010] The applicant has now found that by employing certain menthane carboxamides in a flavour composition in combination with at least one TRPM8 modulators of specific chemical formula (hereinafter also referred also as “coolant mixture”) in a specific ratio, it is possible to significantly reduce the amount of menthol conventionally employed in such compositions, whilst at the same time providing compositions having acceptable, if not better, coolant and freshness effects and which are favourably received by consumers in preference tests. The applicant has also found that the coolant mixtures as described in the present invention provides superior performance, as demonstrated in the examples.

[0011] The invention provides in one aspect a flavour composition comprising: a) at least one menthane carboxamide selected from N-(4-cyanomethylphenyl) p- menthanecarboxamide, 2- isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide, or a mixture of N-(4-cyanomethylphenyl) p-menthanecarboxamide and 2- isopropyl-5-methyl-N-(2- (pyridin-4-yl)ethyl)cyclohexanecarboxamide and mixtures thereof; b) at least one transient receptor potential melastatin member 8 (TRPM8) modulator compound of formula (I), a salt or solvate thereof wherein n is 0 or 1 ;

[0012] R1is selected from i) halogen, ii) Ce - C-io aryl, iii) C5-C10 mono- or bicyclic heteroaryl wherein up to 2 C-atoms are replaced by a hetero atoms independently selected from sulfur, nitrogen, and oxygen, iv) Ce - C10 aryl substituted with up to four substituents independently selected from the group consisting of halogen; OH; C=N; NO2; C1-C6 alky;

[0013] C1-C6 alkyl comprising up to 5 halogen atoms;

[0014] C1-C3 alkyl comprising up to 3 OH groups;

[0015] C2-C6 alkenyl;

[0016] Ci-Ce alkoxy;

[0017] Ci-Ce alkoxy comprising up to 3 halogen atoms;

[0018] 31511 PCT C1-C3 alkoxy C1-C3 alkyl;

[0019] C3-C7 cycloalkyl;

[0020] -C(O)R10wherein R10is selected from C1-C3 alkyl;

[0021] -OC(O)R11wherein R11is selected from H, and C1-C3 alkyl;

[0022] -C(O)O-R12wherein R12is selected from hydrogen and C1-C3 alkyl;

[0023] - (CH2)mN(R13)R14wherein m is 0 or 1 , R13is selected from hydrogen, C1-C3 alkyl, and -SO2R15wherein R15is C1-C3 alkyl, and R14is selected from hydrogen, C1-C3 alkyl, and -SO2R16wherein R16is C1-C3 alkyl, or wherein R13and R14form together with the N atom to which they are attached morpholine, thiomorpholine, or 1 ,1-dioxothiomorpholine;

[0024] -SR17wherein R17is selected from hydrogen and C1-C3 alkyl; and

[0025] -S(O)2R18wherein R18is selected from hydrogen and C1-C3 alkyl; with the proviso that when the aryl ring is substituted with two or more substituents, two substituents may form a cyclic ring together with the carbon atoms to which they are attached, and v) C5-C10 mono- or bicyclic heteroaryl wherein up to 2 C-atoms are replaced by a hetero atoms independently selected from sulfur, nitrogen, and oxygen, substituted with up to four substituents selected from the group consisting of halogen; OH (hydroxyl); C=N (cyano); NO2 (nitro); Ci-Ce alky;

[0026] Ci-Ce alky comprising up to 5 halogen atoms;

[0027] C2-C6 alkenyl;

[0028] Ci-Ce alkoxy;

[0029] Ci-Ce alkoxy comprising up to 3 halogen atoms;

[0030] C1-C3 alkoxy C1-C3 alkyl;

[0031] C3-C7 cycloalkyl;

[0032] -C(O)R20wherein R20is selected from C1-C3 alkyl;

[0033] -OC(O)R21wherein R21is selected from H, and C1-C3 alkyl;

[0034] -C(O)O-R22wherein R22is selected from hydrogen and C1-C3 alkyl;

[0035] -(CH2)mN(R23)R24wherein m is 0 or 1 , R23is selected from hydrogen, C1-C3 alkyl, and -SO2R25 wherein R25is C1-C3 alkyl, and R24is selected from hydrogen, C1-C3 alkyl, and -SO2R26wherein R26is C1-C3 alkyl, or wherein R23and R24form together with the N atom to which they are attached morpholine, thiomorpholine, or 1 ,1-dioxothiomorpholine;

[0036] -SR27wherein R27is selected from hydrogen and C1-C3 alkyl; and

[0037] -S(O)2R28wherein R28is selected from hydrogen and C1-C3 alkyl;

[0038] Y is a monocyclic or bicyclic, unsaturated or aromatic heterocyclic ring comprising one, two, three or four heteroatoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally mono-, di-, or tri-substituted with a group selected from halogen, methyl, ethyl, - N(R40)R41, -CON(R40)R41, -[CR40R41]P-C(O)OR40, -C(O)R40, and -SO2N(R40)R41wherein R40and R41are independently selected from hydrogen and C1-C4 alkyl, and p is 0, 1 , or 2;

[0039] A is a 5 to 7 membered heterocyclic ring optionally comprising one additional hetero atom selected from oxygen and sulfur, wherein the heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =0;

[0040] 31511 PCT Z is either C, S or S(O); and

[0041] R4, R5and R6form together with the carbon atom to which they are attached a hydrocarbon group optionally comprising up to five hetero atoms selected from O, N, S, and F; c) optionally menthol; wherein the ratio of the amount of a) and b) in the composition is from about 10:1 to about 1 :10.

[0042] The invention provides in another aspect a non-medical method of inducing a cooling sensation in a human or animal comprising contacting the human or animal with the flavor composition

[0043] The invention provides in a third aspect a method of compacting the amount of menthol contained in a composition comprising the steps of:

[0044] I) screening the composition comprising menthol against a panel of consumers to determine a first preference score for said composition;

[0045] II) removing an amount of menthol from said composition and adding an amount of the coolant mixture, which amount added is lower than the amount of menthol removed on a weight basis, and subjecting it to a screening against a panel of consumers to obtain a second preference score that is higher than said first preference score.

[0046] TRPM8 (transient receptor potential melastatin member 8, also known as Trp-p8 or MCR1) is activated by innocuous cool and thus plays an important role as sensor for temperature. The channels are widely distributed in different tissues (such as human skin and mucosa (such as oral mucosa, throat mucosa, and nasal mucosa), male urogenital tract, lung epithelium cells and artery myoctes). They are Ca2+-permeable, nonselective cation channels that exhibit polymodal gating mechanisms, being activated by innocuous cool to cold temperature, membrane depolarization, and molecules which are known as cooling agents including natural and synthetic compounds. The receptor was described for the first time in 2002 as cold receptor in a number of publications.

[0047] In a particular or preferred embodiment of the invention, the TRPM8 modulator b) of formula (I) may be of formula (Ic), a salt or solvate thereof: wherein n is 0 or 1 ;

[0048] R1is selected from halogen (including Br, Cl, and F),

[0049] Ce - C10 aryl (e.g. phenyl, or naphthyl) optionally substituted with up to four (e.g. 1 , 2, or 3) substituents independently selected from the group consisting of halogen (including F, Cl, Br); OH (hydroxyl); C=N (cyano); NO2 (nitro);

[0050] 31511 PCT Ci-C6alky optionally comprising up to 5 halogen atoms (e.g F), such as CH3, CF3, or CHF2;

[0051] C1-C3 alkyl comprising up to 3 OH groups, such as CH2OH;

[0052] C2-C6 alkenyl, such as -CH=CH2;

[0053] Ci-Ce alkoxy optionally comprising up to 3 halogen atoms (e.g. F), such as OCH3, OCH3, OCF3;

[0054] C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl;

[0055] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0056] -C(O)R10wherein R10is selected from C1-C3 alkyl;

[0057] -OC(O)R11wherein R11is selected from H, and C1-C3 alkyl;

[0058] -C(O)O-R12wherein R12is selected from hydrogen and C1-C3 alkyl;

[0059] - (CH2)mN(R13)R14wherein m is 0 or 1 , R13is selected from hydrogen, C1-C3 alkyl, and -SO2R15wherein R15is C1-C3 alkyl, and R14is selected from hydrogen, C1-C3 alkyl, and -SO2R16wherein R16is C1-C3 alkyl, or wherein R13and R14form together with the N atom to which they are attached morpholine, thiomorpholine, or 1 ,1-dioxothiomorpholine;

[0060] -SR17wherein R17is selected from hydrogen and C1-C3 alkyl; and

[0061] -S(O)2R18wherein R18is selected from hydrogen and C1-C3 alkyl; with the proviso that when the aryl ring is substituted with two or more substituents two substituents may form a cyclic ring together with the carbon atoms to which they are attached, and C5-C10 mono- or bicyclic heteroaryl wherein up to 2 C-atoms are replaced by a hetero atoms independently selected from sulfur, nitrogen, and oxygen, optionally substituted with up to four (e.g. 1 , 2, or 3) substituents selected from the group consisting of halogen (including F, Cl, Br); OH (hydroxyl); C=N (cyano); NO2 (nitro);

[0062] Ci-Ce alky optionally comprising up to 5 halogen atoms (e.g F), such as CH3, CF3, or CHF2;

[0063] C2-C6 alkenyl, such as -CH=CH2;

[0064] Ci-Ce alkoxy optionally comprising up to 3 halogen atoms (e.g. F), such as OCH3, OCH3, OCF3;

[0065] C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl;

[0066] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0067] -C(O)R20wherein R20is selected from C1-C3 alkyl;

[0068] -OC(O)R21wherein R21is selected from H, and C1-C3 alkyl;

[0069] -C(O)O-R22wherein R22is selected from hydrogen and C1-C3 alkyl);

[0070] -(CH2)mN(R23)R24wherein m is 0 or 1 , R23is selected from hydrogen, C1-C3 alkyl, and -SO2R25wherein R25is C1-C3 alkyl, and R24is selected from hydrogen, C1-C3 alkyl, and -SO2R26wherein R26is C1-C3 alkyl, or wherein R23and R24form together with the N atom to which they are attached morpholine, thiomorpholine, or 1 ,1-dioxothiomorpholine;

[0071] -SR27wherein R27is selected from hydrogen and C1-C3 alkyl; and

[0072] -S(O)2R28wherein R28is selected from hydrogen and C1-C3 alkyl;

[0073] Z is either C, S or S(O); and

[0074] R4, R5and R6form together with the carbon atom to which they are attached a hydrocarbon group optionally comprising up to five (e.g. 1 , 2, 3, 4) hetero atoms selected from O, N, S, and F (preferably the hydrocarbon group comprises 2 to 15 C-atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 C-atoms);

[0075] X1is NH or O; and

[0076] 31511 PCT X2and X3are independently selected from C, N, and O, with the proviso that either X2or X3is not C.

[0077] Further non-limiting examples are compounds of formula (Ic), a salt or solvate thereof wherein Z is C.

[0078] Further non-limiting examples are compounds of formula (Ic), a salt or solvate thereof wherein Z is C,

[0079] R4is selected from hydrogen and methyl;

[0080] R5is selected from hydrogen, C1-C2 alkyl, and C2-C3 alkenyl; and

[0081] R6is selected from C1-C4 alkyl, C2-C5 alkenyl containing one or two double bonds, C1-C3 alkoxy, Ci- 04 alkyl-C(O)-, C1-C4 alky I— S— , C1-C4 alkyl-SCFh-, C1-C4 alkenyl-S-, C1-C4 alkyl-S(O) -, C1-C4 alkyl-S(O)2-, C1-C4 alkenyl-S(O) -, C1-C4 alkenyl-S(O)2-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl (e.g. 2-furyl or 3-furyl) optionally substituted with methyl , Ci-Ce fluoro-alkyl (such as pentafuloroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethy I or difluoroethyl), and -NR30R31wherein R30and R31are independently selected from hydrogen and C1-C3 alkyl; or

[0082] R6and R5form together with the carbon atom to which they are attached a) a carbonyl group (C=O) or vinyl group (C=CR32R33wherein R32and R33are independently selected from H or C1-C3 alkyl); or b) a 3 to 7-membered saturated or unsaturated cycle ring comprising up to 3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the cyclic ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl (e.g. methyl, ethyl, isopropyl), C1-C3 alkoxy; (e.g. R5and R6form together with the carbon atom to which they are attached thiodiazole, or furanyl).

[0083] Further non-limiting examples are compounds of formula (Ic), a salt or solvate thereof wherein Z is C, R4is selected from hydrogen and methyl; R5is selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl; and R6is selected from C1-C4 alkyl, C2-C5 alkenyl containing one or two double bonds, C1-C3 alkoxy, C1-C4 alkyl-C(O) -, C1-C4 alkyl— S-, C1-C4 alkyl-SCFh-, C1-C4 alkenyl-S-, C1-C4 alkyl-S(O) -, C1-C4 alkyl-S(O)2-, C1-C4 alkenyl-S(O) -, C1-C4 alkenyl-S(O)2-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl (e.g. 2-furyl or 3-furyl) optionally substituted with methyl, Ci-Ce fluoroalkyl (such as pentafuloroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl), and -NR30R31wherein R30and R31are independently selected from hydrogen and C1-C3 alkyl.

[0084] Further non-limiting examples are compounds of formula (Ic) wherein Z is C, and R4, R5and R6form together with the carbon atom to which they are attached a hydrocarbon group selected from 3-thiabut-2-yl, 2-methyl-3-thiabut-2-yl, 3-thiapent-2-yl, 4-thiapent-2-yl, 2-thiaprop-1 -y I, 2- methyl-3-thiapent-2-yl, 3-oxo-3-thiabut-2-yl, 3-oxo-2-methyl-3-thiabut-2-yl, 3-oxo-3-thiapent-2-yl, 4- oxo-4-thiapent-2-yl, 2-oxo-2-thiaprop-1-yl, 3-oxo-2-methyl-3-thiapent-2-yl, but-2-yl, pent-2-yl, but-3- en-2-yl, pent-3-en-2-yl, but-2-en-2-yl, pent-2-en-2-yl, but-1-en-2-yl, pent-1 -en-2-yl, 2-methylbut-2-yl, 2-methylpent-2-yl, 2-methylbut-3-en-2-yl, 3-methylbut-2-yl, 3-methylbut-3-en-2-yl, 3-methylbut-2-en- 2-yl, 2,3-dimethylbut-2-yl, 2,3-dimethylpent-2-yl, 2,3-dimethylbut-3-en-2-yl, 2,3-dimethylpent-3-en-2- yl, 2-methylpent-3-en-2-yl, prop-2-yl, prop-1-yl, ethyl, cyclopropyl, 1 ,1-dimethylcycloprop-2-yl, 1- methylcycloprop-2-yl, 1 -methylcycloprop-1 -y I, 3-thiahex-5-en-2-yl, 2-methyl-3-thiahex-5-en-2-yl, 1- mercaptoeth-1-yl, 2-mercaptoprop-2-yl, 3,3,3-trifluoroprop-2-yl, 2-methyl-3,3,3-trifluoroprop-2-yl, 1-

[0085] 31511 PCT (2-furyl)eth-1-yl, 1-(5-methylfur-2-yl)eth-1-yl, 2-(2-furyl)prop-2-yl, 1-(3-furyl)eth-1-yl, 1-(5-methylfur-3- yl)eth-1-yl, 2-(3-furyl)prop-2-yl, 1-(2-tetrahydrofuryl)eth-1-yl, 2-(2-tetrahydrofuryl)prop-2-yl, 1-(3- tetrahydrofuryl)eth-1-yl, 2-(3-tetrahydrofuryl)prop-2-yl, 1-cyclopropyleth-1-yl, 2-cyclopropylprop-2-yl, 1 -cyclobuty leth-1 -y I, 2-cyclobutylprop-2-yl, cyclobutyl, cyclopentyl, pent-2-en-3-yl, 1 -methoxyprop-1 - yl, 1-methoxyeth-1-yl, 1 ,1 , 1 -trifluorobut-3-yl and 3-thiacyclobut-1-yl.

[0086] The compounds as defined herein comprise several chiral centers (two of which are indicated by *) and as such may exist as a mixture of stereoisomers, or they may be resolved as isomerically pure forms. Resolving stereoisomers adds to the complexity of manufacture and purification of these compounds and so it is preferred to use the compounds as mixtures of their stereoisomers simply for economic reasons. However, if it is desired to prepare individual stereoisomers, this may be achieved according to methods known in the art, e.g. preparative HPLC and GC, crystallization or stereoselective synthesis. The compounds as defined herein may also exist in various tautomeric forms, including the enol - keto form, lactam - lactim form, amide - imidic acid form, amine - imine form and 1 H-I midazole - 3H-lmidazole form. Accordingly, the chemical structures depicted herein encompass all possible stereoisomers and tautomeric forms of the illustrated compounds.

[0087] It is also noted that the compounds as defined herein may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

[0088] "Solvate" means a compound formed by solvation (the combination of solvent molecules with molecules or ions of the solute), or an aggregate that consists of a solute ion or molecule, i.e., a compound as defined by the formulae herein, with one or more solvent molecules. When water is the solvent, the corresponding solvate is "hydrate". Further suitable solvents can be but are not limited to: acetone, acetonitrile, benzene, cyclohexane, dihydrolevoglucosenone, methyltetrahydrofuran, pentylene glycol, ethylene glycol, petroleum ether, ethyl lactate, methyl lactate, propyl lactate, diethylether, tert-butyl methyl ether, dimethylsulfoxide, N,N-dimethylformamide, N,N- dimethylacetamide, dioxane, ethanol, ethyl acetate, ethylene glycol, diethylene glycol, propylene glycol, heptane, hexane, methanol, toluene and xylene.

[0089] "Salt" refers to a salt of a compound as defined by the formulae herein, which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as amino acids, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-( 4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1 -carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl

[0090] 31511 PCT sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like.

[0091] The compounds as defined by the formulae herein are “TRPM8 agonists”, which means that they have an agonistic effect on the cellular Ca2+ ion permeability of the TRPM8 channels. Accordingly, by “TRPM8 agonist” is meant any compound, which when brought into contact with the TRPM8 receptor, produces an increase in fluorescence over background, using the FLIPR method as described, e.g., by Klein et al., (Chem. Senses 36: 649-658, 2011), which is also described in more details in the experimental part.

[0092] In a another embodiment of the invention, the TRPM8 modulator b) of formula (I) is selected from the group consisting of (2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)(1 ,2,3-thiadiazol-5- yl)methanone, (2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1 -y l)(thietan-3-yl)methanone, (2,2- dimethylcyclopropyl)(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)methanone, (2- ethoxycyclopropyl)(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)methanone, (2- methoxycyclopropyl)(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1 -y l)methanone, (2- methylcyclopropy l)(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1 -yl)methanone, (2S)-2-methyl-1 -(2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1 H- imidazol-2-yl)piperidin-1-yl)methanone, (E)-1-(2-(5-(3,4-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1- yl)-2-methylbut-2-en-1-one, (E)-2-methyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-2-en-1- one, (E)-2-methyl-1 -(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1 -yl)pent-3-en-1 -one, (R)-2- (methylthio)-1-((R)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1- ((R)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1-((S)-2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-methyl-1-((R)-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)butan-1-one, (tetrahydrofuran-3-yl)(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1- yl)methanone, 1 -(2-(1 H-benzo[d]imidazol-2-y l)pi peridin-1 -yl)-2-(methylthio)propan-1 -one, 1 -(2-(4-(1 - methyl-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2- (4-(2,3-dihydrobenzofuran-5-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4- (2,3-dihydrobenzofuran-6-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-

[0093] (2,5-dimethylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2- chlorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2- cyclopropyloxazol-5-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2- fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2- hydroxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-

[0094] ((dimethylamino)methyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-

[0095] (4-(3,5-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3,5- dimethylisoxazol-4-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-chloro-

[0096] 4-methylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-methylfuran-

[0097] 2-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-((1 ,1-

[0098] 31511 PCT dioxidothiomorpholino)methy l)phenyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-2-(methylthio)propan-1 -one, 1-(2-(4-(4-(1-hydroxyethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2- (4-(4-(difluoromethoxy)-3-fluorophenyl)-1 H-imidazol-2-yl)pi peridin-1 -yl)-2-(methylthio)propan-1 -one, 1 -(2-(4-(4-(difluoromethyl)thiophen-3-yl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2-(methylthio)propan-1- one, 1-(2-(4-(4-(methylsulfonyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1 -(2-(4-(4-(tert-butyl)phenyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-2-(methylthio)propan-1 -one, 1 -(2-(4-(4- cyclobutylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- cyclopropyl-2-fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- hydroxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- isopropylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-methyl-3-

[0099] (trifluoromethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-

[0100] ((dimethylamino)methyl)thiophen-2-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-methylfuran-2-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5- methylpyridin-3-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(6- methylpyridin-3-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-

[0101] (benzo[b]thiophen-6-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-methyl- 5-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-phenyl-1 H-imidazol-2- yl)piperidin-1-yl)-2-((trifluoromethyl)thio)ethan-1-one, 1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1- yl)butan-1-one, 1 -(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-dien-1-one, 1-(2-(4-phenyl- 1 H-imidazol-2-yl)piperidin-1 -yl)pent-4-en-1-one, 1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, 1 -(2-(5-(2,3-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan- 1-one, 1-(2-(5-(2,4-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2- (5-(2,5-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-fluoro-

[0102] 4-methoxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-fluoro-4- methylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2- methoxypyrimidin-5-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3- (methylamino)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4- difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4- difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-3-en-1-one, 1-(2-(5-(3,4- dimethoxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4- dimethylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluoro-4- (methoxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3- fluoro-4-methylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3- fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3- methoxyisothiazol-4-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3- methoxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-

[0103] ((methylamino)methyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5- (4-(2-methoxyethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4- (aminomethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4- (dimethylamino)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-

[0104] 31511 PCT (hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4- acetylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-aminophenyl)- 1 H-imidazol-2-yl)piperidin-1 -yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-chloro-3-fluorophenyl)-1 H- imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-chlorophenyl)-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-ethylphenyl)-1 H-imidazol-2-yl)piperidin-1- yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-fluorophenyl)-4H-1 ,2,4-triazol-3-yl)piperidin-1-yl)-2- (methylthio)propan-l-one, 1-(2-(5-(4-methoxy-2-methylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2- (methylthio)propan-l-one, 1-(2-(5-(4-methoxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-

[0105] (methylthio)propan-l-one, 1-(2-(5-(4-methyl-6-(methylthio)pyridin-3-yl)-1 H-imidazol-2-yl)piperidin-1- yl)-2-(methylthio)propan-1-one, 1-(2-(5-(5-(methoxymethyl)thiophen-3-yl)-1 H-imidazol-2-yl)piperidin-

[0106] 1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(6-methoxypyridin-3-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2- (methylthio)propan-l-one, 1-(2-(5-(benzo[d][1 ,3]dioxol-5-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2- (methylthio)propan-l -one, 1 - (2-(5- (p-toly l)-1 H-imidazol-2-yl)piperidin-1 -yl)propan-1 -one, 1 -(2-(5- benzyl-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-bromo-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H- imidazol-5-yl)benzonitrile, 2-(2-(4-phenyl-1 H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1- carbonitrile, 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2- (allylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(dimethylamino)-1-(2-(4- phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-(dimethylamino)-1-(2-(4-phenyl-1 H-imidazol-

[0107] 2-y I) pi pe ri d i n- 1 -yl)propan-1 -one, 2- (ethy Ith io)- 1 -(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1 - yl)propan-1-one, 2-(furan-2-yl)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan- 2-y l)-1 -(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1 -yl)propan-1 -one, 2-(furan-3-yl)-1 -(2-(4-phenyl-1 H- imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan-3-yl)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, 2-(methylamino)-N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5- yl)phenyl)acetamide, 2-(methylsulfinyl)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1- one, 2-(methylsulfonyl)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2- (methylsulfonyl)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(2- (p-toly l)-2H-tetrazo l-5-y I) pi perid i n- 1 -y l)propan-1 -one, 2-(methylthio)-1 -(2-(3-phenyl-1 ,2,4-oxadiazol- 5-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(1-(trifluoromethyl)-1 H-pyrazol-4-yl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophen-2-yl)- 1 H-imidazol-2-yl)piperidin-1 -yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(m-tolyl)-1 H-imidazol-2-yl)piperidin- 1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(o-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2- (methylthio)-1-(2-(4-(pyridin-3-yl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2- (4-(pyridin-4-yl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(pyrimidin-5-yl)- 1 H-imidazol-2-yl)piperidin-1 -yl)propan-1-one, 2-(methylthio)-1-(2-(4-(quinoxalin-6-yl)-1 H-imidazol-2- yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(thiophen-3-yl)-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, 2-(methylthio)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2- (methylthio)-1-(2-(5-(2-(trifluoromethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-

[0108] 31511 PCT (methylthio)-l -(2-(5-(2,3,4-trifluorophenyl)-1 H-imidazol-2-yl)piperidin-1 -yl)propan-1 -one, 2-

[0109] (methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-

[0110] (methylthio)-1-(2-(5-(3-(trifluoromethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-

[0111] (methylthio)-1-(2-(5-(4-(trifluoromethoxy)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-

[0112] (methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-

[0113] (methylthio)-1-(2-(5-(4-propylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1- (2-(5-(4-vinylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(5- methylthiophen-2-yl)-1 H-imidazol-2-yl)piperidin-1 -y l)propan-1 -one, 2-(methylthio)-1 -(2-(5-(p-to ly I)- 1 ,3,4-oxadiazol-2-yl)piperidin-1 -yl)propan-1 -one, 2-(methylthio)-1 - (2-(5-(p-toly l)-1 H-imidazol-2- yl)azepan-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan- 1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1 ,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one, 2- (methylthio)-l -(2-(5-(p-tolyl)isoxazol-3-y I) pi pe ri d i n- 1 -yl)propan-1 -one, 2-(methylthio)-1 -(2-(5-(p- tolyl)oxazol-2-yl)piperidin-1 -yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)thiazol-2-yl)piperidin-1- yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2- (methylthio)-1-(2-(5-phenyl-1 H-imidazol-2-yl)pyrrolidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5- phenyl-4H-1 ,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyloxazol-2- yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(4-(5-(p-tolyl)-1 H-imidazol-2-yl)thiazolidin-3- yl)propan-1-one, 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,2-dimethyl-1-(2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2,2-dimethyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)butan-1-one, 2,3-dimethoxy-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-

[0114] 1-one, 2,3-dimethyl-1 -(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,5-difluoro-4-(2-(1- (2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-4-yl)benzonitrile, 2-amino-1-(2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-cyclobutyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, 2-cyclopentyl-2-ethoxy-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)ethan-1-one,

[0115] 2-cyclopropyl-1 -(2-(4-phenyl-1 H-imidazol-2-y I) pi pe ri di n- 1 -yl)ethan-1 -one, 2-cyclopropyl-1 -(2-(4- phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-cyclopropyl-2-methoxy-1-(2-(4-phenyl-1 H- imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-ethoxy-1-(2-(5-(3-fluorophenyl)-1 H-imidazol-2- yl)piperidin-1-yl)propan-1-one, 2-ethyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one, 2-ethyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-fluoro-4-(2-(1-(2-

[0116] (methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)benzonitrile, 2-mercapto-1-(2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methoxy-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1- yl)butan-1-one, 2-methoxy-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1 -one, 2-methoxy-

[0117] 1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-1-(2-(4-phenyl-1 H-imidazol-

[0118] 2-y I) pi pe ri d i n- 1 -yl)butan-1 -one, 2-methyl-1 -(2-(4-pheny 1-1 H-imidazol-2-y I) pi pe ri di n- 1 -yl)propan-1 - one, 2-methyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2-methyl-1-(2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2- y I) pi perid i n- 1 -yl)butane-1 ,3-dione, 2-methyl-1 - (2-(5- (p-toly l)-1 H-imidazol-2-yl)piperidin-1 -yl)pentan- 1 -one, 2-methyl-1 -(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1 -yl)prop-2-en-1 -one, 2-methyl-1 -(2-(5- (p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-3-(methylthio)-1-(2-(4-phenyl-1 H-imidazol-2-

[0119] 31511 PCT y I) pi perid i n- 1 -yl)propan-1 -one, 2-methy lene-1 - (2-(5- (p-toly l)-1 H-imidazol-2-yl)piperidin-1 -yl)butan-1 - one, 3-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-4-yl)benzonitrile, 3,3,3-trifluoro-2- methyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 3,3,4,4,4-pentafluoro-1-(2-(4- phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 3,3-difluoro-1-(2-(4-phenyl-1 H-imidazol-2- yl)piperidin-1-yl)butan-1-one, 3-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5- yl)benzonitrile, 3-methyl-1 -(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1 -yl)but-2-en-1 -one, 3-methyl-1 - (2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 4-(2-(1-(2-(methylthio)propanoyl)piperidin- 2-y l)-1 H-imidazol-4-y I) be nzonitri le , 4-(2-(1 -(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5- yl)benzaldehyde, 4,4,4-trifluoro-2-methyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, bicyclo[1 .1.1]pentan-1-yl(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)methanone, cyclobutyl(2-(5-(3- fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)methanone, cyclopentyl(2-(4-phenyl-1 H-imidazol-2- yl)piperidin-1-yl)methanone, cyclopropyl(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)methanone, methyl 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)benzoate, N-(2- hydroxyethyl)-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-4- yl)benzenesulfonamide, 2-(methylthio)-1-(2-(5-(3-nitrophenyl)-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-4- yl)phenyl)methane-sulfonamide, 2-(methy Ith io)- 1 -(2-(5-(4-nitrophenyl)-1 H-imidazol-2-yl)piperidin-1 - yl)propan-1-one, 1-(sec-butylsulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, l-(sec-butylsulfonyl)- 2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(isopropylsulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidine, 1-(isopropylsulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((1-

[0120] (methylthio)ethyl)sulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((1-(methylthio)ethyl)sulfonyl)- 2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((2-(methylthio)propan-2-yl)sulfinyl)-2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidine, 1-((2-(methylthio)propan-2-yl)sulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidine, 1-(but-3-en-2-ylsulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(but-3-en-2- ylsulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(pent-3-en-2-ylsulfinyl)-2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidine, 1 -(pent-3-en-2-ylsulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((2- methylbut-3-en-2-yl)sulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((2-methylbut-3-en-2- yl)sulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(2-(5-(4-(hydroxymethyl)-phenyl)-1 H- imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-

[0121] (methylthio)propan-l-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-

[0122] (methylthio)propan-l-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan- 1 -one, 1 -(5-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-2-methylbutan-1 -one, 1 -(2-(5-(4- (hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(4- hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(5-hydroxy- 2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(2-hydroxy-6-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin- 1-yl)-2-methylbutan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-

[0123] 31511 PCT (methylsulfonyl)propan-l-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-

[0124] (methylsulfinyl)-propan-l-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2-

[0125] (methylsulfinyl)propan-l-one, 1 -(5-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2-

[0126] (methylsulfinyl)propan-l-one, 1 -(2-hydroxy-6-(5-(p-tolyl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2-

[0127] (methylsulfinyl)propan-l-one, 1 -(3-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2-

[0128] (methylsulfinyl)propan-l-one, 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1 H- imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(4-hydroxy-2-(5-(4-

[0129] (hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(3-hydroxy-2- (5-(4-(hydroxymethyl)-phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2- hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(5- hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(4- hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(3- hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 4-(2-

[0130] (1 -(2-methylbutanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)benzaldehyde, 4-(2-(1 -(2-

[0131] (methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)benzoic acid, 4-(2-(1-(2- methylbutanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)benzoic acid, (2,2-dimethylcyclopropyl)(2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(5-bromo-1 H-imidazol-2-yl)piperidin-1-yl)-2- methylbutan-1-one, 1-(2-(5-(4-chlorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1 -(2- methylbutanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1 -(2- methylbutanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)phenyl)acetonitrile, 2,3-dimethyl-1-(2-(5-(p-tolyl)-1 H- imidazol-2-y I) pi pe ri di n- 1 -yl)butan-1 -one, 2-methyl-1 -(2-(5-(o-tolyl)-1 H-imidazol-2-yl)piperidin-1 - yl)butan-1 -one, 2-methy 1-1 -(2-(5-(m-tolyl)-1 H-imidazol-2-yl)piperidin-1 -yl)butan-1 -one, 1 -(2-(5-(4- (hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, l-(isopropylsulfonyl)- 2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(sec-butylsulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidine, 2-methyl-1-(2-(5-(5-methylthiophen-2-yl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperazin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4- (p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, and 2-methyl-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1- yl)butan-1-one.

[0132] In a particular or preferred embodiment of the invention, the TRPM8 modulator b) of formula (I) may be of formula (Id), a salt or solvate thereof: wherein R is an C3-C7 branched alkyl or alkenyl optionally comprising one S atom.

[0133] Non-limiting examples are compounds of formula (Id) wherein R is C4-C5 branched alkyl or alkenyl, e.g., R is but-2-yl or 2-methyl-but-3-en-2-yl.

[0134] 31511 PCT Further non-limiting examples are compound of formula (Id) wherein R is C3 - C4 branched alkyl comprising one S atom, e.g., R is 2-methyl-3-thiabut-2-yl or 3-thiabut-2-y I.

[0135] In a particular or preferred embodiment, The compounds of formula (Id) selected from the group consisting of 2-methyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one (including (2S)-2-methyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, and (2R)-2-methyl-1-(2- (5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one), 2-(methylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol- 2-yl)piperidin-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin- 1-yl)propan-1-one and 2,2-dimethyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one or mixtures thereof.

[0136] Further suitable TRPM8 modulators, as described herein, and their methods of synthesis are described in international publication WO 2021 / 074281 , incorporated herein by reference.

[0137] In a preferred embodiment of the invention, the menthane carboxamide a) in the coolant mixture may be N-(4-cyanomethylphenyl) p-menthanecarboxamide alone or in combination with 2- isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide.

[0138] In a particular embodiment of the invention, the menthane carboxamide a) is present in at least about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, 10 ppm, 20 ppm, 30 ppm, 40 ppm, 50 ppm, 60 ppm, 70 ppm, 80 ppm, 90 ppm, 100 ppm, 150 ppm, 200 ppm, 250 ppm, 300 ppm, 350 ppm, 400 ppm, 500 ppm, 600 ppm, 700 ppm, 800 ppm, 900 ppm or even 1000 ppm in the total flavour composition.

[0139] In a particular embodiment of the invention, the menthane carboxamide a) is present in at least from about 1 ppm to to about 1000 ppm, preferably from about 30 ppm to about 500 ppm, even more preferably from about 50 ppm to about 200 ppm.

[0140] In a particular embodiment of the invention the total amount of menthane carboxamide a) in the total flavour is about 0.1 to 10% by weight, still more particularly 0.5 to 8% by weight or from 0.1 to 5%.

[0141] In a particular embodiment the menthane carboxamide a) consists of N- (4- cyanomethylphenyl) p-menthanecarboxamide in an amount of 0.1 to 3% by weight in the total flavour, more particularly 0.5 to 2% by weight.

[0142] In yet another particular embodiment the menthane carboxamide a) consists of 2- isopropyl- 5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide in an amount of 0.1 to 10% by weight, more particularly 0.5 to 7% by weight.

[0143] In yet another particular embodiment the menthane carboxamide a) consists of a mixture of N-(4-cyanomethylphenyl) p-menthanecarboxamide and 2- isopropyl-5-methyl-N-(2-(pyridin-4- yl)ethyl)cyclohexanecarboxamide, said mixture being provided in an amount of 0.1 to 13% by weight, more particularly 1 to 9% by weight of the total flavour composition.

[0144] In yet another particular aspect of the invention the mixture of N- (4-cyanomethylphenyl) p- menthanecarboxamide and 2- isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide is provided in a ratio of 1 :100 to 30:1 , more particularly 1 :15 to 4:1 .

[0145] In a particular embodiment of the invention, the TRPM8 modulator b) is present in at least about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, 9 ppm, 10 ppm, 20 ppm, 30 ppm, 40 ppm, 50 ppm, 60 ppm, 70 ppm, 80 ppm, 90 ppm, 100 ppm, 150 ppm, 200 ppm, 250 ppm, 300

[0146] 31511 PCT ppm, 350 ppm, 400 ppm, 500 ppm, 600 ppm, 700 ppm, 800 ppm, 900 ppm or even 1000 ppm in the total flavour composition.

[0147] In a particular embodiment of the invention, the TRPM8 modulator b) is present in at least from about 1 ppm to to about 1000 ppm, preferably from about 30 ppm to about 500 ppm, even more preferably from about 50 ppm to about 200 ppm.

[0148] In a particular embodiment of the invention the amount of menthol c) from about 10 ppm to about 20000 ppm, preferably from about 200 ppm to about 10000 ppm, even more preferably from about 500 ppm to about 6000 ppm.

[0149] The total amount of the optional component (menthol) c) used in the flavour compositions of the present invention is an effective amount, when taken in conjunction with the coolant mixture, to provide a good cooling and breath freshening perception without bitterness. The exact amount of the menthol employed in the cooling compositions is a matter of preference subject to such factors as the degree of vapour action desired. Thus, the amount of menthol may be varied within the limits stated herein in order to obtain the result desired in the final product and such variations are within the capabilities of those skilled in the art without the need for undue experimentation.

[0150] In a particular embodiment of the invention the flavour composition as described herein does not contain any menthol.

[0151] In a particular embodiment of the invention there is provided a flavour composition comprising the coolant mixture, wherein the amount of menthol represents less than 70%, more particularly less than 50% by weight of the total flavour compositions and the total amount of menthane carboxamide is about 0.1 to 10%.

[0152] As used herein, the component menthol c) refers exclusively to any added menthol to a flavour composition over and above that derived from or already contained in the other ingredients used as part of the flavour composition. As an example if the flavour composition contains ingredients derived from peppermint (e.g. as an oil), the menthol c) would refer to extra added menthol over and above that already present in the peppermint (oil). A skilled person is able to adjust the amount of the added menthol to provide specific flavour profiles and / or benefits.

[0153] In a particular embodiment of the invention the amount of menthol c) in the total flavour is about 90 % to about 99.98 % or about 1% to 50 % by weight, still more particularly 5 to 30% by weight.

[0154] In a particular embodiment of the invention, the flavor composition comprises, by weight; a) from about 0.1% to about 5%; and / or b) from about 0.01% to about 5%; and / or c) from about 99.98% to about 90%.

[0155] In a particular embodiment of the invention, the ratio of the amount of menthane carboxamide a) and TRPM8 modulator b) in the composition is from about 5:1 to about 1 :5, preferably from about 3:1 to about 1 :3. It was found that when the components a) and b) are in the defined ratios in the flavor composition, a better sensorial benefit is observed for a consumer, such as but not limited to, cooling, freshness, liking, flavor characteristic and overall effect.

[0156] The flavour compositions of the present invention surprisingly provided cooling and freshening effects that meet with high ratings in consumer preference testing despite reducing or

[0157] 31511 PCT compacting the amount of menthol and not replacing it with equivalent amount of other coolants or when compared to known coolant mixtures and / or simply menthol. In other words, both menthol and the total coolant compounds are compacted. This result is indeed surprising as one cannot simply rationalise the finding on the basis that the coolant mixture is simply exerting a far greater cooling effect than menthol. The consumer preference tests do not merely reflect the intensity of cooling, indeed, if a coolant composition is too intense it can be offensive and unpleasant and rate poorly in consumer preference tests. Rather, the tests reflect an overall impression of liking and pleasantness. In one embodiment, it was surprisingly observed that the flavour composition comprising the coolant mixture provides overall better flavour characteristics, at least when compared to menthol.

[0158] Furthermore, particularly in consumer product compositions that are functional, such as oral care compositions, the coolant properties of a composition can act as a sensorial cue, informing the user of the compositions efficacy, and this can drive preference or liking for these types of products also. The coolant mixture employed in the present invention exhibits a rather pronounced tingling sensation when applied to mucosal surfaces, particular the oral mucosa, which is particularly of interest in imparting this sensorial cue.

[0159] The invention provides in another of its aspects a method of compacting the amount of menthol employed in a flavour composition, comprising the step of adding to said flavour composition a coolant mixture as hereinabove defined.

[0160] The invention provides in yet another of its aspects a method of compacting the amount of coolant compounds employed in a flavour composition, comprising the step adding to said flavour composition a coolant mixture as hereinabove defined.

[0161] In a particular embodiment of the present invention there is provided a method of compacting the amount of menthol contained in a composition comprising the steps of:

[0162] I) screening the composition comprising menthol against a panel of consumers to determine a first preference score for said composition;

[0163] II) removing an amount of menthol from said composition and adding an amount of the coolant mixture, which amount added is lower than the amount of menthol removed on a weight basis, and subjecting it to a screening against a panel of consumers to obtain a second preference score that is higher than said first preference score.

[0164] The consumer test employed may be any of those test designs known and used by market researchers for determining preference or liking for taste of consumer products. For example, the test may be a Sequential Monadic evaluation of a pre-defined balanced Latin Square design wherein all products are tested by respondents. Further particulars of a suitable test are provided in the examples, below.

[0165] The menthane carboxamides as referred to above are described in international publications WO 2005 / 049553 and WO 2007 / 019719, incorporated herein by reference.

[0166] The menthane carboxamides employed in the present invention contain asymmetric carbon atoms. Such diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known per se, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the

[0167] 31511 PCT enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound separating the diastereomers and converting the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers mixtures and pure enantiomers are considered as part of the invention.

[0168] Particular examples of menthane carboxamides are the optical isomers shown below:

[0169] ( 17?, 25, 57?)- V-(4-(cyanomethyl)- (17?,25,57?)-2-isopropyl-5-methyl- phenyl)-2-isopropyl-5-methyl- V-(2-(pyridin-2-yl)ethyl)- cyclohexanecarboxamide cyclohexanecarboxamide

[0170] The flavor compositions according to the invention may additionally comprise flavoring agents, sweetening agents and other auxiliaries commonly used in the formulation of such compositions. Flavouring agents include but are not limited to: natural flavors, artificial flavors, spices, seasonings, and the like. Exemplary flavoring agents include synthetic flavor oils and flavoring aromatics and / or oils, oleoresins, essences, distillates, and extracts derived from plants, leaves, flowers, fruits, and so forth, and a combination comprising at least one of the foregoing.

[0171] Exemplary flavor oils include spearmint oil, cinnamon oil, oil of Wintergreen (methyl salicylate), peppermint oil, Japanese mint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, allspice, oil of sage, mace, oil of bitter almonds, and cassia oil; useful flavoring agents include artificial, natural and synthetic fruit flavors such as vanilla, and citrus oils including lemon, orange, lime, grapefruit, yazu, sudachi, and fruit essences including apple, pear, peach, grape, blueberry, strawberry, raspberry, cherry, plum, prune, raisin, cola, guarana, neroli, pineapple, apricot, banana, melon, apricot, ume, cherry, raspberry, blackberry, tropical fruit, mango, mangosteen, pomegranate, papaya and so forth. Additional exemplary flavors imparted by a flavoring agent include a milk flavor, a butter flavor, a cheese flavor, a cream flavor, and a yogurt flavor; a vanilla flavor; tea or coffee flavors, such as a green tea flavor, an oolong tea flavor, a tea flavor, a cocoa flavor, a chocolate flavor, and a coffee flavor; mint flavors, such as a peppermint flavor, a spearmint flavor, and a Japanese mint flavor; spicy flavors, such as an asafetida flavor, an ajowan flavor, an anise flavor, an angelica flavor, a fennel flavor, an allspice flavor, a cinnamon flavor, a chamomile flavor, a mustard flavor, a cardamom flavor, a caraway flavor, a cumin flavor, a clove flavor, a pepper flavor, a coriander flavor, a sassafras flavor, a savory flavor, a Zanthoxyli Fructus flavor, a perilla flavor, a juniper berry flavor, a ginger flavor, a star anise flavor, a horseradish flavor, a thyme flavor, a tarragon flavor, a dill flavor, a capsicum flavor, a nutmeg flavor, a basil flavor, a marjoram flavor, a rosemary flavor, a bayleaf flavor, and a wasabi (Japanese horseradish) flavor; a nut flavor such as an almond flavor, a hazelnut flavor, a macadamia nut flavor, a peanut flavor, a pecan flavor, a pistachio flavor, and a walnut flavor; alcoholic flavors, such as a wine flavor, a whisky flavor, a brandy flavor, a rum flavor, a gin flavor, and a liqueur flavor;

[0172] 31511 PCT floral flavors; and vegetable flavors, such as an onion flavor, a garlic flavor, a cabbage flavor, a carrot flavor, a celery flavor, mushroom flavor, and a tomato flavor.

[0173] In some embodiments, other flavoring agents include aldehydes and esters such as cinnamyl acetate, cinnamaldehyde, citral diethylacetal, dihydrocarvyl acetate, eugenyl 49 formate, p-methylamisol, and so forth can be used. Further examples of aldehyde flavorings include acetaldehyde (apple), benzaldehyde (cherry, almond), anisic aldehyde (licorice, anise), cinnamic aldehyde (cinnamon), citral, i.e., alpha-citral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), ethyl vanillin (vanilla, cream), heliotrope, i.e., piperonal (vanilla, cream), vanillin (vanilla, cream), alpha-amyl cinnamaldehyde (spicy fruity flavors), butyraldehyde (butter, cheese), valeraldehyde (butter, cheese), citronellal (modifies, many types), decanal (citrus fruits), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C- 12 (citrus fruits), 2-ethyl butyraldehyde (berry fruits), hexenal, i.e., trans-2 (berry fruits), tolyl aldehyde (cherry, almond), veratraldehyde (vanilla), 2,6-dimethyl-5-heptenal, i.e., melonal (melon), 2,6-dimethyloctanal (green fruit), and 2-dodecenal (citrus, mandarin), and the like. Generally, any flavoring or food additive such as those described in Chemicals Used in Food Processing, publication 1274, pages 63-258, by the National Academy of Sciences, can be used. This publication is incorporated herein by reference.

[0174] Some of the flavour ingredients useful in the present invention may contain menthol, for example peppermint oil. For the purpose of the present invention, the amounts of menthol referred to herein relate to the amounts of free menthol added to the flavour composition and it does not relate to any menthol that might be contained in a flavour ingredient, such as a flavour oil.

[0175] The amount of flavouring agents employed in the flavour formulation may typically be from about 1% to about 99%, and the particular amounts may vary depending on the nature of the flavour formulation created.

[0176] Sweetening agents include but are not limited: high intensity sweetening agents. High intensity sweetening agents have a sweetness intensity substantially greater than that of sucrose. Suitable high intensity sweetening agents include water-soluble natural sweetening agents such as dihydrochalcones, monellin, Stevia Rebaudiana (steviosides), glycyrrhizin, and mixtures thereof. Suitable water-soluble artificial sweetening agents include saccharin and its soluble salts, i.e., sodium and calcium saccharin salts, cyclamate and its salts, 3,4-dihydro-6-methyl 1.2,3- oxathiazine4-one-2.2-dioxide (Acesulfame) and the sodium ammonium, and calcium salts thereof, and especially the potassium salt of 3,4-dihydro-6-methyl-1 ,2,3- oxathiazine4-one-2.2-dioxide (Acesulfa me-K).

[0177] Suitable dipeptide based sweetening agents include L-aspartic acid derived sweetening agents such as L-aspartyl-L-phenvIalanine methyl ester (Aspartame), compounds described in United States patent no. 3,492,131 , L-alpha aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D- alaninamide hydrate (Alitame), methyl esters of L-aspartvI-L-phenylglycerine and L-aspartyl-L-2,5- dihvdrophenylglycine, Laspartyl-2.5-dihydro-L-phenyl-alanine, and L-aspartyl-L-(l cyclohexen)alanine.

[0178] Other suitable water-soluble sweetening agents include those derived from naturally occurring water-soluble sweetening agents such as chlorinated derivatives of sucrose, e.g.,

[0179] 31511 PCT chlorodeoxysugar derivatives such as derivatives of chlorodeoxysucrose and chlorodeoxygalactosucrose. Examples of chlorodeoxysucrose and chlorodeoxygalactosucrose derivatives include but are not limited to l-chloro-l'- deoxysucrose; 4-chloro-4-deoxy-alpha-D-galacto-pyranosyl- alpha-D-fructofuranoside, or 4-chloro-4-deoxygalactosucrose; 4-chloro-4-deoxy-alpha-D-galacto- pyranosyl- 1- chloro- 1 deoxy-beta-D-fructo-ftrranoside, or 4,1 '-dichloro-4, 1 'dideoxygalactosucrose; 1',6'-dichloro-l ',6'-dideoxysucrose; 4-chloro-4-deoxy-alpha-D-galacto-pyranosyl- 1 ,6- dichloro- I ,6- dideoxy-beta-D-fructo-furanoside, or 4,1 ',6'-trichloro-4, 1 ',6'- trideoxygalacto-sucrose; 4,6dichloro- 4,6-dideoxy-alpha-D-galacto-pvranosvl-6-chloro- 6-deoxy-beta-D-fructo-furanoside, or 4,6,6'- trichloro-4,6,6'-trideoxygalacto-sucrose, 6,1 ',6'-trichloro-6, 1 ',6'-trideoxysucrose; 4,6-dichloro4,6- dideoxy-alpha-D-galacto- pvranosyl-l .6-dichloro-l ,6-di-deoxy-beta-D-fructofuranoside, or 4,6,1 ',6'- tetrachloro- 4,6,1 ',6'-tetradeoxygalacto-sucrose; and 4,6,1 ',6'-tetrachloro4,6, 1 ',6'-tetradeoxy- sucrose. In a preferred embodiment, the chlorodeoxysugar derivative is 4,1 ',6' trichloro-4,1',6'- trideoxygalacto-sucrose, or 4-chloro 4-deoxy-alpha-D- galactopyranosyl- 1 ,6dichloro 1 ,6dideoxy- beta-D-fructofuranoside, which is commercially available under the tradename Sucralose from McNeil Specialty Products

[0180] Company, Skillman, New Jersey.

[0181] Other suitable high intensity sweetening agents include protein based sweetening agents such as talin (thaumaoccous danielli, Thaumatin I and II).

[0182] The amount of sweetening agent employed in the flavour formulation may typically be from about 0.001% to about 1 %, but greater or lesser amounts may be employed depending on the nature of the flavour formulation created.

[0183] Auxiliaries are materials used in flavour formulations for their attributes and properties other than their ability to impart flavour or sweetening effects. Auxiliaries include additives, surfactants, emulsifiers, superfatting agents, bodying agents, thickeners, polymers, silicone compounds, fats, waxes, stabilizers, preservatives, antioxidants, dyes, antimicrobial agents, solvents and co-solvents; viscosity and rheology modifiers; gelling agents; preservative materials such as fungicides and bactericides; pigments, dyestuffs and colouring matters; extenders, fillers and reinforcing agents; stabilisers against the detrimental effects of heat and light; bulking agents, which may include mineral adjuvants, which may serve as fillers and textural agents. Suitable mineral adjuvants include calcium carbonate, magnesium carbonate, alumina, aluminum hydroxide, aluminum silicate, talc, tricalcium phosphate, tricalcium phosphate and the like, which can serve as fillers and textural agents.

[0184] Additional bulking agents (carriers, extenders) suitable for use include sweetening agents such as monosaccharides, disaccharides, polysaccharides, sugar alcohols, polydextrose, and maltodextrins; minerals, such as calcium carbonate, talc, titanium dioxide, dicalcium phosphate; and combinations thereof.

[0185] Fillers modify the texture and aid processing. Examples of such fillers include magnesium and aluminum silicates, clay, alumina, talc, titanium oxide, cellulose polymers, and the like.

[0186] Other suitable and desirable additives are described in standard texts, such as “Handbook of Industrial Chemical Additives”, ed. M. and I. Ash, 2ndEd., (Synapse 2000).

[0187] 31511 PCT The flavour compositions, or particular ingredients thereof may be provided in many distinct physical forms, for example solid, liquid or encapsulated forms. Selection of the particular form may be selected by reason of ease of handling or storage, or in order to achieve a particular effect such as sustained or controlled release. By “encapsulated form” is meant that a material or ingredient is contained within an encapsulating material, which protects and / or retains it and permits its release either gradually or completely. All known methods of encapsulation, may be used, for example, coacervation, spray drying, absorption into a porous substrate and the like. All possible encapsulation materials may also be used, for example, natural fibres, minerals of large surface area and polymeric materials.

[0188] The amount of flavour composition employed in a consumer product may vary according to the particular effect that is desired. Typically, however, the flavour composition may be used in an amount of about 0.01 to 2 % by weight based on the weight of the consumer product, more particularly 0.1 to 1.5% by weight.

[0189] The flavour compositions according to the invention may be used in any manner of consumable products. By “consumable products” is meant any product intended to be applied to the body, or placed in the mouth before discarding (e.g. by rinsing) or ingesting, for the purpose of therapy, treatment, nourishment or enjoyment. Consumable products may be in any physical form such as creams, gels, lotions, alcoholic and aqueous / alcoholic solutions, emulsions, dispersions, stick preparations or the like.

[0190] Flavour compositions may be employed in consumable products for use in oral care. In relation to consumable products, “oral care” relates to any product applied to the oral cavity for the purposes of cleaning, freshening, healing, deodorising the cavity or any part thereof. Such compositions include, but are not limited to, toothpastes, tooth gels, tooth powders, tooth whitening products, mouthwashes, lozenges, dental floss, tooth picks, anti-plaque and anti-gingivitis compositions, throat lozenges, throat drops, inflammatory compositions, compositions for treatment of nasal symptoms, cold symptoms and upper gastrointestinal tract distress, compositions for cold relief, for alleviating discomfort of hot flash, gargle compositions.

[0191] Oral care products utilising these compounds may be prepared by blending a flavour composition with one or more of the conventional ingredients normally associated with such products, in standard quantities. Examples of such standard ingredients include, but are not limited to, Mentha Arvensis, Mentha Piperita, Mentha Spicata, Mentha Cardiaca, Synthetic Mints, Anethole, Methyl Salicylate, Eucalyptol, Cinnamic Aldehyde, Eugenol, Calcium Carbonate, Silica (Precipitates & Xerogels), Dicalcium Phosphate, Alumina, Sodium Lauryl Sulphate, Betaine, Glycerine, Sorbitol, Water, Saccharin, Sodium Cyclamate, Aspartame, Xylitol, Sodium Carboymethyl Cellulose, Methyl Cellulose, Sodium Carageenate, Xanthan Gum, Polyvinyl Pyrrolidone, Sodium Tripolyphosphate, Ethyl Alcohol, Sodium Fluoride, Sodium Monofluorophosphate, Stannous Fluoride, Potassium Citrate, Potassium Chloride, Potassium Nitrate, Strontium Acetate, Strontium Chloride, Sodium Tripolyphosphate, Cetyl Pyridinium Chloride, Hexetidine, Sanguinarine, Triclosan, Chlorhexidine, Zinc Citrate, Zinc Sulphate, Zinc Chloride, Calcium Glycerophosphate, Sodium Bicarbonate, Tetra Sodium Pyrophosphate, Tetra Potassium Pyrophosphate.

[0192] 31511 PCT In some embodiments the oral care products or flavour compositions may also contain fluoride alternatives, such as but not limited to, xylitol, amorphous calcium phosphate (ACP), casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), Hydroxyapatite.

[0193] Some of these materials may be present in encapsulated form, as this term is described above.

[0194] The flavour compositions according to the invention may be used in personal care products such as pharmaceuticals, cosmetics and toiletries. When used within cosmetics and toiletries, the formulations can be used in any of the “Reported Product Categories” listed by the Cosmetic, Toiletries and Fragrance Association’s ‘International Cosmetic Ingredient Dictionary and Handbook’, and with any one or more of the ingredients cited as being used for the reported product categories. The Reported Product Categories are: Aftershave lotions, Baby lotions, oils, powders and creams, Baby products miscellaneous, Baby shampoos, Basecoats and undercoats, Bath capsules, Bath oils, tablets and salts, Bath preparations miscellaneous, Bath soaps and detergents, Beard softeners, Blushers, Body and hand preparations, Bubble baths, Cleaning products, Colognes and toilet waters, Cuticle softeners, Dentifrices, Deodorants, Depilatories, Douches, Eye lotions, Eye makeup preparations miscellaneous, Eye makeup removers, Eye shadows, Eyebrow pencils, Eyeliners, Face and neck preparations, Face powders, Feminine hygiene deodorants, Foot powders and sprays, foundations, Fragrance preparations miscellaneous, Hair bleaches, Hair colour sprays, Hair colouring preparations miscellaneous, Hair conditioners, Hair dyes and colours, Hair lighteners with colour, Hair preparations, Hair rinses, Hair shampoos, Hair sprays, Hair straighteners, Hair tints, Hair wave sets, Indoor tanning preparations, Leg and body paints, Lipsticks, Makeup bases, Makeup fixatives, Makeup preparations, Manicuring preparations miscellaneous, Mascara, Men’s talcum, Moisturising preparations, Mouthwashes and breath fresheners, Nail creams and lotions, Nail extenders, Nail polish and enamel removers, Nail polish and enamels, Night skin care preparations, Oral hygiene products miscellaneous, Paste masks, Perfumes, Permanent waves, Personal cleanliness products miscellaneous, Powders, Preshave lotions, Rouges, Sachets, Shampoos, Shaving cream, Shaving preparations miscellaneous, Shaving soap, Skin care preparations miscellaneous, Skin fresheners, Suntan gels, creams and liquids, Suntan preparations miscellaneous, Tonics, dressings and other hair grooming aids.

[0195] In the preparation of the abovementioned products, there may be used all or any of the standard Auxiliaries found in such products and described above, used in art-recognised quantities. Other suitable and desirable additives or auxiliaries are described in standard texts, such as “Handbook of Industrial Chemical Additives”, ed. M. and I. Ash, 2ndEd., (Synapse 2000).

[0196] Further formulation details useful in association with these compounds may be found in standard texts, for example, “Handbook of Cosmetic Science and Technology”, ed. Pays, Barel & Maibach, 2ndEd. (Dekker, 2005).

[0197] Flavour compositions according to the invention may be used in foodstuffs of all kinds, confectionery, baked goods, sweet goods, dairy products and beverages. The term "confectionery" includes, but is not limited to: chewing gum (which includes sugarized gum, sugar-free gum, functional gum and bubble gum), center-fill confections, chocolate and other chocolate confectionery, medicated confectionery , lozenges, tablets, pastilles, mints, standard mints, power

[0198] 31511 PCT mints, chewy candies, hard candies, boiled candies, breath and other oral care films or strips, candy canes, lollipops, gummies, jellies, fudge, caramel, hard and soft panned goods, toffee, taffy, liquorice, gelatin candies, gum drops, jelly beans, nougats, fondants, or combinations of one or more of these, or edible compositions incorporating one or more of these.

[0199] The confectionery compositions can be incorporated into an otherwise conventional hard or soft confectionery format using standard techniques and equipment known to those of ordinary skill in the art. The confectionery compositions can also be center filled and / or coated with hard, soft, or particulate coatings.

[0200] The term "baked goods" includes, but is not limited to: alfajores, bread, packaged / industrial bread, unpackaged / artisanal bread, pastries, cakes, packaged / industrial cakes, unpackaged / artisanal cakes, cookies, chocolate coated biscuits, sandwich biscuits, filled biscuits, savory biscuits and crackers, bread substitutes.

[0201] The term "sweet goods" includes, but is not limited to: breakfast cereals, ready-to-eat (“rte”) cereals, family breakfast cereals, flakes, muesli, other rte cereals, children's breakfast cereals and hot cereals.

[0202] The term "dairy products" includes, but is not limited to: ice cream, impulse ice cream, single portion dairy ice cream, single portion water ice cream, multi-pack dairy ice cream, multi-pack water ice cream, take-home ice cream, take-home dairy ice cream, ice cream desserts, bulk ice cream, take-home water ice cream, frozen yoghurt, artisanal ice cream, dairy products, milk, fresh / pasteurized milk, full fat fresh / pasteurized milk, semi skimmed fresh / pasteurized milk, long- life / uht milk, full fat long life / uht milk, semi skimmed long life / uht milk, fat-free long life / uht milk, goat milk, condensed / evaporated milk, plain condensed / evaporated milk, flavored, functional and other condensed milk, flavored milk drinks, dairy only flavored milk drinks, flavored milk drinks with fruit juice, soy milk, sour milk drinks, fermented dairy drinks, coffee Whiteners, powder milk, flavored powder milk drinks, cream, yoghurt, plain / natural yoghurt, flavored yoghurt, fruited yoghurt, probiotic yoghurt, drinking yoghurt, regular drinking yoghurt, probiotic drinking yoghurt, chilled and shelfstable desserts, dairy-based desserts and soy-based desserts.

[0203] Other foodstuff includes, but is not limited to: chilled snacks, sweet and savory snacks, fruit snacks, chips / crisps, extruded snacks, tortilla / corn chips, popcorn, pretzels, nuts, other sweet and savory snacks, snack bars, granola bars, breakfast bars, energy bars, fruit bars, other snack bars, meal replacement products, slimming products, convalescence drinks, ready meals, canned ready meals, frozen ready meals, dried ready meals, chilled ready meals, dinner mixes, frozen pizza, chilled pizza, soup, canned soup, dehydrated soup, instant soup, chilled soup, uht soup, frozen soup, pasta, canned pasta, dried pasta, chilled / fresh pasta, noodles, plain noodles, instant noodles, cups / bowl instant noodles, pouch instant noodles, chilled noodles, snack noodles, dried food, dessert mixes, sauces, dressings and condiments, herbs and spices, spreads, jams and preserves, honey, chocolate spreads, nut-based spreads, and yeast-based spreads.

[0204] The term "beverage" as used herein means any drinkable liquid or semi-liquid, including for example: flavored water, soft drinks, fruit drinks, coffee-based drinks, tea-based drinks, juice-based drinks (includes fruit and vegetable), milk-based drinks, gel drinks, carbonated or non-carbonated drinks, powdered drinks, alcoholic or non-alcoholic drinks.

[0205] 31511 PCT In the preparation of the abovementioned products, there may be used all or any of the standard ingredients found in such products, used in art-recognised quantities. Examples of such ingredients include (but are by no means limited to) solvents and co-solvents; surfactants and emulsifiers; viscosity and rheology modifiers; thickening and gelling agents; preservative materials; pigments, dyestuffs and colouring matters; extenders, fillers and reinforcing agents; stabilisers against the detrimental effects of heat and light, bulking agents, flavoring and flavor-enhancing agents, warming agents, breath fresheners, mouth moisteners, coloring agents, acidulants, buffering agents and antioxidants.

[0206] With respect to chewing gum compositions in particular, suitable components include in addition to a water-insoluble gum base portion, a water soluble bulk portion and various additives. The water soluble portion may include sweetening agents, bulking agents, softening agents and / or plasticizers, waxes, emulsifiers, thickening agents, flavor enhancing agents, warming agents, breath fresheners, mouth moisteners, acidulants, coloring agents, buffering agents, antioxidants, nutraceuticals, medicaments and other conventional chewing gum additives that provide desired attributes. Other conventional chewing gum additives known to one having ordinary skill in the art may also be used in the water soluble bulk portion.

[0207] Softeners and plasticizers may be used to provide a variety of desirable textures and consistency properties. Suitable plasticizers and softeners may include lanolin, palmitic acid, oleic acid, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate, glyceryl lecithin, glyceryl monostearate, propylene glycol monostearate, acetylated monoglyceride, glycerine, and a combination comprising at least one of the foregoing. Because of the low molecular weights of these softeners and plasticizers, they are able to penetrate the fundamental structure of the gum base, making it plastic and less viscous.

[0208] Waxes may be used in the gum base to soften the elastomer, improve the elasticity of the gum base, and obtain a variety of desirable textures and consistency properties. Suitable waxes may include natural and synthetic waxes, hydrogenated vegetable oils, petroleum waxes such as polyurethane waxes, polyethylene waxes, paraffin waxes, microcrystalline waxes, fatty waxes, sorbitan monostearate, tallow, and propylene glycol. Low melting waxes may be used in the gum compositions. These waxes typically have a melting point below about 60°C, and specifically about 45 to about 55°C. High melting waxes may also be used in the gum base. Such high melting waxes include beeswax, vegetable wax, candelilla wax, carnauba wax, most petroleum waxes, and the like, and combinations thereof.

[0209] Suitable emulsifiers include distilled monoglycerides, acetic acid esters of mono and diglycerides, citric acid esters of mono and diglycerides, lactic acid esters of mono and diglycerides, mono and diglycerides, polyglycerol esters of fatty acids, ceteareth-20, polyglycerol polyricinoleate, propylene glycol esters of fatty acids, polyglyceryl laurate, glyceryl cocoate, gum arabic, acacia gum, sorbitan monostearates, sorbitan tristearates, sorbitan monolaurate, sorbitan monooleate, sodium stearoyl lactylates, calcium stearoyl lactylates, diacetyl tartaric acid esters of mono- and diglycerides, glyceryl tricaprylate-caprate / medium chain triglycerides, glyceryl dioleate, glyceryl oleate, glyceryl lacto esters of fatty acids, glyceryl lacto palmitate, glyceryl stearate, glyceryl laurate, glycerlyl di laurate, glyceryl monoricinoleate, triglyceryl monostearate, hexaglyceryl distearate,

[0210] 31511 PCT decaglyceryl monostearate, decaglyceryl dipalmitate, decaglyceryl monooleate, polyglyceryl 10 hexaoleate, medium chain triglycerides, caprylic / capric triglyceride, propylene glycol monostearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 65, hexylglyceryl distearate, triglyceryl monostearate, tweens, spans, stearoyl lactylates, calcium stearoyl-2- lactylate, sodium stearoyl-2-lactylate lecithin, ammonium phosphatide, sucrose esters of fatty acids, sucroglycerides, propane- 1 ,2-diol esters of fatty acids, and combinations comprising at least one of the foregoing.

[0211] Suitable thickening agents include cellulose ethers (e.g., hydroxyethyl cellulose, hydroxypropylmethyl cellulose, or hydroxypropyl cellulose), methylcellulose, carboxymethylcellulose, and combinations thereof. Additional polymers useful as thickeners include carbomer, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, natural gums like xanthan gum, tragacantha, guar gum, acacia gum, arabic gum, water-dispersible polyacrylates like polyacrylic acid, methyl methacrylate copolymer, and carboxyvinyl copolymers. A chewing gum composition may additionally contain bulking agents and fillers, nutraceuticals, medicaments and flavoring agents, as hereinabove described.

[0212] The chewing gum composition may be coated or compressed, and be in the form of slabs, sticks, pellets, cubes, trapezoids, rectangles, or balls. The compositions of the different forms of the gum compositions will be similar but may vary with regard to the ratios of the ingredients. Center- filled gum is another common gum form, the center-fill is typically an aqueous liquid or gel, which is injected into the center of the gum during processing. The center-filled gum may also be optionally coated and may be prepared in various forms, such as in the form of a lollipop.

[0213] In another aspect, the present invention relates to a non-medical method of inducing a cooling sensation in a human or animal comprising contacting the human or animal with the flavor composition as described herein.

[0214] In yet another aspect, the present invention relates to the use of the flavor composition, as described herein, for inducing a cooling sensation in a human or animal comprising contacting the human or animal with the flavor composition.

[0215] There now follows a series of examples that serve to illustrate the invention.

[0216] EXAMPLES

[0217] A TRPM8 modulator: 2-(methylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan- 1-one was prepared as follows:

[0218] Intermediate 01 : tert-butyl 2-(5-(p-tolyl)-1 / 7-imidazol-2-yl)piperidine-1 -carboxylate: A pressure vessel was charged with tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1 -carboxylate (400 mg, 1.211 mmol), p-tolylboronic acid (181 mg, 1.332 mmol, 1.1 equiv.), sodium carbonate (257 mg, 2.42 mmol, 2 equiv.), 1 ,1'-bis(diphenylphosphino)-ferrocene-palladium(ll)dichloride dichloromethane complex (49 mg, 0.061 mmol, 0.05 equiv.), tetrahydrofuran (5 mL) and water (1 mL). The mixture was degassed by purging with nitrogen and the vessel was sealed. The mixture was stirred and heated to 100°C overnight. The resulting mixture was cooled to 0°C, the vessel was opened and the contents poured into aq. sat. NaHCOs solution (50 mL), extracted with EtOAc (2x 50 mL), washed

[0219] 31511 PCT with water (50 mL) and brine (50 mL), dried over MgSC and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography eluting with a gradient of EtOAc in Heptane to give tert-butyl 2-(5-(p-tolyl)imidazol-2-yl)piperidine-1 -carboxylate (314 mg, 0.920 mmol, 76% yield) as a white solid. MS (El, 70 eV): 341 (4, [M]+«), 285 (11), 268 (3), 240 (30), 185 (100), 172 (16), 91 (6), 57 (99). 1 H NMR (DMSO-d6, 400MHz, mixture of rotamers and tautomers): <5 11 .66-12.09 (m, 1 H), 7.49-7.70 (m, 2H), 7.20-7.48 (m, 1 H), 7.08-7.23 (m, 2H), 5.34 - 5.23 (m, 1 H), 3.89 (br d, J=12.1 Hz, 1 H), 3.05 (br t, J=10.9 Hz, 1 H), 2.28 (s, 3H), 2.18-2.25 (m, 1 H), 1.65-1.78 (m, 1 H), 1.22-1.63 (m, 13H) ppm.13C NMR (75 MHz, DMSO, mixture of tautomers) 5

[0220] 155.1 (q), 147.5 (q), 140.2 (q), 135.3 (q), 132.7 (q), 129.4 (t), 124.6 (t), 112.5 (t), 79.3 (q), 63.3 (d), 49.7 (t), 41.2 (d), 28.5 (s), 28.4 (d), 26.8 (d), 25.3 (d), 21.2 (s), 19.9 (d) ppm.

[0221] Intermediate 02: 2-(5-(p-tolyl)-1 / 7-imidazol-2-yl)piperidine: A solution of tert-butyl 2-(5-(p- tolyl)imidazol-2-yl)piperidine-1 -carboxylate (304 mg, 0.890 mmol) in dichloromethane (3 mL) was treated dropwise at 5°C with trifluoroacetic acid (0.549 mL, 7.12 mmol, 8 equiv.) and the resulting mixture stirred at room temperature for 2 hours or until complete consumption of the starting material. The mixture was poured into iced water (30 mL) and the pH made basic by the addition of aqueous 1 M NaOH solution. The mixture was then extracted with dichloromethane (3x 20 mL), dried over MgSC and concentrated under reduced pressure to give 2-(5-(p-tolyl)imidazol-2- yl)piperidine (160 mg, 0.664 mmol, 74% yield) as a pale yellow oil which was used in the next step without further purification. MS (El, 70 eV): 241 (6, [M]+«), 185 (100), 172 (13), 158 (8), 91 (3), 84 (4). 1 H NMR (CHLOROFORM-d, 400MHz): 5 8.67-8.89 (br s, 1 H), 7.50 (d, J=8.1 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 7.13 (s, 1 H), 4.14 (dd, J=12.3, 3.1 Hz, 1 H), 3.30 (br d, J=12.7 Hz, 1 H), 2.71-2.84 (m, 1 H), 2.37 (s, 3H), 2.15-2.27 (m, 1 H), 2.01 (br dd, J=14.4, 3.2 Hz, 1 H), 1.90 (br d, J=13.4 Hz, 1 H), 1 .67-1 .77 (m, 2H), 1 .32-1 .46 ppm (m, 1 H).

[0222] TRPM8 modulator: 2-(methylthio)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one: To a solution of 2-(5-(p-tolyl)imidazol-2-yl)piperidine (400 mg, 1.66 mmol) in dichloromethane (4 mL) was added HOBt (305 mg, 1 .99 mmol, 1.2 equiv.) and 3-(((ethylimino)methylene)amino)-N,N- dimethylpropan-1 -amine hydrochloride (381 mg, 1.99 mmol, 1.2 equiv.) at 0~5 °C and the mixture was stirred at room temperature for 0.5 h. The mixture was then treated with 2- (methylthio)propanoic acid (200 mg, 1.66 mmol, 1 .0 equiv.) and N,N-diisopropylethylamine (214 mg, 1.66 mmol, 1.0 equiv.) and the resulting mixture was stirred at rt. for 16 h. The mixture was filtered and solvent was removed and the crude purified by silica gel chromatography (gradient of EtOAc in Heptane) to give 2-(methylthio)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one (150 mg, 0.44 mmol, 26% yield) as a white solid. MS (El, 70 eV): 343 (2, [M]+«), 241 (17), 240 (100), 213 (13), 185 (18), 184 (9), 75 (55), 56 (11), 55 (9), 47 (10), 41 (11).1H NMR (400 MHz, DMSO-de, mixture of stereoisomers and tautomers) <5 12.07, 1 1.99, 1 1.95, 11.76 (brs, 1 H), 7.72 - 7.60 (m, 2H), 7.59 - 7.42 (m, 1 H), 7.26 - 7.08 (m, 2H), 5.75 - 5.39 (m, 1 H), 4.49 - 3.00 (m, 3H), 2.71 - 2.15 (m, 1 H), 2.30 (s, 3H), 2.07 - 1.96 (m, 3H), 1.94 - 1.48 (m, 5H), 1.43 - 1.34 (m, 3H) ppm.13C NMR (101 MHz, DMSO-de, mixture of stereoisomers and tautomers) <5 170.2 (q), 170.2 (q), 170.0 (q), 147.0 (q), 146.8 (q), 146.7 (q), 140.4 (q), 140.3 (q), 139.9 (q), 135.3 (q), 135.2 (q),

[0223] 135.1 (q), 132.7 (q), 132.6 (q), 132.6 (q), 129.7 (t), 129.3 (t), 124.6 (t), 113.0 (t), 112.6 (t), 112.5 (t), 51.5 (t), 47.3 (t), 47.0 (t), 43.1 (d), 43.0 (d), 38.8 (d), 38.0 (t), 37.6 (t), 37.3 (t), 28.8 (d), 28.6 (d),

[0224] 31511 PCT 28.1 (d), 27.9 (d), 26.1 (d), 25.7 (d), 25.4 (d), 21.2 (s), 20.3 (d), 20.1 (d), 18.3 (s), 18.0 (s), 17.8 (s), 11.9 (s), 11.7 (s), 11.6 (s) ppm.

[0225] The menthane carboxamide “M” used, along with the TRPM8 modulator “T”, in the following tests was N-(4-cyanomethylphenyl)-2-isopropyl p-menthanecarboxamide.

[0226] Sensory Evaluation

[0227] A trained oral care sensory panel was employed for sensory assessments. The members of the sensory panel were selected on a basis of their olfactory and gustatory sensory acuity and then trained for a period of 4 to 6 months. Their training enables them to identify individual flavour characteristics and score their perceived intensity in a consistent manner. The trained panelist’s performance is continuously monitored and regular training is provided to maintain high standards.

[0228] For the assessment a toothpaste containing between 30 - 35 % menthol was selected as “control”. To said control was added around 80 ppm of either T, M or a flavor composition comprising of T and M. The flavour composition contained T and M in around 20 ppm and 60 ppm, respectively, thereby giving a ratio of T :M or about 1 :3.

[0229] Around 1.5 cm of the product, was dispensed onto a clean plastic spoon immediately prior to assessment. Each sample was coded with a 3-digit random number.

[0230] The attributes were assessed by the trained sensory panel using a 0-100 line scale. The panelists brushed with the toothpaste samples for 1 minute before expectorating and rinsing with 10 ml of water. The panelists were then asked to rate attributes immediately after brushing (i.e. after rinse) and after 10 and 20 minutes (aftertaste). The following attributes were scored by the panelists for assessing immediately after brushing: “fresh”, “effect” and “cooling” for immediately after brushing and aftertaste assessments. As used herein the term “effect” is the overall sensation of the product in the mouth i.e. a combination of both flavor and mouthfeel attributes. A higher score for the attribute “effect” generally means a highly effective product, for the end consumer.

[0231] The study size (total amount of data to be collected) was determined so that a difference of 10% of the scale could be detected with 95% power (e.g. 10 points on the 0-100 linear scale). For this study 10 panelists were included, each completing 3 replicates, therefore giving 30 assessments in total.

[0232] The order of samples assessed was pre-determined using a balanced randomization (Latin Square design) to minimize any carry over or order effects. The samples were assessed in a sequential monadic format. Before analysis, the data was checked for outliers and extreme violations to normality. Reliability of the data was checked and data of panelists with poor discrimination, consensus or repeatability may have been removed from the analysis, if required. The data was analyzed using analysis of variance (ANOVA). A 5% significance level (95% confidence level) was used. Separate ANOVAs were carried out per time point. The ANOVAs have product, panelist, and replicates as factors. The estimated product means are reported. It is indicated with letters if the product means are statistically significantly different from each other: if they are not, then they share the same letter. Attributes scoring < 10 on the scale have been excluded from the report (unless they are attributes of specific interest) as it cannot be certain that any differences seen are true or part of the variance in the data. The results are shown in tables 01 .

[0233] 31511 PCT When comparing the values, a higher value denotes higher impact or perception of a particular attribute.

[0234] Table 01 :

[0235] * The letters in the brackets indicate the statistical difference of the perceived attribute. Where the same letter is shown in the column there is no statistically significant differences between the relevant figures.

[0236] As seen from the data, the flavour comprising a combination of T:M scores much higher on the overall effect among the trained sensory panel members. This can be gauged from the significantly higher absolute scores for the combination, especially after 10 and 20 minutes. The higher score opens the possibility to reduce menthol content in a consumer product, without compromising at least on attributes like, but not limited to, freshness, effect and cooling. In another aspect, the coolant combination of T and M leads to improved performance from an end-consumer perspective in terms of freshness, effect and cooling.

[0237] To assess the effect of different ratios of T:M in a sample, an expert panel comprising of 4 panelists was asked to gauge the overall performance (cooling, effect and freshness) immediately after use and at 10 and 20 minutes, along with flavor intensity. The scoring was based on a scale of 0 - 10. The results are shown in table 02.

[0238] Table 02:

[0239] 31511 PCT As can be seen the data, various ratios of T:M provide a pronounced overall effect, especially even after 10 and 20 minutes.

[0240] 31511 PCT

Claims

CLAIMS1 . A flavour composition comprising: a) at least one menthane carboxamide selected from N-(4-cyanomethylphenyl) p- menthanecarboxamide, 2-isopropyl-5-methyl-N-(2-(pyridin-4-yl)ethyl)cyclohexanecarboxamide, or a mixture of N- (4-cyanomethylphenyl) p-menthanecarboxamide and 2- isopropyl-5-methyl-N-(2- (pyridin-4-yl)ethyl)cyclohexanecarboxamide and mixtures thereof; b) at least one transient receptor potential melastatin member 8 (TRPM8) modulator compound of formula (I), a salt or solvate thereofwherein n is 0 or 1 ;R1is selected from i) halogen, ii) Ce - C-io aryl, iii) C5-C10 mono- or bicyclic heteroaryl wherein up to 2 C-atoms are replaced by a hetero atoms independently selected from sulfur, nitrogen, and oxygen, iv) Ce - C10 aryl substituted with up to four substituents independently selected from the group consisting of halogen; OH; C=N; NO2; C1-C6 alky;C1-C6 alkyl comprising up to 5 halogen atoms;C1-C3 alkyl comprising up to 3 OH groups;C2-C6 alkenyl;Ci-Ce alkoxy;Ci-Ce alkoxy comprising up to 3 halogen atoms;C1-C3 alkoxy C1-C3 alkyl;C3-C7 cycloalkyl;-C(O)R10wherein R10is selected from C1-C3 alkyl;-OC(O)R11wherein R11is selected from H, and C1-C3 alkyl;-C(O)O-R12wherein R12is selected from hydrogen and C1-C3 alkyl;- (CH2)mN(R13)R14wherein m is 0 or 1 , R13is selected from hydrogen, C1-C3 alkyl, and -SO2R15wherein R15is C1-C3 alkyl, and R14is selected from hydrogen, C1-C3 alkyl, and -SO2R16wherein R16is C1-C3 alkyl, or wherein R13and R14form together with the N atom to which they are attached morpholine, thiomorpholine, or 1 ,1-dioxothiomorpholine;-SR17wherein R17is selected from hydrogen and C1-C3 alkyl; and31511 PCT-S(O)2R18wherein R18is selected from hydrogen and C1-C3 alkyl; with the proviso that when the aryl ring is substituted with two or more substituents, two substituents may form a cyclic ring together with the carbon atoms to which they are attached, and v) C5-C10 mono- or bicyclic heteroaryl wherein up to 2 C-atoms are replaced by a hetero atoms independently selected from sulfur, nitrogen, and oxygen, substituted with up to four substituents selected from the group consisting of halogen; OH (hydroxyl); C=N (cyano); NO2 (nitro); Ci-Ce alky;Ci-Ce alky comprising up to 5 halogen atoms;C2-C6 alkenyl;Ci-Ce alkoxy;Ci-Ce alkoxy comprising up to 3 halogen atoms;C1-C3 alkoxy C1-C3 alkyl;C3-C7 cycloalkyl;-C(O)R20wherein R20is selected from C1-C3 alkyl;-OC(O)R21wherein R21is selected from H, and C1-C3 alkyl;-C(O)O-R22wherein R22is selected from hydrogen and C1-C3 alkyl;-(CH2)mN(R23)R24wherein m is 0 or 1 , R23is selected from hydrogen, C1-C3 alkyl, and -SO2R25 wherein R25is C1-C3 alkyl, and R24is selected from hydrogen, C1-C3 alkyl, and -SO2R26wherein R26is C1-C3 alkyl, or wherein R23and R24form together with the N atom to which they are attached morpholine, thiomorpholine, or 1 ,1-dioxothiomorpholine;-SR27wherein R27is selected from hydrogen and C1-C3 alkyl; and-S(O)2R28wherein R28is selected from hydrogen and C1-C3 alkyl;Y is a monocyclic or bicyclic, unsaturated or aromatic heterocyclic ring comprising one, two, three or four heteroatoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally mono-, di-, or tri-substituted with a group selected from halogen, methyl, ethyl, - N(R40)R41, -CON(R40)R41, -[CR40R41]P-C(O)OR40, -C(O)R40, and -SO2N(R40)R41wherein R40and R41are independently selected from hydrogen and C1-C4 alkyl, and p is 0, 1 , or 2;A is a 5 to 7 membered heterocyclic ring optionally comprising one additional hetero atom selected from oxygen and sulfur, wherein the heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =0;Z is either C, S or S(O); andR4, R5and R6form together with the carbon atom to which they are attached a hydrocarbon group optionally comprising up to five hetero atoms selected from O, N, S, and F; c) optionally menthol; wherein the ratio of the amount of a) and b) in the composition is from about 10:1 to about 1 :10.

2. The flavour composition according to claim 1 , wherein the TRPM8 modulator b) is of formula (Id), a salt or solvate thereof:31511 PCTwherein R is an C3-C7 branched alkyl or alkenyl optionally comprising one S atom, wherein preferably the compound of formula (Id) is selected from the group consisting of 2-methyl-1-(2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one (including (2S)-2-methyl-1-(2-(5-(p-tolyl)-1 H- imidazol-2-y I) pi pe ri di n- 1 -yl)butan-1 -one, and (2R)-2-methy 1-1 -(2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)butan-1-one), 2-(methylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan- 1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one and 2,2-dimethyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one or mixtures thereof.

3. The flavour composition according to claim 1 or 2, wherein the ratio of the amount of a) and b) in the composition is from about 5:1 to about 1 :5, preferably from about 3:1 to about 1 :3.

4. The flavour composition according to claims 1 to 3, wherein a) is present from about 1 ppm to about 1000 ppm, preferably from about 30 ppm to about 500 ppm, even more preferably from about 50 ppm to about 200 ppm.

5. The flavour composition according to claims 1 to 4, wherein b) is present from 1 ppm to about 1000 ppm, preferably from about 30 ppm to about 500 ppm, even more preferably from about 50 ppm to about 200 ppm.

6. The flavour composition according to claims 1 to 5, wherein c) is present from about 10 ppm to about 20000 ppm, preferably from about 200 ppm to about 10000 ppm, even more preferably from about 500 ppm to about 6000 ppm.

7. The flavour composition according to claims 1 to 6, comprising; a) from about 0.1 wt.% to about 5 wt.%; and / or b) from about 0.01 wt.% to about 5 wt.%; and / or c) from about 99.98 wt.% to about 90 wt.%.

8. The flavour composition according to claims 1 to 7, comprising a further cooling compound.

9. The flavour composition according to claims 1 to 8, wherein the compound of formula (I) or (Id) is selected from the group consisting of (2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)(1 ,2,3-thiadiazol- 5-yl)methanone, (2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)(thietan-3-yl)methanone, (2,2- dimethylcyclopropyl)(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)methanone, (2- ethoxycyclopropyl)(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)methanone, (2-31511 PCTmethoxycyclopropyl)(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1 -y l)methanone, (2- methylcyclopropy l)(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1 -yl)methanone, (2S)-2-methyl-1 -(2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1 H- imidazol-2-yl)piperidin-1-yl)methanone, (E)-1-(2-(5-(3,4-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1- yl)-2-methylbut-2-en-1-one, (E)-2-methyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-2-en-1- one, (E)-2-methyl-1 -(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1 -yl)pent-3-en-1 -one, (R)-2- (methylthio)-1-((R)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1- ((R)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1-((S)-2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-methyl-1-((R)-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)butan-1-one, (tetrahydrofuran-3-yl)(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1- yl)methanone, 1 -(2-(1 H-benzo[d]imidazol-2-yl)pi peridin-1 -yl)-2-(methylthio)propan-1 -one, 1 -(2-(4-(1 - methyl-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2- (4-(2,3-dihydrobenzofuran-5-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4- (2,3-dihydrobenzofuran-6-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4- (2,5-dimethylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2- chlorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2- cyclopropyloxazol-5-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2- fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2- hydroxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-((dimethylamino)methyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2- (4-(3,5-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3,5- dimethylisoxazol-4-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-chloro- 4-methylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-methylfuran- 2-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-((1 ,1- dioxidothiomorpholino)methyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(1-hydroxyethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2- (4-(4-(difluoromethoxy)-3-fluorophenyl)-1 H-imidazol-2-yl)pi peridin-1 -yl)-2-(methylthio)propan-1 -one, 1 -(2-(4-(4-(difluoromethyl)thiophen-3-yl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2-(methylthio)propan-1- one, 1-(2-(4-(4-(methylsulfonyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1 -(2-(4-(4-(tert-butyl)phenyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-2-(methylthio)propan-1 -one, 1 -(2-(4-(4- cyclobutylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- cyclopropyl-2-fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- hydroxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- isopropylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-methyl-3- (trifluoromethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5- ((dimethylamino)methyl)thiophen-2-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-methylfuran-2-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5- methylpyridin-3-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(6- methylpyridin-3-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-31511 PCT(benzo[b]thiophen-6-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-methyl- 5-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-phenyl-1 H-imidazol-2- yl)piperidin-1-yl)-2-((trifluoromethyl)thio)ethan-1-one, 1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1- yl)butan-1-one, 1 -(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-dien-1-one, 1-(2-(4-phenyl- 1 H-imidazol-2-yl)piperidin-1 -yl)pent-4-en-1-one, 1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, 1 -(2-(5-(2,3-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan- 1-one, 1-(2-(5-(2,4-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2- (5-(2,5-difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-fluoro- 4-methoxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-fluoro-4- methylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2- methoxypyrimidin-5-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3- (methylamino)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4- difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4- difluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-3-en-1-one, 1-(2-(5-(3,4- dimethoxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4- dimethylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluoro-4-(methoxymethyl)phenyl)-1 H-i midazol-2-yl) pi peridin-1 -yl)-2-(methylthio)propan-1 -one, 1-(2-(5-(3- fluoro-4-methylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3- fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3- methoxyisothiazol-4-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3- methoxyphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-((methylamino)methyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5- (4-(2-methoxyethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4- (aminomethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4- (dimethylamino)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4- (hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4- acetylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-aminophenyl)- 1 H-imidazol-2-y I) pi pe ri d i n- 1 -y l)-2-(methylthio)propan-1 -one, 1-(2-(5-(4-chloro-3-fluorophenyl)-1 H- imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1 -(2-(5-(4-chlorophenyl)-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1 -(2-(5-(4-ethylphenyl)-1 H-i midazol-2-yl) pi peridin-1 - yl)-2-(methylthio)propan-1 -one, 1-(2-(5-(4-fluorophenyl)-4H-1 , 2, 4-triazol-3-yl) pi peridin-1 -yl)-2- (methylthio)propan-l-one, 1 -(2-(5-(4-methoxy-2-methylpheny l)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2- (methylthio)propan-l-one, 1 -(2-(5-(4-methoxypheny l)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2- (methylthio)propan-l-one, 1-(2-(5-(4-methyl-6-(methylthio)pyridin-3-yl)-1 H-i midazol-2-yl) pi peridin-1 - yl)-2-(methylthio)propan-1-one, 1-(2-(5-(5-(methoxymethyl)thiophen-3-yl)-1 H-imidazol-2-yl)piperidin- 1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(6-methoxypyridin-3-yl)-1 H-imidazol-2-yl)piperidin-1-yl)-2- (methylthio)propan-l-one, 1 -(2-(5-(benzo[d][1 ,3]dioxol-5-yl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2- (methylthio)propan-l-one, 1 - (2-(5- (p-toly l)-1 H-imidazol-2-yl)piperidin-1 -yl)propan-1 -one, 1 -(2-(5- benzyl-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1 -(2-(5-bromo-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H- imidazol-5-yl)benzonitrile, 2-(2-(4-phenyl-1 H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-31511 PCTcarbonitrile, 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2- (allylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(dimethylamino)-1-(2-(4- phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-(dimethylamino)-1-(2-(4-phenyl-1 H-imidazol- 2-y I) pi pe ri d i n- 1 -yl)propan-1 -one, 2- (ethy Ith io)- 1 -(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1 - yl)propan-1-one, 2-(furan-2-yl)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan- 2-y l)-1 -(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1 -yl)propan-1 -one, 2-(furan-3-yl)-1 -(2-(4-phenyl-1 H- imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan-3-yl)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, 2-(methylamino)-N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5- yl)phenyl)acetamide, 2-(methylsulfinyl)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1- one, 2-(methylsulfonyl)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2- (methylsulfonyl)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(2- (p-toly l)-2H-tetrazo l-5-y I) pi perid i n- 1 -y l)propan-1 -one, 2-(methylthio)-1 -(2-(3-phenyl-1 ,2,4-oxadiazol- 5-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(1-(trifluoromethyl)-1 H-pyrazol-4-yl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophen-2-yl)- 1 H-imidazol-2-yl)piperidin-1 -yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(m-tolyl)-1 H-imidazol-2-yl)piperidin- 1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(o-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2- (methylthio)-1-(2-(4-(pyridin-3-yl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2- (4-(pyridin-4-yl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(pyrimidin-5-yl)- 1 H-imidazol-2-yl)piperidin-1 -yl)propan-1-one, 2-(methylthio)-1-(2-(4-(quinoxalin-6-yl)-1 H-imidazol-2- yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(thiophen-3-yl)-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, 2-(methylthio)-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(methylthio)-1-(2-(5-(2-(trifluoromethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(2,3,4-trifluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(3-(trifluoromethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-(trifluoromethoxy)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-propylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1- (2-(5-(4-vinylphenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(5- methylthiophen-2-yl)-1 H-imidazol-2-yl)piperidin-1 -y l)propan-1 -one, 2-(methylthio)-1 -(2-(5-(p-to ly I)- 1 ,3,4-oxadiazol-2-yl)piperidin-1 -yl)propan-1 -one, 2-(methylthio)-1 - (2-(5-(p-toly l)-1 H-imidazol-2- yl)azepan-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan- 1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1 ,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one, 2- (methylthio)-l -(2-(5-(p-tolyl)isoxazol-3-y I) pi pe ri d i n- 1 -yl)propan-1 -one, 2-(methylthio)-1 -(2-(5-(p- tolyl)oxazol-2-yl)piperidin-1 -yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)thiazol-2-yl)piperidin-1- yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2- (methylthio)-1-(2-(5-phenyl-1 H-imidazol-2-yl)pyrrolidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5- phenyl-4H-1 ,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyloxazol-2-31511 PCTyl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(4-(5-(p-tolyl)-1 H-imidazol-2-yl)thiazolidin-3- yl)propan-1-one, 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,2-dimethyl-1-(2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2,2-dimethyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)butan-1-one, 2,3-dimethoxy-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2,3-dimethyl-1 -(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,5-difluoro-4-(2-(1- (2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-4-yl)benzonitrile, 2-amino-1-(2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-cyclobutyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, 2-cyclopentyl-2-ethoxy-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)ethan-1-one,2-cyclopropyl-1 -(2-(4-phenyl-1 H-imidazol-2-y I) pi pe ri di n- 1 -yl)ethan-1 -one, 2-cyclopropyl-1 -(2-(4- phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-cyclopropyl-2-methoxy-1-(2-(4-phenyl-1 H- imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-ethoxy-1-(2-(5-(3-fluorophenyl)-1 H-imidazol-2- yl)piperidin-1-yl)propan-1-one, 2-ethyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one, 2-ethyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)benzonitrile, 2-mercapto-1-(2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methoxy-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1- yl)butan-1-one, 2-methoxy-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1 -one, 2-methoxy-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-1-(2-(4-phenyl-1 H-imidazol-2-y I) pi pe ri d i n- 1 -yl)butan-1 -one, 2-methyl-1 -(2-(4-pheny 1-1 H-imidazol-2-y I) pi pe ri di n- 1 -yl)propan-1 - one, 2-methyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2-methyl-1-(2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1 H-imidazol-2- y I) pi perid i n- 1 -yl)butane-1 ,3-dione, 2-methyl-1 - (2-(5- (p-toly l)-1 H-imidazol-2-yl)piperidin-1 -yl)pentan- 1 -one, 2-methyl-1 -(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1 -yl)prop-2-en-1 -one, 2-methyl-1 -(2-(5- (p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-3-(methylthio)-1-(2-(4-phenyl-1 H-imidazol-2- y I) pi perid i n- 1 -yl)propan-1 -one, 2-methy lene-1 - (2-(5- (p-toly l)-1 H-imidazol-2-yl)piperidin-1 -yl)butan-1 - one, 3-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-4-yl)benzonitrile, 3,3,3-trifluoro-2- methyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 3,3,4,4,4-pentafluoro-1-(2-(4- phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 3,3-difluoro-1-(2-(4-phenyl-1 H-imidazol-2- yl)piperidin-1-yl)butan-1-one, 3-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5- yl)benzonitrile, 3-methyl-1 -(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1 -yl)but-2-en-1 -one, 3-methyl-1 - (2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 4-(2-(1-(2-(methylthio)propanoyl)piperidin- 2-y l)-1 H-imidazol-4-y I) be nzonitri le , 4-(2-(1 -(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5- yl)benzaldehyde, 4,4,4-trifluoro-2-methyl-1-(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, bicyclo[1 .1.1]pentan-1-yl(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)methanone, cyclobutyl(2-(5-(3- fluorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)methanone, cyclopentyl(2-(4-phenyl-1 H-imidazol-2- yl)piperidin-1-yl)methanone, cyclopropyl(2-(4-phenyl-1 H-imidazol-2-yl)piperidin-1-yl)methanone, methyl 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)benzoate, N-(2- hydroxyethyl)-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-4- yl)benzenesulfonamide, 2-(methylthio)-1-(2-(5-(3-nitrophenyl)-1 H-imidazol-2-yl)piperidin-1- yl)propan-1-one, N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-4-31511 PCTyl)phenyl)methane-sulfonamide, 2-(methy Ith io)- 1 -(2-(5-(4-nitrophenyl)-1 H-imidazol-2-yl)piperidin-1 - yl)propan-1-one, 1-(sec-butylsulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, l-(sec-butylsulfonyl)- 2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(isopropylsulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidine, 1-(isopropylsulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((1-(methylthio)ethyl)sulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((1-(methylthio)ethyl)sulfonyl)- 2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((2-(methylthio)propan-2-yl)sulfinyl)-2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidine, 1-((2-(methylthio)propan-2-yl)sulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidine, 1-(but-3-en-2-ylsulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(but-3-en-2- ylsulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(pent-3-en-2-ylsulfinyl)-2-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidine, 1 -(pent-3-en-2-ylsulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((2- methylbut-3-en-2-yl)sulfinyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-((2-methylbut-3-en-2- yl)sulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(2-(5-(4-(hydroxymethyl)-phenyl)-1 H- imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-l-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-l-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan- 1 -one, 1 -(5-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-2-methylbutan-1 -one, 1 -(2-(5-(4- (hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(4- hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(5-hydroxy- 2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(2-hydroxy-6-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1 H- imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin- 1-yl)-2-methylbutan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-l-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2- (methylsulfinyl)-propan-l-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2- (methylsulfinyl)propan-l-one, 1 -(5-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2- (methylsulfinyl)propan-l-one, 1 -(2-hydroxy-6-(5-(p-tolyl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2- (methylsulfinyl)propan-l-one, 1 -(3-hydroxy-2-(5-(p-tolyl)-1 H-imidazol-2-yl) pi peridin-1 -yl)-2- (methylsulfinyl)propan-l-one, 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2- yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1 H- imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(4-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(3-hydroxy-2- (5-(4-(hydroxymethyl)-phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2- hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(5- hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(4- hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(3- hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 4-(2- (1-(2-methylbutanoyl)piperidin-2-yl)-1 H-imidazol-5-yl) benzaldehyde, 4-(2-(1-(2- (methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)benzoic acid, 4-(2-(1-(2-31511 PCTmethylbutanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)benzoic acid, (2,2-dimethylcyclopropyl)(2-(5-(p- tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(5-bromo-1 H-imidazol-2-yl)piperidin-1-yl)-2- methylbutan-1-one, 1-(2-(5-(4-chlorophenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1 -(2- methylbutanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1 -(2- methylbutanoyl)piperidin-2-yl)-1 H-imidazol-5-yl)phenyl)acetonitrile, 2,3-dimethyl-1-(2-(5-(p-tolyl)-1 H- imidazol-2-y I) pi pe ri di n- 1 -yl)butan-1 -one, 2-methyl-1 -(2-(5-(o-tolyl)-1 H-imidazol-2-yl)piperidin-1 - yl)butan-1 -one, 2-methy 1-1 -(2-(5-(m-tolyl)-1 H-imidazol-2-yl)piperidin-1 -yl)butan-1 -one, 1 -(2-(5-(4- (hydroxymethyl)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, l-(isopropylsulfonyl)- 2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidine, 1-(sec-butylsulfonyl)-2-(5-(p-tolyl)-1 H-imidazol-2- yl)piperidine, 2-methyl-1-(2-(5-(5-methylthiophen-2-yl)-1 H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperazin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4- (p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, and 2-methyl-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1- yl)butan-1-one.

10. The flavour composition according to claims 1 to 9, for use in providing cooling sensation.11 . A consumer product comprising the flavour composition according to claims 1 to 9.

12. The consumer product according to claim 1 1 , wherein said product is selected from the group consisting of confectionery, toothpastes, rinses, gels or sprays.

13. A non-medical method of inducing a cooling sensation in a human or animal comprising contacting the human or animal with the flavour composition according to claims 1 to 9.31511 PCT

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