Organic compounds as TRPM8 activators

Abstract

Disclosed are TRPM8 modulators, as defined by formula (I), for exerting a cooling effect on the skin and mucous membranes.

Description

[Technical field]

[0001] Technical Field The present invention relates to a particular class of compounds capable of activating the TRPM8 ion channel, and further to the use of said compounds to induce a sensation of coldness, and to consumer products containing these compounds. [Background technology]

[0002] background TRPM8 (transient receptor potential melastatin member 8, also known as Trp-p8 or MCR1) is activated by harmless cool and thus plays an important role as a thermosensor. The channel is widely distributed in various tissues, including human skin and mucous membranes (such as oral, pharyngeal and nasal mucosa), male urogenital tract, lung epithelial cells and arterial muscle cells. They are Ca channels that exhibit a polymodal gating mechanism. 2+ It is a permeable, nonselective cation channel that is activated by harmless cold temperature, membrane depolarization, and molecules known as cooling agents, including natural and synthetic compounds. The receptor was first described in 2002 in a number of publications as the cold receptor.

[0003] The present invention is based on the discovery that a particular class of compounds can be used to promote a cooling response when they come into contact with TRPM8 receptors in-vitro and in-vivo.

[0004] Compounds that provide a cooling sensation have long played an important role in the flavor / fragrance industry to provide a link between freshness and cleanliness. Cooling compounds are widely used in a variety of products such as foodstuffs, tobacco products, beverages, dentifrices, mouthwashes, toothpastes, and toiletries. The cooling sensation provided has contributed to the appeal and acceptability of the products to consumers. In particular, oral care products such as dentifrices and mouthwashes are formulated with coolants to provide breath freshening benefits and a clean, cool, fresh feeling in the mouth.

[0005] Numerous compounds that provide a cooling sensation have been described. The most well-known naturally occurring compound is menthol, especially L-menthol. Among the synthetic compounds that provide a cooling sensation, many are derivatives of menthol or structurally related to menthol, i.e., those that contain a cyclohexane moiety and are derivatized with functional groups including carboxamides, ketals, esters, ethers, and alcohols.

[0006] The present applicant has surprisingly discovered a new class of chemical compounds that differ significantly in structure from previously known TRPM8 modulators, which have been surprisingly found to be capable of providing long-lasting cooling on human skin and / or mucous membranes at extremely low concentrations, as further described herein. Summary of the Invention

[0007] overview In a first aspect, the compound of formula (I) [ka] During the ceremony X 1 , X2 , and X 3 one of which is >NC(O)R and the other two are independently selected from C, N, and O, provided that neither of these is C, and where R is a C1-C aryl group that may optionally contain one heteroatom selected from O and S; 15 selected from hydrocarbon residues; and a)R 1 is H; and B is a monovalent residue (a) [ka] represents, or b)R 1 is selected from: halogens (including Br, Cl, and F); C6 to C6 optionally substituted with up to four (e.g., one, two, or three) substituents independently selected from the group consisting of 10 Aryl (e.g., phenyl or naphthyl): Halogens (including F, Cl, Br); OH (hydroxyl); C≡N(cyano); NO2(nitro); C1-C6 alkyl, optionally containing up to five halogen atoms (e.g., F), such as CH3, CF3, or CHF2; C1-C3 alkyl containing up to three OH groups, such as CH2OH; C2-C6 alkenyl, such as -CH=CH2; C1-C6 alkoxy, optionally containing up to three halogen atoms (e.g., F), such as OCH3, OCH3, OCF3; C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl; C3-C7 cycloalkyl, such as cyclopropyl and cyclobutyl; -C(O)R 10 , where R 10 is selected from C1-C3 alkyl; -OC(O)R 11 , where R 11 is selected from H, and C1-C3 alkyl; -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl; -(CH2) m N(R 13 )R 14 , where m is 0 or 1, and R 13 is hydrogen, C1-C3 alkyl, and -SO2R 15 is selected from, where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 is selected from, where R 16 is C1-C3 alkyl, or where R 13 and R 14 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 17 , where R 17 is selected from hydrogen and C1-C3 alkyl; and -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl; With the proviso that when an aryl ring is substituted with two or more substituents, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring; and C5~C 10 Monocyclic or bicyclic heteroaryl, where up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen, and may be optionally substituted with up to four (e.g., 1, 2, or 3) substituents selected from the group consisting of: Halogens (including F, Cl, Br); OH (hydroxyl); C≡N(cyano); NO2(nitro); C1-C6 alkyl, optionally containing up to five halogen atoms (e.g., F), such as CH3, CF3, or CHF2; C2-C6 alkenyl, such as -CH=CH2; C1-C6 alkoxy, optionally containing up to three halogen atoms (e.g., F), such as OCH3, OCH3, OCF3; C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl; C3-C7 cycloalkyl, such as cyclopropyl and cyclobutyl; -C(O)R 20 , where R 20 is selected from C1-C3 alkyl; -OC(O)R 21 , where R 21 is selected from H, and C1-C3 alkyl; -C(O)OR 22 , where R 22 is selected from hydrogen and C1-C3 alkyl; -(CH2) m N(R 23 )R 24 , where m is 0 or 1, and R 23 is hydrogen, C1-C3 alkyl, and -SO2R 25 is selected from, where R 25 is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 is selected from, where R 26 is C1-C3 alkyl, or where R 23 and R 24 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 27 , where R 27 is selected from hydrogen and C1-C3 alkyl; and -S(O)2R 28 , where R 28is selected from hydrogen and C1-C3 alkyl; and B is a monovalent residue (b) [ka] In the formula R 4 , R 5 , and R 6 form together with the carbon atom to which they are attached a hydrocarbon group which may optionally contain up to 5 (e.g. 1, 2, 3, 4) heteroatoms selected from O, N, S and F (preferably the hydrocarbon group contains 2 to 15 C atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms); and Z is either C, S, or S(O); or a salt or solvate thereof, particularly for use in providing a cooling sensation.

[0008] According to a second aspect, there is provided a method for modulating (in vitro and in vivo modulation) transient receptor potential channel melastatin member 8 (TRPM8), said method comprising contacting said receptor with a compound of formula (I), or a salt or solvate thereof.

[0009] In a third aspect, there is provided a method of inducing a cooling sensation in a human or animal comprising contacting the human or animal with a compound of formula (I), or a salt or solvate thereof.

[0010] In a fourth aspect, there is provided a consumer product, particularly a consumer product intended to be contacted with human skin and / or mucosa, comprising a compound as defined by formula (I), or a salt or solvate thereof.

[0011] In a fifth aspect, there is provided a composition comprising a cool sensation, the composition comprising at least one compound of formula (I), a salt or solvate thereof, and a further cooling compound. In a sixth aspect, there is provided a pharmaceutical composition comprising one or more compounds as defined by formula (I), or a salt or solvate thereof.

[0012] The details, examples, and preferences provided with respect to any particular one or more of the defined aspects of the invention will be described further herein and will apply equally to all aspects of the invention. Any combination of the embodiments, examples, and preferences described herein in all their possible variations is covered by the present invention unless otherwise indicated herein or clearly contradicted by context. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description The present invention provides a novel class of chemical compounds that are significantly different in structure from previously known TRPM8 modulators, capable of activating the TRPM8 ion channel and mediating Ca(2+) uptake in cold-sensitive neurons. 2+ This is based, at least in part, on the surprising finding that electrical signals produced by the endothelial cells lead to an influx of cold into the skin. The resulting electrical signals are ultimately sensed as a sensation of cold. Applicants have surprisingly found that this class of chemical compounds can provide long-lasting cooling on human skin and / or mucous membranes at extremely low concentrations, as further described herein.

[0014] Thus, in a first aspect, a compound of formula (I) [ka] X in the formula 1 , X 2 , and X 3one of which is >NC(O)R and the other two are independently selected from C, N, and O, provided that neither of these is C, and where R is a C1-C aryl group that may optionally contain one heteroatom selected from O and S; 15 selected from hydrocarbon residues; and a)R 1 is H; and B is a monovalent residue (a) [ka] represents, or b)R 1 is selected from: halogens (including Br, Cl, and F); C6 to C6 optionally substituted with up to four (e.g., one, two, or three) substituents independently selected from the group consisting of 10 Aryl (e.g., phenyl or naphthyl): Halogens (including F, Cl, Br); OH (hydroxyl); C≡N(cyano); NO2(nitro); C1-C6 alkyl, optionally containing up to five halogen atoms (e.g., F), such as CH3, CF3, or CHF2; C1-C3 alkyl containing up to three OH groups, such as CH2OH; C2-C6 alkenyl, such as -CH=CH2; C1-C6 alkoxy, optionally containing up to three halogen atoms (e.g., F), such as OCH3, OCH3, OCF3; C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl; C3-C7 cycloalkyl, such as cyclopropyl and cyclobutyl; -C(O)R 10 , where R 10 is selected from C1-C3 alkyl; -OC(O)R 11 , where R11 is selected from H, and C1-C3 alkyl; -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl; -(CH2) m N(R 13 )R 14 , where m is 0 or 1, and R 13 is hydrogen, C1-C3 alkyl, and -SO2R 15 is selected from, where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 is selected from, where R 16 is C1-C3 alkyl, or where R 13 and R 14 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 17 , where R 17 is selected from hydrogen and C1-C3 alkyl; and -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl; With the proviso that when an aryl ring is substituted with two or more substituents, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring; and C5~C 10 Monocyclic or bicyclic heteroaryl, where up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen, and may be optionally substituted with up to four (e.g., 1, 2, or 3) substituents selected from the group consisting of: Halogens (including F, Cl, Br); OH (hydroxyl); C≡N(cyano); NO2(nitro); C1-C6 alkyl, optionally containing up to five halogen atoms (e.g., F), such as CH3, CF3, or CHF2; C2-C6 alkenyl, such as -CH=CH2; C1-C6 alkoxy, optionally containing up to three halogen atoms (e.g., F), such as OCH3, OCH3, OCF3; C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl; C3-C7 cycloalkyl, such as cyclopropyl and cyclobutyl; -C(O)R 20 , where R 20 is selected from C1-C3 alkyl; -OC(O)R 21 , where R 21 is selected from H, and C1-C3 alkyl; -C(O)OR 22 , where R 22 is selected from hydrogen and C1-C3 alkyl; -(CH2) m N(R 23 )R 24 , where m is 0 or 1, and R 23 is hydrogen, C1-C3 alkyl, and -SO2R 25 is selected from, where R 25 is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 is selected from, where R 26 is C1-C3 alkyl, or where R 23 and R 24 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 27 , where R 27 is selected from hydrogen and C1-C3 alkyl; and -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl; and B is a monovalent residue (b) [ka] In the formula R 4 , R 5 , and R 6 form together with the carbon atom to which they are attached a hydrocarbon group which may optionally contain up to 5 (e.g. 1, 2, 3, 4) heteroatoms selected from O, N, S and F (preferably the hydrocarbon group contains 2 to 15 C atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms); and Z is either C, S, or S(O); or a salt or solvate thereof, particularly for use in providing a cooling sensation.

[0015] Further non-limiting examples include compounds of formula (Ib): [ka] or a salt or solvate thereof, R is a C1-C aryl group optionally containing one heteroatom selected from O and S. 15 selected from hydrocarbon residues; R 1 is selected from: halogens (including Br, Cl, and F); C6 to C6 optionally substituted with up to four (e.g., one, two, or three) substituents independently selected from the group consisting of 10 Aryl (e.g., phenyl or naphthyl): Halogens (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl, optionally containing up to five halogen atoms (e.g., F), such as CH3, CF3, or CHF2; C1-C3 alkyl containing up to three OH groups, such as CH2OH; C2-C6 alkenyl, such as -CH=CH2; C1-C6 alkoxy, optionally containing up to three halogen atoms (e.g., F), such as OCH3, OCH3, OCF3; C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl; C3-C7 cycloalkyl, such as cyclopropyl and cyclobutyl; -C(O)R 10 , where R 10 is selected from C1-C3 alkyl; -OC(O)R 11 , where R 11 is selected from H, and C1-C3 alkyl; -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl; -(CH2) m N(R 13 )R 14 , where m is 0 or 1, and R 13 is hydrogen, C1-C3 alkyl, and -SO2R 15 is selected from, where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 is selected from, where R 16 is C1-C3 alkyl, or where R 13 and R 14 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 17 , where R 17 is selected from hydrogen and C1-C3 alkyl; and -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl; With the proviso that when an aryl ring is substituted with two or more substituents, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring; and C5~C 10 Monocyclic or bicyclic heteroaryl, where up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen, and may be optionally substituted with up to four (e.g., 1, 2, or 3) substituents selected from the group consisting of: Halogens (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl, optionally containing up to five halogen atoms (e.g., F), such as CH3, CF3, or CHF2; C2-C6 alkenyl, such as -CH=CH2; C1-C6 alkoxy, optionally containing up to three halogen atoms (e.g., F), such as OCH3, OCH3, OCF3; C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl; C3-C7 cycloalkyl, such as cyclopropyl and cyclobutyl; -C(O)R 20 , where R 20 is selected from C1-C3 alkyl; -OC(O)R 21 , where R 21 is selected from H, and C1-C3 alkyl; -C(O)OR 22 , where R 22 is selected from hydrogen and C1-C3 alkyl; -(CH2) m N(R 23 )R 24 , where m is 0 or 1, and R 23 is hydrogen, C1-C3 alkyl, and -SO2R 25 is selected from, where R 25 is C1-C3 alkyl, and R 24is hydrogen, C1-C3 alkyl, and -SO2R 26 is selected from, where R 26 is C1-C3 alkyl, or where R 23 and R 24 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 27 , where R 27 is selected from hydrogen and C1-C3 alkyl; and -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl; R 4 , R 5 , and R 6 form together with the carbon atom to which they are attached a hydrocarbon group which may optionally contain up to 5 (e.g. 1, 2, 3, 4) heteroatoms selected from O, N, S and F (preferably the hydrocarbon group contains 2 to 15 C atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms); and X 2 and X 3 is independently selected from C, N, and O, with the proviso that X 2 or X 3 None of the following are C.

[0016] Further non-limiting examples include compounds of formula (Ic): [ka] or a salt or solvate thereof, wherein R, R 1 , and R 4 ~R 6 has the same meaning as in formula (Ib).

[0017] Further non-limiting examples include compounds of formula (Id): [ka] or a salt or solvate thereof, wherein R and R 4 ~R 6 has the same meaning as in formula (Ic).

[0018] Further non-limiting examples include compounds of formula (Ie): [ka] or a salt or solvate thereof, In the formula, R is a C1-C aryl group which may optionally contain one heteroatom selected from O and S. 15 The aryl group is selected from hydrocarbon residues.

[0019] Further non-limiting examples include those in which R is C1-C 15 Linear or branched alkyl (ethyl, isopropyl, C5-, C6-, C7-, C8-, C9-, C 10 -, C 11 -, C 12 -, C 13 - and C 14 -Alkyl, etc., linear C4-C 15 and 3-phenyl-2-oxa-prop-1-yl.

[0020] Further non-limiting examples include R 4 is selected from hydrogen and methyl; R 5 is selected from hydrogen, C1-C2 alkyl, and C2-C3 alkenyl; and R 6is 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-SCH2-, 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 optionally substituted with methyl (e.g., 2-furyl or 3-furyl), C1-C6 fluoro-alkyl (e.g., pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, or difluoroethyl), and -NR 30 R 31 (where R 30 and R 31 are independently selected from hydrogen and C1-C3 alkyl; or R 6 and R 5 together with the carbon atom to which they are attached, a) Carbonyl group (C=O) or vinyl group (C=CR 32 R 33 , where R 32 and R 33 are independently selected from H or C1-C3 alkyl; or b) 3-7 membered saturated or unsaturated cycle rings containing up to three heteroatoms selected from oxygen, nitrogen, and sulfur, where the cyclic rings are optionally substituted with one or two groups independently selected from C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy; (e.g., R 5 and R 6 form, together with the carbon atom to which they are attached, a thiodiazole or a furanyl. The compounds of formula (I), (Ia), (Ib), (Ic), and (Id) form

[0021] Further non-limiting examples include those in which R 4 is selected from hydrogen and methyl; R 5 is selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl; and R 6 is 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-SCH2-, 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 optionally substituted with methyl (e.g., 2-furyl or 3-furyl), C1-C6 fluoro-alkyl (such as pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, or difluoroethyl), and -NR 30 R 31 (where R 30 and R 31 are independently selected from hydrogen and C1-C3 alkyl.

[0022] Further non-limiting examples include R 4 , R 5 and R 6together with the carbon atom to which they are attached, 3-thiabut-2-yl, 2-methyl-3-thiabut-2-yl, 3-thiapent-2-yl, 4-thiapent-2-yl, 2-thiaprop-1-yl, 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- lop-1-yl, ethyl, cyclopropyl, 1,1-dimethylcycloprop-2-yl, 1-methylcycloprop-2-yl, 1-methylcycloprop-1-yl, 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-(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- The compounds represented by formulae (I), (Ia), (Ib), (Ic), and (Id) form a hydrocarbon group selected from 2-yl, 1-cyclopropyleth-1-yl, 2-cyclopropylprop-2-yl, 1-cyclobutyleth-1-yl, 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.

[0023] Further non-limiting examples include R 4 is selected from hydrogen and methyl; R 5 is selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl, and R 6 are compounds represented by formulae (I), (Ia), (Ib), (Ic), and (Id) 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-SCH2-, 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-, and -SH.

[0024] Further non-limiting examples include R 1 is p-tolyl, and R 4 , R 5 and R 6together with the carbon atom to which they are attached form 2-methyl-3-thiabut-2-yl or but-2-yl, compounds of formula (Ic).

[0025] Further non-limiting examples include 1-(2-(1-propionyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one; 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylpropan-1-one; 2-(methylthio)-1-(2-(1-(2-(methylthio)propanoyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one; 1-(2-(1-acetyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one; 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one; 1-(2-(1-benzoyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one; 1-(2-(1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one; 1-(2-(1-acetyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one; 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one; 1-(2-(1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one; 1-(2-(1-(2-methoxyacetyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one; 1-(2-(1-(2-(benzyloxy)acetyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one; 1-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)dodecan-1-one; 1-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)dodecan-1-one; 1-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)hexan-1-one; 1-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)hexan-1-one; N-(1-benzoyl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide; N-(1-isobutyryl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide; and N-(1-acetyl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide The compound of formula (I) is selected from the group consisting of:

[0026] The compounds as defined by formula (I), which encompasses the compounds represented by formulae (Ia), (Ib), (Ic), (Id) and (Ie), contain several chiral centers (two of which are indicated by * in each formula) and may themselves exist as a mixture of stereoisomers or they may be resolved in isomerically pure form. Since resolving stereoisomers would add to the complexity of the manufacture and purification of these compounds, it is preferred, for purely economic reasons, to use the compounds as a mixture of their stereoisomers. 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). Additionally, compounds as defined by formula (I), which encompasses compounds represented by formulae (Ia), (Ib), (Ic), (Id), and (Ie), may exist in various tautomeric forms, including 1H-imidazole to 3H-imidazole forms. Accordingly, the chemical structures depicted herein encompass all viable stereoisomeric and tautomeric forms of the described compounds.

[0027] It is also noted that compounds as defined by formula (I), which encompasses compounds represented by formulae (Ia), (Ib), (Ic), (Id), and (Ie), may exist in unsolvated 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 intended to be within the scope of the present invention.

[0028] "Solvate" refers to a compound formed by solvation (combination of a solvent molecule with a molecule or ion of a solute) or an aggregate consisting of an ion or molecule of a solute, i.e., a compound as defined by formula (I) with one or more solvent molecules (this encompasses compounds represented by formulae (Ia), (Ib), and (Ic)). When water is the solvent, the corresponding solvate is a "hydrate". Further suitable solvents can be, but are not limited to, the following: acetone, acetonitrile, benzene, cyclohexane, dihydrolevoglucosenone, methyl-tetrahydrofuran, pentylene glycol, ethylene glycol, petroleum ether, ethyl lactate, methyl lactate, propyl lactate, diethyl ether, tert-butyl methyl ether, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, ethanol, ethyl acetate, ethylene glycol, diethylene glycol, propylene glycol, heptane, hexane, methanol, toluene, and xylene.

[0029] "Salt" refers to salts of compounds as defined by Formula (I) (which encompasses compounds represented by Formulas (Ia), (Ib), (Ic), (Id), and (Ie)) that possess 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 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, or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or salts formed when the acidic proton is coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

[0030] The compounds as defined by formula (I), which encompasses compounds represented by formulae (Ia), (Ib), (Ic), (Id), and (Ie), are "TRPM8 agonists" and are intended to be used to inhibit the cellular Ca2+ receptor of the TRPM8 channel. 2+It means that it has an agonistic effect on ion permeability.Consequently, "TRPM8 agonist" means any compound that, when it comes into contact with the TRPM8 receptor, causes an increase in fluorescence over background, for example using the FLIPR method as described by Klein et al., (Chem.Senses 36:649-658,2011) (also described in more detail in the experimental part).

[0031] Accordingly, in a second aspect, there is provided a method of modulating (in vitro and in vivo modulation) transient receptor potential channel melastatin member 8 (TRPM8), said method comprising contacting said receptor with a compound of formula (I), or a salt or solvate thereof. In one embodiment of the second aspect of the invention, the modulating method is an in vitro method.

[0032] In a third aspect, there is provided a non-medical method of inducing a cooling sensation in a human or animal, said method comprising contacting the human or animal with a compound of formula (I) (which encompasses compounds of formulae (Ia), (Ib), (Ic), (Id) and (Ie)), or a salt or solvate thereof.

[0033] In one embodiment, the method is a method of exerting a cooling effect on the skin or mucosa comprising contacting the skin or mucosa with a product comprising one or more compounds of formula (I), or salts or solvates thereof.

[0034] Without wishing to be bound by theory, it is believed that the acyl group (>NC(O)R) of a compound of formula (I) as defined herein may be cleaved under certain conditions, thus forming a compound of formula (I') [ka] X in the formula 1 , X 2 , and X 3one of is >NH and the other two are independently selected from C, N, and O, provided that neither of these is C; and R 1 and B has the same meaning as in formula (I). It is believed that the compound represented by the formula:

[0035] The nature of the acyl group may allow modulation of the release kinetics of the compound of formula (I'). Compounds of formula (I') (i.e., hydrolyzed compounds of formula (I)) are disclosed, for example, in patent application PCT / EP2020 / 079009 (WO 2021 / 074281).

[0036] Thus, in a further aspect, there is provided a method of exerting a cooling effect on the skin or mucosa comprising hydrolysing the acetyl group (>NC(O)R) of a compound of formula (I) prior to contact with the skin or mucosa.

[0037] The compounds of formula (I), which encompasses compounds of formula (Ia), (Ib), (Ic), (Id), and (Ie), may be applied directly or as a solution or suspension containing an effective amount of a compound of formula (I). The amount that is effective depends, among other things, on the target TRPM8 area of ​​the body, but also on the cooling potency of the compound or mixture of compounds.

[0038] In a fourth aspect, there is provided a consumer product comprising a compound as defined by formula (I), which encompasses compounds of formulae (Ia), (Ib), (Ic), (Id) and (Ie), in particular said consumer product intended to be contacted with human skin and / or mucosa.

[0039] Consumer products that are intended to come into contact with mucous membranes include, but are not limited to, food products, beverages, chewing gum, tobacco and tobacco replacement products, dental care products, personal care products (including lip care products, sexual health and intimate care products).

[0040] In some embodiments, the dental care product is an oral care product, a tooth care product, a dental prosthesis cleaner, a dental prosthesis adhesive, and the like.

[0041] In some embodiments, the food products are iced consumable products such as ice cream, sorbet, etc.; confectioneries such as candies and chocolates; food products, sauces, dairy products containing mint or mint flavors, e.g., milk-based drinks and yogurt; and snacks.

[0042] In some embodiments, the tobacco replacement product is a liquid or solid suitable for consumption by electrical means, such as liquids to vape an electronic cigarette. In certain embodiments, personal care products that are brought into contact with mucous membranes are lip balms, nasal sprays, and eye drops.

[0043] Consumer products that are intended to come into contact with human skin include, but are not limited to, cosmetic products. In some embodiments, the cosmetic products are skincare products, particularly bath products, skin washing and cleaning products, skincare products, eye makeup, nail care products, foot care products, etc. In some embodiments, the cosmetic products are products with specific effects, particularly sunscreens, insect repellents, tanning products, bleaching products, deodorants, antiperspirants, depilatories, and shaving products. In some embodiments, the cosmetic products are haircare products, particularly hair shampoos, haircare products, hair setting products, hair-shaping products, and hair coloring products, as well as scalp care products such as scalp cooling shampoos and creams.

[0044] In some embodiments, the consumer product is selected from air care products, such as air fresheners or "ready to use" powdered air fresheners, that can be used in residential spaces (rooms, refrigerators, cupboards, shoes, or cars) and / or in public spaces (hall, hotel, mall, etc.).

[0045] The consumer product can be in any physical form, such as a solid, semi-solid, plaster, solution, suspension, lotion, cream, foam, gel, paste, or combinations thereof. The physical form of a suitable consumer product depends primarily on the particular task that such consumer product is to accomplish, such as cleaning, softening, caring, cooling, etc.

[0046] In some embodiments, the consumer product that is contacted with human skin is a fabric care product (such as a fabric cleaner, a fabric conditioner (including tumble dryer sheets), and a scent booster (liquid or solid)) that is applied to the fabric in a first step (e.g., when the fabric is washed) and the treated fabric is then contacted with human skin.

[0047] The use level of the compounds of the present invention (compounds as defined by formula (I), which encompasses compounds represented by formulas (Ia), (Ib), (Ic), (Id) and (Ie)) depends, among other things, on the target TRPM8 area of ​​the body, but also on the cooling efficacy of the compound or mixture of compounds. For example, in oral applications of the compounds of the present invention, such as toothpaste, floss, chewing gum or white strips, the use level may be from about 0.00001% (0.01 ppm) to about 0.1% (1000 ppm); from about 0.00005% (0.5 ppm) to about 0.1% (1000 ppm); from about 0.0001% (1 ppm) to about 0.05% (500 ppm); or from about 0.001% (10 ppm) to about 0.01% (100 ppm) by weight of the composition. When the compounds of the present invention are used in mouthwashes, the use level may be from about 0.000001% (10 ppb) to about 0.01% (100 ppm), or from about 0.0001% (1 ppm) to about 0.001% (10 ppm), by weight of the composition. When the compounds of the present invention are delivered topically, for example in shampoos and lotions, the level may be from about 0.001% (10 ppm) to about 0.5% (5000 ppm), or from about 0.01% (100 ppm) to about 0.4% (4000 ppm), by weight of the composition.

[0048] The cooling efficacy (strength) of a compound depends on its EC 50 Defined by the value. EC 50 EC (median effective concentration) refers to the concentration of a compound that induces a response halfway between the baseline and maximum after a specific exposure time. It is commonly used as a measure of efficacy. 50 is a measure of concentration expressed in μM (μmolar), where 1 μM is equivalent to 1 μmol / L.

[0049] EC 50 Compounds with an EC below 10 μM are perceived by humans as cooling. 50The lower the value, the greater the cooling effect. For example, an EC of approximately 0.1 μM 50 Compounds having this value are perceived as strong cooling compounds.

[0050] However, the cooling properties of a compound are defined not only by its strength (potency; EC50), but also by its longevity, which refers to the period (in minutes) over which the cooling effect is noticeable. Longevity can range from a few minutes to several hours or even days after rinsing. In the context of oral care products, a preferred "long-lasting" effect typically lasts between 20 minutes and 3 hours after rinsing.

[0051] Compounds as defined by formula (I), which encompasses compounds represented by formulae (Ia), (Ib), (Ic), (Id), and (Ie), are generally sufficiently soluble in water at the desired concentration. However, to increase solubility, a specific isomer may be used instead of a mixture of isomers. As is well known to those skilled in the art, cis / trans-isomers and / or diastereomers may have different solubility properties, and thus either a mixture of isomers or individual isomers may be selected for use in a consumer product depending on which cooling effect is to be achieved.

[0052] The compounds of formula (I) (which encompasses the compounds of formula (Ia), (Ib), (Ic), (Id), and (Ie)) are very potent at relatively low concentrations. Therefore, it is preferable to prepare a stock solution, which is further diluted before mixing with the consumer product. In addition to water, specific suitable solvents are triacetin and propylene glycol. Also mentioned are acetone, benzyl alcohol, dihydrolevoglucosenone, methyl-tetrahydrofuran, pentylene glycol, ethylene glycol, ethyl lactate, methyl lactate, propyl lactate, dimethyl sulfoxide, ethanol, ethyl acetate, ethylene glycol, diethylene glycol, propylene glycol, and triacetin, which are suitable solvents for the compounds of formula (I) (which encompasses the compounds of formula (Ia), (Ib), (Ic), (Id), and (Ie)). However, other solvent systems, including surfactants, may also be used.

[0053] In order to modify the cooling effect of a compound as defined herein by formula (I), which encompasses compounds represented by formulae (Ia), (Ib), (Ic), (Id) and (Ie), said compound, salt or solvate thereof may be combined with a compound selected from calcium ions and salts, magnesium ions and salts, arginine or any chelating agent capable of binding calcium or magnesium.

[0054] These compounds are known to be able to modulate the concentration of such ions in the extracellular space, thus affecting the response of the TRPM8 ion channel, leading to changes in the perceived cooling effect.

[0055] According to Kizilbash et al. (WO2019 / 121193 A1), both cooling intensity and flavor intensity may be enhanced when combined with an agent that possesses properties that enhance said effect. Thus, the compound as defined by formula (I) herein may in one specific embodiment be combined with an enhancer as disclosed in WO2019 / 121193 (which is incorporated by reference, particularly with respect to the enhancer).

[0056] Further enhancement agents may include, for example, N-lactoylethanolamine (2-hydroxy-N-(2-hydroxyethyl)propanamide; CAS 5422-34-4), which is known as a cooling agent enhancer from PCT International Publication WO 2008 / 107137 (which relates inter alia to cooling enhancers as defined by formula (I) and which is incorporated by reference).

[0057] The compounds of formula (I), which encompasses compounds of formulas (Ia), (Ib), (Ic), (Id), and (Ie), may be used in combination with other cooling compounds known in the art.

[0058] Thus, in a fifth aspect, there is provided a cooling composition, wherein the composition comprises at least one compound of formula (I), a salt or solvate thereof, and a further cooling compound.

[0059] In a specific embodiment, the compound of formula (I) (which encompasses the compounds of formulae (Ia), (Ib), (Ic), (Id), and (Ie)) is selected from the group consisting of menthol (e.g., in the form of peppermint oil and / or spearmint oil), menthone, p-menthane carboxamide, N-2,3-trimethyl-2-isopropyl-butanamide (WS-23), menthyl lactate (Frescolat® ML), menthone glycerol acetal (Frescolat® MGA), 3-(1-menthoxy)-propane-1,2-diol (TK-10), p-menthane-3,8-diol (known as Coolact 38D), isopulegol (Coolact 38D), p-menthane glycerol acetal (Frescolat® MGA ... P), monomenthyl succinate (Physcool®), monomenthyl glutarate, o-menthyl glycerol, menthyl N,N-dimethylsuccinamate, 2-(sec-butyl)cyclohexan-1-one (Freskomenthe), N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide, 2-(4-ethylphenoxy)-N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide, 3-(benzo[d][1,3]dioxol-5-yl)-N,N-diphenylacrylamide, 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-ethoxypropyl)-N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide, 5 ... N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5,4-phenyl-2,6-dimethoxyphenol, 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol (including 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol), N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5,4-phenyl-2,6-dimethoxyphenol, 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-(((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol,5-dimethylcyclohexane-1-carboxamide, N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide, and N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide.

[0060] Examples of p-methanecarboxamides are N-ethyl-p-menthane-3-carboxamide (commercially known as WS-3), N-ethoxycarbonylmethyl-p-menthane-3-carboxamide (WS-5), N-(4-methoxyphenyl)-p-menthane-3-carboxamide (WS-12), and N-tert-butyl-p-menthane-3-carboxamide (WS-14), N-(4-(cyanomethyl)phenyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (commercially known as Evercool 180), 2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexane-1-carboxamide (commercially known as Evercool 180), and N-tert-butyl-p-menthane-3-carboxamide (WS-14). 190), as well as compounds such as (1R,2S,5R)-N-((S)-2-((R)-2-aminopropanamido)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide.

[0061] In order to provide more than just a cooling effect, the compounds of formula (I) (which encompasses compounds of formulae (Ia), (Ib), (Ic), (Id) and (Ie)), their salts or solvates may be combined with other actives such as flavours, fragrances and sweeteners.

[0062] Examples of flavor ingredients include natural flavors, artificial flavors, spices, seasonings, etc. Exemplary flavor ingredients include synthetic flavor oils, as well as flavoring aromatic compounds and / or oils, oleoresins, extracts, and distillates, and combinations comprising at least one of the foregoing.

[0063] 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, nutmeg oil, allspice, sage oil, mace, bitter almond oil, and cassia oil; useful flavoring agents include artificial, natural, and synthetic fruit flavors (such as vanilla), as well as citrus oils (including lemon, orange, lime, grapefruit, yuzu, sudachi), and fruit extracts (including apple, pear, peach, grape, raspberry, blackberry, gooseberry, blueberry, strawberry, cherry, plum, prune, raisin, cola, guarana, neroli, pineapple, apricot, banana, melon, apricot, cherry, tropical fruit, mango, mangosteen, pomegranate, papaya), and the like.

[0064] Additional exemplary flavors delivered by the flavoring composition include dairy flavors, butter flavors, cheese flavors, cream flavors, and yogurt flavors; vanilla flavors; tea or coffee flavors, such as green tea flavors, oolong tea flavors, tea flavors, cocoa flavors, chocolate flavors, and coffee flavors; mint flavors, such as peppermint flavors, spearmint flavors, and peppermint flavors; ajwain flavors, anise flavors, angelica flavors, fennel flavors, allspice flavors, cinnamon flavors, chamomile flavors, mustard flavors, cardamom flavors, caraway flavors, cumin flavors, clove flavors, pepper flavors, coriander flavors, sassafras flavors, savory flavors, Japanese pepper (Zanthoxyli Fructus flavors, perilla flavors, juniper berry flavors, ginger flavors, star anise flavors, horseradish flavors, thyme flavors, tarragon flavors, dill flavors, chili pepper flavors, nutmeg flavors, basil flavors, marjoram flavors, rosemary flavors, bay leaf flavors, and wasabi (Japanese horseradish) flavors; nut flavors, such as almond flavors, hazel nut flavors, macadamia nut flavors, peanut flavors, pecan flavors, pistachio flavors, and walnut flavors; alcoholic flavors, such as wine flavors, whiskey flavors, brandy flavors, rum flavors, gin flavors, and liqueur flavors; floral flavors; and vegetable flavors, such as onion flavors, garlic flavors, cabbage flavors, carrot flavors, celery flavors, mushroom flavors, and tomato flavors.

[0065] Generally, any flavoring or food additive (including food colorants) may be used, such as those described in "Essential guide to food additives", Third edition 2008, page 101-321 (ISBN: 978-1-905224-50-0) by Leatherhead Food International Ltd., which publication is incorporated herein by reference.

[0066] In a specific embodiment, the compound represented by formula (I) (which encompasses the compounds represented by formulae (Ia), (Ib), (Ic), (Id), and (Ie)) is selected from the group consisting of anethole, laevo-menthol, laevo-carvone, ethyl maltol, vanillin, eucalyptol, eugenol, racemic menthol, cis-3-hexenol, linalool, mint oils (e.g., peppermint arvensis oil, peppermint piperita oil, spearmint native oil, spearmint scotch oil, and the like). scotch oil), corylone, ethyl butyrate, cis-3-hexenyl acetate, citral, eucalyptus oil, ethyl vanillin, methyl salicylate, 2'-hydroxypropiophenone, ethyl acetate, methyl dihydrojasmonate, geraniol, lemon oil, isoamyl acetate, thymol, ionone beta, linalyl acetate, decanal, (±)-dihydromint lactone (3,6-dimethyl-3a,4,5,6,7,7a-hexahydro-3H-benzofuran-2-one), cis jasmone, ethyl hexanoate, melonal (2,6-dimethylhept-5-enal), citronellol, ethyl acetoacetate, nutmeg oil, and clove oil, or mixtures thereof.

[0067] In one particular embodiment, the compound of formula (I) is 1 is p-tolyl, and R 4, R 5 , and R 6 together with the carbon atom to which they are attached form 2-methyl-3-thiabut-2-yl or but-2-yl, compounds of formula (Ic).

[0068] Examples of sweetening agents include, but are not limited to, sucrose, fructose, glucose, high fructose corn syrup, corn syrup, xylose, arabinose, rhamnose, erythritol, xylitol, mannitol, sorbitol, inositol, acesulfame potassium, aspartame, neotame, sucralose, and saccharin, and mixtures thereof; trilobatin, hesperetin dihydrochalcone glucoside, naphthalene glycol, glyceryl stearate ... Lingin dihydrochalcone, mogroside V, Monk fruit extract, rubusoside, Rubus extract, glycyphyllin, isomogroside V, mogroside IV, siamenoside I, neomogroside, mukuroziosid IIb, (+)-hernandulcin, 4β-hydroxyhernandulcin, bayunoside, phlomisoside I, bryodulcoside, bryoside, bryonoside, abru Sosides A-E, cyclocarioside A, cyclocaryoside I, albiziasaponins A-E, glycyrrhizin, araboglycyrrhizin, periandrins I-V, pterocaryosides A and B, osladin, polypodosides A and B, telesmosides A8-18, phyllodulcin, huangqioside E, neoasti These include rubin, monatin, 3-acetoxy-5,7-dihydroxy-4'-methoxyflavanone, 2R,3R-(+)-3-acetoxy-5,7,4'-trihydroxyflavanone, (2R,3R)-dihydroquercetin 3-O-acetate, dihydroquercetin 3-O-acetate 4'-methyl ether, brazzein, curculin, mabinlin, monellin, neoculin, pentadin, thaumatin, and combinations thereof. Some of the compounds listed above are known as sweetness enhancers and sweeteners. When used as sweetness enhancers, they are usually used below their sweetness detection threshold.

[0069] In certain embodiments, the compounds of Formula (I) may be combined with additional ingredients collectively referred to as orally acceptable carrier materials.

[0070] In some aspects, the orally acceptable carrier may comprise one or more compatible solid or liquid excipients or diluents suitable for topical oral administration. "Compatible" as used herein means that the components of the composition are capable of being mixed together without interaction in a manner that would substantially reduce stability and / or efficacy. Carriers may include the usual and traditional components of dentifrices, non-abrasive gels, subgingival gels, mouthwashes or rinses, mouth sprays, chewing gums, lozenges, and breath mints. The choice of carrier to be used is essentially determined by the form in which the composition is introduced into the oral cavity. Carrier materials for toothpastes, tooth gels, or the like include abrasives, sudsing agents, binders, humectants, flavoring agents, and sweetening agents, etc., as disclosed, for example, in U.S. Patent No. 3,988,433 to Benedict. Carrier materials for two-phase dentifrice formulations are disclosed in U.S. Patents 5,213,790; 5,145,666 and 5,281,410, all to Lukacovic et al., and U.S. Patents 4,849,213 and 4,528,180 to Schaeffer. Carrier materials for mouthwashes, rinses, or mouth sprays typically include water, flavoring agents, and sweeteners, as disclosed, for example, in U.S. Patent 3,988,433 to Benedict. Carrier materials for lozenges typically include candy base; carrier materials for chewing gums typically include gum base, flavoring agents, and sweeteners, as disclosed, for example, in U.S. Patent 4,083,955 to Grabenstetter et al. Carrier materials for sachets typically include a sachet bag, flavoring agents, and sweeteners. For subgingival gels used for delivery of active agents to or around the periodontal pocket, a "subgingival gel carrier" is selected, for example, as disclosed in U.S. Patent Nos. 5,198,220 and 5,242,910, both to Damani. Carriers suitable for preparing compositions of the present disclosure are well known in the art.Their choice will depend on secondary considerations such as taste, cost, and storability.

[0071] Further suitable types of orally acceptable carrier materials or excipients are listed in WO2010 / 059289, especially on pages 17-31, which are incorporated by reference.

[0072] Scientific literature indicates that activation of TRPM8 channels may be useful for treating most TRPM8-mediated pathological conditions (J.Med.Chem.2016,59(22),10006-10029). Thus, it can be inferred that the compounds of formula (I) may also be suitable for treating prostate cancer, bladder weakness, inflammation, or pain, including contacting a patient with one or more compounds of formula (I) as defined herein. It can also be inferred that the compounds of formula (I) as defined herein may be suitable for relieving symptoms of coughs and colds, irritation, sore throat or hoarseness, and for treating laryngopharyngeal dysphagia (Int.J.Mol.Sci.2018,19,4113).

[0073] Thus, in a sixth aspect, there is provided a pharmaceutical composition comprising one or more compounds as defined by formula (I) (which covers compounds of formulae (Ia), (Ib), (Ic), (Id) and (Ie)), or a salt or solvate thereof.

[0074] Depending on the particular treatment regimen envisaged, pharmaceutical compositions containing one or more compounds of formula (I) may be administered parenterally, topically, orally, or locally. Pharmaceutical compositions may be liquid, suspension, or solid formulations.

[0075] In some embodiments, the pharmaceutical composition is a nasal spray, topical cream, skin spray, throat spray, eye drops, or cough syrup. The compounds of formula (I) as defined above have not been described in the literature and are therefore novel in themselves.

[0076] Thus, in a further aspect of the invention, a compound of formula (I) [ka] X in the formula 1 , X 2 , and X 3 and the other two are independently selected from C, N, and O, provided that neither of these is C; and where R is a C1-C aryl group that may optionally contain one heteroatom selected from O and S. 15 selected from hydrocarbon residues; and c)R 1 is H; and B is a monovalent residue (a) [ka] represents, or d) R 1 is selected from: halogens (including Br, Cl, and F); C6 to C6 optionally substituted with up to four (e.g., one, two, or three) substituents independently selected from the group consisting of 10 Aryl (e.g., phenyl or naphthyl): Halogens (including F, Cl, Br); OH (hydroxyl); C≡N(cyano); NO2(nitro); C1-C6 alkyl, optionally containing up to five halogen atoms (e.g., F), such as CH3, CF3, or CHF2; C1-C3 alkyl containing up to three OH groups, such as CH2OH; C2-C6 alkenyl, such as -CH=CH2; C1-C6 alkoxy, optionally containing up to three halogen atoms (e.g., F), such as OCH3, OCH3, OCF3; C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl; C3-C7 cycloalkyl, such as cyclopropyl and cyclobutyl; -C(O)R 10 , where R 10 is selected from C1-C3 alkyl; -OC(O)R 11 , where R 11 is selected from H, and C1-C3 alkyl; -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl; -(CH2) m N(R 13 )R 14 , where m is 0 or 1, and R 13 is hydrogen, C1-C3 alkyl, and -SO2R 15 is selected from, where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 is selected from, where R 16 is C1-C3 alkyl, or where R 13 and R 14 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 17 , where R 17 is selected from hydrogen and C1-C3 alkyl; and -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl; With the proviso that when an aryl ring is substituted with two or more substituents, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring; and C5~C 10Monocyclic or bicyclic heteroaryl, where up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen, and may be optionally substituted with up to four (e.g., 1, 2, or 3) substituents selected from the group consisting of: Halogens (including F, Cl, Br); OH (hydroxyl); C≡N(cyano); NO2(nitro); C1-C6 alkyl, optionally containing up to five halogen atoms (e.g., F), such as CH3, CF3, or CHF2; C2-C6 alkenyl, such as -CH=CH2; C1-C6 alkoxy, optionally containing up to three halogen atoms (e.g., F), such as OCH3, OCH3, OCF3; C1-C3 alkoxy C1-C3 alkyl, such as 2-methoxy-ethyl; C3-C7 cycloalkyl, such as cyclopropyl and cyclobutyl; -C(O)R 20 , where R 20 is selected from C1-C3 alkyl; -OC(O)R 21 , where R 21 is selected from H, and C1-C3 alkyl; -C(O)OR 22 , where R 22 is selected from hydrogen and C1-C3 alkyl; -(CH2) m N(R 23 )R 24 , where m is 0 or 1, and R 23 is hydrogen, C1-C3 alkyl, and -SO2R 25 is selected from, where R 25 is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 is selected from, where R 26 is C1-C3 alkyl, or where R 23 and R24 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 27 , where R 27 is selected from hydrogen and C1-C3 alkyl; and -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl; and B is a monovalent residue (b) [ka] In the formula R 4 , R 5 , and R 6 form together with the carbon atom to which they are attached a hydrocarbon group which may optionally contain up to 5 (e.g. 1, 2, 3, 4) heteroatoms selected from O, N, S and F (preferably the hydrocarbon group contains 2 to 15 C atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms); and Z is either C, S, or S(O); The compound is represented by the formula:

[0077] Compounds of formula (I) can generally be prepared from compounds of formula (I') as defined herein above (which can be prepared, for example, as described in International Patent Application PCT / EP2020 / 079009 (WO 2021 / 074281)) by reacting them with the respective activated carboxylic acid derivatives of the RC(O)-X type (wherein R has the same meaning as provided herein for formula (I) and where X is a halogen, such as chloride, bromide, or fluoride). This reaction can take place in the presence of a base, such as an organic base (for example, triethylamine, diisopropylethylamine) or an inorganic base (for example, potassium carbonate, potassium phosphate, sodium bicarbonate, sodium hydroxide), in a suitable solvent (for example, dichloromethane, water, dioxane, N,N-dimethylformamide, tetrahydrofuran) or under solvent-free conditions. The reaction may also benefit from the addition of a nucleophilic catalyst, such as N,N-dimethyl-4-aminopyridine (DMAP). Alternatively, the activated carboxylic acid may be an anhydride or the like (e.g., a mixed anhydride) of the type RC(O)-OC(O)-R, where R has the same meaning as provided herein for formula (I). Other reagents and conditions for the synthesis of compounds of formula (I) may also be used and are well known to those skilled in the art of organic synthesis.

[0078] The invention will now be further described with reference to the following non-limiting examples, which are intended for illustrative purposes only and it will be understood that variations and modifications may be made by those skilled in the art.

[0079] example Example A: 2-(Methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Example Aa: tert-Butyl-2-(1H-imidazol-2-yl)piperidine-1-carboxylate: To a solution of tert-butyl-2-formylpiperidine-1-carboxylate (9.5 g, 35.6 mmol) and glyoxal solution (40% in water, 25.9 g, 178 mmol) in methanol (100 mL) was added ammonia solution (25% in water, 17.0 g, 249 mmol) dropwise at 0° C. The solution was allowed to warm up to rt. (room temperature) and stirred at rt. for 16 h. The solution was then concentrated under reduced pressure and the resulting residue was extracted with ethyl acetate (100 mL*3). Any precipitate was removed by filtration and the organic phase was washed with saturated aqueous NaHCO3 solution (100 mL) and brine (100 mL). The solution was then concentrated under reduced pressure to give tert-butyl-2-(1H-imidazol-2-yl)piperidine-1-carboxylate (5.2 g, yield: 58%) as a white solid. GC / MS(EI):m / z(%):251(3)[M + ], 195(4), 178(10), 150(20), 134(13), 122(5), 95(100), 82(10), 57(21).

[0080] Example Ab: tert-Butyl-2-(4,5-dibromo-1H-imidazol-2-yl)piperidine-1-carboxylate: N-Bromosuccinimide (7.4 g, 41.8 mmol) was added portionwise to a solution of tert-butyl-2-(1H-imidazol-2-yl)piperidine-1-carboxylate (5.0 g, 19.9 mmol) in dichloromethane (100 mL) over 10 min at 0° C. The mixture was stirred at 0° C. for another 2 h and then concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (250 mL), washed with water (100 mL*2) and brine (100 mL), dried over MgSO4, and concentrated to give a very brown residue. The residue was recrystallized from dichloromethane / hexane (1:1) to give tert-butyl-2-(4,5-dibromo-1H-imidazol-2-yl)piperidine-1-carboxylate (6.0 g, yield: 74%) as a white solid. GC / MS(EI):m / z(%):411(2)[M + ],409(4)[M +],407(2)[M + ],355(6),353(12),351(6),311(11),309(22),307(11),294(11),292(22),290(11),255(50),253(100),251(50),242(12),240(24),238(12),148(9),57(50).

[0081] Example Ac: tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate: A suspension of tert-butyl-2-(4,5-dibromo-1H-imidazol-2-yl)piperidine-1-carboxylate (34.0 g, 90%, 74.8 mmol) and Na2SO3 (94 g, 748 mmol) in ethanol (300 mL) and water (300 mL) was refluxed overnight. Then it was cooled and concentrated. The residue was partitioned between CHCl2 (200 mL) and H2O (200 mL). The aqueous layer was extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel to give tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (23.0 g, yield: 93%) as a white solid. GC / MS(EI):m / z(%):329(3)[M + ],331(3)[M + ],275(10),273(10),258(9),256(9),230(20),228(20),214(26),212(26).175(100),173(100),162(9),160(9),93(8),57(44).

[0082] Example Ad: tert-Butyl 2-(5-(p-tolyl)-1H-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(II) 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 were poured into aq.sat.NaHCO3 solution (50 mL), extracted with EtOAc (2× 50 mL), washed with water (50 mL) and brine (50 mL), dried over MgSO4, 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 (EI, 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): δ11.66-12.09(m,1H),7.49-7.70(m,2H),7.20-7.48(m,1H),7.08-7.23(m,2H),5.34-5.23(m,1H),3.89(br d,J=12.1Hz,1H),3.05(br t,J=10.9Hz,1H),2.28(s,3H),2.18-2.25(m,1H),1.65-1.78(m,1H),1.22-1.63(m,13H)ppm. 13C NMR (75MHz, DMSO, mixture of tautomers) δ155.1(q),147.5(q),140.2(q),135.3(q),132.7(q),129.4(t),124.6(t),1 12.5(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.

[0083] Example Ae: 2-(5-(p-tolyl)-1H-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 with a drop of trifluoroacetic acid (0.549 mL, 7.12 mmol, 8 equiv.) at 5° C., and the resulting mixture was stirred at room temperature for 2 h or until the starting material was completely consumed. The mixture was poured into ice water (30 mL) and the pH was made basic by addition of 1 M aqueous NaOH solution. The mixture was then extracted with dichloromethane (3× 20 mL), dried over MgSO4, 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 (EI, 70 eV): 241 (6, [M] +· ), 185(100), 172(13), 158(8), 91(3), 84(4). 1 H NMR (chloroform-d,400MHz): δ8.67-8.89(br s,1H),7.50(d,J=8.1Hz,2H),7.19(d,J=7.8Hz,2H),7.13(s,1H),4.14(dd,J=12.3,3.1Hz,1H),3.30(br d,J=12.7Hz,1H),2.71-2.84(m,1H),2.37(s,3H),2.15-2.27(m,1H),2.01(br dd,J=14.4,3.2Hz,1H),1.90(br d,J=13.4Hz,1H),1.67-1.77(m,2H),1.32-1.46ppm(m,1H).

[0084] Example Af: 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 (0.88 mmol) in dichloromethane (2 mL) was added HOBt (1.056 mmol, 1.2 equiv.) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (1.056 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 (0.968 mmol, 1.1 equiv.) and N,N-diisopropylethylamine (0.88 mmol, 1 equiv.) and the resulting mixture was stirred at rt for 16 h. The mixture was filtered, the solvent removed, and the crude was 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 as a white solid. MS(EI,70eV):343(2,[M] +· ), 241(17), 240(100), 213(13), 185(18), 184(9), 75(55), 56(11), 55(9), 47(10), 41(11). 1 H NMR (400MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.07,11.99,11.95,11.76(brs,1H),7.72-7.60(m,2H),7.59-7.42(m,1H),7.26-7.08(m, 2H),5.75-5.39(m,1H),4.49-3.00(m,3H),2.71-2.15(m,1H),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-d6, mixture of stereoisomers and tautomers) δ 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), 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),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.

[0085] Example B: 2-Methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Preparation using the same protocol as in Example Af using 2-methylbutanoic acid instead of 2-(methylthio)propanoic acid gave 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one as a white solid. GC / MS(EI):m / z(%):325(10)[M + ], 268(2), 240(100), 224(3), 185(10), 159(2), 142(1), 84(2), 57(4). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.05-11.72(m,1H),7.73-7.53(m,2H),7.51-7.40(m,1H),7.27-7.03(m,2H),5.81-5.28(m, 1H),4.61-3.16(m,2H),2.87-2.58(m,1H),2.38-2.19(m,4H),1.86-1 .49(m,5H),1.46-1.23(m,2H),1.09-0.95(m,3H),0.94-0.80(m,3H). 13C NMR (75MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ175.4(q),175.2(q),147.3(q),147.2(q),140.5(q),140.1( q),135.2(q),132.7(q),129.7(t),129.3(t),124.6(t),112.9(t),112.6(t),51.5(t),46.9(t),46.8( t),42.6(d),38.6(d),36.8(t),36.5(t),36.1(t),29.2(d),28.9(d),28.4(d),27.2(d),26.9(d),26.2 (d),25.4(d),25.2(d),21.2(s),20.3(d),18.4(s),17.7(s),17.3(s),12.2(s),12.0(s),11.9(s)ppm.

[0086] Example 1: 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one: A solution of 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one (0.2 g, 0.58 mmol, 1.0 equiv) in dichloromethane (2 mL) was treated with isobutyryl chloride (0.074 g, 0.70 mmol, 1.2 equiv). The reaction mixture was stirred at ambient temperature for 30 min, then poured onto ice water (50 mL), extracted with DCM (3x 50 mL), washed with water and brine (50 mL each), dried over magnesium sulfate and concentrated. The resulting crude material was purified by flash chromatography on silica gel (7-50% EtoAc in heptane) to give 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (0.21 g, 0.51 mmol, 87% yield) as an off-white solid.

[0087] GC / MS(EI):m / z(%):413(3)[M + ], 398(4), 367(6), 343(4), 338(5), 268(37), 240(100). 13C NMR(101MHz,DMSO-d6):δ=176.7,176.2,171.5,170.8,170.6,151.5,151.4,150.5,139.5,137.2,13 7.1,137.0,130.6,130.5,130.4,129.6,129.6,129.4,125.3,125.2,124.6,114.5,114.0,113.8,60 .2,51.1,48.1,47.9,44.2,43.7,42.2,38.5,38.3,37.4,34.7,34.5,28.9,28.4,28.1,25.6,25.3,21.3,21.2,19.5,19.5,19.5,19.4,19.4,19.1,18.1,17.9,17.7,17.3,15.5,14.5,12.2,12.1,11.3.

[0088] Example 2: 1-(2-(1-acetyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one: Prepared analogously to Example 1 from 2-(methylthio)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one and acetyl chloride to give the title compound as an off-white solid.

[0089] GC / MS(EI):m / z(%):385(7)[M + ], 370(2), 339(19), 268(36), 240(100). 13 C NMR (101MHz, DMSO-d6): δ=171.5,170.8,170.6,170.0,169.5,151.3,139.2,137. 1,137.0,130.5,130.5,129.7,129.6,125.2,125.1,115.4,114.9,114.7,60.2,51 .0, 48.1, 47.9, 44.3, 43.8, 38.5, 38.2, 37.4, 31.7, 28.8, 28.3, 28.0, 25.6, 25.3, 25.2, 25.1, 22.6, 21.3, 21.2, 19.4, 18.1, 17.9, 17.7, 14.6, 14.4, 12.2, 12.1, 11.3.

[0090] Example 3: 1-(2-(1-propionyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one: a) To a solution of tert-butyl 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (7.6 g, 20.03 mmol) in dichloromethane (200 mL) was added 2,2,2-trifluoroacetic acid (18.3 g, 160 mmol) at 5° C. and the mixture was stirred at rt for 2 h. Completion of the reaction was monitored by TLC. The reaction solution was cooled to room temperature, saturated NaHCO3 solution (200 mL) was added, extracted with EA (100 mL *3) and the organic phase was concentrated to give 2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)piperidine as a yellow solid (4.9 g, yield: 91%). b) To a solution of 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (300 mg, 1.243 mmol) and triethylamine (189 mg, 1.865 mmol) in dichloromethane (30 ml) was added propionyl chloride (138 mg, 1.492 mmol) at 0-5° C. and the mixture was stirred at rt for 6 h. The mixture was filtered to remove the solvent and purified by silica gel chromatography (hexane:EA=2:1) ​​to give 1-(2-(3-propionyl-5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one (165 mg, 38% yield) as a white solid.

[0091] GC / MS(EI):m / z(%):353(2)[M + ], 296(3), 280(20), 240(100), 224(16), 185(26), 130(4), 117(6), 84(4). 1H NMR(300MHz,DMSO-d6)δ8.29-8.06(m,1H),7.84-7.62(m,2H),7.32-7.13(m,2H),6.22-5.86(m,1H),4.55-3.59(m ,2H),3.18-2.94(m,2H),2.46-2.21(m,5H),2.31(s,3H),2.10-1.25(m,6H),1.19-1.09(m,3H),1.01-0.89(m,3H). 13 C NMR(75MHz,DMSO-d6)δ173.6(q),173.3(q),172.7(q),151.5(q),150.7(q),139.5( q),139.3(q),137.0(q),130.4(q),130.3(q),129.6(t),125.2(t),114.3(t),113. 8(t),51.0(t),47.5(t),43.4(d),29.7(d),28.9(d),28.1(d),26.7(d),26.2(d),2 5.5(d),25.0(d),21.2(s),19.4(d),19.3(d),9.8(s),9.6(s),8.6(s),8.5(s)ppm.

[0092] Example 4: 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylpropan-1-one: Following a procedure similar to that of Example 3, 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (300 mg, 1.243 mmol), isobutyryl chloride (159 mg, 1.492 mmol), and triethylamine (189 mg, 1.865 mmol) in dichloromethane (30 ml) were reacted to give the title product (140 mg, yield: 29%) as a white solid.

[0093] GC / MS(EI):m / z(%):381(2)[M + ], 310(13), 294(19), 240(100), 224(18), 185(26), 159(4), 130(3), 117(5), 71(9). 1H NMR(300MHz,DMSO-d6)δ8.38-8.17(m,1H),7.73(d,J=7.5Hz,2H),7.21(d,J=7.5Hz,2H),6.16-5.95(m,1H), 4.56-3.83(m,2H),3.08-2.58(m,1H),2.30(s,3H),2.12-1.28(m,7H),1.28-1.12(m,6H),1.08-0.67(m,6H). 13 C NMR(75MHz,DMSO-d6)δ176.5(q),176.1(q),151.7(q),139.5(q),137.1(q),130.5(q),129.6(t),125.2(t),113.7(t) ,47.7(t),43.4(d),34.5(t),29.9(t),28.1(d),25.7(d),21.2(s),19.8(s),19.5(d),19.4(s),19.4(s),18.9(s)ppm.

[0094] Example 5 2-(methylthio)-1-(2-(1-(2-(methylthio)propanoyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one: A solution of 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (2.1 g, 8.7 mmol, 1.0 equiv) in dichloromethane (DCM) (15 mL) at 0° C. was treated with triethylamine (1.82 mL, 13.1 mmol, 1.5 equiv), followed by dropwise addition of 2-(methylthio)propanoyl chloride (1.33 g, 9.59 mmol, 1.1 equiv). The mixture was stirred for 13 h, then poured onto ice-cold 1M aq. HCl (50 mL), extracted with EtOAc (3× 50 mL), washed with sat. aq. NaHCO3 (50 mL), water (50 mL), brine (50 mL), dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel (7-80% EtOAc in heptane) to give 2-(methylthio)-1-(2-(1-(2-(methylthio)propanoyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one (1.96 g, 4.4 mmol, 50% yield) as a yellow wax.

[0095] DIP / MS(EI):m / z(%):370(1)[M + -C3H7S],268(5),240(26),185(14),75(100)[C3H7S + ]. 1 H NMR (400MHz, chloroform-d, 25℃): δ=7.63-7.76(m,2H),7.52-7.62(m,1H),7.15-7.25(m,2H),5.87-6.56(m,1H),4.22-4.76( m,1H),3.88-4.15(m,2H),3.65-3.81(m,1H),2.38(s,3H),2.07-2.18(m,4H),1.22-1.76(m,10H),0.84-0.98ppm(m,4H).

[0096] Example 6: 1-(2-(1-benzoyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one: A solution of 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one (0.2 g, 0.582 mmol) in dichloromethane (2 mL) at ambient temperature was treated with benzoyl chloride (0.098 g, 0.699 mmol). The reaction mixture was stirred at ambient temperature for 2 h, then poured into ice water, extracted with DCM (3x25 mL), washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel (7–60% EtOAc in heptane) to give 1-(2-(1-benzoyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (0.13 g, 0.290 mmol, 50% yield) as a yellow oily wax.

[0097] DIP / MS(EI):m / z(%):447(1)[M +], 432(1), 401(1), 372(2), 344(4), 240(35), 105(100), 75(32). 1 H NMR(400MHz,DMSO-d6,25℃):δ=7.69-8.11(m,6H),7.48-7.68(m,2H),7.11-7.27(m,2H),5.73 -6.36(m,1H),3.73-4.09(m,3H),2.31(s,3H),1.94-2.13(m,4H),1.75-1.88(m,2H),1.62(br s,2H),1.13-1.41 ppm(m,4H).

[0098] Example 7: N-(1-benzoyl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide: A solution of N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide (0.150 g, 0.458 mmol) and triethylamine (0.056 g, 0.550 mmol) in dichloromethane (3 mL) was treated with benzoyl chloride (0.077 g, 0.550 mmol) at 5° C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 2 h, then poured into ice water, extracted with DCM (3× 25 mL), washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel (7–30% EtOAc in heptane) to give N-(1-benzoyl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide (0.17 g, 0.394 mmol, 86% yield) as a white solid.

[0099] DIP / MS(EI):m / z(%):431(1)[M + ], 324(2), 282(2), 121(5), 105(100), 97(57), 91(18), 77(37). 1H NMR(400MHz,DMSO-d6,25℃):δ=8.61(d,J=2.9Hz,1H),7.77-8.03(m,2H),7.65-7.73(m,1H),7.50-7.58(m,2H),7.39-7.47(m, 1H),7.04(d,J=8.3Hz,3H),6.83-6.99(m,2H),6.61-6.77(m,2H),5.06-5.35(m,2H),4.49-5.05(m,2H),2.19-2.25ppm(m,3H).

[0100] Example 8: N-(1-isobutyryl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide: A solution of N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide (0.15 g, 0.458 mmol) and triethylamine (0.056 g, 0.550 mmol) in dichloromethane (3 mL) was treated with isobutyryl chloride (0.059 g, 0.550 mmol) at 5° C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 2 h, then poured into ice water, extracted with DCM (3× 25 mL), washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel (7–30% EtOAc in heptane) to give N-(1-isobutyryl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide (0.175 g, 0.440 mmol, 96% yield) as a colorless liquid.

[0101] GC / MS(EI):m / z(%):397(7)[M + ], 327(1), 290(2), 220(29), 178(21), 121(8), 97(100), 71(15), 43(33). 1H NMR (400MHz, DMSO-d6, 25℃): δ=8.41(d,J=2.9Hz,1H),7.44(dd,J=5.0,1.1Hz,1H),7.01-7.11(m,3H),6.95(br dd,J=4.9,3.7Hz,1H),6.77-6.90(m,1H),6.68-6.76(m,2H),5.10-5.32(m,2H),4.98(brs,2H),3.67(dt,J=13.3,6.5Hz,1H),2.22(s,3H),1.18 ppm(d,J=6.8Hz,6H)

[0102] Example 9: N-(1-acetyl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide: A solution of N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide (0.15 g, 0.458 mmol) and triethylamine (0.056 g, 0.550 mmol) in dichloromethane (3 mL) was treated with acetyl chloride (0.043 g, 0.550 mmol) at 5° C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 2 h, then poured into ice water, extracted with DCM (3× 25 mL), washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel (7-30% EtOAc in heptane) to give N-(1-acetyl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide (0.140 g, 0.379 mmol, 83% yield) as a white solid. GC / MS (EI): m / z (%): 369 (8) [M + ], 262(6), 220(35), 178(23), 97(100), 43(15). 1H NMR (400MHz, chloroform-d, 25℃): δ=8.21(d,J=2.7Hz,1H),7.25(dd,J=5.1,1.2Hz,1H),7.07(d,J=8.3Hz,2H),7.01(br s,1H),6.95(dd,J=5.0,3.5Hz,1H),6.75(br d,J=8.1Hz,2H),6.14-6.56(m,1H),5.06-5.43(m,2H),4.87(s,2H),2.58-2.68(m,3H),2.29ppm(s,3H).

[0103] Example 10: 1-(2-(1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one: A solution of 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one (1 g, 2.91 mmol) and ethyldi(isopropyl)amine (DIPEA) (0.508 mL, 2.91 mmol) in dichloromethane (5 mL) was treated with a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl chloride (0.590 g, 2.91 mmol) in dichloromethane (5 mL) at 5° C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, then poured into ice-cold 1M aq. HCl (5 mL), extracted with DCM (3× 25 mL), washed with 1M aq. NaOH (10 mL), water (25 mL), and brine (25 mL), dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel (7-30% EtOAc in heptane) to give 1-(2-(1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (1.1 g, 2.158 mmol, 74% yield) as a yellow viscous liquid. DIP / MS (EI): m / z (%): 509 (2) [M +], 463(2), 434(1), 342(9), 296(6), 268(23), 240(100), 75(27). 1 H NMR(400MHz,DMSO-d6,25℃):δ=8.39-8.56(m,1H),7.64-7.89(m,2H),7.09-7 .40(m,2H),5.90-6.37(m,1H),3.76-4.28(m,3H),3.21-3.49(m,3H),2.32(s, 3H),2.13(td,J=11.6,3.4Hz,1H),1.83-2.07(m,4H),1.53-1.82(m,13H),1.2 2-1.42(m,7H),1.03-1.21(m,4H),0.84-0.93(m,13H),0.69-0.81ppm(m,5H).

[0104] Example 11 1-(2-(1-acetyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one: A solution of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (0.5 g, 1.536 mmol) and DIPEA (0.295 mL, 1.690 mmol) in dichloromethane (5 mL) was treated with a solution of acetyl chloride (0.120 mL, 1.690 mmol) in dichloromethane (5 mL) at 5° C. After addition, the cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, then poured into ice-cold 1M aq. HCl (5 mL), extracted with DCM (3× 25 mL), washed with 1M aq. NaOH (10 mL), water (25 mL), and brine (25 mL), dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel (7-30% EtOAc in heptane) to give 1-(2-(1-acetyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one (0.30 g, 0.816 mmol, 53% yield) as a white solid. GC / MS (EI): m / z (%): 367 (5) [M + ], 324(1), 282(2), 240(100), 43(42). 1H NMR(400MHz,DMSO-d6,25℃):δ=8.09-8.22(m,1H),7.72(d,J=8.1Hz,2H),7.22(br d,J=7.8Hz,2H),5.86-6.24(m,1H),3.60-4.54(m,2H),2.73-2.92(m,1H),2.62-2.71(m,3H),2.26-2.43(m ,3H),1.91-1.99(m,1H),1.66-1.89(m,2H),1.22-1.64(m,5H),0.92-1.05(m,3H),0.69-0.90(m,3H),0.43 ppm(t,J=7.3Hz,1H). 13 C NMR (101MHz, DMSO-d6, 25℃): δ=176.3,175.9,169.4,151.6,151.5,139.2,139.2,137.0,137.0,130.6,129.6,129.6,125.2,125.1,125.1,12 0.0,114.7,60.2,47.8,47.7,43.6,43.5,36.7,36.4,28.1,28.0,27.0 ,26.9,25.8,25.1,21.3,21.2,19.6,17.8,16.8,14.5,12.2,11.8ppm.

[0105] Example 12: 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one: A solution of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (0.5 g, 1.536 mmol) and DIPEA (0.295 mL, 1.690 mmol) in dichloromethane (5 mL) was treated with a solution of isobutyryl chloride (0.180 g, 1.690 mmol) in dichloromethane (5 mL) at 5° C. After addition, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 2 h, then poured into ice-cold 1M aq. HCl (5 mL), extracted with DCM (3× 25 mL), washed with 1M aq. NaOH (10 mL), water (25 mL), and brine (25 mL), dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel (1-30% EtOAc in heptane) to give 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one (0.13 g, 0.329 mmol, 21% yield) as a white solid. DIP / MS (EI): m / z (%): 395.3 (10) [M + ], 352.3(1), 324.2(4), 240.2(100), 185.2(38), 71.2(16), 57.1(44), 43.1(96). 1 H NMR(400MHz,DMSO-d6,25℃):δ=8.23-8.38(m,1H),7.74(br d,J=7.8Hz,2H),7.17-7.25(m,2H),5.87-6.21(m,1H),3.92-4.51(m,2H),3.44-3.70(m,1H),2.73-2.90(m,1H),2.25 -2.42(m,3H),1.66-1.98(m,3H),1.27-1.64(m,5H),1.23(t,J=6.7Hz,6H),0.91-1.08(m,3H),0.67-0.87(m,3H),0.43 ppm(br t,J=7.2Hz,1H).

[0106] Example 13:1-(2-(1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one: A solution of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (2 g, 6.15 mmol) and DIPEA (1.073 mL, 6.15 mmol) in dichloromethane (15 mL) was treated with a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl chloride (1.246 g, 6.15 mmol) in dichloromethane (5 mL) at 5° C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight. Thin layer chromatography (TLC) analysis indicated starting material remained. N,N-Dimethyl-4-aminopyridine (DMAP) (0.1 g, 0.81 mmol) was added and the reaction mixture was stirred at ambient temperature for 3 h, then poured into ice-cold 1 M aq. HCl (15 mL), extracted with DCM (3x 75 mL), washed with 1 M aq. NaOH (30 mL), water (75 mL), and brine (75 mL), dried over magnesium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel (7-30% EtOAc in heptane) to give 1-(2-(1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one (2.8 g, 5.69 mmol, 93% yield) as a white solid. DIP / MS(EI):m / z(%):491(2)[M + ], 448(1), 406(1), 324(10), 240(100), 185(93), 43(12). 1H NMR(400MHz,DMSO-d6,25℃):δ=8.41-8.55(m,1H),7.75(br d,J=7.8Hz,2H),7.18-7.27(m,2H),5.78-6.26(m,1H),3.94-4.50(m,2H),3.25-3.73(m,4H),2.73-2.90(m,1H),2.36(br dd,J=11.6,3.3Hz,1H),1.51-1.98(m,13H),1.22-1.50(m,6H),0.63-1.16ppm(m,25H).

[0107] Example 14: 1-(2-(1-(2-methoxyacetyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one: A solution of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (2 g, 6.15 mmol), DMAP (0.075 g, 0.615 mmol), and triethylamine (TEA) (0.942 mL, 6.76 mmol) in dichloromethane (10 mL) was treated with a solution of 2-methoxyacetyl chloride (0.734 g, 6.76 mmol) in dichloromethane (10 mL) at 5° C. After addition, the cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight. TLC analysis indicated approximately 50% conversion. The reaction mixture was treated with 2-methoxyacetyl chloride (0.4 g, 3.69 mmol) and stirred at ambient temperature for an additional 3 h, then poured into ice-cold 1 M aq. HCl (15 mL), extracted with DCM (3x 75 mL), washed with 1 M aq. NaOH (30 mL), water (75 mL), and brine (75 mL), dried over magnesium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel (1-30% EtOAc in heptane) to give 1-(2-(1-(2-methoxyacetyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one (1.70 g, 4.28 mmol, 70% yield) as a white solid. DIP / MS (EI): m / z (%): 397 (5) [M +], 352(5), 324(2), 312(13), 240(49), 84(50), 45(100). 1 H NMR (400MHz, DMSO-d6, 25℃): δ=8.00-8.13(m,1H),7.67-7.76(m,2H),7.18-7.27(m,2H),5.90-6.25(m,1H),4.68-4.83(m,2H),3. 63-4.53(m,2H),3.44(s,3H),2.75-2.92(m,1H),2.32(s,3H),1.93-2.05(m,1H),1.69-1.91(m,2H),1.23-1.64(m,5H),0.40-1.07 ppm(m,6H).

[0108] Example 15: 1-(2-(1-(2-(benzyloxy)acetyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one: A solution of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (2 g, 6.15 mmol), DMAP (0.075 g, 0.615 mmol), and TEA (0.942 mL, 6.76 mmol) in dichloromethane (10 mL) was treated with a solution of 2-(benzyloxy)acetyl chloride (1.248 g, 6.76 mmol) in dichloromethane (10 mL) at 5° C. After the addition, the cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight. TLC indicated starting material remained, so additional 2-(benzyloxy)acetyl chloride (0.5 g, 2.71 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 3 h, then poured into ice-cold 1 M aq. HCl (15 mL), extracted with DCM (3× 75 mL), washed with 1 M aq. NaOH (30 mL), water (75 mL), and brine (75 mL), dried over magnesium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel (1-30% EtOAc in heptane) to give 1-(2-(1-(2-(benzyloxy)acetyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one (2.70 g, 5.70 mmol, 93% yield) as a white solid.

[0109] DIP / MS(EI):m / z(%):473(6)[M + ], 388(7), 382(5), 352(9), 324(6), 240(62), 91(100), 57(32). 1 H NMR (400MHz, chloroform-d, 25℃): δ=7.60-7.71(m,2H),7.32-7.47(m,6H),7.19 (d,J=7.8Hz,2H),5.96-6.47(m,1H),4.49-4.81(m,4H),4.13-4.37(m,1H), 3.87-4.13(m,1H),2.68-2.87(m,1H),2.38(s,3H),2.03-2.15(m,1H),1.81 -2.02(m,2H),1.63-1.80(m,2H),1.35-1.59(m,2H),0.53-1.21ppm(m,6H).

[0110] Example 16: 1-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)dodecan-1-one: A solution of 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one (1.5 g, 4.37 mmol), DMAP (0.053 g, 0.437 mmol), and DIPEA (1.068 mL, 6.11 mmol) in dichloromethane (10 mL) was treated with a solution of dodecanoyl chloride (1.146 g, 5.24 mmol) in dichloromethane (10 mL) at 5° C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, then poured into ice-cold 1M aq. HCl (25 mL), extracted with DCM (3× 75 mL), washed with 1M aq. NaOH (50 mL), water (75 mL), and brine (75 mL), dried over magnesium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel (7–30% EtOAc in heptane) to give 1-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)dodecan-1-one (1.1 g, 2.09 mmol, 48% yield) as an off-white solid.

[0111] DIP / MS(EI):m / z(%):525(3)[M + ], 510(1), 479(3), 450(2), 422(1), 240(93), 185(100), 75(28). 1H NMR (400MHz, DMSO-d6, 25℃): δ=8.14-8.28(m,1H),7.69-7.78(m,2H),7.16-7.25(m,2H),5.89-6.28(m,1H),4.11-4.52(m,1H),3.47-4.11(m,3H) ),2.93-3.12(m,2H),2.31(d,J=2.7Hz,3H),2.02-2.28(m,2H),1.89-1. 98(m,1H),1.44-1.76(m,6H),1.21-1.40(m,25H),0.81-0.90ppm(m,4H).

[0112] Example 17: 1-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)dodecan-1-one: A solution of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (1.5 g, 4.61 mmol), DMAP (0.056 g, 0.461 mmol), and DIPEA (1.127 mL, 6.45 mmol) in dichloromethane (10 mL) was treated with a solution of dodecanoyl chloride (1.210 g, 5.53 mmol) in dichloromethane (10 mL) at 5° C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, then poured into ice-cold 1M aq. HCl (25 mL), extracted with DCM (3× 75 mL), washed with 1M aq. NaOH (50 mL), water (75 mL), and brine (75 mL), dried over magnesium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel (7-30% EtOAc in heptane) to give 1-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)dodecan-1-one (1.75 g, 3.45 mmol, 75% yield) as a white solid.

[0113] DIP / MS(EI):m / z(%):507(5)[M + ], 422(1), 240(100), 185(26), 57(20). 1H NMR(400MHz,DMSO-d6,25℃):δ=8.13-8.29(m,1H),7.69-7.77(m,2H),7.14-7.26(m,2H),5.88 -6.25(m,1H),3.58-4.54(m,2H),2.93-3.13(m,2H),2.72-2.89(m,1H),2.31(s,3H),1.95(br d,J=13.0Hz,1H),1.60-1.84(m,4H),1.41-1.59(m,3H),1.21-1.40(m,19H),0.37-1.06ppm(m,10H).

[0114] Example 18: 1-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)hexan-1-one: A solution of 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one (2 g, 5.82 mmol), DMAP (0.071 g, 0.582 mmol), and DIPEA (1.525 mL, 8.73 mmol) in dichloromethane (10 mL) was treated with a solution of hexanoyl chloride (1.176 g, 8.73 mmol) in dichloromethane (10 mL) at 5° C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, then poured into ice-cold 1M aq. HCl (25 mL), extracted with DCM (3× 75 mL), washed with 1M aq. NaOH (50 mL), water (75 mL), and brine (75 mL), dried over magnesium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel (7–30% EtOAc in heptane) to give 1-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)hexan-1-one (2.2 g, 4.98 mmol, 86% yield) as a white solid.

[0115] DIP / MS(EI):m / z(%):441(5)[M +], 426(2), 395(5), 366(4), 240(80), 185(100), 99(16), 75(44), 43(66). 1 H NMR(400MHz,DMSO-d6,25℃):δ=8.15-8.29(m,1H),7.69-7.79(m,2H),7.14-7.25(m,2H),5.90-6.32(m,1H),3.49-4.52(m,3 H),2.93-3.14(m,2H),2.15-2.50(m,4H),1.86-2.06(m,3H),1.45-1.82(m,8H),1.20-1.42(m,11H),0.83-0.96ppm(m,5H).

[0116] Example 19: 1-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)hexan-1-one: A solution of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (1.5 g, 4.61 mmol), DMAP (0.056 g, 0.461 mmol), and DIPEA (1.127 mL, 6.45 mmol) in dichloromethane (10 mL) was treated with a solution of hexanoyl chloride (0.869 g, 6.45 mmol) in dichloromethane (10 mL) at 5° C. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, then poured into ice-cold 1M aq. HCl (25 mL), extracted with DCM (3× 75 mL), washed with 1M aq. NaOH (50 mL), water (75 mL), and brine (75 mL), dried over magnesium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel (7–30% EtOAc in heptane) to give 1-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)hexan-1-one (1.85 g, 4.37 mmol, 95% yield) as a white solid.

[0117] DIP / MS(EI):m / z(%):423(5)[M +], 338(2), 240(100), 185(52), 99(6), 57(10). 1 H NMR(400MHz,DMSO-d6,25℃):δ=8.12-8.31(m,1H),7.67-7.78(m,2H),7.13-7.30(m,2H),5.87-6.26(m,1H), 3.56-4.55(m,2H),2.73-3.14(m,3H),2.14-2.49(m,4H),1.62-2.01(m,5H),1.21-1.61(m,14H),0.38-1.06 ppm(m,12H).

[0118] Example 20: Assays for TRPM8 Modulators HEK293 cell lines stably expressing hTRPM8 were generated according to Klein et al., (Chem.Senses 36:649-658,2011), and receptor activation was monitored by calcium imaging in a Flexstation. For Ca imaging assay of TRPM8 channel activation, cells were seeded at a density of 12000 cells per well in Dulbecco's Modified Eagle Medium (DMEM) containing 9% fetal bovine serum in black clear-bottom 96-well plates coated with 0.001% polyethyleneimine (molecular weight=60 000, Acros Organics) on day 0. On day 2, agonists were assessed via calcium imaging using Fluo-4. Briefly, growth medium was discarded and cells were incubated in 50 μL loading buffer containing 2.7 μM Fluo-4 AM (Invitrogen) and 2.5 μM probenecid (Sigma-Aldrich) in DMEM (without serum) for 1 h at 37° C. in the dark. After incubation, plates were washed 5 times with 100 μL assay buffer (in mM: 130 NaCl, 5 KCl, 10 HEPES, 2 CaCl2, and 10 glucose, pH 7.4) and further incubated at room temperature for 30 min in the dark. Cells were then washed 5 times with 100 μL assay buffer, and calcium influx into serial dilutions of the compounds of the invention was then measured in a Flexstation 3 (Molecular Devices). Receptor activation was initiated following the addition of 20 μl of a 10-fold concentrated ligand stock solution (also prepared in assay buffer). Fluorescence was constantly monitored for 15 seconds prior to and 105 seconds after ligand addition (total 120 seconds). Maximal receptor activation was determined with respect to the solvent control and relative to 31.6 μM menthol. Data from the serial dilutions were processed with the KNIME workflow to fit a sigmoidal dose-response curve to estimate EC50 values.

[0119] TRPM8 agonists exhibiting EC50 values ​​below 35 μM are presented in Table 1 below. Table 1: [Table 1-1] [Table 1-2] ++++EC in the range of 0.05 μM or less 50 value +++ EC in the range of 0.05-0.3 μM 50 value ++EC in the range of 0.3-1.00 μM 50 value + EC in the range of 1.00–35 μM 50 value

Claims

1. A method of modulating the transient receptor potential channel melastatin member 8 (TRPM8), comprising: 【Chemistry 1】 During the ceremony X 1 , X 2 , and X 3 and the other two are independently selected from C, N, and O, provided that neither of these is C, and where R optionally contains one heteroatom selected from O and S. 1 ~C 15 selected from hydrocarbon residues; and a) R 1 is H; and B is a monovalent residue (a) 【Chemistry 2】 represents, or b) R 1 is selected from: i) halogens, ii) C, which is optionally substituted with up to four substituents independently selected from the group consisting of: 6 ~C 10 Aryl: Halogens; OH (hydroxyl); C≡N (cyano); NO 2 (Nitro); C, which may optionally contain up to 5 halogen atoms 1 ~C 6 Alkyl; C containing up to 3 OH groups 1 ~C 3 Alkyl; C 2 ~C 6 Alkenyl; C, which may optionally contain up to three halogen atoms 1 ~C 6 Alkoxy; C 1 ~C 3 Alkoxy C 1 ~C 3 Alkyl; C 3 ~C 7 Cycloalkyl; -C(O)R 10 , where R 10 is C 1 ~C 3 selected from alkyl; -OC(O)R 11 , where R 11 H, and C 1 ~C 3 selected from alkyl; -C(O)OR 12 , where R 12 is hydrogen and C 1 ~C 3 selected from alkyl; -(CH 2 ) m N(R 13 )R 14 , where m is 0 or 1, and R 13 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 15 is selected from, where R 15 is C 1 ~C 3 alkyl, and R 14 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 16 is selected from, where R 16 is C 1 ~C 3 alkyl, or where R 13 and R 14 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 17 , where R 17 is hydrogen and C 1 ~C 3 alkyl; and -S(O) 2 R 18 , where R 18 is hydrogen and C 1 ~C 3 selected from alkyl; With the proviso that when an aryl ring is substituted with two or more substituents, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring; and iii) C 5 ~C 10 Monocyclic or bicyclic heteroaryl, in which up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, and which may be optionally substituted with up to four substituents selected from the group consisting of: Halogen; OH; C≡N; NO 2 ; C, which may optionally contain up to 5 halogen atoms 1 ~C 6 Alkyl; C 2 ~C 6 Alkenyl; C, which may optionally contain up to three halogen atoms 1 ~C 6 Alkoxy; C 1 ~C 3 Alkoxy C 1 ~C 3 Alkyl; C 3 ~C 7 Cycloalkyl; -C(O)R 20 , where R 20 is C 1 ~C 3 selected from alkyl; -OC(O)R 21 , where R 21 H, and C 1 ~C 3 selected from alkyl; -C(O)OR 22 , where R 22 is hydrogen and C 1 ~C 3 selected from alkyl; -(CH 2 ) m N(R 23 )R 24 , where m is 0 or 1, and R 23 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 25 is selected from, where R 25 is C 1 ~C 3 alkyl, and R 24 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 26 is selected from, where R 26 is C 1 ~C 3 alkyl, or where R 23 and R 24 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 27 , where R 27 is hydrogen and C 1 ~C 3 alkyl; and -S(O) 2 R 28 , where R 28 is hydrogen and C 1 ~C 3 selected from alkyl; and B is a monovalent residue (b) 【Chemistry 3】 In the formula R 4 , R 5 , and R 6 together with the carbon atom to which they are attached form a hydrocarbon radical which may optionally contain up to five heteroatoms selected from O, N, S, and F; and Z is either C, S, or S(O); The method (excluding a method of treatment) comprises bringing a patient into contact with a compound represented by the formula:

2. The compound represented by formula (I) is 1-(2-(1-propionyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one; 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylpropan-1-one; 2-(methylthio)-1-(2-(1-(2-(methylthio)propanoyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one; 1-(2-(1-acetyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one; 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one; 1-(2-(1-benzoyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one; 1-(2-(1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one; 1-(2-(1-acetyl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one; 1-(2-(1-isobutyryl-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one; 1-(2-(1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-1-carbonyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one; 1-(2-(1-(2-methoxyacetyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one; 1-(2-(1-(2-(benzyloxy)acetyl)-4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one;1-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)dodecan-1-one; 1-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)dodecan-1-one; 1-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)hexan-1-one; 1-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-4-(p-tolyl)-1H-imidazol-1-yl)hexan-1-one; 2. The method of claim 1, wherein the compound is selected from the group consisting of N-(1-benzoyl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide; N-(1-isobutyryl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide; and N-(1-acetyl-1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide.

3. A method (excluding therapeutic methods) of inducing a cooling sensation in a human or animal which comprises contacting said human or animal with a compound of formula (I) as defined in claim 1, or a salt or solvate thereof.

4. A method (excluding therapeutic methods) for exerting a cooling effect on the skin or mucous membranes, comprising contacting the skin or mucous membranes with a product comprising one or more compounds of formula (I) as defined in claim 1.

5. Formula (I) 【Chemistry 4】 A compound represented by the formula: X 1 , X 2 , and X 3 and the other two are independently selected from C, N, and O, provided that neither of these is C, and where R optionally contains one heteroatom selected from O and S. 1 ~C 15 selected from hydrocarbon residues; and a) R 1 is H; and B is a monovalent residue (a) 【Chemistry 5】 represents, or b) R 1 is selected from: i) halogens, ii) C, which is optionally substituted with up to four substituents independently selected from the group consisting of: 6 ~C 10 Aryl: Halogens; OH (hydroxyl); C≡N (cyano); NO 2 (Nitro); C, which may optionally contain up to 5 halogen atoms 1 ~C 6 Alkyl; C containing up to 3 OH groups 1 ~C 3 Alkyl; C 2 ~C 6 Alkenyl; C, which may optionally contain up to three halogen atoms 1 ~C 6 Alkoxy; C 1 ~C 3 Alkoxy C 1 ~C 3 Alkyl; C 3 ~C 7 Cycloalkyl; -C(O)R 10 , where R 10 is C 1 ~C 3 selected from alkyl; -OC(O)R 11 , where R 11 H, and C 1 ~C 3 selected from alkyl; -C(O)OR 12 , where R 12 is hydrogen and C 1 ~C 3 selected from alkyl; -(CH 2 ) m N(R 13 )R 14 , where m is 0 or 1, and R 13 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 15 is selected from, where R 15 is C 1 ~C 3 alkyl, and R 14 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 16 is selected from, where R 16 is C 1 ~C 3 alkyl, or where R 13 and R 14 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 17 , where R 17 is hydrogen and C 1 ~C 3 alkyl; and -S(O) 2 R 18 , where R 18 is hydrogen and C 1 ~C 3 selected from alkyl; With the proviso that when an aryl ring is substituted with two or more substituents, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring; and iii) C 5 ~C 10 Monocyclic or bicyclic heteroaryl, in which up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, and which may be optionally substituted with up to four substituents selected from the group consisting of: Halogen; OH; C≡N; NO 2 ; C, which may optionally contain up to 5 halogen atoms 1 ~C 6 Alkyl; C 2 ~C 6 Alkenyl; C, which may optionally contain up to three halogen atoms 1 ~C 6 Alkoxy; C 1 ~C 3 Alkoxy C 1 ~C 3 Alkyl; C 3 ~C 7 Cycloalkyl; -C(O)R 20 , where R 20 is C 1 ~C 3 selected from alkyl; -OC(O)R 21 , where R 21 H, and C 1 ~C 3 selected from alkyl; -C(O)OR 22 , where R 22 is hydrogen and C 1 ~C 3 selected from alkyl; -(CH 2 ) m N(R 23 )R 24 , where m is 0 or 1, and R 23 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 25 is selected from, where R 25 is C 1 ~C 3 alkyl, and R 24 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 26 is selected from, where R 26 is C 1 ~C 3 alkyl, or where R 23 and R 24 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 27 , where R 27 is hydrogen and C 1 ~C 3 alkyl; and -S(O) 2 R 28 , where R 28 is hydrogen and C 1 ~C 3 selected from alkyl; and B is a monovalent residue (b) 【Chemistry 6】 In the formula R 4 , R 5 , and R 6 together with the carbon atom to which they are attached form a hydrocarbon radical which may optionally contain up to five heteroatoms selected from O, N, S, and F; and Z is either C, S, or S(O); A compound represented by formula (I).

6. A consumer product comprising one or more compounds of formula (I) as defined in claim 5.

7. A pharmaceutical composition comprising one or more compounds of formula (I) as defined in claim 5.

8. A composition for providing a cooling sensation, the composition comprising a compound represented by formula (I) as defined in claim 5.

9. 9. The composition according to claim 8, comprising at least one compound of formula (I), a salt or a solvate thereof, and a further cooling compound.

10. Further cooling compounds include menthol, menthone, p-menthanecarboxamide, N-2,3-trimethyl-2-isopropyl-butanamide, menthyl lactate, menthone glycerol acetal, 3-(1-menthoxy)-propane-1,2-diol, p-menthane-3,8-diol, isopulegol, monomenthyl succinate, monomenthyl glutarate, o-menthyl glycerol, menthyl N,N-dimethyl succinamate, 2-(sec-butyl)cyclohexan-1-one, N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide, 2-(4-ethylphenoxy)-N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide, 3-(benzo[d][1,3]dioxadiamine, 3-(methylphenyl)-2-(phenylphenyl)acetamide ...

10. The composition of claim 9, wherein the isomer is selected from the group consisting of 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-ethoxypropyl)-2-methoxyphenol, 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-((2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol, N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexane-1-carboxamide, N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide, and N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide.

11. Formula (I) as defined in claim 1 【Chemistry 7】 During the ceremony X 1 , X 2 , and X 3 one of is >NH and the other two are independently selected from C, N, and O, with the proviso that neither of them is C; and a) R 1 is H; and B is a monovalent residue (a) 【Chemistry 8】 represents, or b) R 1 is selected from: i) halogens, ii) C, which is optionally substituted with up to four substituents independently selected from the group consisting of: 6 ~C 10 Aryl: Halogen; OH (hydroxyl); C≡N (cyano); NO 2 (Nitro); C, which may optionally contain up to 5 halogen atoms 1 ~C 6 Alkyl; C containing up to 3 OH groups 1 ~C 3 Alkyl; C 2 ~C 6 Alkenyl; C, which may optionally contain up to three halogen atoms 1 ~C 6 Alkoxy; C 1 ~C 3 Alkoxy C 1 ~C 3 Alkyl; C 3 ~C 7 Cycloalkyl; -C(O)R 10 , where R 10 is C 1 ~C 3 selected from alkyl; -OC(O)R 11 , where R 11 H, and C 1 ~C 3 selected from alkyl; -C(O)OR 12 , where R 12 is hydrogen and C 1 ~C 3 selected from alkyl; -(CH 2 ) m N(R 13 )R 14 , where m is 0 or 1, and R 13 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 15 is selected from, where R 15 is C 1 ~C 3 alkyl, and R 14 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 16 is selected from, where R 16 is C 1 ~C 3 alkyl, or where R 13 and R 14 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 17 , where R 17 is hydrogen and C 1 ~C 3 alkyl; and -S(O) 2 R 18 , where R 18 is hydrogen and C 1 ~C 3 selected from alkyl; With the proviso that when an aryl ring is substituted with two or more substituents, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring; and iii) C 5 ~C 10 Monocyclic or bicyclic heteroaryl, in which up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, and which may be optionally substituted with up to four substituents selected from the group consisting of: Halogen; OH; C≡N; NO 2 ; C, which may optionally contain up to 5 halogen atoms 1 ~C 6 Alkyl; C 2 ~C 6 Alkenyl; C, which may optionally contain up to three halogen atoms 1 ~C 6 Alkoxy; C 1 ~C 3 Alkoxy C 1 ~C 3 Alkyl; C 3 ~C 7 Cycloalkyl; -C(O)R 20 , where R 20 is C 1 ~C 3 selected from alkyl; -OC(O)R 21 , where R 21 H, and C 1 ~C 3 selected from alkyl; -C(O)OR 22 , where R 22 is hydrogen and C 1 ~C 3 selected from alkyl; -(CH 2 ) m N(R 23 )R 24 , where m is 0 or 1, and R 23 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 25 is selected from, where R 25 is C 1 ~C 3 alkyl, and R 24 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 26 is selected from, where R 26 is C 1 ~C 3 alkyl, or where R 23 and R 24 together with the N atom to which they are attached form morpholine, thiomorpholine, or 1,1-dioxothiomorpholine; -SR 27 , where R 27 is hydrogen and C 1 ~C 3 alkyl; and -S(O) 2 R 28 , where R 28 is hydrogen and C 1 ~C 3 selected from alkyl; and B is a monovalent residue (b) 【Chemistry 9】 In the formula R 4 , R 5 and R 6 together with the carbon atom to which they are attached form a hydrocarbon radical which may optionally contain up to five heteroatoms selected from O, N, S, and F; and Z is either C, S, or S(O); A method for exerting a cooling effect on the skin or mucous membrane (excluding therapeutic methods), comprising hydrolyzing the acetyl group (>NC(O)R) of a compound represented by formula (I') to obtain a compound represented by formula (I').

12. 11. The composition of any one of claims 8 to 10 for use as a mediator of transient receptor potential channel melastatin member 8 (TRPM8) selected from the group consisting of food products, beverages, chewing gum, tobacco and tobacco substitute products, dental care products, personal care products, and intimate care products.

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