Substituted azayls as TRMP8 modulators

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 temperatures 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, throat, and nasal mucosa), the male urogenital tract, lung epithelial cells, and arterial muscle cells. They are Ca channels that exhibit a polymodal gating mechanism. 2+ The receptor is a permeable, nonselective cation channel that is activated by harmless cold temperatures, membrane depolarization, and molecules (including natural and synthetic compounds) known as cooling agents. The receptor was first described in 2002 in several 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 because of their association with 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 they provide has contributed to the appeal and acceptability of these consumer products. 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 containing a cyclohexane moiety, which are derivatized with functional groups including carboxamide, ketal, ester, ether, and alcohol.

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

[0007] overview In a first aspect, the compound of formula (I) [ka] n is 0 or 1; R1 is selected from: i) halogens, ii) C6 to C 10 aryl, iii) C5~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, iv) C6~C 10 Although it is aryl, Halogen; OH; C≡N; NO2; C1-C6 alkyl; C1-C6 alkyl containing up to five halogen atoms; C1-C3 alkyl containing up to three OH groups; C2-C6 alkenyl; C1-C6 alkoxy; C1-C6 alkoxy containing up to three halogen atoms; C1-C3 alkoxyC1-C3 alkyl; C3-C7 cycloalkyl; -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 (where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 (where R 16 is C1-C3 alkyl), or where R 13and R 14 together with the N atom to which they are attached to 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), provided that when an aryl ring is substituted with two or more substituents, two of the substituents, taken together with the carbon atoms to which they are attached, may form a cyclic ring; and v) C5~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen; Halogen; OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl; C1-C6 alkyl containing up to five halogen atoms; C2-C6 alkenyl; C1-C6 alkoxy; C1-C6 alkoxy containing up to three halogen atoms; C1-C3 alkoxyC1-C3 alkyl; C3-C7 cycloalkyl; -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 )R24 (where m is 0 or 1, and R 23 is hydrogen, C1-C3 alkyl, and -SO2R 25 (where R 25 is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 (where R 26 is C1-C3 alkyl), or where R 23 and R 24 together with the N atom to which they are attached to 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 substituted with up to four substituents selected from the group consisting of: Y is a monocyclic or bicyclic, unsaturated or aromatic heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen, wherein the ring is optionally substituted with halogen, methyl, ethyl, -N(R 40 )R 41 , -CON(R 40 )R 41 , -[CR 40 R 41 ] p -C(O)OR 40 , -C(O)R 40 , and -SO2N(R 40 )R 41 (where R 40 and R 41 is independently selected from hydrogen and C1-C4 alkyl, and p is 0, 1, or 2; A is a 5-7 membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen and sulfur, wherein heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =O; Z is either C, S, or S(O); and R 4 , R 5 , and R 6 together with the carbon atom to which they are attached form a hydrocarbon group (optionally containing up to five heteroatoms selected from O, N, S, and F);

[0010] There is provided a compound represented by the formula:

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

[0010] In a fifth aspect, there is provided a composition comprising a cool sensation, wherein the composition comprises 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.

[0011] The details, examples, and preferences provided with respect to any particular one or more of the specified aspects of the invention are further described 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 otherwise clearly contradicted by context. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description The present invention provides a novel class of chemical compounds that are significantly different in structure from previously known TRPM8 modulators and are capable of activating the TRPM8 ion channel, thereby increasing Ca₂ transport into cold-sensitive neurons. 2+ This is based, at least in part, on the surprising finding that electrical signals produced by the ionizing radiation lead to an influx of electrical signals that are ultimately perceived as a sensation of cold. Applicants have surprisingly found that this class of chemical compounds, as further described herein, can provide long-lasting cooling on human skin and / or mucous membranes at extremely low concentrations.

[0013] Thus, in a first aspect, a compound of formula (I) [ka] During the ceremony n is 0 or 1; R 1 is selected from: halogens (including Br, Cl, and F); C6~C 10 aryl (e.g., phenyl or naphthyl), Halogens (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (such as CH3, CF3, or CHF2), optionally containing up to five halogen atoms (e.g., F); C1-C3 alkyl containing up to three OH groups (e.g. CH2OH); C2-C6 alkenyl (-CH=CH2, etc.); C1-C6 alkoxy (OCH3, OCH3, OCF3, etc.), optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (such as 2-methoxy-ethyl); C3-C7 cycloalkyl (cyclopropyl, cyclobutyl, etc.); -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 (where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 (where R 16 is C1-C3 alkyl), or where R 13 and R 14 together with the N atom to which they are attached to 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 R18 is selected from hydrogen and C1-C3 alkyl), provided that when an aryl ring is substituted with more than one substituent, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring; and C5~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, and optionally Halogens (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (such as CH3, CF3, or CHF2), optionally containing up to five halogen atoms (e.g., F); C2-C6 alkenyl (-CH=CH2, etc.); C1-C6 alkoxy (OCH3, OCH3, OCF3, etc.), optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (such as 2-methoxy-ethyl); C3-C7 cycloalkyl (cyclopropyl, cyclobutyl, etc.); -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 (where R 25is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 (where R 26 is C1-C3 alkyl), or where R 23 and R 24 together with the N atom to which they are attached to 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 substituted with up to four (e.g., one, two, or three) substituents selected from the group consisting of: Y is a monocyclic or bicyclic, unsaturated or aromatic heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen, wherein the ring is optionally substituted with halogen (including Br, Cl, and F), methyl, ethyl, -N(R 40 )R 41 , -CON(R 40 )R 41 , -[CR 40 R 41 ] p -C(O)OR 40 , -C(O)R 40 , and -SO2N(R 40 )R 41 (where R 40 and R 41 are independently mono-, di-, or tri-substituted with groups selected from hydrogen and C1-C4 alkyl (including ethyl and propyl), and p is 0, 1, or 2; A is a 5-7 membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen and sulfur, wherein heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =O; Z is either C, S, or S(O); and R 4 , R 5 , and R 6 together with the carbon atom to which they are attached form a hydrocarbon group (optionally containing 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)),

[0010] There is provided a compound represented by the formula:

[0014] Non-limiting examples include formula (I), R 4 is selected from hydrogen and methyl; and R 5 is selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl; R 6 is 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-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl (e.g., 2-furyl or 3-furyl), but optionally methyl, C1-C6 fluoro-alkyl (such as pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, or difluoroethyl), and -NR 30 R 31 (where R 30and R 31 are substituted with independently selected from hydrogen and C1-C3 alkyl; or R 6 and R 5 together with the carbon atoms 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) a 3-7 membered saturated or unsaturated cyclic ring containing up to three heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the cyclic ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy; (For example, R 5 and R 6 together with the carbon atom to which they are attached form a thiodiazole or furanyl) or a salt or solvate thereof.

[0015] Further non-limiting examples include those of formula (I), Y is a 5-membered unsaturated heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen (for example, Y is selected from imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, thiadiazole, pyrrole, furan, thiophene, and isoxazole), or Y is benzimidazole; or a salt or solvate thereof.

[0016] Further non-limiting examples include those of formula (I), Z is C; R 1are independently halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (such as CH3, CF3, or CHF2) optionally containing up to five halogen atoms (e.g., F); C1-C3 alkyl (such as CH2OH) containing up to three OH groups; C2-C6 alkenyl (such as -CH=CH2); C1-C6 alkoxy (such as OCH3, OCH3, OCF3) optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (such as 2-methoxy-ethyl); C3-C7 cycloalkyl (such as cyclopropyl, 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 (where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 (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)R 18 (where R 18is selected from hydrogen and C1-C3 alkyl), optionally substituted with up to four (e.g., 1, 2, or 3) substituents selected from the group consisting of 10 aryl (e.g., phenyl or naphthyl) (provided that when an aryl ring is substituted with two or more substituents, the two substituents, together with the carbon atoms to which they are attached, may form a cyclic ring); and R 4 , R 5 and R 6together with the carbon atom to which they are attached, include 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- prop-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 forming a hydrocarbon group selected from -(3-tetrahydrofuryl)prop-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, or a salt or solvate thereof.

[0017] Further non-limiting examples include compounds of formula (Ia): [ka] During the ceremony n is 0 or 1; R 1 is selected from: halogens (including Br, Cl, and F); C6~C 10Aryl (e.g., phenyl or naphthyl) including halogens (F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (e.g., CH3, CF3, or CHF2) optionally containing up to five halogen atoms (e.g., F); C1-C3 alkyl (e.g., CH2OH) containing up to three OH groups; C2-C6 alkenyl (e.g., -CH=CH2); C1-C6 alkoxy (e.g., OCH3, OCH3, OCF3) optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (e.g., 2-methoxy-ethyl); C3-C7 cycloalkyl (e.g., cyclopropyl, 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 (where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 (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)R 18 (where R 18is selected from hydrogen and C1-C3 alkyl), provided that when an aryl ring is substituted with two or more substituents, two of the substituents, taken together with the carbon atoms to which they are attached, may form a cyclic ring; and C5~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen, and optionally Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (such as CH3, CF3, or CHF2), optionally containing up to five halogen atoms (e.g., F); C2-C6 alkenyl (such as -CH=CH2); C1-C6 alkoxy (such as OCH3, OCH3, OCF3), optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (such as 2-methoxy-ethyl); C3-C7 cycloalkyl (such as cyclopropyl, 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 (where R 25 is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 (where R 26 is C1-C3 alkyl), or where R 23and 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)R 28 (where R 28 is selected from hydrogen and C1-C3 alkyl substituted with up to four (e.g., one, two, or three) substituents selected from the group consisting of: Y is a monocyclic or bicyclic, unsaturated or aromatic heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen, wherein the ring is optionally substituted with halogen, methyl, ethyl, -N(R 40 )R 41 , -CON(R 40 )R 41 , -[CR 40 R 41 ] p -C(O)OR 40 , -C(O)R 40 , and -SO2N(R 40 )R 41 (where R 40 and R 41 are independently mono-, di-, or tri-substituted with groups selected from hydrogen and C1-C4 alkyl (including ethyl and propyl), and p is 0, 1, or 2; Z is either C, S, or S(O); and R 4 , R 5 , and R 6 form together with the carbon atom to which they are attached a hydrocarbon group (optionally containing 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)), or a salt or solvate thereof.

[0018] Further non-limiting examples include compounds of formula (Ia): R 4 is selected from hydrogen and methyl; R 5 is selected from hydrogen, C1-C2 alkyl, and C2-C3 alkenyl; and R 6 is 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-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl (e.g., 2-furyl or 3-furyl), but optionally methyl, 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; or R 6 and R 5 together with the carbon atoms 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) a 3-7 membered saturated or unsaturated cyclic ring containing up to three heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the cyclic ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy. (For example, R 5 and R 6 together with the carbon atom to which they are attached form a thiodiazole or furanyl), or a salt or solvate thereof.

[0019] Further non-limiting examples include compounds of formula (Ia): Z is C, and R 4 , R 5 , and R 6together with the carbon atom to which they are attached, include 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- prop-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 forming a hydrocarbon group selected from -(3-tetrahydrofuryl)prop-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, or a salt or solvate thereof.

[0020] Further non-limiting examples include compounds of formula (Ib): [ka] During the ceremony n is 0 or 1; R 1 is selected from: halogens (including Br, Cl, and F); C6~C 10Aryl (e.g., phenyl or naphthyl), optionally independently containing halogen (F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (e.g., CH3, CF3, or CHF2) optionally containing up to five halogen atoms (e.g., F); C1-C3 alkyl (e.g., CH2OH) containing up to three OH groups; C2-C6 alkenyl (e.g., -CH=CH2); C1-C6 alkoxy (e.g., OCH3, OCH3, OCF3) optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (e.g., 2-methoxy-ethyl); C3-C7 cycloalkyl (e.g., cyclopropyl, 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 (where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 (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)R 18 (where R 18is selected from hydrogen and C1-C3 alkyl) (provided that when an aryl ring is substituted with more than one substituent, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring); and C5~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen, and optionally halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (such as CH3, CF3, or CHF2) optionally containing up to five halogen atoms (e.g., F); C2-C6 alkenyl (such as -CH=CH2); C1-C6 alkoxy (such as OCH3, OCH3, OCF3) optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (such as 2-methoxy-ethyl); C3-C7 cycloalkyl (cyclopropyl, cyclobutyl, etc.); -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 (where R 25 is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 (where R 26 is C1-C3 alkyl), or where R 23 and R 24together 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)R 28 (where R 28 is substituted with up to four (e.g., one, two, or three) substituents selected from the group consisting of: hydrogen and C1-C3 alkyl; A is a 5-7 membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen and sulfur, wherein the heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =O; Z is either C, S, or S(O); R 4 , R 5 and R 6 form together with the carbon atom to which they are attached a hydrocarbon group (optionally containing 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)); X 1 is NH, O, or S; and X 2 and X 3 are independently selected from C, N, and O, with the proviso that X 2 or X 3 Isn't either C, or a salt or solvate thereof.

[0021] Further non-limiting examples include those of formula (Ib), R 1 is selected from: halogens (including Br, Cl, and F); C6~C 10Aryl (e.g., phenyl or naphthyl), optionally independently containing halogen (F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (e.g., CH3, CF3, or CHF2) optionally containing up to five halogen atoms (e.g., F); C1-C3 alkyl (e.g., CH2OH) containing up to three OH groups; C2-C6 alkenyl (e.g., -CH=CH2); C1-C6 alkoxy (e.g., OCH3, OCH3, OCF3) optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (e.g., 2-methoxy-ethyl); C3-C7 cycloalkyl (e.g., cyclopropyl, 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 (where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 (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)R 18 (where R 18is selected from hydrogen and C1-C3 alkyl) (provided that when an aryl ring is substituted with more than one substituent, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring); and C5~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen, and optionally halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (such as CH3, CF3, or CHF2) optionally containing up to five halogen atoms (e.g., F); C2-C6 alkenyl (such as -CH=CH2); C1-C6 alkoxy (such as OCH3, OCH3, OCF3) optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (such as 2-methoxy-ethyl); C3-C7 cycloalkyl (cyclopropyl, cyclobutyl, etc.); -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 (where R 25 is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 (where R 26 is C1-C3 alkyl), or where R 23 and R 24together 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)R 28 (where R 28 is substituted with up to four (e.g., one, two, or three) substituents selected from the group consisting of: hydrogen and C1-C3 alkyl; and R 4 , R 5 and R 6together with the carbon atom to which they are attached, include 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- prop-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 forming a hydrocarbon group selected from -(3-tetrahydrofuryl)prop-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, or a salt or solvate thereof.

[0022] A further non-limiting example is a compound of formula (Ib) wherein Z is C, a salt or solvate thereof.

[0023] Further non-limiting examples include those of formula (Ib), Z, C, R 4 is selected from hydrogen and methyl; R 5 is selected from hydrogen, C1-C2 alkyl, and C2-C3 alkenyl; and R 6is 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-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl (e.g., 2-furyl or 3-furyl), but optionally methyl, 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; or R 6 and R 5 together with the carbon atoms 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) a 3-7 membered saturated or unsaturated cyclic ring containing up to three heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the cyclic ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy. (For example, R 5 and R 6 together with the carbon atom to which they are attached form a thiodiazole or furanyl), or a salt or solvate thereof.

[0024] Further non-limiting examples include compounds of formula (Ic): [ka] During the ceremony n is 0 or 1; R 1 is selected from: halogens (including Br, Cl, and F); C6~C 10 Aryl (e.g., phenyl or naphthyl), optionally independently containing halogen (F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (e.g., CH3, CF3, or CHF2) optionally containing up to five halogen atoms (e.g., F); C1-C3 alkyl (e.g., CH2OH) containing up to three OH groups; C2-C6 alkenyl (e.g., -CH=CH2); C1-C6 alkoxy (e.g., OCH3, OCH3, OCF3) optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (e.g., 2-methoxy-ethyl); C3-C7 cycloalkyl (e.g., cyclopropyl, 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 (where R 15 is C1-C3 alkyl, and R 14 is hydrogen, C1-C3 alkyl, and -SO2R 16 (where R 16 is C1-C3 alkyl), or where R 13 and R 14together 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)R 18 (where R 18 is selected from hydrogen and C1-C3 alkyl) (provided that when an aryl ring is substituted with more than one substituent, two of the substituents, together with the carbon atoms to which they are attached, may form a cyclic ring); and C5~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen, and optionally halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl (such as CH3, CF3, or CHF2) optionally containing up to five halogen atoms (e.g., F); C2-C6 alkenyl (such as -CH=CH2); C1-C6 alkoxy (such as OCH3, OCH3, OCF3) optionally containing up to three halogen atoms (e.g., F); C1-C3 alkoxy C1-C3 alkyl (such as 2-methoxy-ethyl); C3-C7 cycloalkyl (cyclopropyl, cyclobutyl, etc.); -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 (where R 25is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 (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)R 28 (where R 28 is selected from hydrogen and C1-C3 alkyl); Z is either C, S, or S(O); and R 4 , R 5 , and R 6 form together with the carbon atom to which they are attached a hydrocarbon group (optionally containing 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)); X 1 is NH or O; and X 2 and X 3 are independently selected from C, N, and O, with the proviso that X 2 or X 3 Isn't either C, or a salt or solvate thereof.

[0025] A further non-limiting example is a compound represented by formula (Ic) wherein Z is C, a salt or solvate thereof.

[0026] Further non-limiting examples include compounds of formula (Ic), wherein Z is C, R 4 is selected from hydrogen and methyl; R 5 is selected from hydrogen, C1-C2 alkyl, and C2-C3 alkenyl; and R 6 is 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-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl (e.g., 2-furyl or 3-furyl), but optionally methyl, 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 substituted with independently selected from hydrogen and C1-C3 alkyl; or R 6 and R 5 together with the carbon atoms 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) forming a 3-7 membered saturated or unsaturated cyclic ring containing up to three heteroatoms selected from oxygen, nitrogen, and sulfur (wherein the cyclic ring is optionally substituted independently with one or two groups selected from C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy); (e.g., R 5and R 6 together with the carbon atom to which they are attached form a thiodiazole or furanyl), or a salt or solvate thereof.

[0027] Further non-limiting examples include compounds of formula (Ic), wherein Z is C, R 4 is selected from hydrogen and methyl; R 5 is selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl; and R 6 is 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-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl (e.g., 2-furyl or 3-furyl), but optionally methyl, 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; or a salt or solvate thereof.

[0028] Further non-limiting examples include compounds of formula (Ic), wherein Z is C, and R 4 , R 5 , and R 6together with the carbon atom to which they are attached, include 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- prop-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 forming a hydrocarbon group selected from -(3-tetrahydrofuryl)prop-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, It is a compound represented by the formula:

[0029] Further non-limiting examples are compounds represented by formulas (I), (Ia), (Ib), and (Ic) where n is 0. Further non-limiting examples include those of formula (I), (Ia), (Ib), and (Ic) (wherein R 1 is para-methyl-phenyl).

[0030] Further non-limiting examples include compounds of formula (I), (Ia), (Ib), and (Ic) where n is 0 and R 1 is para-methyl-phenyl). Further non-limiting examples include compounds of formula (I), (Ia), (Ib), and (Ic) where Z is C, n is 0, and R 1 is para-methyl-phenyl).

[0031] Further non-limiting examples include compounds of formula (I), (Ia), (Ib), and (Ic), n is 0, Z is C, R4 is selected from hydrogen and methyl; R 5 is selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl, and R 6 is 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; It is a compound represented by the formula:

[0032] Further non-limiting examples include (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(1,2,3-thiadiazol-5-yl)methanone, (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(thietan-3-yl)methanone, (2,2-dimethylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-ethoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-methoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-methylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (E)-1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-2-en-1-one, (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one, (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pent-3-en-1-one, (R)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1-((S)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-methyl-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,(Tetrahydrofuran-3-yl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,2-difluorobenzo[d][1,3]dioxole-5 -yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,3-dihydrobenzofuran-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,3-dihydrobenzofuran-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,5-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-cyclopropyloxazol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-cyclopropyloxazol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2 -(methylthio)propan-1-one, 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-((dimethylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(4-(3,5-dimethylisoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-chloro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-((1,1-dioxide 1-(2-(4-(4-(difluoromethoxy)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(difluoromethyl)thio)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(difluoromethyl)thio)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(difluoromethyl)thio)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(tert-butyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(tert-butyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(4-(4-isopropylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-methyl-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-((dimethylamino)methyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one -2-(Methylthio)propan-1-one, 1-(2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-((trifluoromethyl)thio)ethan-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-diene 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(5-(2,3-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(5-(2,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-methoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-(methylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-3-en-1-one, 1-(2-(5-(3,4-dimethoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-methoxyisothiazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(5-(4-((methylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(aminomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(dimethylamino)phenyl)-1H -imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-acetylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-aminophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-chloro-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine-1-yl)-2-(methylthio)propan-1-one Lysin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-methoxy-2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(5-(5-(methoxymethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(benzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one -one, 1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(5-benzyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzyl benzonitrile, 2-(2-(4-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile, 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(allylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile 2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(ethylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan-2-yl, )-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(furan-3-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan-3-yl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylamino)-N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5 -yl)phenyl)acetamide, 2-(methylsulfinyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(2-(p-tolyl)-2H-tetrazole, 2-(methylthio)-1-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl) propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,2-(methylthio)-1-(2-(4-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(quinoxalin-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(2,3,4-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)ethan ... 2-(methylthio)-1-(2-(5-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,2-(methylthio)-1-(2-(5-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1,3 ,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)azepan-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)isoxazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)thiaz ...phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, p-tolyl)-1-(2-(5-phenyl-1H-imidazol-2-yl)pyrrolidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyloxazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(4-(5-(p-tolyl)-1H-imidazol-2-yl)thiazolidin-3-yl)propan-1-one,2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one ) butan-1-one, 2,3-dimethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2,3-dimethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,5-difluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile, 2-amino-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one propan-1-one, 2-cyclobutyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-cyclopentyl-2-ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one -one, 2-cyclopropyl-2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-ethoxy-1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one, 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,2-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile, 2-mercapto-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Methoxy-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2-methyl-1-( 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butane-1,3-dione, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pentan-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)prop-2-en-1-one, 2-methyl-1-(2 -(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-3-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methylene-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,3-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile, 3,3,3-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 3,3,4,4,4-pentafluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 3,3-difluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Tan-1-one, 3-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile, 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one, 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile aryl, 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde, 4,4,4-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, bicyclo[1.1.1]pentan-1-yl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, cyclobutyl(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl) methanone, cyclopentyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, cyclopropyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, methyl 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoate, N-(2-hydroxyethyl)-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzenesulfonamide,2-(methylthio)-1-(2-(5-(3-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methanesulfonamide, 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(sec-butylsulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2 -yl)piperidine, 1-(sec-butylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-(isopropylsulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-(isopropylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-(isopropylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-((1-(methylthio)ethyl)sulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-((1-(methylthio)ethyl)sulfonyl)-2- (5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-((2-(methylthio)propan-2-yl)sulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-((2-(methylthio)propan-2-yl)sulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-(but-3-en-2-ylsulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-(but-3-en-2-ylsulfonyl)-2-(5-(p -tolyl)-1H-imidazol-2-yl)piperidine, 1-(pent-3-en-2-ylsulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-(pent-3-en-2-ylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-((2-methylbut-3-en-2-yl)sulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-((2-methylbut-3-en-2-yl)sulfonyl)-2-(5-(p-tolyl, )-1H-imidazol-2-yl)piperidine, 1-(2-(5-(4-(hydroxymethyl)-phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)-propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(4-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(3-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(4-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,1-(3-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde, 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid, 4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzo Fragrance, (2,2-dimethylcyclopropyl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl) Acetonitrile, 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2,3-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5-(o-tolyl)-1H-imidazol-2-yl)piperidine-1 -yl)butan-1-one, 2-methyl-1-(2-(5-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(isopropylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, 1-(sec-butylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,The compound is represented by formula (I), (Ia), or (Ib), and is selected from the group consisting of 2-methyl-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperazin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, and 2-methyl-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)butan-1-one.

[0033] The compounds as defined by formula (I) (which encompasses compounds represented by formulae (Ia), (Ib), and (Ic)) contain several chiral centers (two of which are indicated by * in each formula) and may themselves exist as a mixture of stereoisomers, or these may be resolved into isomerically pure forms. Because resolving stereoisomers would add to the complexity of the manufacture and purification of these compounds, it is preferred, solely for 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). Compounds as defined by Formula (I), which encompasses compounds represented by Formulas (Ia), (Ib), and (Ic), may also exist in various tautomeric forms, including enol-keto, lactam-lactim, amide-imidic acid, amine-imine, and 1H-imidazole-3H-imidazole forms. Accordingly, the chemical structures depicted herein encompass all viable stereoisomeric and tautomeric forms of the depicted compounds.

[0034] It is also noted that compounds as defined by Formula (I), which encompasses compounds represented by Formulas (Ia), (Ib), and (Ic), 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 equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

[0035] "Solvate" refers to a compound formed by solvation (combination of solvent molecules with solute molecules or ions) or an aggregate consisting of solute ions or molecules, i.e., a compound as defined by Formula (I) with one or more solvent molecules (this encompasses compounds represented by Formulas (Ia), (Ib), and (Ic)). When water is the solvent, the corresponding solvate is a "hydrate." Further suitable solvents may 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.

[0036] "Salt" refers to a salt of a compound as defined by Formula (I) (which encompasses compounds represented by Formulas (Ia), (Ib), and (Ic)) that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or 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 coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

[0037] Compounds as defined by formula (I), which encompasses compounds represented by formulas (Ia), (Ib), and (Ic), are "TRPM8 agonists," meaning that they act to stimulate 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) (which is also described in more detail in the experimental part).

[0038] Accordingly, in 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. In one embodiment of the second aspect of the invention, the modulating method is an in vitro method.

[0039] 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) and (Ic)), or a salt or solvate thereof.

[0040] In some embodiments, 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.

[0041] The compounds of formula (I), which encompass compounds of formulas (Ia), (Ib), and (Ic), 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.

[0042] In a fourth aspect, there is provided a consumer product comprising a compound as defined by formula (I) (which encompasses compounds represented by formulae (Ia), (Ib), and (Ic)), in particular said consumer product intended to be brought into contact with human skin and / or mucous membranes.

[0043] Consumer products that come into contact with mucous membranes include, but are not limited to, food products, beverages, chewing gum, tobacco and tobacco substitute products, dental care products, personal care products (including lip care products, sexual health and intimate care products).

[0044] In some embodiments, the dental care product is an oral care product, a tooth care product, a dental prosthesis cleaner, a dental prosthesis adhesive, or the like.

[0045] 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.

[0046] In some embodiments, the tobacco substitute product is a liquid or solid suitable for consumption by electrical means, such as liquids to vape an electronic cigarette. In some embodiments, the personal care products that are brought into contact with the mucous membrane are balms, nasal sprays, and eye drops.

[0047] Consumer products that come into contact with human skin include, but are not limited to, cosmetic products. In some embodiments, cosmetic products are skin care products, particularly bath products, skin washing and cleansing products, skin care products, eye makeup, nail care products, foot care products, etc. In some embodiments, cosmetic products are products with specific benefits, particularly sunscreens, insect repellents, tanning products, bleaching products, deodorants, antiperspirants, depilatories, and shaving products. In some embodiments, cosmetic products are hair care products, particularly hair shampoos, hair care products, hair styling products, hair-shaping products, and hair color products, as well as scalp care products such as cooling shampoos and creams.

[0048] 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.).

[0049] 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 will depend primarily on the particular function that such consumer product is to accomplish, such as cleaning, softening, caring, cooling, etc.

[0050] In some embodiments, the consumer product that is contacted with human skin is a fabric care product (such as a fabric detergent, fabric conditioner (including tumble dryer sheets), and scent booster (liquid or solid)) that is applied to fabrics in a first step (e.g., when the fabrics are washed), and the treated fabrics are then contacted with human skin.

[0051] The use level of the compounds of the present invention (compounds as defined by Formula (I), which encompasses compounds represented by Formulas (Ia), (Ib), and (Ic)) 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) by weight of the composition; 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). When the compounds of the present invention are used in mouthwashes, the level of use 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.

[0052] The cooling potency (strength) of a compound depends on its EC 50 Defined by the value EC 50 EC (half effective concentration) refers to the concentration of a compound that induces a response halfway between baseline and maximum after a specified exposure time. It is commonly used as a measure of efficacy. 50 is a measure of concentration expressed in μM (micromolar concentration), where 1 μM is equivalent to 1 μmol / L.

[0053] EC 50 Compounds with an EC below 10 μM are perceived by humans as cooling. 50 The lower the value, the greater the cooling effect. For example, an EC of approximately 0.1 μM50 Compounds with this value are perceived as strong cooling compounds.

[0054] 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 perceived. Longevity can range from a few minutes to several hours or even days after rinsing. In the context of oral care products, a desirable "long-lasting" effect typically lasts between 20 minutes and 3 hours after rinsing.

[0055] Compounds defined by formula (I) (which encompasses compounds represented by formulas (Ia), (Ib), and (Ic)) 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 known to those skilled in the art, cis / trans isomers and / or diastereomers may have different solubility properties, and therefore, either a mixture of isomers or individual isomers may be selected for use in consumer products depending on the cooling effect to be exerted.

[0056] The compounds of formula (I) (which encompasses compounds of formulae (Ia), (Ib), and (Ic)) are extremely 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 compounds of formulae (Ia), (Ib), and (Ic)). However, other solvent systems containing surfactants may also be used.

[0057] In order to modify the cooling effect of a compound as defined herein by formula (I), which encompasses compounds represented by formulas (Ia), (Ib), and (Ic), 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.

[0058] These compounds are known to be able to modulate the concentrations of such ions in the extracellular space, thus affecting the response of the TRPM8 ion channel and leading to changes in the perceived cooling effect.

[0059] 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 a potentiating agent as disclosed in WO2019 / 121193 (which is incorporated by reference, particularly with regard to potentiating agents).

[0060] 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 is incorporated by reference).

[0061] The compounds of formula (I), which encompasses compounds of formulas (Ia), (Ib), and (Ic), may be used in combination with other cooling compounds known in the art.

[0062] 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.

[0063] In a specific embodiment, the compound of formula (I) (which encompasses compounds of formulae (Ia), (Ib), and (Ic)) is selected from the group consisting of menthol (e.g., in the form of peppermint oil and / or spearmint oil), menthone, p-menthanecarboxamide, 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), and the like. P), monomenthyl succinate (Physcool®), monomenthyl glutarate, o-menthylglycerol, 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)-2-methoxyphenol, 4-(2-(4-allyl) ... N-(4-allyl-2,6-dimethoxyphenoxy)-1-((2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol (including 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-(((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol and 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-5,5-dimethylcyclohexane-1-carboxamide, N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide, and N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide.

[0064] 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 2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexane-1-carboxamide (commercially known as Evercool 180). 190), as well as compounds such as (1R,2S,5R)-N-((S)-2-((R)-2-aminopropanamido)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide.

[0065] To provide more than just a cooling effect, the compounds of formula (I) (which encompasses compounds of formulas (Ia), (Ib) and (Ic)), salts or solvates thereof may be combined with other actives such as flavors, fragrances and sweeteners.

[0066] 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.

[0067] 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, thuja 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, and 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, and papaya), and the like.

[0068] Additional exemplary flavors delivered by the flavoring composition include milk flavor, butter flavor, cheese flavor, cream flavor, and yogurt flavor; vanilla flavor; tea or coffee flavor, such as green tea flavor, oolong tea flavor, tea flavor, cocoa flavor, chocolate flavor, and coffee flavor; mint flavor, such as peppermint flavor, spearmint flavor, and mint flavor; agi flavor, ajowan flavor, anise flavor, angelica flavor, fennel flavor, allspice flavor, cinnamon flavor, chamomile flavor, mustard flavor, cardamom flavor, caraway flavor, cumin flavor, clove flavor, pepper flavor, coriander flavor, sassafras flavor, savory flavor, Zanthoxyli Fructus flavor, perilla flavor, juniper berry flavor, ginger flavor, star anise flavor, horseradish flavor, thyme flavor, tarragon flavor, dill flavor, chili pepper flavor, nutmeg flavor, basil flavor, marjoram flavor, rosemary flavor, bay leaf flavor, and wasabi (Japanese horseradish) flavor; nut flavors such as almond flavor, hazelnut flavor, macadamia nut flavor, peanut flavor, pecan flavor, pistachio flavor, and walnut flavor; alcoholic flavors such as wine flavor, whiskey flavor, brandy flavor, rum flavor, gin flavor, and liqueur flavor; floral flavors; and vegetable flavors such as onion flavor, garlic flavor, cabbage flavor, carrot flavor, celery flavor, mushroom flavor, and tomato flavor.

[0069] Generally, any flavoring or food additive (including food colorants) may be used, such as those described in "Essential guide to food additives" by Leatherhead Food International Ltd., Third edition 2008, pages 101-321 (ISBN: 978-1-905224-50-0), which publication is incorporated herein by reference.

[0070] In a specific embodiment, the compound of formula (I) (which encompasses compounds of formulas (Ia), (Ib), and (Ic)) is selected from the group consisting of anethole, laevomenthol, laevocarvone, ethyl maltol, vanillin, eucalyptol, eugenol, racemic menthol, cis-3-hexenol, linalool, mint oil (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, cis-jasmone, ethyl hexanoate, melonal (2,6-dimethylhept-5-enal), citronellol, ethyl acetoacetate, nutmeg oil, and clove oil, or mixtures thereof.

[0071] In a particular embodiment, the compound of formula (I) is 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (including (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, or a racemic mixture), 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2 -(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2-(methylthio)-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, and 2-methyl-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)butan-1-one, or mixtures thereof.

[0072] Examples of sweeteners 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, na Lingin dihydrochalcone, mogroside V, Monk fruit extract, rubusoside, Rubus extract, glycyphyllin, isomogroside V, mogroside IV, siamenoside I, neomogroside, mukuroziosid IIb, (+)-hernandulcin, 4β-hydroxyhernandulcin, baionoside, phlomisoside I, bryodulcoside, bryoside, bryonoside, abru Sosides A-E, cyclocarioside A, cyclocaryoside I, albiziasaponins A-E, glycyrrhizin, aboglycyrrhizin, periandrins I-V, pterocaryosides A and B, osladin, polypodosides A and B, telesmosides A8-18, phyllodulcin, huangqioside E, neoasci These compounds 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.

[0073] In certain embodiments, the compounds of Formula (I) may be combined with additional ingredients collectively referred to as orally acceptable carrier materials.

[0074] 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 can be mixed together without interacting in a manner that would substantially reduce stability and / or efficacy. Carriers may include the usual and conventional components of dentifrices, non-abrasive gels, subgingival gels, mouthwashes or rinses, mouth sprays, chewing gum, lozenges, and breath mints. The choice of carrier to be used is primarily determined by the form in which the composition will be introduced into the oral cavity. Carrier materials for toothpastes, tooth gels, or the like, include, for example, abrasives, sudsing agents, binders, humectants, flavoring agents, sweetening agents, and the like, as disclosed in U.S. Patent No. 3,988,433 to Benedict. Carrier materials for two-phase dentifrice formulations are all disclosed in U.S. Patents 5,213,790; 5,145,666; and 5,281,410 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 a candy base; carrier materials for chewing gums typically include a 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 sweetening agents. For subgingival gels used to deliver 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 shelf life.

[0075] 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.

[0076] Scientific literature indicates that activating the TRPM8 channel may be useful for treating most TRPM8-mediated pathological conditions (J.Med.Chem.2016,59(22),10006-10029). Therefore, it can be inferred that the compound 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 compound of formula (I) as defined herein may be suitable for relieving the symptoms of coughs and colds, irritability, sore throat, or hoarseness, and for treating pharyngeal dysphagia (Int.J.Mol.Sci.2018,19,4113).

[0077] Thus, in a sixth aspect, there is provided a pharmaceutical composition comprising one or more compounds as defined by formula (I) (which encompasses compounds of formulae (Ia), (Ib), and (Ic)), or a salt or solvate thereof.

[0078] 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.

[0079] In some embodiments, the pharmaceutical composition is a nasal spray, a topical cream, a skin spray, a throat spray, or eye drops.

[0080] Although some such compounds are known from the literature, other compounds falling within the definition of formula (I) as defined herein above have not been described in the literature and are therefore novel per se.

[0081] Thus, in a further aspect of the invention, a compound of formula (Ib) [ka] During the ceremony n is 0 or 1; R 1 is selected from: i) C6 aryl or heteroaryl, where up to two C atoms are replaced by N atoms, and is selected from the group consisting of halogen, OH (hydroxyl), C≡N (cyano), NO2 (nitro), C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkoxy containing up to three halogen atoms, C1-C3 alkoxy, C1-C3 alkyl, C3-C7 cycloalkyl, -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 (where R 25 is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 (where R 26 is C1-C3 alkyl), or where R 23 and R 24together 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)R 28 (where R 28 is selected from hydrogen and C1-C3 alkyl) (provided that one substituent is selected from the group consisting of R 1 is attached in the para position relative to the attachment to the other moieties of formula (Ib) (e.g., R 1 is a para-trill); and ii) Thiophene, but not including halogen; OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl; C1-C6 alkyl containing up to five halogen atoms; C2-C6 alkenyl; C1-C6 alkoxy; C1-C6 alkoxy containing up to three halogen atoms; C1-C3 alkoxy C1-C3 alkyl; C3-C7 cycloalkyl; -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 (where R 25 is C1-C3 alkyl, and R 24 is hydrogen, C1-C3 alkyl, and -SO2R 26 (where R 26 is C1-C3 alkyl), or where R 23 and R 24together 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)R 28 (where R 28 is selected from hydrogen and C1-C3 alkyl); A is a 5-7 membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen and sulfur, wherein the heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =O; Z is either C, S, or S(O); X 1 is NH, O, or S; X 2 and X 3 are independently selected from C, N, and O, with the proviso that X 2 or X 3 Either is not C; R 4 is selected from hydrogen and methyl; R 5 is selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl; R 6 is 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-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl (e.g., 2-furyl or 3-furyl), but optionally methyl, C1-C6 fluoro-alkyl (such as pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, or difluoroethyl), and -NR 30 R31 (where R 30 and R 31 are substituted with independently selected from hydrogen and C1-C3 alkyl; or R 6 and R 5 are carbonyl groups (C=O), vinyl groups (C=CR), and the like, along with the carbon atoms to which they are attached. 32 R 33 , where R 32 and R 33 are independently selected from H or C1-C3 alkyl), or form 2,2-dimethylcyclopropyl; However, R 5 and R 6 comprises, together with the carbon atom to which they are attached, at least 4 C atoms (for example 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 C atoms), wherein one C atom is optionally replaced by one heteroatom selected from S and N, The compound is represented by the formula:

[0082] Compounds of formula (I) may generally be prepared by reacting a secondary amine of type 2 with a suitable reaction partner 3. When the reaction partner is an acyl halide, sulfonyl halide, or sulfinyl halide (e.g., the halide is chloride, bromide, or fluoride) (3a), the reaction can occur in a suitable solvent (e.g., dichloromethane, water, dioxane, N,N-dimethylformamide, tetrahydrofuran) or under solvent-free conditions in the presence of a base such as an organic base (e.g., triethylamine, diisopropylethylamine) or an inorganic base (e.g., potassium carbonate, potassium phosphate, sodium bicarbonate, sodium hydroxide). When the reaction partner is carboxylic acid 3b, the reaction can take place in a suitable solvent such as N,N-dimethylformamide or dichloromethane utilizing an amide-coupling reagent (e.g., dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or EDCI), or its hydrochloride salt, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl)), a nucleophilic mediator (e.g., 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole (HOBt)), and an organic base (e.g., triethylamine, diisopropylethylamine). In some cases, the amide coupling reagent and nucleophilic mediator can be combined into a single commercially available reagent, such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) or N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU). Other conditions for functionalization of amine 2, known to those skilled in the art of organic synthesis, can also be employed. [ka]

[0083] Secondary amine 2 can be prepared by deprotection of its carbamate-protected form (4). When the carbamate is tert-butyl carbamate (PG = Boc group = tert-butoxycarbonyl), this deprotection can be achieved by treating 4 with an acid (e.g., a protic acid such as trifluoroacetic acid or hydrochloric acid) in a suitable solvent such as dichloromethane. When the carbamate is benzyl carbamate (PG = Cbz group = benzyloxycarbonyl), this deprotection can be achieved through hydrogenolysis of the benzyl group by exposing 4 to hydrogen gas (typically at atmospheric pressure, but sometimes also at higher pressures) in the presence of a hydrogenation catalyst (such as palladium on charcoal) and a suitable solvent (such as tetrahydrofuran, ethyl acetate, ethanol, or methanol). Other conditions for the deprotection of carbamate 4 known to those skilled in the art of organic synthesis can also be employed. It should be noted that the use of a protecting group for the secondary amine may not always be necessary, as the secondary amine may be orthogonal to other functional groups present in the compound, allowing for direct preparation in its unprotected form. Protection is explicitly mentioned here because it provides a more generally applicable synthetic methodology. [ka]

[0084] Preparation of 4 may be achieved by cross-coupling reaction (e.g., Suzuki cross-coupling) of heterocyclic halide 5 with an organometallic compound, such as an organoboron compound of type 6 (note that -B(pin) is a 4,4,5,5-tetramethyl-1,3,2-dioxaborolyl group), or similar organotin, zinc, or magnesium compound. This is typically achieved by reacting 5 with 6 or a similar compound in the presence of a transition metal catalyst (often a palladium or nickel catalyst), such as palladium acetate or tris(dibenzylideneacetone)-dipalladium (Pd2(dba)3), often in conjunction with a suitable ligand (typically a phosphine-based ligand, such as triphenylphosphine or 1,1'-bis(diphenylphosphino)ferrocene (dppf)). The metal catalyst and ligand can be added to the reaction in the form of a preformed complex, such as tetrakis(triphenylphosphine)palladium(0) complex or 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex. The reaction is typically carried out in the presence of a base, typically an inorganic base (such as sodium carbonate, potassium carbonate, or cesium carbonate), and a suitable solvent system, typically a mixture of water and an organic solvent (such as tetrahydrofuran or dioxane), although a single solvent system may also be suitable. The reaction is usually carried out at elevated temperatures (e.g., 80°C or 100°C), often under an atmosphere of an inert gas such as dinitrogen or argon. Other conditions for the cross-coupling of halide 5 with organometallic compound 6 or similar compounds, known to those skilled in the art of organic synthesis, can also be employed. [ka]

[0085] Halides of type 5 can be prepared by halogenation of heterocycle Y. This is typically done by exposing heterocycle 6 to a halogenating agent such as bromine, chlorine, iodine, N-bromosuccinimide, N-chlorosuccinimide, or N-iodosuccinimide in a suitable solvent such as dichloromethane or chloroform. In some cases, the reaction can lead to over-halogenation, illustratively producing a compound bearing two halogen atoms on heterocycle Y. In this case, selective removal of the undesired halogen is achieved by exposing the resulting over-halogenated intermediate to a reducing agent such as sodium sulfite or sodium thiosulfate at elevated temperature (e.g., 100°C) in a suitable solvent such as an ethanol / water mixture. [ka]

[0086] The formation of heterocycle Y in compounds 6 and 4 can be achieved in a number of ways by applying synthetic strategies known to those skilled in the art.

[0087] By way of illustration, imidazole 7 may be prepared by reaction of aldehyde 8 with a C2 building block (such as glyoxal) in a suitable oxidation state and an ammonia source (such as aqueous ammonia). The reaction is carried out in a suitable solvent, such as methanol, at a suitable temperature, such as, but not limited to, ambient temperature. Those skilled in the art will recognize that by extending the C2 building block to a variety of 1,2-dicarbonyl compounds, this preparative methodology allows for the production of more substituted imidazoles of type 4 (where Y is imidazole). [ka]

[0088] Oxazoles of type 9 may be prepared in two steps starting with amide bond formation from carboxylic acid 10 and a suitable primary amine 11 (which may be taken as a salt, e.g., hydrochloride salt) under conditions similar to those described for the preparation of (I) from 3b above. The resulting amide intermediate may then be subjected to dehydrative condensation by reacting it with a dehydrating agent such as phosphoryl chloride (POCl) or sulfuric acid in a suitable solvent such as MeCN at elevated temperatures (e.g., 80-100°C). [ka]

[0089] Furthermore, the amide intermediate prepared by coupling of carboxylic acid 10 with amine 11 can be directly converted to imidazole 4 by exposing it to an ammonia source (such as ammonium acetate or ammonium carbonate) at elevated temperature (e.g., 100°C, 140°C, or 160°C) in a suitable solvent such as toluene or xylene, optionally catalyzed by an acid additive such as acetic acid or propionic acid.

[0090] Oxadiazoles of type 12 may be prepared in two steps starting with amide bond formation from carboxylic acid 10 and a suitable hydrazide 13 (which may be taken as a salt, e.g., the hydrochloride salt) under conditions similar to those described for the preparation of (I) from 3b above. The resulting intermediate may be subjected to dehydrative condensation by reacting it with a dehydrating agent such as p-toluenesulfonyl chloride (TsCl) in a suitable solvent such as acetonitrile, often in combination with a base (e.g., an amine base such as triethylamine or diisopropylethylamine) at a suitable temperature (e.g., 0°C or room temperature). [ka]

[0091] Isoxazole 14 can be prepared by 1,3-dipolar cycloaddition between alkyne 15 and the nitrile oxide obtained from aldehyde 8. Aldehyde 8 is typically first reacted with hydroxylamine, which can be used as the free base or as a salt (e.g., hydrochloride), in which case a base (e.g., an inorganic base such as sodium carbonate or potassium carbonate) is added. The reaction is carried out in a suitable solvent, such as a mixture of ethanol and water or a mixture of methanol and water, at a suitable temperature (e.g., between 0°C and room temperature). The oxime formed is then oxidized by reacting it with a suitable oxidizing agent, such as N-chlorosuccinimide, chlorine, or diacetoxyiodobenzene, in a suitable solvent, such as N,N-dimethylformamide or tetrahydrofuran, at a suitable temperature (e.g., 40°C or room temperature). The resulting intermediate can then be exposed to a base, such as an organic base (illustratively, triethylamine or diisopropylethylamine) or an inorganic base, in a suitable solvent such as dichloromethane or tetrahydrofuran, and reacted in the presence of alkyne 15. [ka]

[0092] Triazole 16 can be prepared by reacting nitrile 17 with a suitable hydrazide 13 (which may be taken as a salt, for example, the hydrochloride salt) in the presence of a base, such as an inorganic base (for example, potassium carbonate or sodium carbonate), in a suitable solvent, such as ethanol or butanol, typically at elevated temperatures (for example, 70°C or 120°C). [ka]

[0093] Thiazoles of type 18 are obtained in a similar manner to oxazoles of type 9, but can be prepared from acids 10 and amines 11 by subjecting the intermediately formed amide to a sulfur source such as 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (Lawesson's reagent) or 2,4-bis(p-tolylthio)-1,3,2,4-dithiadiphosphetane 2,4-disulfide in a suitable solvent such as tetrahydrofuran, dichloromethane, or toluene at a suitable temperature (e.g., 40°C, 70°C, or 100°C). [ka]

[0094] Nitrile 17 can be prepared from aldehyde 8 by condensing it with hydroxylamine, which can be used as its salt (e.g., hydrochloride), or in the case of the salt, by adding a base (e.g., an inorganic base such as sodium carbonate or potassium carbonate) in a suitable solvent such as a mixture of water and ethanol or a mixture of water and methanol at a suitable temperature (e.g., between 0°C and room temperature). The resulting oxime can then be dehydrated, illustratively by reaction with catalytic copper(II) acetate in a suitable solvent such as acetonitrile at elevated temperature (e.g., 70°C or 80°C). Other conditions for the conversion of aldehyde 8 to nitrile 17 known to those skilled in the art of organic synthesis can also be employed.

[0095] Aldehydes of type 8 can be prepared from acids of type 10 by selective reduction. This is typically done in a two- or three-step protocol, first reacting acid 10 with an activating agent such as thionyl chloride, oxalyl chloride (with the addition of catalytic N,N-dimethylformamide), or carbonyldiimidazole in a suitable solvent (such as, but not limited to, dichloromethane or tetrahydrofuran) or under solvent-free conditions at a suitable temperature (0°C to 100°C, depending on the activating agent). The activated acid is then, either in the same step or in a separate step, exposed to N,O-dimethylhydroxylamine (optionally in its salt form, e.g., as the hydrochloride salt) in a suitable solvent such as dichloromethane or tetrahydrofuran, optionally in the presence of a base, illustratively an inorganic base (such as sodium carbonate or potassium carbonate) or an organic base (such as triethylamine, pyridine, or diisopropylethylamine), at a suitable temperature (e.g., 0°C or room temperature). The resulting amide can then be selectively reduced by reaction with a reducing agent (such as, but not limited to, lithium aluminum hydride or diisobutylaluminum hydride) in a suitable solvent such as tetrahydrofuran or dichloromethane at a suitable temperature (-78°C, -20°C, 0°C, or room temperature).

[0096] Hydrazides 13 can be prepared from simple esters 19 by reacting them with a hydrazine source such as hydrazine monohydrate in a suitable solvent such as ethanol or methanol at a suitable temperature (e.g., 70°C or 80°C). [ka]

[0097] It should be added that a different order of steps is also possible and may be advantageous in some cases. For example, the formation of the amide described for the formation of (I) may be carried out first (i.e., formation of the NZ bond), followed by the steps used for the installation of the aromatic heterocycle Y. As those skilled in the art will appreciate, this also obviates the need for a protecting group for the secondary amine.

[0098] Furthermore, it should be mentioned that certain sensitive functional groups may be kept in protected or masked form throughout the preparative sequence and removed at the end of the synthetic sequence by standard methods known to those skilled in the art.

[0099] In Equations 2-19 depicted in the reaction scheme above, the parameters A, Y, Z, n, and R 1 , R 4 , R 5 , and R 6 has the same meaning as defined for formula (I) (which includes compounds of formulae (Ia), (Ib), and (Ic)).

[0100] The present invention will now be further described with reference to the following non-limiting examples, which are illustrative only and it will be understood that variations and modifications may occur to those skilled in the art.

[0101] example Example 1: tert-Butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate Example 1a: 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 room temperature and stirred at room temperature 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 (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).

[0102] Example 1b: 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).

[0103] Example 1c: 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 NaSO (94 g, 748 mmol) in ethanol (300 mL) and water (300 mL) was refluxed overnight. It was then cooled and concentrated. The residue was partitioned between CHCl (200 mL) and HO (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 NaSO, filtered, and evaporated. The residue was purified by column chromatography on silica gel to afford 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).

[0104] Example 2: 1-(2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Example 2a: tert-butyl-2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate: A mixture of tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (300 mg, 0.91 mmol), (2-fluoro-4-methylphenyl)boronic acid (182 mg, 1.18 mmol), sodium carbonate (193 mg, 1.82 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (37 mg, 0.045 mmol) in tetrahydrofuran (9 mL) and water (1.5 mL) was stirred and refluxed overnight under an argon atmosphere. The reaction completion was monitored by TLC. The mixture was cooled to room temperature, and the reaction solution was poured into water (30 mL) and extracted with MTBE (methyl tert-butyl ether) (30 mL). The combined organic layers were washed once with brine (30 mL), dried over MgSO, filtered, and concentrated. The crude oil was purified by silica gel chromatography (hexane:MTBE=5:1) to afford tert-butyl-2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (300 mg, yield: 92%) as a white solid. GC / MS(EI):m / z(%):359(5)[M + ],303(18),258(35),242(18),203(100),190(15),177(6),134(6),84(3),57(14).

[0105] Example 2b: 1-(2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one: a) To a solution of tert-butyl-2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (300 mg, 0.835 mmol) in dichloromethane (20 mL) was added 2,2,2-trifluoroacetic acid (761 mg, 6.68 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 (20 mL) was added, and extracted with EA (ethyl acetate) (40 mL*3), and the organic phase was concentrated to give 2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)piperidine as a pale yellow oil (111 mg, 0.925 mmol).

[0106] b) To a solution of 2-(methylthio)propanoic acid (111 mg, 0.925 mmol) in dichloromethane (20 mL) was added HOBt (1-hydroxybenzotriazole hydrate) (142 mg, 0.925 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (144 mg, 0.925 mmol) at 0-5°C, and the mixture was stirred at rt for 0.5 h. Then, 2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidine (200 mg, 0.771 mmol) and DIPEA (N,N-diisopropylethylamine) (0.269 mL, 1.54 mmol) were added, and the mixture was stirred at rt for 16 h. The mixture was filtered to remove the solvent and purified by silica gel chromatography (hexane:MTBE=3:1) to give 1-(2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (200 mg, yield: 72%) as a white solid. GC / MS(EI):m / z(%):361(8)[M + ],346(6),315(2),286(9),258(100),231(13),203(16),177(5),103(2),75(8). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.19,11.96(brs,1H),8.05-7.58(m,1H),7.47-7.16(m,1H),7.12-6.94(m,2H), 5.82-5.44(m,1H),4.55-2.97(m,3H),2.69-2.14(m,1H),2.31(s,3H),2.10-1.95(m,3H),1.93-1.47(m,5H),1.44-1.31(m,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.8(q), 170.3(q), 170.0(q), 160.7(q), 157.4(q), 146.9(q), 146.8(q), 146.6(q), 137.6(q), 137.5(q), 137.4(q), 133.9(q), 133.8(q), 133.4(q), 127.4(t), 125.4(t), 119.9(q), 119.8(q), 116.4(t), 116 .3(t),116.1(t),115.9(t),51.4(t),47.2(t),46.9(t),43.2(d),43.0(d),38.8(d),37.9(t),37.6(t),37.3(t),28.5(d),2 8.1(d),27.9(d),26.0(d),25.7(d),25.4(d),20.9(s),20.3(d),20.1(d),18.2(s),17.9(s),17.8(s),11.8(s),11.6(s)ppm.

[0107] Example 3: 1-(2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (2,4-difluorophenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):365(8)[M + ],350(5),319(3),290(11),262(100),235(11),207(24),75(9). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.52-12.03(m,1H),8.34-7.57(m,1H),7.53-7.03(m,3H),5.91 -5.47(m,1H),4.67-3.04(m,3H),2.81-2.18(m,1H),2.15-1.97(m,3H),1.93-1.52(m,5H),1.49-1.32(m,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.3(q), 170.1(q), 169.8(q), 162.5(q), 162.3(q), 160.6(q), 160.5(q), 159.2(q), 159.0(q), 157.3(q), 157.2(q), 148.1(q), 147.9(q), 147.2(q), 147.1(q), 146.9(q), 133.0(q), 132.9(q), 132.6(q), 132.3(t), 132.2(t), 128.7(t), 128.6(t), 128.5(t), 119.6(q), 119.4(q), 116 .6(t),116.4(t),116.2(t),116.1(t),116.0(t),112.1(t),111.8(t),104.7(t) ,104.6(t),104.4(t),104.0(t),51.4(t),47.2(t),46.9(t),43.2(d),43.0(d),3 8.8(d),37.9(t),37.6(t),37.3(t),28.5(d),28.1(d),28.0(d),26.0(d),25.6(d ),25.4(d),20.2(d),20.1(d),18.1(s),17.9(s),17.8(s),11.7(s),11.6(s)ppm.

[0108] Example 4: 3-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-cyano-2-fluorophenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):372(9)[M + ],357(10),326(6),297(11),269(100),75(16). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.49,12.37(brs,1H),8.36-8.09(m,1H),7.88-7.84(m,1H),7.76-7.55(m ,2H),5.82-5.32(m,1H),4.54-3.00(m,3H),2.68-2.31(m,1H),2.14-1.92(m,3H),1.89-1.49(m,5H),1.46-1.32(m,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.4(q), 170.1(q), 159.8(q), 156.5(q), 148.2(q), 148.0(q), 147.9(q), 132.3(q), 129.4(t), 129.3(t), 128.3(t), 128.3(t), 127.9(q), 127.8(q), 120.1(t), 119.8(t), 119.5(t), 119.3(t), 118 .6(q),109.0(q),108.9(q),51.4(t),47.2(t),46.9(t),43.2(d),43.0(d),38.9(d),37.7(t),37.6(t),37.3(t),28.5( d),28.0(d),27.8(d),25.9(d),25.6(d),25.4(d),20.2(d),20.0(d),18.1(S),17.9(S),17.8(S),11.7(S),11.6(S)ppm.

[0109] Example 5: 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-chlorophenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):363(8)[M +],348(5),317(4),288(10),260(100),233(9),75(11). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.21,12.14,11.92(brs,1H),7.91-7.74(m,2H),7.73-7.57(m,1H),7.52-7.2 7(m,2H),5.79-5.42(m,1H),4.57-2.99(m,3H),2.72-2.16(m,1H),2.13-1.97(m,3H),1.93-1.50(m,5H),1.46-1.30(m,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.3(q), 170.1(q), 147.5(q), 147.4(q), 147.2(q), 139.2(q), 139.1(q), 134.3(q), 134.2(q), 130.6(q), 130.5(q), 128.8(t), 126.3(t), 114.2(t), 113.9(t), 113.7(t) ,51.5(t),47.3(t),47.0(t),43.2(d),43.0(d),38.8(d),38.0(t),37.6(t),37.3(t),28.5(d),28.1(d),2 7.9(d),26.0(d),25.6(d),25.4(d),20.3(d),20.1(d),18.2(s),17.9(s),17.8(s),11.8(s),11.7(s)ppm.

[0110] Example 6: 1-(2-(5-(3,4-dimethoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (3,4-dimethoxyphenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):389(10)[M + ],374(5),314(5),286(100),259(14),231(11),75(9). 1H NMR (300 MHz, CDCl3, mixture of stereoisomers and tautomers) δ 11.97, 11.73 (brs, 1H), 7.49-7.15 (m, 3H), 6.98-6.90 (m, 1H), 5.76-5.40 (m, 1H), 4.40-3.11 (m, 9H), 2.51-2.15 (m, 1H), 2.05-2.03 (m, 3H), 1.93-1.49 (m, 5H), 1.45-1.31 (m, 3H) ppm.

[0111] Example 7: 1-(2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (3-fluoro-4-methylphenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):361(8)[M + ],346(5),315(2),286(8),258(100),231(11),203(17),75(8). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.10-11.88(m,1H),7.63-7.17(m,4H),5.79-5.42(m,1H),4 .49-3.00(m,3H),2.67-2.33(m,1H),2.22(s,3H),2.12-1.95(m,3H),1.94-1.49(m,5H),1.44-1.28(m,3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 169.9 (q), 169.7 (q), 162.6 (q), 159.4 (q), 146.9 (q), 146.7 (q), 146.6 (q), 138.8 (q), 135.1 (q), 135.0 (q), 131.6 (t), 131.5 (t), 121.3 (q), 121.0 (q), 119.9 (t), 119.9 (t), 113.7 (t), 113.3 (t), 113.2 (t), 110.5 ( t),110.2(t),51.1(t),46.9(t),46.6(t),42.8(d),42.6(d),38.3(d),37.5(t),37.2(t),36.9(t),28.2(d),28.1(d),27.7(d) ,27.5(d),25.6(d),25.2(d),25.0(d),19.9(d),19.7(d),17.8(s),17.5(s),17.4(s),13.9(s),13.9(s),11.4(s),11.2(s)ppm.

[0112] Example 8: 2-(methylthio)-1-(2-(5-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (3-trifluoromethylphenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):397(5)[M + ],382(3),351(9),322(10),294(100),267(9),239(29),75(12). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.26,12.03(s,1H),8.21-8.02(m,2H),7.85-7.79(m,1H),7.65-7.40(m, 2H),5.83-5.46(m,1H),4.57-2.89(m,3H),2.65-2.14(m,1H),2.14-1.99(m,3H),1.96-1.51(m,5H),1.47-1.34(m,3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 169.9(q), 169.6(q), 147.3(q), 147.2(q), 147.0(q), 138.4(q), 137.9(q), 136.1(q), 136.1(q), 136.0(q), 130.0(q), 129.8(q), 129.7(q), 129.6(q), 129.4(t), 129.2(q), 128.8(q), 128.6(q), 127.9(t), 127.9(t), 126.2(q), 122.6(q), 122.2(t), 122.1(t), 1 20.3(t),120.3(t),114.8(t),114.4(t),114.2(t),51.1(t),46.9(t),46. 7(t),42.8(d),42.6(d),38.4(d),37.3(t),37.2(t),36.9(t),29.0(d),28. 7(d),28.2(d),28.0(d),27.6(d),27.4(d),25.5(d),25.2(d),25.0(d),20. 5(d),19.9(d),19.7(d),17.8(s),17.5(s),17.3(s),11.2(s),11.2(s)ppm.

[0113] Example 9: 1-(2-(5-(3,4-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (3,4-dimethylphenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):357(8)[M + ],342(6),282(8),254(100),227(13),199(13),173(4),131(6),115(3),75(8). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.05-11.75(m,1H),7.60-7.02(4,1H),5.77-5.40(m,1H),4.49 -2.93(m,3H),2.66-2.34(m,1H),2.27-2.16(m,6H),2.08-1.98(m,3H),1.95-1.52(m,5H),1.43-1.31(m,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.4(q), 170.3(q), 170.0(q), 146.9(q), 146.8(q), 146.7(q), 140.5(q), 137.0(q), 136.3(q), 136.2(q), 134.1(q), 134.0(q), 133.0(q), 132.9(q), 130.2(t), 129.9(t), 125.9(t), 122.2(t), 113.0(t), 112.6(t), 112.4 (t),51.6(t),47.4(t),47.1(t),43.2(d),43.0(d),38.8(d),38.0(t),37.6(t),37.4(t),29.5(d),28.5(d),28.2(d),28.0(d),26. 1(d),25.7(d),25.5(d),20.3(d),20.1(d),20.0(s),19.9(s),19.6(s),18.3(s),18.0(s),17.8(s),12.0(s),11.7(s),11.6(s)ppm.

[0114] Example 10: 1-(2-(5-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-(dimethylamino)phenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):372(18)[M + ],357(5),297(5),269(100),240(13),214(10),188(4),159(3),146(5),75(6). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ11.86-11.63(m,1H),7.80-6.92(m,3H),6.69(d,J=8.4Hz,2H),5.77-5. 38(m,1H),4.48-3.01(m,3H),2.89(s,6H),2.57-2.24(m,1H),2.04(s,3H),1.91-1.47(m,5H),1.42-1.34(m,3H)ppm.

[0115] Example 11: 1-(2-(5-(4-chloro-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-chloro-3-fluorophenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):381(5)[M + ],366(4),335(5),306(8),278(100),223(29),75(17). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.22,12.15,12.01(brs,1H),7.81-7.41(m,4H),5.80-5.4 3(m,1H),4.52-3.00(m,3H),2.64-2.13(m,1H),2.11-1.98(m,3H),1.94-1.49(m,5H),1.42-1.34(m,3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers, major peaks) δ 170.8 (q), 170.3 (q), 170.1 (q), 159.6 (q), 156.4 (q), 147.8 (q), 147.6 (q), 147.5 (q), 138.3 (q), 138.2 (q), 136.9 (q), 136.8 (q), 131.3 (t), 131.0 (t), 121.6 (t), 121.6 (t), 116.7 (q), 116.6 (q), 116.5 (q), 116.4 (q), 115.4 (t), 115.0 (t), 114.9 (t), 112.5 (t),112.2(t),51.5(t),47.3(t),47.0(t),43.2(d),43.0(d),38.8(d),37.9(t),37.6(t),37.3(t),28.5(d),28. 1(d),27.9(d),26.0(d),25.7(d),25.4(d),20.3(d),20.1(d),18.2(s),18.0(s),17.8(s),11.8(s),11.7(s)ppm.

[0116] Example 12: 1-(2-(5-(4-acetylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-acetylphenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):371(6)[M + ],356(5),325(4),296(9),268(100),241(9),213(16),75(10). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.27,12.05(s,1H),8.17-7.87(m,5H),5.83-5.46(m,1H),4 .61-2.97(m,3H),2.58(s,3H),2.68-2.38(m,1H),2.06,2.05(s,3H),1.95-1.50(m,5H),1.43-1.34(m,3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 197.6 (q), 170.4 (q), 170.3 (q), 147.9 (q), 147.7 (q), 140.0 (q), 139.9 (q), 139.4 (q), 139.3 (q), 138.8 (q), 134.7 (q), 134.6 (q), 129.2 (t), 124.4 (t), 116.0 (t), 115.6 (t), 51. 6(t),47.3(t),47.1(t),43.2(d),43.1(d),38.9(d),38.0(t),37.6(t),37.4(t),28.5(d),28.1(d),27.9(d) ,26.9(s),26.0(d),25.7(d),25.5(d),20.3(d),20.2(d),18.2(s),18.0(s),17.9(s),11.9(s),11.7(s)ppm.

[0117] Example 13: 2-(ethylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-methylphenyl)boronic acid, and 2-(ethylthio)propanoic acid to afford the title product as a white solid. GC / MS (EI, mixture of stereoisomers, ratio 1:1): Isomer 1: m / z (%): 357 (6) [M + ],328(20),268(9),240(100),213(9),185(15),117(6),89(6).Isomer 2:m / z(%):357(7)[M + ],328(21),268(9),240(100),213(10),185(15),117(6),89(6). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.02,11.79(brs,1H),7.65(d,J=6.6Hz,2H),7.49(s,1H),7.14(d,J=7.2Hz,2 H),5.79-5.42(m,1H),4.49-3.00(m,3H),2.70-2.36(m,2H),2.29(s,3H),1.95-1.51(m,5H),1.40(m,3H),1.27-1.13(m,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.7 (q), 170.5 (q), 147.0 (q), 146.7 (q), 140.4 (q), 140.0 (q), 135.3 (q), 132.7 (q), 129.4 (t), 124.7 (t), 113.1 (t), 112.6 (t), 51.6 (t), 47.3 (t), 47.0 (t), 43.2 ( d),43.0(d),38.8(d),38.0(t),37.6(t),37.5(t),28.7(d),28.1(d),26.2(d),25.7(d),25.3(d),23.3 (d),23.0(d),21.2(s),20.3(d),20.1(d),19.3(s),19.1(s),19.0(s),15.4(s),14.9(s),14.9(s)ppm.

[0118] Example 14: (E)-2-Methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-methylphenyl)boronic acid, and (E)-2-methylbut-2-enoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):323(6)[M + ],308(3),268(1),240(100),185(10),172(3),83(5),55(13). 1H NMR (300MHz, DMSO-d6, mixture of tautomers) δ12.08,11.86(s,1H),7.76-7.52(m,2H),7.49(s,1H),7.27-7.09( m,2H),5.76-5.46(m,2H),4.22-2.81(m,2H),2.55-2.33(m,1H),2.29(s,3H),1.85-1.27(m,11H)ppm.

[0119] Example 15: 2-methylene-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-methylphenyl)boronic acid, and 2-methylenebutanoic acid to give the title product as a pale yellow solid. GC / MS(EI):m / z(%):323(8)[M + ],308(4),240(100),185(12),172(3),159(43),83(4),55(15). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ12.11-11.86(m,1H),7.72-7.01(m,5H),5.76-5.0 5(m,3H),4.67-2.61(m,2H),2.42-2.17(m,6H),1.84-1.16(m,5H),1.12-0.93(m,3H). 13 C NMR (75MHz, DMSO-d6, mixture of tautomers) δ171.1(q),171.0(q),146.7(q),146.6(q),140.2(q),136.2(q),135.3(q),132.6(q),129.7(t),129.4(t),124 .6(t),113.0(t),112.4(d),53.6(t),46.7(t),44.4(d),38.5(d),29.3( d),28.5(d),27.2(d),25.8(d),25.6(d),21.2(s),20.4(d),12.1(s)ppm.

[0120] Example 16: 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (3,4-difluorophenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):365(10)[M + ],350(5),319(4),290(10),262(100),235(6),75(13). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.2-11.9 (m, 1H), 7.78-7.33 (m, 4H), 5.77-5.41 (m, 1H), 4.40-3.07 (m, 3H), 2.56-2.38 (m, 1H), 2.16-1.37 (m, 11H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.8 (q), 170.4 (q), 170.1 (q), 151.8 (q), 151.6 (q), 149.9 (q), 149.7 (q), 148.6 (q), 148.4 (q), 147.6 (q), 147.4 (q), 147.3 (q), 146.7 (q), 146.5 (q), 138.4 (q), 138.0 (q), 133.3 (q), 133.1 (q), 121.1 (t), 118.0 (t), 117. 8(t),114.6(t),114.2(t),114.0(t),113.2(t),113.0(t),51.4(t),47.3(t),47.0(t),43.2(d),43.0(d),38.8(d),37.9(t),37.6 (t),37.3(t),28.0(d),27.9(d),26.0(d),25.6(d),25.4(d),20.3(d),20.1(d),18.2(s),17.9(s),17.8(s),11.8(s),11.7(s)ppm.

[0121] Example 17: 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-nitrophenyl)boronic acid, and 2-(methylthio)propanoic acid to give the title product as a pale yellow solid. GC / MS(EI):m / z(%):374(1)[M + ],359(2),328(3),299(4),271(100),216(11),170(8),156(3),75(54). 1 H NMR (300 MHz, CDCl3, mixture of stereoisomers and tautomers) δ 10.3-9.76 (m, 1H), 8.24-7.38 (m, 5H), 5.83-5.75 (m, 1H), 3.88-3.63 (m, 2H), 3.16-3.07 (m, 1H), 2.81-1.47 (m, 12H) ppm.

[0122] Example 18: 1-(2-(5-(4-aminophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one A solution of 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one (100 mg, 0.24 mmol) in ethyl acetate (10 mL) was treated with Pd / C (palladium on charcoal) (10 wt%) (48.1 mg, 0.048 mmol) under a nitrogen atmosphere, and the mixture was purged with hydrogen and reacted under a hydrogen atmosphere (1 bar) at room temperature overnight. The resulting mixture was purged with nitrogen, filtered over Celite, and concentrated to give the title product (51 mg, yield: 58%) as a yellow solid. GC / MS(EI):m / z(%):344(9)[M + ],329(4),269(6),241(100),214(16),198(8),185(20),75(44). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ11.80-11.57(m,1H),7.42-7.23(m,3H),6.59-6.53(m,2H),5.76-5.37(m, 1H),5.14-4.98(m,2H),4.38-3.16(m,3H),2.50-2.37(m,1H),2.04-1.94(m,3H),1.70-1.58(m,5H),1.38-1.36(m,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.8 (q), 170.3 (q), 170.1 (q), 168.7 (q), 148.0 (q), 147.4 (q), 146.3 (q), 141.3 (q), 140.9 (q), 125.7 (t), 123.7 (t), 122.5 (t), 118.7 (t), 114.4 ( t),110.7(t),110.3(t),51.5(t),47.3(t),43.2(d),43.0(d),38.8(d),38.1(t),37.6(t),37. 4(t),28.6(d),28.2(d),26.2(d),25.8(d),25.5(d),18.3(s),17.9(s),12.0(s),11.7(s)ppm.

[0123] Example 19: 2-(methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (2,4,5-trifluorophenyl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. GC / MS(EI):m / z(%):383(7)[M + ],368(5),337(5),308(10),280(100),253(5),225(25),75(13). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.37-11.82(m,1H),8.00-7.76(m,1H),7.67-7.28(m,2 H),5.82-5.31(m,1H),4.55-3.00(m,3H),2.65-2.18(m,1H),2.10-1.93(m,3H),1.84-1.29(m,8H)ppm.

[0124] Example 20: 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-3-en-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (3,4-difluorophenyl)boronic acid, and 2-methylbut-3-enoic acid to give the title product as a pale yellow solid. GC / MS (EI, mixture of stereoisomers, ratio 4:5): isomer 1: GC / MS (EI): m / z (%): 345 (1) [M + ],330(1),290(8),262(100),234(9),219(10),194(68),55(49).Isomer 2:GC / MS(EI):m / z(%):345(1)[M + ],330(1),290(6),262(100),234(8),219(9),207(30),194(56),55(45). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.21-1.94(brs,1H),7.73-7.58(m,3H),7.39-7.33(m,1H),5.9 2-5.77(m,2H),5.24-4.91(m,2H),4.44-3.10(m,3H),2.52-2.20(m,1H),1.72-1.30(m,5H),1.21-1.10(m,3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 173.2 (q), 173.0 (q), 172.7 (q), 151.8 (q), 151.6 (q), 149.9 (q), 149.7 (q), 148.6 (q), 148.4 (q), 147.6 (q), 147.3 (q), 146.7 (q), 146.5 (q), 139.5 (t), 139.3 (t), 139.0 (t), 138.5 (t), 138.0 (t), 133.1 (q), 121.1 (t), 1 18.0(t),117.8(t),115.6(d),115.3(d),114.5(t),114.1(t),113.2(t),113.0(t),51.3(t),47.2(t),47.0(t),42.8(d),42.7(d ),38.7(d),29.3(d),29.0(d),28.3(d),28.0(d),27.7(d),25.9(d),25.6(d),25.1(d),20.1(d),18.3(s),18.0(s),17.9(s)ppm.

[0125] Example 21: (E)-1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-2-en-1-one Obtained as an isomerized by-product in the final step of the preparation of Example 20 following the general procedure of Example 2. The title product was obtained as a pale yellow solid. GC / MS(EI):m / z(%):345(3)[M + ],330(2),290(1),262(100),234(6),219(7),181(12),83(24),55(49). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ12.2-12.0(m,1H),7.77-7.33(m,4H),5.6 6-5.46(m,2H),4.77-2.89(m,2H),2.35-2.20(m,1H),1.76-1.32(m,11H)ppm.

[0126] Example 22: 1-(2-(5-(2,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Example 22a: 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one: a) To a solution of tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (6.00 g, 18.17 mmol) in dichloromethane (100 mL) was added 2,2,2-trifluoroacetic acid (16.57 g, 145.00 mmol) at 5 °C, and the mixture was stirred at rt for 16 h. After the solution was cooled to 5 °C, diluted NaHCO3 solution was added, extracted with ethyl acetate (50 mL*3), and the organic phase was concentrated to give 2-(5-bromo-1H-imidazol-2-yl)piperidine as a yellow solid.

[0127] b) To a solution of 2-(methylthio)propanoic acid (2.51 g, 20.86 mmol) in dichloromethane (150 mL), HOBt (1-hydroxybenzotriazole hydrate) (3.19 g, 20.86 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (3.24 g, 20.86 mmol) were added at 0-5°C, and the mixture was stirred at rt for 0.5 h. Then, 2-(5-bromo-1H-imidazol-2-yl)piperidine (5.00 g, 17.38 mmol) and DIPEA (6.07 mL, 34.80 mmol) were added, and the mixture was stirred at rt for 16 h. The mixture was filtered to remove the solvent and purified by silica gel chromatography (hexane:MTBE=2:1) ​​to give 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (4.40 g, yield: 75%) as a white solid. GC / MS(EI):m / z(%):333(5)[M + ],331(5)[M + ],318(5),316(5),287(25),285(26),258(15),256(15),230(100),228(100),175(36),173(36),75(44). 1H NMR (300 MHz, CDCl3, mixture of stereoisomers and tautomers) δ 10.90-9.90 (m, 1H), 7.06-6.80 (m, 1H), 5.75-5.24 (m, 1H), 3.90-3.08 (m, 3H), 2.64-1.37 (m, 12H).

[0128] Example 22b: 1-(2-(5-(2,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one A mixture of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (150 mg, 0.451 mmol), (2,5-difluorophenyl)boronic acid (143 mg, 0.903 mmol), sodium carbonate (96 mg, 0.903 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (74 mg, 0.090 mmol) in tetrahydrofuran (6 mL) and water (1.2 mL) was stirred and refluxed under an argon atmosphere for 16 h. The reaction was monitored by GC-MS. The mixture was cooled to 10° C., and the reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed once with brine solution, dried over MgSO4, filtered, and concentrated. The crude oil was purified by silica gel chromatography (hexane:MTBE=3:1) to give 1-(2-(5-(2,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (95 mg, yield: 58%) as a pale yellow solid. GC / MS(EI):m / z(%):365(9)[M + ],350(5),319(8),290(13),262(100),235(12),75(13). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.34,12.11(brs,1H),7.87-7.64(m,1H),7.59-7.41(m,1H),7.38-7.18(m,1H),7.17 -6.98(m,1H),5.81-5.45(m,1H),4.54-3.00(m,3H),2.69-2.15(m,1H),2.11-1.96(m,3H),1.93-1.49(m,5H),1.45-1.33(m,3H)ppm.

[0129] Example 23: 1-(2-(5-(2,3-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following the general procedure described in Example 22b: 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (150 mg, 0.451 mmol), (2,3-difluorophenyl)boronic acid (143 mg, 0.903 mmol), sodium carbonate (96 mg, 0.903 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (74 mg, 0.09 mmol) in tetrahydrofuran (6 mL) and water (1.2 mL) gave the title product (100 mg, yield: 61%) as a pale yellow solid. GC / MS(EI):m / z(%):365(6)[M + ],350(5),319(6),290(11),262(100),235(9),75(11). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.39,12.16(s,1H),8.00-7.79(m,1H),7.70-7.43(m,1H),7.39-7.13(m, 2H),5.85-5.49(m,1H),4.57-3.04(m,3H),2.75-2.18(m,1H),2.14-1.99(m,3H),1.97-1.51(m,5H),1.47-1.35(m,3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.4(q), 170.1(q), 152.3(q), 152.1(q), 149.1(q), 148.9(q), 148.6(q), 148.4(q), 147.5(q), 147.3(q), 147.2(q), 145.3(q), 145.2(q), 132.8(q), 132.5(q), 125.1(t), 125.0(t), 124.9(t), 122.7(t), 117.8(t), 117 .6(t),117.4(t),117.3(t),114.6(t),114.4(t),51.4(t),47.2(t),46.9(t),43.2(d),43.0(d),38.8(d),37.9(t),37.7(t),37.3 (t),28.5(d),28.1(d),27.9(d),26.0(d),25.6(d),25.4(d),20.2(d),20.1(d),18.1(s),17.9(s),17.8(s),11.8(s),11.6(s)ppm.

[0130] Example 24: 2-(methylthio)-1-(2-(5-(2,3,4-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (200 mg, 0.602 mmol), (2,3,4-trifluorophenyl)boronic acid (212 mg, 1.204 mmol), sodium carbonate (128 mg, 1.204 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (98 mg, 0.120 mmol) in tetrahydrofuran (6 mL) and water (1.2 mL) gave the title product (95 mg, yield: 41%) as a pale yellow solid. GC / MS(EI):m / z(%):383(8)[M + ],368(5),337(7),308(11),280(100),225(28),75(13). 1¹H NMR (300MHz, DMSO-d6, a mixture of stereoisotopes) δ 12.38–12.16 (m, 1H), 8.04–7.76 (m, 1H), 7.71–7.44 (m, 1H), 7.41–7.22 (m, 1H), 5.84, 5.48 (brs, 1H), 4.67–3.02 (m, 3H), 2.79–2.18 (m, 1H), 2.16–1.97 (m, 3H), 1.91–1.51 (m, 5H), 1.49–1.32 (m, 3H). 13 C NMR (75MHz, DMSO-d6, mixture of stereoisotropic entities) δ170.4(q), 170.1(q), 150.4(q), 15 0.3(q),149.2(q),149.1(q),147.6(q),147.4(q),147.3(q),147.1(q),147.0 (q),146.0(q),145.8(q),141.6(q),141.4(q),141.1(q),138.3(q),138.1(q) ,137.9(q),132.1(q),131.8(q),121.6(t),121.5(t),121.4(t),121.3(t),121 .1(q),121.0(q),120.9(q),120.8(q),117.2(t),117.0(t),116.8(t),116.7( t),113.0(t),112.8(t),51.4(t),47.2(t),46.9(t),43.2(d),43.0(d),38.8(d ),37.9(t),37.6(t),37.3(t),28.5(d),28.0(d),27.9(d),25.9(d),25.6(d), 25.4(d),20.2(d),20.0(d),18.1(s),17.9(s),17.8(s),11.7(s),11.6(s)ppm.

[0131] Example 25: 1-(2-(5-(benzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (200 mg, 0.602 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (300 mg, 1.806 mmol), sodium carbonate (191 mg, 1.806 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (98 mg, 0.120 mmol) in tetrahydrofuran (6 mL) and water (1.2 mL) gave the title product (81 mg, yield: 36%) as a pale yellow solid. GC / MS(EI):m / z(%):373(10)[M + ],358(5),327(2),298(6),270(100),243(11),75(9). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ11.98-11.76(m,1H),7.57-7.39(m,1H),7.35-7.11(m,2H),6.88(d,J=7.8Hz,1H) ,5.99(s,2H),5.76-5.32(m,1H),4.50-3.01(m,3H),2.65-2.14(m,1H),2.00(s,3H),1.92-1.44(m,5H),1.38(d,J=6.5Hz,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.2 (q), 170.1 (q), 147.9 (q), 146.8 (q), 146.6 (q), 145.8 (q), 140.1 (q), 129.9 (q), 117.9 (t), 112.9 (t), 112.5 (t), 112.5 (t), 108.8 (t), 105.3 (t),101.1(d),51.5(t),47.3(t),47.0(t),43.0(d),38.8(d),37.9(t),37.6(t),37.3(t),29. 5(d),28.2(d),27.9(d),25.7(d),25.5(d),20.1(d),17.9(s),17.8(s),11.9(s),11.7(s)ppm.

[0132] Example 26: 1-(2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (200 mg, 0.602 mmol), (4-methoxyphenyl)boronic acid (274 mg, 1.806 mmol), sodium carbonate (191 mg, 1.806 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (98 mg, 0.120 mmol) in tetrahydrofuran (6 mL) and water (1.2 mL) gave the title product (143 mg, yield: 66%) as a white solid. GC / MS(EI): m / z(%): 359(9)[M + ],344(5),256(100),229(13),75(10). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ11.96,11.74(brs,1H),7.76-7.42(m,3H),6.91(d,J=7.9Hz,2H), 5.78-5.32(m,1H),4.52-3.01(m,6H),2.68-2.13(m,1H),2.04(s,3H),1.80-1.50(m,5H),1.38(d,J=6.6Hz,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers, major peaks) δ 170.2 (q), 158.2 (q), 146.8 (q), 140.2 (q), 128.2 (q), 125.9 (t), 114.3 (t), 111.9 (t), 55.5 (s), 51.5 (t), 47.3 (t), 47.0 (t), 43.0 (d), 43.0 (d), 38.8 (d), 38.0 (t), 37.6 (t), 37.4 (t), 28.2 (d), 25.7 (d), 25.5 (d), 20.3 (d), 20.1 (d), 18.0 (s), 17.9 (s), 11.9 (s), 11.7 (s) ppm.

[0133] Example 27: 2-(methylthio)-1-(2-(5-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (200 mg, 0.602 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (372 mg, 1.806 mmol), sodium carbonate (191 mg, 1.806 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (98 mg, 0.120 mmol) in tetrahydrofuran (6 mL) and water (1.2 mL) gave the title product (95 mg, yield: 38%) as a pale yellow solid. GC / MS(EI):m / z(%):413(9)[M + ],398(5),367(4),338(9),310(100),281(19),75(14). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.16,11.94(brs,1H),8.05-7.72(m,2H),7.65(t,J=8.2Hz,1H),7.47-7.24(m ,2H),5.80-5.32(m,1H),4.54-2.99(m,3H),2.65-2.17(m,1H),2.11-1.97(m,3H),1.94-1.51(m,5H),1.39(d,J=6.6Hz,3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.3 (q), 170.1 (q), 147.7 (q), 147.5 (q), 147.3 (q), 146.9 (q), 139.0 (q), 134.9 (q), 126.2 (t), 122.3 (q), 122.0 (t), 121.6 (t), 118.9 (q), 114.5 (t), 114.1 (t), 113.9 (t) ,51.5(t),47.3(t),47.0(t),43.2(d),43.0(d),38.8(d),37.9(t),37.6(t),37.3(t),28.6(d),28.1(d),2 7.9(d),26.1(d),25.7(d),25.5(d),20.3(d),20.1(d),18.2(s),18.0(s),17.8(s),11.8(s),11.7(s)ppm.

[0134] Example 28: 2-Fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (200 mg, 0.602 mmol), (4-(trifluoromethoxy)phenyl)boronic acid (372 mg, 1.806 mmol), sodium carbonate (191 mg, 1.806 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (49 mg, 0.060 mmol) in tetrahydrofuran (6 mL) and water (1 mL) gave the title product (108 mg, yield: 48%) as a white solid. GC / MS(EI):m / z(%):372(5)[M + ],357(6),326(14),269(100),75(16). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.42,12.22(brs,1H),7.98-7.74(m,4H),5.87-5.45(m, 1H),4.56-2.96(m,3H),2.62-2.14(m,1H),2.10-1.92(m,3H),1.91-1.51(m,5H),1.39(d,J=6.5Hz,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.4(q), 170.1(q), 165.2(q), 161.8(q), 148.5(q), 148.4(q), 148.2(q), 143.2(q), 143.1(q), 137.8(q), 134.4(t), 121.1(t), 118.0(t), 117.7(t), 117.5(t), 115.1(t), 111.4(t), 111.1(t), 96.7(q), 96.5(q), 51.5(t), 47.2(t), 47.0(t), 43.2(d),43.0(d),38.9(d),37.8(t),37.6(t),37.3(t),28.5(d),28.0(d),27.8(d),26.0( d),25.6(d),25.4(d),20.3(d),20.1(d),18.2(s),18.0(s),17.8(s),11.8(s),11.6(s)ppm.

[0135] Example 29: 2-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (150 mg, 0.451 mmol), (2-cyanophenyl)boronic acid (133 mg, 0.903 mmol), sodium carbonate (144 mg, 1.354 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (55 mg, 0.068 mmol) in tetrahydrofuran (6 mL) and water (1 mL) gave the title product (90 mg, yield: 56%) as a white solid. GC / MS(EI):m / z(%):354(5)[M +],339(6),308(8),279(14),251(100),224(10),196(32),75(13). 1 ¹H NMR (300MHz, DMSO-d6, a mixture of stereoisos and anaerostomoses) δ 12.39, 12.19 (brs, 1H), 8.15–7.95 (m, 1H), 7.87–7.62 (m, 3H), 7.40 (t, J = 7.5 Hz, 1H), 5.83–5.47 (m, 1H), 4.48–2.99 (m, 3H), 2.71–2.12 (m, 1H), 2.09–1.95 (m, 3H), 1.91–1.47 (m, 5H), 1.44–1.32 (m, 3H). 13 C NMR (75MHz, DMSO-d6, mixture of stereoisotropic entities) δ170.8(q), 170.4(q), 169.9(q), 147.9(q), 147.6(q), 147.5(q), 137.9 (q),136.9(q),136.8(q),134.5(t),133.7(t),127.6(t),127.1(t),120.0(q),116.7(t),116.3(t),116.2(t),107 .1(q),106.4(q),51.4(t),47.1(t),46.7(t),43.1(d),43.0(d),38.8(d),38.0(t),37.7(t),37.3(t),28.6(d),28 .2(d),28.0(d),26.1(d),25.7(d),25.5(d),20.2(d),20.0(d),18.2(s),18.0(s),17.8(s),11.8(s),11.7(s)ppm.

[0136] Example 30: 2-(methylthio)-1-(2-(5-(3-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (200 mg, 0.602 mmol), (3-nitrophenyl)boronic acid (0.201 g, 1.204 mmol), sodium carbonate (191 mg, 1.806 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (49 mg, 0.060 mmol) in tetrahydrofuran (6 mL) and water (1 mL) gave the title product (90 mg, yield: 40%) as a pale yellow solid. GC / MS(EI):m / z(%):374(6)[M + ],359(5),328(9),299(10),271(100),216(25),75(16). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.31,12.08(s,1H),8.57(s,1H),8.22-8.15(m,1H),8.05-7.98(m,1H),7.92-7.83(m,1H) ),7.67-7.58(m,1H),5.82-5.44(m,1H),4.43-3.05(m,3H),2.58-2.21(m,1H),2.05-2.04(m,3H),1.72-1.50(m,5H),1.42-1.33(m,3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.3(q), 170.0(q), 148.7(q), 147.9(q), 147.8(q), 147.7(q), 138.1(q), 137.8(q), 137.3(q), 137.2(q), 137.1(q), 132.1(t), 130.8(t), 130.7(t), 130.4(t), 129.1(t), 120.8(t), 120.7(t), 118. 6(t),115.9(t),115.5(t),115.5(t),47.3(t),47.1(t),43.2(d),43.1(d),38.8(d),37.7(t),37.6(t),37.3(t),28.6( d),28.0(d),27.8(d),26.0(d),25.7(d),25.5(d),20.3(d),20.2(d),18.2(s),17.9(s),17.8(s),11.7(s),11.6(s)ppm.

[0137] Example 31: 2-(methylthio)-1-(2-(5-(2-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (150 mg, 0.451 mmol), (2-(trifluoromethyl)phenyl)boronic acid (171 mg, 0.903 mmol), sodium carbonate (144 mg, 1.354 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (37 mg, 0.045 mmol) in tetrahydrofuran (6 mL) and water (1 mL) gave the title product (90 mg, yield: 50%) as a white solid. GC / MS(EI): m / z(%): 397(8)[M + ],382(10),351(23),322(13),294(100),254(36),139(21),75(19). 1¹H NMR (300MHz, DMSO-d6, a mixture of stereoisos and mutated heteros) δ 12.21, 11.98 (s, 1H), 7.93–7.39 (m, 4H), 7.35–6.89 (m, 1H), 5.81–5.44 (m, 1H), 4.53–2.96 (m, 3H), 2.70–2.11 (m, 1H), 2.09–1.89 (m, 3H), 1.88–1.47 (m, 5H), 1.36 (t, J = 5.8 Hz, 3H). 13 C NMR (75MHz, DMSO-d6, mixture of stereoisotropic compounds) δ170.4(q),170.3(q),169 .9(q),147.0(q),146.8(q),146.6(q),137.2(q),137.1(q),136.6(q) ,134.6(q),132.7(t),132.5(t),131.7(t),131.6(t),131.5(t),127 .2(t),127.1(t),127.0(t),126.7(t),126.6(t),126.5(t),125.9(q) ,125.5(q),123.1(q),116.3(t),116.2(t),115.8(t),51.4(t),47.1 (t),46.7(t),43.1(d),42.9(d),38.7(d),38.1(t),37.6(t),37.3(t) ,28.27(d),28.3(d),28.1(d),26.1(d),25.7(d),25.5(d),20.2(d), 20.0(d),19.9(d),18.2(s),17.9(s),17.8(s),11.8(s),11.6(s)ppm.

[0138] Example 32: 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (500 mg, 1.505 mmol), (4-formylphenyl)boronic acid (451 mg, 3.01 mmol), sodium carbonate (478 mg, 4.51 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (184 mg, 0.226 mmol) in tetrahydrofuran (10 mL) and water (1.5 mL) gave the title product (385 mg, yield: 72%) as a white solid. GC / MS(EI):m / z(%):357(9)[M + ],342(6),311(6),282(9),254(100),227(5),199(15),75(8). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.29,12.09(s,1H),9.95(s,1H),8.00(d,J=7.9Hz,2H),7.93-7.79(m,3H ),5.82-5.45(m,1H),4.57-2.91(m,3H),2.66-2.17(m,1H),2.08-2.00(m,3H),1.56-1.48(m,5H),1.39(d,J=6.5Hz,3H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 192.7 (t), 170.4 (q), 170.3 (q), 170.0 (q), 148.2 (q), 148.1 (q), 147.9 (q), 141.3 (q), 141.2 (q), 139.2 (q), 139.1 (q), 134.3 (q), 134.2 (q), 130.7 (t), 130.5 (t), 124.8 (t), 116. 6(t),116.2(t),116.1(t),51.5(t),47.3(t),47.0(t),43.2(d),43.0(d),38.8(d),37.3(t),28.5(d),28.0(d ),27.9(d),26.0(d),25.6(d),25.4(d),20.3(d),20.1(d),18.2(s),17.9(s),17.8(s),11.8(s),11.6(s)ppm.

[0139] Example 33: 1-(2-(5-(4-(aminomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one To a solution of 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde (300 mg, 0.839 mmol) in methanol (10 mL) was added 25% aqueous ammonium hydroxide (1176 mg, 8.390 mmol), and the mixture was stirred at rt for 24 h under an argon atmosphere. The mixture was then treated with NaBH (32 mg, 0.839 mmol) at 10 °C and stirred at rt for 6 h. The mixture was filtered to remove the solvent, and purified by silica gel chromatography (hexane:EA=1:2) to give 1-(2-(5-(4-(aminomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (62 mg, yield: 21%) as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.11-11.80(m,1H),7.78-7.15(m,5H),5.78-5.41(m, 1H),5.17-5.13(m,1H),4.55-4.42(m,2H),4.41-2.17(m,5H),2.09-1.97(m,3H),1.86-1.22(m,8H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.2(q), 170.1(q), 147.1(q), 147.0(q), 146.8(q), 140.5(q), 140.4(q), 140.3(q), 140.3(q), 133.9(q), 127.3(t), 127.0(t), 124.4(t), 113.3(t), 113.0(t), 63.3(d), 63. 1(d),51.5(t),47.3(t),47.0(t),43.2(d),43.0(d),38.8(d),38.0(t),37.6(t),37.3(t),28.6(d),28.1(d) ,28.0(d),26.1(d),25.7(d),25.4(d),20.3(d),20.1(d),18.3(s),18.0(s),17.8(s),11.9(s),11.7(s)ppm.

[0140] Example 34: 1-(2-(5-(4-((methylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one To a solution of 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde (200 mg, 0.559 mmol) in methanol (10 mL) was added methanamine hydrochloride (378 mg, 5.59 mmol) and triethylamine (566 mg, 5.59 mmol), and the mixture was stirred at rt for 24 h under an argon atmosphere. The mixture was then treated with NaBH (21 mg, 0.559 mmol) at 10 °C and stirred at rt for 6 h. The mixture was filtered, the solvent removed and purified by silica gel chromatography (hexane:EA=1:2) to give 1-(2-(5-(4-((methylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (25 mg, yield: 12%) as a pale yellow solid. GC / MS(EI):m / z(%):370(3)[M-2] + ,355(5),295(10),267(100),240(11),212(12),75(40). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.12-11.81 (m, 1H), 8.06-7.16 (m, 5H), 5.87-5.32 (m, 1H), 4.55-2.24 (m, 9H), 2.09-1.96 (m, 4H), 1.83-1.21 (m, 8H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.2(q), 170.1(q), 147.0(q), 146.9(q), 140.3(q), 140.2(q), 137.0(q), 137.0(q), 134.1(q), 134.0(q), 129.5(t), 129.2(t), 124.5(t), 113.4(t), 113.0(t), 61.2(d), 61.0(d), 51.5(t) ,47.3(t),47.0(t),43.2(d),43.0(d),42.1(S),38.8(d),38.0(t),37.6(t),37.3(t),29.4(d),29.1(d),28.5(d),2 8.1(d),28.0(d),26.1(d),25.7(d),25.4(d),20.2(d),20.1(d),18.3(s),18.0(s),17.8(s),11.9(s),11.7(s)ppm.

[0141] Example 35: Methyl 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoate Following the general procedure described in Example 22b: reaction of 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (500 mg, 1.505 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (542 mg, 3.01 mmol), sodium carbonate (478 mg, 4.51 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (184 mg, 0.226 mmol) in tetrahydrofuran (10 mL) and water (1.5 mL) gave the title product (478 mg, yield: 82%) as a white solid. GC / MS(EI):m / z(%):387(9)[M +],341(3),312(10),284(100),257(10),229(16),75(8). 1 ¹H NMR (300MHz, DMSO-d6, a mixture of stereoisotopes) δ 12.26–12.04 (m, 1H), 7.96–7.77 (m, 5H), 5.81–5.44 (m, 1H), 4.55–2.95 (m, 3H), 3.86 (s, 3H), 2.66–2.16 (m, 1H), 2.13–1.33 (m, 11H). 13 C NMR (75MHz, DMSO-d6, mixture of stereoisotropic entities) δ170.7(q), 170.4(q), 170.3(q), 170.0(q), 166.6(q), 148.0(q), 147.8(q) ),147.7(q),140.1(q),140.0(q),139.2(q),138.8(q),130.0(t),127.1(t),127.0(t),124.5(q),115.9(t),115.5(t ),115.4(t),52.3(S),51.5(t),47.3(t),47.0(t),43.2(d),43.0(d),38.8(d),38.0(t),37.6(t),37.3(t),28.5(d), 28.0(d),27.9(d),26.0(d),25.6(d),25.4(d),20.3(d),20.1(d),18.2(s),17.9(s),17.8(s),11.8(s),11.6(s)ppm.

[0142] Example 36: 2-(furan-2-yl)-1-(2-(5-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one To a solution of 2-(5-phenylimidazol-2-yl)piperidine (200 mg, 0.88 mmol) in dichloromethane (2 mL) was added HOBt (162 mg, 1.056 mmol, 1.2 equiv.) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (202 mg, 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-(furan-2-yl)acetic acid (122 mg, 0.968 mmol, 1.1 equiv.) and N,N-diisopropylethylamine (114 mg, 0.88 mmol, 1 equiv.), and the resulting mixture was stirred at rt for 16 h. The mixture was filtered to remove the solvent, and the crude was purified by silica gel chromatography (gradient of EtOAc in heptane) to give 2-(furan-2-yl)-1-(2-(5-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one (270 mg, 0.81 mmol, 91% yield) as a yellow liquid. MS(EI,70eV):335(5,[M]+·),227(13),226(79),171(28),170(11),145(16),118(12),91(13),82(10),81(100),53(52). 1 H NMR (400MHz, DMSO, mixture of stereoisomers and tautomers) δ12.16,12.07,11.88(brs,1H),7.82-7.72(m,2H),7.71-7.51(m,2H),7.45-7.29(m,2H),7.28-7.11(m,1H) ),6.46-6.19(m,2H),5.79,5.75,5.33(brs,1H),4.46-3.14(m,4H),2.76- 2.17(m,1H),1.75-1.48(m,4H),1.43-1.13(m,2H),0.86(t,J=6.9Hz,1H).

[0143] Example 37: 2-(methylthio)-1-(2-(5-phenylimidazol-2-yl)piperidin-1-yl)propan-1-one Prepared in the same manner as in example 36 using 2-(5-phenylimidazol-2-yl)piperidine and 2-(methylthio)propanoic acid to give the target compound as a white solid. MS(EI,70eV):329(2,[M]+·),227(16),226(100),199(13),171(25),170(12),75(69),56(16),55(15),47(19),41(19). 1 H NMR (400MHz, DMSO, mixture of stereoisomers and tautomers) δ12.14,12.05,11.82(brs,1H),7.82-7.71(m,2H),7.69-7.50(m,1H),7.45-7.28(m,2H),7.2 7-7.11(m,1H),5.82-5.40(m,1H),4.50-3.06(m,3H),2.76-2.12(m,1H),2.08-1.97(m,3H),1.95-1.44(m,5H),1.41-1.32(m,3H)ppm.

[0144] Example 38: 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Example 38a: 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,70eV):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.

[0145] Example 38b: 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 the 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,70eV):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).

[0146] Example 38c: 2-(methylthio)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one: Prepared in the same manner as in Example 36 using 2-(5-(p-tolyl)imidazol-2-yl)piperidine and 2-(methylthio)propanoic acid to provide 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.

[0147] Example 39: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one To a solution of 2-methylbut-3-enoic acid (0.597 g, 5.97 mmol) in dichloromethane (100 mL) was added HOBt (0.914 g, 5.97 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (0.926 g, 5.97 mmol) at 0-5°C, and the mixture was stirred at rt for 0.5 h. Then 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (1.2 g, 4.97 mmol) and DIPEA (1.563 mL, 8.95 mmol) were added, and the mixture was stirred at rt for 16 h. The suspension was filtered to remove the solvent, and the crude product was purified by silica gel chromatography (hexane:MTBE=3:1) to give 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one (808 mg, yield: 50%) as a white solid. GC / MS (EI, mixture of stereoisomers, ratio 1:2): Isomer 1: m / z (%): 323 (2) [M +],268(5),240(100),172(95),117(7),84(3),55(11). Heterogeneous body 2:m / z(%):323(2)[M + ],268(5),240(100),211(6),172(81),117(7),84(2),55(10). 1 ¹H NMR (300MHz, DMSO-d⁶, a mixture of stereoisos and teratospheric substances) δ 12.06, 11.81 (brs, 1H), 7.69–7.62 (m, 2H), 7.49 (s, 1H), 7.15 (d, J = 7.3 Hz, 2H), 6.12–5.70 (m, 2H), 5.47–4.81 (m, 2H), 4.63–2.90 (m, 3H), 2.81–2.35 (m, 1H), 2.29 (s, 3H), 1.78–1.29 (m, 5H), 1.17 (t, J = 5.6 Hz, 3H). 13 C NMR (75MHz, DMSO-d6, mixture of stereoisotropic entities) δ172.7(q), 172.5(q), 172.3(q), 147.1(q), 146.7(q), 140.3( q),139.8(q),139.6(t),139.1(t),135.3(q),132.7(q),129.4(t),124.6(t),115.4(d),115.3(d),113. 0(t),112.6(t),51.7(t),51.3(t),47.0(t),46.8(t),42.8(d),42.6(d),40.2(t),39.3(t),38.6(d),28 .4(d),28.1(d),26.1(d),25.8(d),25.3(d),21.2(s),20.3(d),20.1(d),18.4(s),18.2(s),18.0(s)ppm.

[0148] Example 40: 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one Following the general procedure described in Example 39: reaction of 2,2-dimethylbut-3-enoic acid (170 mg, 1.492 mmol), HOBt (228 mg, 1.492 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (232 mg, 1.492 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (300 mg, 1.243 mmol), and DIPEA (0.391 ml, 2.238 mmol) in dichloromethane (30 mL) gave the title product (255 mg, yield: 68%) as a white solid. GC / MS(EI):m / z(%):337(1)[M + ],322(3),268(10),240(89),213(6),197(6),172(100),117(8),69(8). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ12.04-11.70(m,1H),7.83-7.51(m,2H),7.51-7.37(m,1H),7.32-7.00(m,2H),6.23-6.1 0(m,1H),5.81-5.34(m,1H),5.27-4.80(m,2H),4.60-2.96(m,2H),2.43-2.17(m,4H),1.87-1.43(m,5H),1.40-1.19(m,6H). 13 C NMR (75MHz, DMSO-d6, mixture of tautomers) δ174.1(q),147.0(q),144.4(t),139.9(q),135.2(q),132.7(q),129.7(t),129.3(t),124. 5(t),112.9(t),112.5(d),52.7(t),47.6(t),45.1(s),43.9(d),28.0(d),27.4(s),27.1(s),25.3(d),21.2(s),20.2(d)ppm.

[0149] Example 41: 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one A solution of 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one (120 mg, 0.356 mmol) in ethyl acetate (20 ml) was treated with Pd / C (10 wt%) (71 mg) under nitrogen, placed under a hydrogen atmosphere and stirred at room temperature overnight. The mixture was then purged with nitrogen, filtered over Celite, and evaporated to give the crude material, which was purified by flash column chromatography (hexane:MTBE=3:1) to give the title product (88 mg, yield: 73%) as a white solid. GC / MS(EI):m / z(%):339(2)[M + ],324(1),268(3),240(100),212(3),185(12),172(3),71(12). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ12.02, 11.70 (brs, 1H), 7.83-7.59 (m, 2H), 7.57-7.38 (m, 1H), 7.26-7.04 (m, 2H) ),5.75-5.69(m,1H),4.20-3.08(m,2H),2.40-2.19(m,4H),1.86-1.32(m,7H),1.20(s,6H),0.88(t,J=7.2Hz,3H). 13 C NMR(75MHz,DMSO-d6, mixture of tautomers) δ175.3(q),147.2(q),139.9(q),135.2(q),132.7(q),129.7(t),129.3(t),124.5(t),112.7(t),48. 9(t),43.0(q),42.7(d),33.2(d),29.4(d),28.6(d),27.0(s),26.8(s),25.8(d),21.2(s),20.3(d),9.8(s)ppm.

[0150] Example 42: 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one Following the general procedure described in Example 39: reaction of 2,2,3-trimethylbut-3-enoic acid (191 mg, 1.492 mmol), HOBt (228 mg, 1.492 mmol), 3-(((ethylimino)methylene)-amino)-N,N-dimethylpropan-1-amine (232 mg, 1.492 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (300 mg, 1.243 mmol), and DIPEA (0.391 ml, 2.238 mmol) in dichloromethane (30 mL) gave the title product (237 mg, yield: 54%) as a white solid. GC / MS(EI):m / z(%):351(6)[M + ],336(6),268(10),240(100),224(39),172(51),117(9),83(6),55(12). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ12.04-11.71(m,1H),7.71-7.49(m,2H),7.46(s,1H),7.23-7.08(m,2H),5. 81-5.34(m,1H),4.91-4.86(m,2H),4.61-3.20(m,2H),2.43-2.17(m,4H),1.94-1.47(m,8H),1.43-1.21(m,6H). 13 C NMR (75MHz, DMSO-d6, mixture of tautomers) δ174.1(q),150.6(q),147.1(q),139.7(q),135.2(q),132.7(q),129.7(t),129.3(t),124.5(t),124. 3(t),112.6(t),109.0(d),48.1(q),47.4(t),43.0(d),29.5(d),28.5(d),27.0(s),26.5(s),25.4(d),21.2(s),20.2(s),20.2(d)ppm.

[0151] Example 43: 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Following the general procedure described in Example 41: hydrogenation of 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one (100 mg, 0.284 mmol) catalyzed by 10% Pd / C (57 mg) in ethyl acetate (20 ml) under hydrogen atmosphere gave the title product (82 mg, yield: 81%) as a white solid. GC / MS(EI):m / z(%):353(1)[M + ],338(1),268(3),240(100),224(3),185(15),172(4),130(4),117(4),85(10). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ12.00,11.70(brs,1H),7.81-7.50(m,2H),7.45(s,1H),7.28-7.05(m,2H),5.79 -5.65(m,1H),4.34-3.02(m,2H),2.54-2.10(m,2H),2.28(s,3H),1.72-1.27(m,5H),1.13(s,6H),0.92-0.81(m,6H). 13 C NMR (75MHz, DMSO-d6, mixture of tautomers) δ176.0(q),147.2(q),140.0(q),135.2(q),132.7(q),129.8(t),129.4(t),124.6(t),112 .7(t),49.2(t),46.2(q),43.3(d),33.3(t),29.4(d),28.6(d),25.8(d),23.1(s),22.9(s),21.2(s),20.4(d),18.1(s)ppm.

[0152] Example 44: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)prop-2-en-1-one Following the general procedure described in Example 39: reaction of methacrylic acid (171 mg, 1.989 mmol), HOBt (305 mg, 1.989 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (309 mg, 1.989 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (400 mg, 1.657 mmol), and DIPEA (0.521 ml, 2.98 mmol) in dichloromethane (30 mL) gave the title product (147 mg, yield: 30%) as a white solid. GC / MS(EI):m / z(%):309(10)[M + ],240(100),185(12),159(36),117(6),69(6). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ12.15-11.91(m,1H),7.66-7.14(m,5H),5.74- 5.11(m,3H),4.52-2.67(m,2H),2.46-2.18(m,4H),1.90(s,3H),1.78-1.30(m,5H). 13 C NMR (75MHz, DMSO-d6, mixture of tautomers) δ171.4(q),146.6(q),141.1(q),140.4(q),135.4(q),132.6(q),129.4(t),124.7 (t),114.7(d),112.9(t),53.7(t),46.8(t),44.4(d),38.4(d),28.5(d),25.6(d),21.2(s),20.7(s),20.3(d)ppm.

[0153] Example 45: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Following the general procedure described in Example 41: hydrogenation of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one (350 mg, 1.082 mmol) catalyzed by 10% Pd / C (216 mg, 0.216 mmol) in ethyl acetate (20 ml) under hydrogen atmosphere gave the title product (290 mg, yield: 82%) 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 ¹H NMR (300MHz, DMSO-d6, a mixture of stereoisos) δ 12.05–11.72 (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). 13 C NMR (75MHz, DMSO-d6, mixture of stereoisotropic entities) 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.

[0154] Example 46: 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 39: reaction of 2-methyl-2-(methylthio)propanoic acid (0.267 g, 1.989 mmol), HOBt (305 mg, 1.989 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (309 mg, 1.989 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (400 mg, 1.657 mmol), and DIPEA (0.521 ml, 2.980 mmol) in dichloromethane (30 mL) gave the title product (287 mg, yield: 48%) as a white solid. GC / MS(EI):m / z(%):357(5)[M + ],342(7),268(11),240(100),185(11),159(5),117(4),89(10). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ12.06,11.82(brs,1H),7.80-7.54(m,2H),7.50(s,1H),7.33-7.08( m,2H),6.15-5.89(m,1H),4.92-2.73(m,2H),2.47-2.23(m,4H),2.19-2.03(m,3H),1.86-1.35(m,11H). 13 C NMR (75MHz, DMSO-d6, mixture of tautomers) δ171.1(q),170.8(q),148.3(q),146.8(q),140.1(q),136.1(q),135.2(q),132.6(q),131.6(q),129.7(t),129. 7(t),129.3(t),124.6(t),112.8(t),53.5(t),48.4(t),47.6(q),44.4( d),29.3(d),28.6(d),27.6(s),25.8(d),21.2(s),20.2(d),12.9(s)ppm.

[0155] Example 47: 2-(allylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 39: reaction of 2-(allylthio)propanoic acid (0.236 g, 1.616 mmol), HOBt (0.228 g, 1.492 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (232 mg, 1.492 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (300 mg, 1.243 mmol), and DIPEA (0.391 ml, 2.238 mmol) in dichloromethane (30 mL) gave the title product (193 mg, yield: 42%) as a white solid. GC / MS (EI, mixture of stereoisomers, ratio 5:4): isomer 1: m / z (%): 369 (2) [M + ],328(31),268(7),240(100),185(25),159(28). Isomer 2:m / z(%):369(2)[M + ],328(43),297(3),268(9),240(100),185(29),159(29),101(6),73(5). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.02,11.79(brs,1H),7.87-7.58(m,2H),7.55-7.36(m ,1H),7.31-7.04(m,2H),5.99-4.93(m,4H),4.49-3.04(m,5H),2.68-2.29(s,4H),1.93-1.30(m,8H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.7(q), 170.6(q), 170.5(q), 147.0(q), 146.9(q), 146.6(q), 140.3(q), 140.0(q), 135.4(q), 135.3(q), 135.1(t), 135.0(t), 134.9(t), 132.6(q), 132.5(q), 129.7(t), 129.4(t), 124.6(t), 117.8(d), 117. .6(d),113.1(t),112.6(t),112.5(t),51.6(t),47.4(t),47.1(t),43.2(d),43.0(d),38.9(d),38.2(t),37.7(t),37.6(t),3 2.7(d),32.6(d),28.6(d),28.0(d),26.1(d),25.7(d),25.2(d),21.2(s),20.2(d),20.1(d),19.1(s),18.9(s),18.7(s)ppm.

[0156] Example 48: (E)-2-Methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pent-2-en-1-one Following the general procedure described in Example 39: reaction of (E)-2-methylpent-2-enoic acid (213 mg, 1.865 mmol), HOBt (381 mg, 2.486 mmol), 3-(((ethylimino)methylene)-amino)-N,N-dimethylpropan-1-amine (386 mg, 2.486 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (300 mg, 1.243 mmol), and DIPEA (0.543 ml, 3.11 mmol) in dichloromethane (50 mL) gave the title product (76 mg, yield: 19%) as a white solid. GC / MS(EI):m / z(%):337(5)[M + ],308(10),240(100),224(3),185(10),159(11),132(3),117(4),97(3),69(6).

[0157] Example 49: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pentan-1-one Following the general procedure described in Example 41: (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pent-2-en-1-one (80 mg, 0.237 mmol) was catalyzed with 10% Pd / C (47 mg, 0.047 mmol) in ethyl acetate (10 ml) under hydrogen atmosphere to give the title product (55 mg, yield: 68%) as a white solid. GC / MS (EI, mixture of stereoisomers, ratio 1:1): Isomer 1: m / z (%): 339 (8) [M + ],310(1),268(2),240(100),224(3),185(8),159(2),117(3),71(2).Isomer 2:m / z(%):339(8)[M + ],310(1),268(2),240(100),224(3),185(8),159(2),117(3),71(1). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.09-11.75(brs,1H),7.71-7.08(m ,5H),5.83-5.32(m,1H),4.47-2.89(m,3H),2.48-2.22(m,4H),1.70-0.84(m,15H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 175.5(q), 175.2(q), 147.2(q), 147.1(q), 146.8(q), 140.4(q), 140.0(q), 139.9(q), 135.3(q), 135.2(q), 132.7(q), 132.6(q), 129.7(t), 129.3(t), 124.6(t), 112.6(t), 112.5(t), 51.5(t), 51 .3(t),46.8(t),46.8(t),42.6(d),38.5(d),38.4(d),37.2(d),36.5(d),36.4(d),36.2(d),34.6(t),34.4(t),29.4(d ),29.1(d),28.4(d),26.2(d),25.4(d),25.2(d),21.2(s),20.4(d),20.3(d),18.2(s),17.6(s),14.6(s),14.5(s)ppm.

[0158] Example 50: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butane-1,3-dione Following the general procedure described in Example 39: reaction of 2-methyl-3-oxobutanoic acid (144 mg, 1.243 mmol), HOBt (254 mg, 1.657 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (257 mg, 1.657 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (200 mg, 0.829 mmol), and DIPEA (0.362 ml, 2.072 mmol) in dichloromethane (50 mL) gave the title product (45 mg, yield: 16%) as a white solid. GC / MS(EI):m / z(%):339(1)[M + ],297(13),268(1),240(100),212(3),198(2),185(11),172(2),117(5),84(2). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ11.94,11.78(brs,1H),7.63(d,J=7.5Hz,2H),7.42(s,1H) ,7.14(d,J=7.5Hz,2H),5.76-5.21(m,1H),4.52-3.04(m,2H),2.70-2.24(m,6H),2.11-1.05(m,10H)ppm.

[0159] Example 51: 1-(2-(5-benzyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared following a procedure similar to that described in Example 2 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(methylthio)propanoic acid to give the title product as a pale yellow solid. GC / MS(EI):m / z(%):343(3)[M + ],328(8),297(10),268(19),240(100),213(15),185(23),130(12),91(19),75(24).

[0160] Example 52: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 39: reaction of isobutyric acid (142 mg, 1.616 mmol), HOBt (228 mg, 1.492 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (232 mg, 1.492 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (300 mg, 1.243 mmol), and DIPEA (0.391 ml, 2.238 mmol) in dichloromethane (30 mL) gave the title product (243 mg, yield: 63%) as a white solid. GC / MS(EI):m / z(%):311(10)[M + ],268(2),240(100),185(12),159(3),117(5). 1H NMR (300MHz, DMSO-d6, mixture of tautomers) δ11.94-11.72(m,1H),7.81-7.53(m,2H),7.52-7.30(m,1H),7.24- 7.02(m,2H),5.78-5.29(m,1H),4.55-2.38(m,3H),2.28(s,3H),1.81-1.16(m,6H),1.12-0.97(m,6H). 13 C NMR (75MHz, DMSO-d6, mixture of tautomers) δ175.8(q),147.4(q),139.8(q),135.4(q),132.4(q),129.4(t),124.6(t),112.8(t),51.4(t) ,46.8(t),42.6(d),38.5(d),29.8(t),28.9(d),28.3(d),26.2(d),25.2(d),21.2(s),20.6(s),20.2(d),20.1(s),19.5(s)ppm.

[0161] Example 53: 1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 39: reaction of propionic acid (120 mg, 1.616 mmol), HOBt (228 mg, 1.492 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (232 mg, 1.492 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (300 mg, 1.243 mmol), and DIPEA (0.391 ml, 2.238 mmol) in dichloromethane (30 mL) gave the title product (239 mg, yield: 65%) as a pale yellow solid. GC / MS(EI):m / z(%):297(10)[M + ],268(1),240(100),185(13),103(3),57(10). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ11.97,11.75(brs,1H),7.75-7.03(m,5H),5.78-5.21(m,1H),4.55-2.33(m,3H),2.28(s,3H),1.86-0.98(m,10H). 13 C NMR (75MHz, DMSO-d6, mixture of tautomers) δ172.7(q),147.2(q),146.8(q),140.3(q),135.3(q),132.6(q),129.3(t),124.67(t),113.0(t),11 2.6(t),51.3(t),46.9(t),42.5(d),38.4(d),28.5(d),28.0(d),26.3(d),26.0(d),25.8(d),25.2(d),21.1(s),20.2(d),9.8(s)ppm.

[0162] Example 54: 2-(furan-3-yl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 39: reaction of 2-(furan-3-yl)propanoic acid (439 mg, 3.13 mmol), HOBt (480 mg, 3.13 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (486 mg, 3.13 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (700 mg, 2.61 mmol), and DIPEA (0.647 ml, 3.92 mmol) in dichloromethane (30 mL) gave the title product (565 mg, yield: 57%) as a white solid. GC / MS (EI, mixture of stereoisomers, ratio 1:1): Isomer 1: m / z (%): 363 (4) [M + ],348(3),334(1),268(6),240(100),185(19),95(41).Isomer 2:m / z(%):363(3)[M + ],348(3),334(1),268(8),240(100),185(18),95(40). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.10-11.79(m,1H),7.91-7.13(m,7H),6.56-6.42 (m,1H),5.52-5.29(m,1H),4.45-3.77(m,2H),3.21-2.67(m,1H),2.29(s,3H),1.58-1.29(m,7H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 172.5 (q), 172.4 (q), 147.2 (q), 147.0 (q), 146.6 (q), 143.8 (t), 143.7 (t), 143.2 (t), 140.5 (t), 139.7 (t), 135.2 (q), 132.7 (q), 129.6 (t), 129.4 (t), 127.9 (q), 126.6 (q), 126.5 (q), 125.8 (q), 124.6(t),113.1(t),112.7(t),110.9(t),110.4(t),51.4(t),47.2(t),43.1(d),42.8(d),40.8(d),39.1(d),38.7(d) ,32.9(t),32.7(t),28.5(d),27.7(d),26.0(d),25.4(d),25.1(d),21.2(s),20.3(d),20.1(s),20.0(s),19.3(s)ppm.

[0163] Example 55: Cyclopentyl(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone Following the general procedure described in Example 39: reaction of cyclopentanecarboxylic acid (255 mg, 2.238 mmol), HOBt (343 mg, 2.238 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (347 mg, 2.238 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (500 mg, 1.865 mmol), and DIPEA (0.462 ml, 2.80 mmol) in dichloromethane (30 mL) gave the title product (286 mg, yield: 43%) as a white solid. GC / MS(EI):m / z(%):337(4)[M + ],268(1),240(100),212(4),185(14),103(2),69(22). 1 H NMR (300MHz, DMSO-d6, mixture of tautomers) δ11.94-11.73(m,1H),7.65-7.12(m,5H), 5.77-5.32(m,1H),4.45-3.02(m,3H),2.43-2.28(m,4H),1.87-1.36(m,13H). 13 C NMR (75MHz, DMSO-d6, mixture of tautomers) δ174.7(q),174.6(q),147.2(q),146.9(q),140. 4(q),140.0(q),135.2(q),132.7(q),129.6(t),129.3(t),124.6(t),112.9(t),1 12.6(t),51.4(t),46.9(t),42.6(d),40.9(t),38.6(d),30.8(d),30.3(d),29.9( d),29.5(d),28.8(d),28.1(d),26.3(d),26.1(d),25.3(d),21.2(s),20.3(d)ppm.

[0164] Example 56: (2S)-2-Methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Following the general procedure described in Example 39: reaction of (S)-2-methylbutanoic acid (0.84 g, 8.20 mmol), HOBt (1.37 g, 8.95 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (1.39 g, 8.95 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (2.00 g, 7.46 mmol), and DIPEA (1.85 mL, 11.19 mmol) in dichloromethane (100 mL) gave the title product (1.62 g, yield: 67%) as a white solid. GC / MS(EI):m / z(%):325(5)[M + ],310(1),268(2),240(100),185(14),171(3),159(3),84(3),57(17). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.03-11.71(m,1H),7.66-7.63(m,2H),7.54-7.46(m 1H),7.20-7.11(m,2H),5.84-5.27(m,1H),4.45-3.83(m,1H),3.39-3.26(m,1H),2.78 -2.74(m,1H),2.69-2.43(m,1H),2.29(s,3H),1.67-1.29(m,7H),1.08-1.04(m,3H),0.89-0.85(m,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 175.3(q), 175.2(q), 175.1(q), 148.5(q), 147.2(q), 147.1(q), 146.8(q), 140.5(q), 140.0(q), 136.0(q), 135.1(q), 132.7(q), 129.7(t), 129.3(t), 1 24.6(t),112.9(t),112.6(t),51.4(t),46.8(t),42.6(d),40.8(t),38.5(d),36.4(d),28.4(d), 27.2(d),26.9(d),26.3(d),25.5(d),21.2(s),20.3(d),17.7(s),17.3(s),12.1(s),12.0(s)ppm.

[0165] Example 57: (E)-2-Methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pent-3-en-1-one Following the general procedure described in Example 39: reaction of (E)-2-methylpent-3-enoic acid (255 mg, 2.24 mmol), HOBt (343 mg, 2.24 mmol), 3-(((ethylimino)methylene)-amino)-N,N-dimethylpropan-1-amine (347 mg, 2.24 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (500 mg, 1.86 mmol), and DIPEA (0.46 ml, 2.80 mmol) in dichloromethane (30 mL) gave the title product (460 mg, yield: 69%) as a white solid. GC / MS (EI, mixture of stereoisomers, ratio 2:3): isomer 1: m / z (%): 337 (1) [M + ],322(1),268(8),240(100),186(96),171(9),103(5),91(3),69(34).Isomer 2:m / z(%):337(1)[M + ],322(1),268(8),240(92),186(100),171(8),159(6),103(6),69(34). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.03-11.75(m,1H),7.62-7.13(m,5H ),5.77-5.16(m,3H),4.41-2.62(m,3H),2.42-2.23(m,4H),1.68-1.09(m,11H)ppm.

[0166] Example 58: 2-Methoxy-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following the general procedure described in Example 39: reaction of 2-methoxypropanoic acid (233 mg, 2.238 mmol), HOBt (343 mg, 2.238 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (347 mg, 2.238 mmol), 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (500 mg, 1.865 mmol), and DIPEA (0.46 ml, 2.80 mmol) in dichloromethane (30 mL) gave the title product (420 mg, yield: 65%) as a white solid. GC / MS (EI, mixture of stereoisomers, ratio 28:72): isomer 1: m / z (%): 327 (6) [M + ],312(9),268(8),240(100),185(17),171(4),159(3),103(3),59(36).Isomer 2:m / z(%):327(6)[M + ],312(8),268(8),240(100),185(17),171(4),159(3),103(3),59(34). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.04-11.80 (m, 1H), 7.66-7.12 (m, 5H), 5.76-5.35 (m, 1H), 4.35-2.73 (m, 6H), 2.44-2.28 (m, 4H), 1.76-1.26 (m, 8H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 171.3 (q), 171.1 (q), 170.7 (q), 148.1 (q), 146.8 (q), 146.6 (q), 140.4 (q), 140.1 (q), 136.2 (q), 135.2 (q), 132.7 (q), 129.7 (t), 129.3 (t), 124.6 (t), 113.0 (t),112.7(t),75.6(t),75.4(t),74.8(t),56.8(s),56.5(s),55.8(s),50.9(t),47.3(t),42.3(d) ,40.8(d),38.9(d),28.6(d),28.2(d),26.0(d),25.3(d),21.2(s),20.2(d),18.1(s),17.0(s)ppm.

[0167] Example 59: 2-(methylthio)-1-(2-(5-(5-methylthiophen-2-yl)imidazol-2-yl)piperidin-1-yl)propan-1-one Prepared following a procedure similar to that described in Example 38 using tert-butyl-2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (5-methylthiophen-2-yl)boronic acid, and 2-(methylthio)propanoic acid to afford the title product as a white solid. MS(EI,70eV):349(3,[M]+·),247(16),246(100),219(13),191(16),84(13),75(69),56(16),55(14),47(17),41(17).

[0168] Example 60: 2-(methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)imidazol-2-yl)piperidin-1-yl)propan-1-one Prepared from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-(trifluoromethyl)phenyl)boronic acid, and 2-(methylthio)propanoic acid following a procedure similar to that described in Example 38 provided 2-(methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)imidazol-2-yl)piperidin-1-yl)propan-1-one as a white solid. MS(EI,70eV):397(4,[M]+·),382(2),378(1),322(8),294(100),239(46),84(64),82(16),75(78),56(18),55(20),47(17),41(26),28(28).

[0169] Example 61: 2-(methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one Example 61a: Benzyl 2-((2-oxo-2-(p-tolyl)ethyl)carbamoyl)piperidine-1-carboxylate: To a stirred solution of 1-((benzyloxy)carbonyl)piperidine-2-carboxylic acid (8.0 g, 0.030 mol) and 2-amino-1-(p-tolyl)ethan-1-one (5.00 g, 0.033 mol) in DMF (N,N-dimethylformamide) (80 ml), EDC.HCl (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride) (8.6 g, 0.045 mol), HOBt (6.18 g, 0.045 mol), and N,N-diisopropylethylamine (16 ml, 0.045 mol) were added at 0°C. The reaction mixture was stirred overnight at rt, diluted with water (300 ml), and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with water (100 ml x 3) and brine (150 ml). It was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography by using silica gel (230-400 mesh) with EtOAc in pet ether (0-25%) as eluent to give benzyl 2-((2-oxo-2-(p-tolyl)ethyl)carbamoyl)piperidine-1-carboxylate (8.0 g, 50%) as a yellow liquid. LC-MS(ESI+):395(100,[M+H]+).

[0170] Example 61b: Benzyl 2-(5-(p-tolyl)oxazol-2-yl)piperidine-1-carboxylate: To a solution of benzyl 2-((2-oxo-2-(p-tolyl)ethyl)carbamoyl)piperidine-1-carboxylate (7.5 g, 0.019 mol) in acetonitrile (140 ml) was added POCl3 (3.5 ml, 0.038 mol) and the reaction mixture was heated to 80 °C for 2 h. The reaction mixture was evaporated under reduced pressure and the pH was adjusted to 8.0 by adding aq. sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (100 ml × 2) and the combined organic layers were washed with water (200 ml) and brine (100 ml). It was dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography by using silica gel (230-400 mesh) with EtOAc in petroleum ether (0-25%) as the eluent to give benzyl 2-(5-(p-tolyl)oxazol-2-yl)piperidine-1-carboxylate (4.5 g, 63%) as a pale yellow liquid. LC-MS(ESI+):377(100,[M+H]+).

[0171] Example 61c: 2-(piperidin-2-yl)-5-(p-tolyl)oxazole: To a stirred solution of benzyl 2-(5-(p-tolyl)oxazol-2-yl)piperidine-1-carboxylate (4.5 g, 0.0119 mol) in methanol (90 ml), 10% Pd / C (0.45 g, 10 mol%) was added and stirred at rt (room temperature) for 16 h. The reaction mixture was filtered through a plug of Celite and washed with methanol (40 mL). The filtrate was concentrated under reduced pressure, diluted with water (50 ml), and extracted with ethyl acetate (50 ml × 3). The combined organic layers were washed with water (50 ml × 3) and brine (50 ml). It was dried under Na2SO4 and concentrated under reduced pressure to give 2-(piperidin-2-yl)-5-(p-tolyl)oxazole (2.5 g, 63%) as a liquid. LC-MS(ESI+):243(100,[M+H]+). 13C NMR(101MHz,DMSO)δ165.1,150.6 138.2,130.0,125.5,124.3,121.9,54.3,46.0,30.3,26.0,24.0,21.3ppm.

[0172] Example 61d: 2-(methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one: Prepared from 2-(piperidin-2-yl)-5-(p-tolyl)oxazole and 2-(methylthio)propanoic acid following the general procedure described in Example 39 to give 2-(methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one as a white solid. MS(EI,70eV): 344(3,[M]+·),241(100),119(27),91(32),84(40),75(76),56(21),55(39),47(20),41(37),28(36). 1 H NMR (400MHz, DMSO, mixture of stereoisomers and tautomers) δ7.64-7.50(m,3H),7.28(d,J=7.9Hz,2H),5.91,5.90,5.64(brs,1H) ,4.51-3.04(m,3H),2.80-2.26(m,1H),2.33(s,3H),2.12-1.94(m,3H),1.90-1.42(m,5H),1.40-1.32(m,3H). 13 C NMR (101 MHz, DMSO, mixture of stereoisomers and tautomers) δ 170.8 (q), 161.8 (q), 151.3 (q), 138.4 (q), 130.0 (t), 125.2 (q), 124.2 (t), 122.2 (t), 47.3 (t), 43.1 (d), 37.9 (t), 28.8 (d), 27.6 (d), 25.4 (d), 21.3 (s), 20.1 (d), 17.8 (s), 11.9 (s).

[0173] Example 62: 2-(methylthio)-1-(2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one Example 62a: tert-butyl 2-(2-(4-methylbenzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate: To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (3.0 g, 0.013 mol) and 4-methylbenzohydrazide (2.16 g, 0.014 mol) in DMF (30 ml) was added EDC.HCl (3.7 g, 0.0195 mol), HOBt (2.60 g, 0.0195 mmol), and N,N-diisopropylethylamine (6.8 ml, 0.039 mmol) at 0°C. The reaction mixture was stirred at rt overnight, diluted with water (15 ml), and extracted with ethyl acetate (25 ml x 3). The combined organic layer was washed with water (15 ml x 3) and brine (15 ml). It was dried under Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 8% methanol in DCM (dichloromethane) as the eluent to give tert-butyl 2-(2-(4-methylbenzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate as a pale yellow gummy solid (3.0 g). LC-MS(ESI-):360(100,[MH]-).

[0174] Example 62b: tert-butyl 2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 2-(2-(4-methylbenzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate (4.5 g, 0.017 mol) in MeCN (50 ml) was added TsCl (p-toluenesulfonyl chloride) (3.56 g, 0.0186 mol) and triethylamine (7.1 ml, 0.051 mmol) at 0° C. The reaction mixture was stirred at rt overnight and quenched with saturated aqueous KCO (50 ml). The reaction mixture was concentrated under reduced pressure, diluted with water (30 ml) and extracted with ethyl acetate (50 ml × 3). The combined organic layer was washed with water (50 ml) and brine (50 ml). It was dried under NaSO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 20% ​​ethyl acetate in petroleum ether as the eluent to give tert-butyl 2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate as a yellow, slow-melting solid (3.5 g). LC-MS(ESI+):344(57,[M+H]+),288(100),244(28). 13 C NMR(101MHz,DMSO)δ165.4,165.1,155.0,142.2,131.4,130.4,130.0,129.7,129.6,127.8 ,127.0,126.8,121.0,80.5,53.5,47.6,42.0,41.3,37.9,28.3,27.2,24.8,21.6,19.8ppm.

[0175] Example 62c: 2-(piperidin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole: Preparation in analogy to Example 38b from tert-butyl 2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate gave 2-(piperidin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole as a yellow oil, which was used without further purification.

[0176] Example 62d: 2-(methylthio)-1-(2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one: Preparation from 2-(piperidin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole in analogy to Example 39 gave 2-(methylthio)-1-(2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one as a white solid. MS(EI,70eV):345(3,[M]+·),242(36),187(27),119(43),91(37),84(100),82(25),75(73),55(32),41(29),28(27). 1 H NMR (400MHz, DMSO, mixture of stereoisomers and tautomers) δ7.86(d,J=8.1Hz,2H),7.42(d,J=8.0Hz,2H),6.05,6.04,5.82(brs,J=47.1 Hz,1H),4.54-2.98(m,3H),2.85-2.22(m,1H),2.41(s,3H),2.11-2.02(m,3H),1.95-1.44(m,5H),1.41-1.32(m,3H). 13 C NMR (101 MHz, DMSO, mixture of stereoisomers and tautomers) δ 170.9 (q), 165.3 (q), 164.8 (q), 142.6 (q), 130.4 (t), 126.9 (t), 121.0 (q), 45.7 (t), 43.2 (d), 37.7 (t), 27.3 (d), 25.2 (d), 21.6 (s), 20.0 (d), 17.7 (s), 11.8 (s).

[0177] Example 63: 2-(methylthio)-1-(4-(5-(p-tolyl)imidazol-2-yl)thiazolidin-3-yl)propan-1-one Example 63a: 3-(2-(methylthio)propanoyl)thiazolidine-4-carboxylic acid: To a suspension of thiazolidine-4-carboxylic acid (2.010 g, 15.09 mmol) in dichloromethane (20 mL) and triethylamine (2.314 mL, 16.60 mmol) was added dropwise a solution of 2-(methylthio)propanoyl chloride (2.301 g, 16.60 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture was allowed to warm to rt and stirred overnight. The resulting mixture was poured onto ice-cold 1 M HCl (100 mL), extracted with dichloromethane (2×50 mL), washed with 1 M HCl (50 mL), water (50 mL), brine (50 mL), dried over MgSO4, and concentrated under reduced pressure to give 3-(2-(methylthio)propanoyl)thiazolidine-4-carboxylic acid (2.83 g, 15.09 mmol, 80% yield) as a colorless oil, which was used without further purification. MS(ESI-):234.2(100,[MH]-).

[0178] Example 63b: 2-oxo-2-(p-tolyl)ethyl 3-(2-(methylthio)propanoyl)thiazolidine-4-carboxylate: A solution of crude 3-(2-(methylthio)propanoyl)thiazolidine-4-carboxylic acid (2.83 g, 12.03 mmol) in DMF (12 ml) was treated with triethylamine (1.844 ml, 13.23 mmol) and 2-bromo-1-(p-tolyl)ethan-1-one (2.82 g, 13.23 mmol) at room temperature. The resulting mixture was stirred at rt overnight, then poured onto water (100 mL), extracted with EtOAc (2 × 100 mL), washed with 1 M HCl (50 mL), sat. aq. NaHCO (50 mL), water (50 mL), brine (50 mL), dried over MgSO and concentrated under reduced pressure to give 2-oxo-2-(p-tolyl)ethyl 3-(2-(methylthio)propanoyl)thiazolidine-4-carboxylate (4.4 g, 12 mmol, quant.) as a yellow oil, which was used in the next step without further purification. MS(EI,70eV):367(1,[M]+·),264(21),234(37),119(47),91(30),75(100).

[0179] Example 63c: 2-(methylthio)-1-(4-(5-(p-tolyl)imidazol-2-yl)thiazolidin-3-yl)propan-1-one: To a solution of 2-oxo-2-(p-tolyl)ethyl 3-(2-(methylthio)propanoyl)thiazolidine-4-carboxylate (4.42 g, 12.03 mmol) in toluene (60 ml) was added acetic acid (0.826 ml, 14.44 mmol) and ammonium acetate (20.40 g, 265 mmol). The mixture was slowly heated to reflux and stirred at reflux for 20 h. The resulting mixture was poured onto water, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography on silica gel eluting with a gradient of EtOAc in heptane to give 2-(methylthio)-1-(4-(5-(p-tolyl)imidazol-2-yl)thiazolidin-3-yl)propan-1-one (2.45 g, 7.05 mmol, 59% yield) as a pale yellow oil. MS(EI,70eV):347(11,[M]+·),332(4),301(14),244(59),217(33),185(100),184(94),103(17),91(15),75(59),28(23). 1 H NMR (400MHz, CDCl3, mixture of stereoisomers and tautomers) δ10.33,10.03,9.87(brs,1H),7.51(d,J=112.3Hz,2H),7.19(d,J=9.2Hz,3H),5.92,5.69 ,5.59(brs,1H),5.14-4.40(m,2H),3.79-3.16(m,2H),2.37(s,3H),2.18-2.11(m,1H),2.06(s,2H),1.98(s,1H),1.60-1.32(m,3H).

[0180] Example 64: 2-(methylthio)-1-((S)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one Example 64a: tert-butyl (S)-2-((2-oxo-2-(p-tolyl)ethyl)carbamoyl)piperidine-1-carboxylate: A solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (3.8 g, 16.57 mmol) in dichloromethane (20 mL) was cooled to 5 °C. HOBt (3.05 g, 19.89 mmol) and EDC.HCl (3.81 g, 19.89 mmol) were added, and the reaction mixture was stirred at ambient temperature for 30 min. 2-Amino-1-(p-tolyl)ethan-1-one hydrochloride (3.08 g, 16.57 mmol) and N,N-diisopropylethylamine (2.89 mL, 16.57 mmol) were added, and the reaction mixture was stirred at ambient temperature overnight. The red reaction mixture was poured into an ice-cold 1 M HCl (100 mL) solution, extracted twice with CHCl (50 mL), washed with water (50 mL), dried over MgSO, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with a gradient of EtOAc in heptane to give tert-butyl (S)-2-((2-oxo-2-(p-tolyl)ethyl)carbamoyl)piperidine-1-carboxylate (4.1 g, 11.37 mmol, 69% yield) as a yellow liquid. 1 H NMR (DMSO-d6,400MHz):δ=8.07(br s,1H),7.90(d,J=8.3Hz,2H),7.35(d,J=7.8Hz,2H),4.45-4.77(m,3H),3.85(br d,J=12.7Hz,1H),2.91-3.24(m,1H),2.39(s,3H),2.09-2.22(m,1H),1.55(range,3H),1.40(br s,9H),1.19-1.35ppm(m,2H). MS(EI,70eV):360(1,[M]+·),287(2),259(2),184(23),128(100),84(81),57(39).

[0181] Example 64b: tert-butyl (S)-2-(5-(p-tolyl)imidazol-2-yl)piperidine-1-carboxylate: tert-Butyl (S)-2-((2-oxo-2-(p-tolyl)ethyl)carbamoyl)piperidine-1-carboxylate (4 g, 11.10 mmol), ammonium acetate (18.82 g, 244 mmol), acetic acid (0.762 mL, 13.32 mmol), and toluene (50 mL) were heated to reflux and stirred overnight. The mixture was cooled to ambient temperature and poured into ice water (50 mL). The organic layer was washed with water (2×50 mL) and brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of EtOAc in heptane to give tert-butyl (S)-2-(5-(p-tolyl)imidazol-2-yl)piperidine-1-carboxylate (1.03 g, 3.02 mmol, 27% yield) as a white solid. MS(EI,70eV):341(4,[M]+·),285(12),268(4),240(23),185(85),91(6),57(100).

[0182] Example 64c: (S)-2-(5-(p-tolyl)imidazol-2-yl)piperidine: Prepared in the same manner as Example 38b from (S)-2-(5-(p-tolyl)imidazol-2-yl)piperidine-1-carboxylate to give (S)-2-(5-(p-tolyl)imidazol-2-yl)piperidine as an orange solid, which was used in the next step without further purification.

[0183] Example 64d: 2-(methylthio)-1-((S)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one: Prepared in the same manner as in Example 36 from (S)-2-(5-(p-tolyl)imidazol-2-yl)piperidine (0.40 g, 1.66 mmol) and racemic 2-(methylthio)propanoic acid (0.20 g, 1.66 mmol) to give 2-(methylthio)-1-((S)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one (0.150 g, 0.44 mmol, 26% yield) as an off-white solid. MS(EI,70eV):343(4,[M]+·),241(17),240(100),213(17),185(21),184(11),132(11),130(11),117(17),75(49),41(13). 1 H NMR (400MHz, DMSO, mixture of stereoisomers and tautomers) δ12.07,12.02,11.99,11.95(brs,1H),7.65(dd,J=8.0,2.8Hz,2H),7.58-7.40(m,1H),7.29-7.07(m ,2H),5.79-5.40(brs,1H),4.49-2.97(m,3H),2.78-2.35(m,1H),2.34 -2.25(m,3H),2.20-1.96(m,3H),1.95-1.42(m,5H),1.42-1.32(m,3H). 13C NMR (101 MHz, DMSO, mixture of stereoisomers and tautomers) δ 170.2(q), 170.0(q), 147.0(q), 146.8(q), 146.7(q), 140.3(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), 124.8(t), 124.7(t), 124.6(t), 113.0(t), 112.6(t), 1 12.5(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),20.1(d),18.3(s),18.0(s),17.8(s),11.9(s),11.7(s),11.6(s).

[0184] Example 65: 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one 2-(Methylthio)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one (30 mg, 0.087 mmol) was treated with water (0.5 mL) and acetic acid (0.5 mL), and finally with 35% aqueous hydrogen peroxide (0.153 mL, 1.747 mmol), and the mixture was stirred at room temperature (rt) overnight. The mixture was extracted with EtOAc (20 mL), washed with water (10 mL), brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with a gradient of EtOAc in heptane to give 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one (25 mg, 0.067 mmol, 76% yield) as a pale yellow foam. HRMS(ESI+):C 19 H 26 Calculated value for O3N3S[M+H]+: 376.1689; Found value: 376.1696.

[0185] Example 66: 2-(methylsulfinyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Obtained as a by-product in the preparation of 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one (Example 65). Purification by silica gel column chromatography eluting with a gradient of EtOAc in heptane gave 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one (4 mg, 0.011 mmol, 13% yield) as a pale yellow film. HRMS(ESI+):C 19 H 26 Theoretical value for O2N3S[M+H]+: 360.1740; Found: 360.1746.

[0186] Example 67: (S)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one Example 67a: (S)-2-(methylthio)propanoic acid: (S)-2-Mercaptopropanoic acid (5.0 g, 47 mmol) was added dropwise to a solution of sodium hydroxide (3.8 g, 94 mmol) in water (12 mL) at 10° C. Iodomethane (10.0 g, 71 mmol) was added dropwise over 30 min. The mixture was stirred at rt for 4 h. The mixture was poured into 2 N HCl solution, MTBE (50 mL) was added, the organic phase was separated, and the solvent was removed to give (S)-2-(methylthio)propanoic acid (4.8 g, yield: 85%) as a pale yellow oil. GC / MS(EI):m / z(%):120(59)[M + ],105(1),91(1),87(1),75(100),59(15),55(6).

[0187] Example 67b: (R)-2-(5-(p-tolyl)imidazol-2-yl)piperidine: Prepared in the same manner as in Example 64, but starting from (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid and using (S)-2-(methylthio)propanoic acid in the final step, gave (S)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one as an off-white solid. MS(EI,70eV):343(2,[M]+·),241(16),240(93),213(16),185(19),75(100),57(14),56(24),55(23),47(24),41(28). 1 H NMR (400MHz, DMSO-d6, mixture of rotamers and tautomers) δ11.95(brs,1H),7.63(d,J=8.0Hz,2H),7.58-7.42(m,1H),7.28-7.06(m,2H),5.64 (brs,1H),4.55-3.38(m,3H),2.80-2.32(m,5H),2.32-2.25(m,3H),2.22-1.96(m,3H),1.96-1.40(m,5H),1.39-1.31(m,3H)ppm.

[0188] Example 68: 2-(methylthio)-1-(2-(5-(p-tolyl)isoxazol-3-yl)piperidin-1-yl)propan-1-one Example 68a: tert-butyl (E)-2-((hydroxyimino)methyl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 2-formylpiperidine-1-carboxylate (4.0 g, 0.0187 mol) in methanol-water (1:1, 80 ml) was added sodium carbonate (1.19 g, 0.01122 mol) and hydroxylamine hydrochloride (1.55 g, 0.0213 mol) at 0 °C. This was stirred at 0 °C for 30 min, followed by stirring at rt overnight. This was concentrated under reduced pressure to half its volume, extracted with ethyl acetate (50 mL × 2), and the combined organic layers were washed with brine (20 ml), dried over Na SO , and concentrated under reduced pressure to give tert-butyl (E)-2-((hydroxyimino)methyl)piperidine-1-carboxylate as a colorless oil. The crude product (4.27 g) was used in the next step without purification.

[0189] Example 68b: tert-butyl (Z)-2-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate: To a solution of tert-butyl (E)-2-((hydroxyimino)methyl)piperidine-1-carboxylate (4.25 g, 16.17 mmol) in DMF (45 ml) was added N-chlorosuccinimide (2.73 g, 17.8 mmol) in portions at rt. The reaction mixture was stirred at 40° C. for 1 h. It was cooled to rt, diluted with ethyl acetate (150 ml), and washed with water (50 ml) and brine (50 ml). The organic layer was dried under sodium sulfate and concentrated under reduced pressure to give tert-butyl (Z)-2-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate as a gummy solid (6.4 g), which was used in the next step without purification.

[0190] Example 68c: tert-butyl 2-(5-(p-tolyl)isoxazol-3-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl (Z)-2-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (6.4 g, 24.35 mmol) in DCM (102 ml) was added 4 (7.54 ml, 64.13 mmol) and triethylamine (4.2 ml, 30.11 mmol) dropwise at 0 °C. After 30 min, it was warmed to rt and stirred at rt for 3 days. The reaction mixture was concentrated, diluted with ethyl acetate (200 ml), and washed with water (30 ml × 2). It was washed with brine (50 ml), dried under sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography using 20% ​​ethyl acetate in petroleum ether as the eluent to give 3.5 g of tert-butyl 2-(5-(p-tolyl)isoxazol-3-yl)piperidine-1-carboxylate as a white solid. LC-MS(ESI+): 343(16,[M+H]+),243(100). 13 C NMR(101MHz,DMSO)δ205.2,169.9,164.5,154.6,140.4,129.7,125.6,124.9,98.3,79.1,48.6,40.6,27.7,27.6,25.1,20.5,19.7ppm.

[0191] Example 68d: 3-(piperidin-2-yl)-5-(p-tolyl)isoxazole: Prepared in a similar manner to Example 38b using tert-butyl 2-(5-(p-tolyl)isoxazol-3-yl)piperidine-1-carboxylate to give 3-(piperidin-2-yl)-5-(p-tolyl)isoxazole as a yellow oil, which was used in the next step without further purification.

[0192] Example 68e: 2-(methylthio)-1-(2-(5-(p-tolyl)isoxazol-3-yl)piperidin-1-yl)propan-1-one: Prepared similarly as in Example 36 using 3-(piperidin-2-yl)-5-(p-tolyl)isoxazole and 2-(methylthio)propanoic acid to give 2-(methylthio)-1-(2-(5-(p-tolyl)isoxazol-3-yl)piperidin-1-yl)propan-1-one as a yellow liquid. MS(EI,70eV):344(3,[M]+·),179(22),119(100),91(36),84(56),82(19),75(75),56(20),55(33),41(30),28(25). 1 H NMR (400MHz, DMSO, mixture of stereoisomers and tautomers) δ7.85-7.66(m,2H),7.34(d,J=7.9Hz,2H),7.00-6.54(m,1H),5.87- 5.55(m,1H),4.13-2.86(m,3H),2.36(s,3H),2.31-2.00(m,4H),1.85-1.42(m,5H),1.37(d,J=5.3Hz,3H)ppm. 13 C NMR (101 MHz, DMSO, mixture of stereoisomers and tautomers) δ 170.8(q), 170.4(q), 169.9(q), 164.4(q), 164.3(q), 140.7(q), 130.2(t), 126.0(t), 124.6(q), 99.4(t), 46.3(t), 42.8(d), 37.7(t), 27.8(d), 25.5(d), 21.4(s), 21.2(s), 20.0(d), 17.8(s), 11.8(s) ppm.

[0193] Example 69: (R)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one Example 69a: (R)-2-(methylthio)propanoic acid: Preparation from (R)-2-mercaptopropanoic acid as in Example 67a gave (R)-2-(methylthio)propanoic acid as a colorless oil. GC / MS(EI):m / z(%):120(62)[M + ].

[0194] Example 69b: (R)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one: Prepared in the same manner as in Example 64, but starting from (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid and using (R)-2-(methylthio)propanoic acid in the final step, gave (R)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one as an off-white solid. MS(EI,70eV):343(4,[M]+·),241(17),240(100),213(17),185(21),184(11),132(11),130(11),117(17),75(49),41(13). 1 H NMR (400MHz, DMSO-d6, mixture of rotamers and tautomers) δ11.98,11.75(brs,1H),7.64(d,J=6.5Hz,2H),7.48(s,1H),7.14(d,J=7.0Hz,2H),5 .77-5.39(m,1H),4.66-3.04(m,3H),2.47-2.32(m,1H),2.29(s,3H),2.14-1.98(m,3H),1.77-1.41(m,5H),1.40-1.33(m,3H)ppm. 13 C NMR (101 MHz, DMSO-d6, mixture of rotamers and tautomers) δ 170.2 (q), 146.9 (q), 140.3 (q), 135.2 (q), 132.6 (q), 129.7 (t), 129.3 (t), 124.6 (t), 113.0 (t), 112.7 (t), 49.7 (t), 47.2 (t), 4 3.2(d),43.0(d),38.7(d),37.6(t),37.3(t),28.8(d),28.1(d),25.7(d),25.4(d),22 .5(d),21.2(s),20.2(d),20.1(d),18.0(s),17.8(s),17.1(s),11.9(s),11.6(s)ppm.

[0195] Example 70: 2-mercapto-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one Example 70a: 1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)-2-(tritylthio)propan-1-one: Prepared in the same manner as in Example 36 using 2-(5-(p-tolyl)imidazol-2-yl)piperidine and 2-(tritylthio)propanoic acid to give 1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)-2-(tritylthio)propan-1-one as a white solid. MS(EI,70eV):328(4),268(2),243(92),240(36),165(100),78(40).

[0196] Example 70b: 2-mercapto-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one: A solution of 1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)-2-(tritylthio)propan-1-one (0.43 g, 0.752 mmol) and triethylsilane (0.024 mL, 0.150 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (0.579 mL, 7.52 mmol) at 5° C. The reaction mixture was stirred at ambient temperature for 2 h and then poured into ice-cold 1 M NaOH (20 mL), extracted with dichloromethane (50 mL), washed with water (20 mL) and brine (20 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 heptane and a mixture of 80% EtOAc, 10% hexane, 9% EtOH, and 1% EtN to give 2-mercapto-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one (0.210 g, 0.637 mmol, 85% yield) as a white solid. MS(EI,70eV):329(3,[M]+·),296(1),268(6),240(83),61(100).

[0197] Example 71: 2-(methylthio)-1-((R)-2-(5-phenylimidazol-2-yl)pyrrolidin-1-yl)propan-1-one Prepared similarly to Example 36 from (R)-5-phenyl-2-(pyrrolidin-2-yl)-1H-imidazole dihydrochloride and 2-(methylthio)propanoic acid, employing an additional 2 molar equivalents of N,N-diisopropylethylamine, to give 2-(methylthio)-1-((R)-2-(5-phenylimidazol-2-yl)pyrrolidin-1-yl)propan-1-one as an orange solid. MS(EI,70eV):315(3,[M]+·),300(5),269(4),240(4),212(36),172(19),77(13),75(100),47(32).

[0198] Example 72: 2-amino-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one Example 72a: tert-butyl (1-oxo-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-2-yl)carbamate: Preparation similar to Example 36 from 2-(5-(p-tolyl)imidazol-2-yl)piperidine and (tert-butoxycarbonyl)alanine gave tert-butyl (1-oxo-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-2-yl)carbamate as a white solid, which was used in the next step without further purification.

[0199] Example 72b: 2-amino-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one: A solution of tert-butyl (1-oxo-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-2-yl)carbamate (0.20 g, 0.49 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.44 g, 3.88 mmol, 8 equiv.) at room temperature. The resulting mixture was stirred for 3 h, then poured into ice water (20 mL), treated with 2 M NaOH (20 mL), extracted with dichloromethane (2 × 30 mL), dried over MgSO and concentrated under reduced pressure to give 2-amino-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one (0.125 g, 0.400 mmol, 83% yield) as a white solid. MS(EI,70eV):312(3,[M]+·),240(41),44(100).

[0200] Example 73: 2,5-Difluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-cyano-2,5-difluorophenyl)boronic acid, and 2-(methylthio)propanoic acid provided 2,5-difluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)imidazol-4-yl)benzonitrile as a yellow film. HRMS(ESI+):C 19 H 20 Calculated value for F2N4OS[M+H]+: 391.1399; Found: 391.1395.

[0201] Example 74: (2-(4-phenylimidazol-2-yl)piperidin-1-yl)(1,2,3-thiadiazol-5-yl)methanone Preparation from 2-(5-phenylimidazol-2-yl)piperidine and 1,2,3-thiadiazole-5-carboxylic acid similar to Example 36 gave (2-(4-phenylimidazol-2-yl)piperidin-1-yl)(1,2,3-thiadiazol-5-yl)methanone as a pale yellow solid. HRMS(ESI+):C 17 H 17Calculated value for N5OS[M+H]+: 340.1227; Found: 340.1223.

[0202] Example 75: 2-(furan-3-yl)-1-(2-(4-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine and 3-furanacetic acid similar to Example 36 gave 2-(furan-3-yl)-1-(2-(4-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one as a pale yellow solid. HRMS(ESI+):C 20 H 21 Theoretical value for N3O2[M+H]+: 336.1707; Measured value: 336.1699.

[0203] Example 76: (Tetrahydrofuran-3-yl)(2-(4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone Preparation from 2-(5-(p-tolyl)imidazol-2-yl)piperidine and tetrahydrofuran-3-carboxylic acid similar to Example 36 gave (tetrahydrofuran-3-yl)(2-(4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone as a pale yellow oil. HRMS(ESI+):C 20 H 25 Theoretical value for N3O2[M+H]+: 340.2020; Measured value: 340.2013.

[0204] Example 77: 3,3-Difluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine and 3,3-difluorobutanoic acid similar to Example 36 gave 3,3-difluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one as a white solid. HRMS(ESI+):C 18 H 21 Theoretical value for F2N3O[M+H]+: 334.1725; Found: 334.1720.

[0205] Example 78: Cyclobutyl(2-(5-(3-fluorophenyl)imidazol-2-yl)piperidin-1-yl)methanone Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (3-fluorophenyl)boronic acid, and cyclobutanecarboxylic acid provided cyclobutyl(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone as a pale yellow film. HRMS(ESI+):C 19 H 22 Calculated value for FNO[M+H]: 328.1820; Found: 328.1814.

[0206] Example 79: 1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (3-fluorophenyl)boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 18 H 22 Theoretical value for FN3OS[M+H]+: 348.1540; Measured value: 348.1532.

[0207] Example 80: 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine and 3-methylbutanoic acid analogously to Example 36 gave 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one as a white solid. HRMS(ESI+):C 19 H 25 Theoretical value for NO[M+H]+: 312.2070; Measured value: 312.2064.

[0208] Example 81: 3-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (3-cyanophenyl)boronic acid, and 2-(methylthio)propanoic acid provided 3-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile as a pale yellow film. HRMS(ESI+):C 19 H 22 Theoretical value for N4OS[M+H]+: 355.1587; Found: 355.1581.

[0209] Example 82: 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-cyanophenyl)boronic acid, and 2-(methylthio)propanoic acid provided 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile as a yellow film. HRMS(ESI+):C 19 H 22 Theoretical value for N4OS[M+H]+: 355.1587; Found: 355.1581.

[0210] Example 83: 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine and 2-(methylsulfonyl)acetic acid similar to Example 36 gave 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one as a pale yellow oil. HRMS(ESI+):C 17 H 21 Theoretical value for N3O3S[M+H]+: 348.1376; Found: 348.1370.

[0211] Example 84: 2-Cyclopentyl-2-ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine and 2-cyclopentyl-2-ethoxyacetic acid similar to Example 36 gave 2-cyclopentyl-2-ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one as a pale yellow oil. HRMS(ESI+):C 23 H 31 Theoretical value for N3O2[M+H]+: 382.2489; Measured value: 382.2481.

[0212] Example 85: 2-methyl-3-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine and 2-methyl-3-(methylthio)propanoic acid similar to Example 36 gave 2-methyl-3-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a yellow oil. HRMS(ESI+):C 19 H 25 Calculated value for N3OS[M+H]+: 344.1791; Found: 344.1786.

[0213] Example 86: 2-(methylthio)-1-(2-(4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 3-thienylboronic acid, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a yellow film. HRMS(ESI+):C 16 H 21 Calculated value for N3OS2[M+H]+: 336.1199; Found: 336.1192.

[0214] Example 87: 1-(2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-fluorophenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS(ESI+):C 18 H 22 Theoretical value for FN3OS[M+H]+: 348.1540; Measured value: 348.1533.

[0215] Example 88: 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine and 2-(methylsulfonyl)propanoic acid similar to Example 36 gave 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a white waxy solid. HRMS(ESI+):C 18 H 23 Theoretical value for N3O3S[M+H]+: 362.1533; Found: 362.1524.

[0216] Example 89: 2-(methylthio)-1-(2-(4-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, o-tolylboronic acid, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a colorless film. HRMS(ESI+):C 19 H 25 Calculated value for N3OS[M+H]+: 344.1791; Found: 344.1786.

[0217] Example 90: 2-(methylthio)-1-(2-(4-(pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-pyridinylboronic acid, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow film. HRMS(ESI+):C 17 H 22 Calculated value for N4OS[M+H]+: 331.1587; Found: 331.1582.

[0218] Example 91: 1-(2-(4-(2-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-chlorophenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(2-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 18 H 22 Calculated value for ClN3OS[M+H]+: 364.1245; Found: 364.1238.

[0219] Example 92: 1-(2-(4-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-ethylphenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 20 H 27 Theoretical value for N3OS[M+H]+: 358.1948; Found: 358.1942.

[0220] Example 93: 1-(2-(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-hydroxyphenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 18 H 23 Theoretical value for N3O2S[M+H]+: 346.1584; Measured value: 346.1578.

[0221] Example 94: 2-(methylthio)-1-(2-(4-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, m-tolylboronic acid, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow film. HRMS(ESI+):C 19 H 25 Calculated value for N3OS[M+H]+: 344.1791; Found: 344.1786.

[0222] Example 95: 1-(2-(4-(2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-fluorophenylboronic acid, and 2-(methylthio)propanoic acid following a procedure similar to that described in Example 38 to provide 1-(2-(4-(2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow oil. HRMS(ESI+):C 18 H 22 Theoretical value for FN3OS[M+H]+: 348.1540; Measured value: 348.1535.

[0223] Example 96: 2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine and isobutyric acid analogously to Example 36 gave 2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a white solid. HRMS(ESI+):C 18 H 23 Calculated value for NO[M+H]: 298.1914; Found: 298.191.

[0224] Example 97: 2-Methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine 2-methoxypropanoic acid analogously to Example 36 gave 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a white solid. HRMS(ESI+):C 18 H 23 Theoretical value for N3O2[M+H]+: 314.1863; Measured value: 314.1859.

[0225] Example 98: 3,3,4,4,4-pentafluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Preparation from 2-(5-phenylimidazol-2-yl)piperidine 3,3,4,4,4-pentafluorobutanoic acid similar to Example 36 gave 3,3,4,4,4-pentafluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one as a pale yellow film. HRMS(ESI+):C 18 H 18 Calculated value for F5N3O[M+H]+: 388.1443; Found: 388.1439.

[0226] Example 99: N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methanesulfonamide Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-(methylsulfonamido)phenyl)boronic acid, and 2-(methylthio)propanoic acid provided N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methanesulfonamide as a pale yellow wax. HRMS(ESI+):C 19 H 26 Theoretical value for N4O3S2[M+H]+: 423.1519; Found: 423.1515.

[0227] Example 100: 1-(2-(4-(4-methoxy-2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-methoxy-2-methylphenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-methoxy-2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 20 H 27 Theoretical value for N3O2S[M+H]+: 374.1897; Measured value: 374.1894.

[0228] Example 101: 2-(methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (5-methylfuran-3-yl)boronic acid, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow film. HRMS(ESI+):C 17 H 23Theoretical value for N3OS2[M+H]+: 350.1355; Found: 350.1352.

[0229] Example 102: 1-(2-(4-(5-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 5-methylpyridine-3-boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(5-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 18 H 24 Theoretical value for N4OS[M+H]+: 345.1744; Found: 345.1743.

[0230] Example 103: 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-hydroxyphenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS(ESI+):C 18 H 23 Theoretical value for N3O2S[M+H]+: 346.1584; Measured value: 346.1584.

[0231] Example 104: 1-(2-(4-(3,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, 1-(2-(4-(3,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one was prepared from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 3,5-difluorophenylboronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(3,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS(ESI+):C 18 H 21 Theoretical value for F2N3OS[M+H]+: 366.1446; Found: 366.1446.

[0232] Example 105: 1-(2-(4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 6-methylpyridine-3-boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 18 H 24 Theoretical value for N4OS[M+H]+: 345.1744; Found: 345.1744.

[0233] Example 106: 1-(2-(4-(5-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 5-methyl-2-furanboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(5-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 17 H 23 Theoretical value for N3O2S[M+H]+: 334.1584; Found: 334.1583.

[0234] Example 107: 1-(2-(4-(4-methyl-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, [4-methyl-3-(trifluoromethyl)phenyl]boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-methyl-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 20 H 24 Theoretical value for F3N3OS[M+H]+: 412.1665; Found: 412.1665.

[0235] Example 108: 1-(2-(4-(2-methoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-methoxypyrimidine-5-boronic acid, and 2-(methylthio)propanoic acid following a procedure similar to that described in Example 38, to provide 1-(2-(4-(2-methoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow oil. HRMS(ESI+):C 17 H 23 Theoretical value for N5O2S[M+H]+: 362.1645; Found: 362.1642.

[0236] Example 109: 1-(2-(4-(benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, 1-(2-(4-(benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one was prepared from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophene, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS(ESI+):C 20 H23 Theoretical value for N3OS2[M+H]+: 386.1355; Found: 386.1353.

[0237] Example 110: 1-(2-(4-(2,3-dihydrobenzofuran-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (2,3-dihydrobenzofuran-6-yl)boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(2,3-dihydrobenzofuran-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 20 H 25 Theoretical value for N3O2S[M+H]+: 372.1740; Measured value: 372.1737.

[0238] Example 111: 2-(methylthio)-1-(2-(4-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-vinylphenylboronic acid, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a white wax. HRMS(ESI+):C 20 H 25 Calculated value for N3OS[M+H]+: 356.1791; Found: 356.1788.

[0239] Example 112: 1-(2-(4-(3-((dimethylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 3-(N,N-dimethylaminomethyl)phenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(3-((dimethylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 21 H 30 Calculated value for N4OS[M+H]+: 387.2213; Found: 387.2208.

[0240] Example 113: 1-(2-(4-(4-isopropylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-isopropylphenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-isopropylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 21 H 29 Calculated value for N3OS[M+H]+: 372.2104; Found: 372.2101.

[0241] Example 114: 1-(2-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-cyclopropyl-2-fluorophenylboronic acid pinacol ester, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 21 H 26Theoretical value for FN3OS[M+H]+: 388.1853; Measured value: 388.1847.

[0242] Example 115: 1-(2-(4-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-fluoro-4-methoxyphenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 19 H 24 Theoretical value for FN3O2S[M+H]+: 378.1646; Found: 378.1642.

[0243] Example 116: 1-(2-(4-(4-(methylsulfonyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-(methanesulfonyl)phenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-(methylsulfonyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a colorless wax. HRMS(ESI+):C 19 H 25 Theoretical value for N3O3S2[M+H]+: 408.1410; Found: 408.1406.

[0244] Example 117: 1-(2-(4-(3,5-dimethylisoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 3,5-dimethylisoxazol-4-yl-4-boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(3,5-dimethylisoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow oil. HRMS(ESI+):C 17 H 24 Theoretical value for N4O2S[M+H]+: 349.1693; Measured value: 349.1689.

[0245] Example 118: 1-(2-(4-(2,3-dihydrobenzofuran-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2,3-dihydro-1-benzofuran-5-ylboranediol, and 2-(methylthio)propanoic acid provided 1-(2-(4-(2,3-dihydrobenzofuran-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS(ESI+):C 20 H 25 Theoretical value for N3O2S[M+H]+: 372.1740; Measured value: 372.1736.

[0246] Example 119: 1-(2-(4-(3-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4,4,5,5-tetramethyl-2-(3-methylfuran-2-yl)-1,3,2-dioxaborolane, and 2-(methylthio)propanoic acid provided 1-(2-(4-(3-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as an off-white solid. HRMS(ESI+):C 17 H23 Theoretical value for N3O2S[M+H]+: 334.1584; Measured value: 334.1580.

[0247] Example 120: 1-(2-(4-(5-((dimethylamino)methyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, dimethyl({[5-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl]methyl})amine, and 2-(methylthio)propanoic acid provided 1-(2-(4-(5-((dimethylamino)methyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 19 H 28 Calculated value for N4OS2[M+H]+: 393.1777; Found: 393.1772.

[0248] Example 121: 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, [5-(trifluoromethyl)thiophen-2-yl]boronic acid, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow oil. HRMS(ESI+):C 17 H 20 Theoretical value for F3N3OS2[M+H]+: 404.1073; Found: 404.1070.

[0249] Example 122: 1-(2-(4-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-methyl-2-(methylthio)-5-pyridylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 19 H 26 Calculated value for N4OS2[M+H]+: 391.1621; Found: 391.1616.

[0250] Example 123: 2-(methylthio)-1-(2-(4-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-propylphenylboronic acid, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow film. HRMS(ESI+):C 21 H 29 Calculated value for N3OS[M+H]+: 372.2104; Found: 372.2101.

[0251] Example 124: 1-(2-(4-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, [4-(2-methoxyethyl)phenyl]boranediol, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 21 H 29Theoretical value for N3O2S[M+H]+: 388.2053; Measured value: 388.2047.

[0252] Example 125: 1-(2-(4-(4-(difluoromethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, [4-(difluoromethyl)thiophen-3-yl]boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-(difluoromethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS(ESI+):C 17 H 21 Theoretical value for F2N3OS2[M+H]+: 386.1167; Found: 386.1162.

[0253] Example 126: 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-cyclobutylphenyl)boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow wax. HRMS(ESI+):C 22 H 29 Calculated value for N3OS[M+H]+: 384.2104; Found: 384.2100.

[0254] Example 127: 1-(2-(4-(3-chloro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 3-chloro-4-methylphenylboronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(3-chloro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 19 H 24 Calculated value for ClN3OS[M+H]+: 378.1401; Found: 378.1397.

[0255] Example 128: 1-(2-(4-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-{[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}thiomorpholine-1,1-dione, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 23 H 32 Theoretical value for N4O3S2[M+H]+: 477.1989; Measured value: 477.1990.

[0256] Example 129: 2-Cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 36, 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one was prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-cyclopropylpropanoic acid to provide an off-white wax. HRMS(ESI+):C 20 H 25Calculated value for NO[M+H]+: 324.2071; Found: 324.2071.

[0257] Example 130: Cyclopropyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and cyclopropanecarboxylic acid provided cyclopropyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as an off-white wax. HRMS(ESI+):C 18 H 21 Calculated value for NO[M+H]: 296.1758; Found: 296.1759.

[0258] Example 131: (2R)-2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and dimethyl-D-alanine provided (2R)-2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow gum. HRMS(ESI+):C 19 H 26 Calculated value for NO[M+H]: 327.2180; Found: 327.2180.

[0259] Example 132: 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 3-methylbut-2-enoic acid provided 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one as a pale yellow oil. HRMS(ESI+):C 19 H 23 Theoretical value for NO[M+H]+: 310.1914; Measured value: 310.1916.

[0260] Example 133: Cyclopentyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and cyclopentanecarboxylic acid provided cyclopentyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a pale yellow oil. HRMS(ESI+):C 20 H 25 Calculated value for NO[M+H]+: 324.2071; Found: 324.2071.

[0261] Example 134: 2-(furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-(furan-2-yl)propanoic acid provided 2-(furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow oil. HRMS(ESI+):C 21 H 23 Theoretical value for N3O2[M+H]+: 350.1863; Measured value: 350.1861.

[0262] Example 135: 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-ethylbut-2-enoic acid provided 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one as a pale yellow oil. HRMS(ESI+):C 20 H 25 Calculated value for NO[M+H]+: 324.2071; Found: 324.2070.

[0263] Example 136: 2-Methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Following a procedure similar to that described in Example 36, 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one was prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-methoxybutanoic acid to provide 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one as a colorless wax. HRMS(ESI+):C 19 H 25 Theoretical value for N3O2[M+H]+: 328.2020; Measured value: 328.2019.

[0264] Example 137: 2-Cyclopropyl-2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one Following a procedure similar to that described in Example 36, 2-cyclopropyl-2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one was prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-cyclopropyl-2-methoxyacetic acid to provide a colorless film. HRMS(ESI+):C 20 H 25 Theoretical value for N3O2[M+H]+: 340.2020; Measured value: 340.2020.

[0265] Example 138: 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and butanoic acid following a procedure similar to that described in Example 36, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one was obtained as a pale yellow oil. HRMS(ESI+):C 18 H 23 Calculated value for NO[M+H]: 298.1914; Found: 298.1914.

[0266] Example 139: (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 5-methyltetrahydrofuran-3-carboxylic acid provided (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a pale yellow film. HRMS(ESI+):C 20 H 25 Theoretical value for N3O2[M+H]+: 340.2020; Measured value: 340.2019.

[0267] Example 140: 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and propionic acid following a procedure similar to that described in Example 36 to provide 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a white solid. HRMS(ESI+):C 17 H 21 Calculated value for NO[M+H]: 284.1758; Found: 284.1757.

[0268] Example 141: 3,3,3-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 36, 3,3,3-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one was prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 3,3,3-trifluoro-2-methylpropanoic acid to provide a yellow film. HRMS(ESI+):C 18 H 20 Theoretical value for F3N3O[M+H]+: 352.1631; Found: 352.1630.

[0269] Example 142: 4,4,4-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Following a procedure similar to that described in Example 36, 4,4,4-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one was prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 4,4,4-trifluoro-2-methylbutanoic acid to provide a yellow film. HRMS(ESI+):C 19 H 22 Theoretical value for F3N3O[M+H]+: 366.1788; Found: 366.1787.

[0270] Example 143: (2,2-Dimethylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2,2-dimethylcyclopropane-1-carboxylic acid provided (2,2-dimethylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a pale yellow film. HRMS(ESI+):C 20 H 25 Calculated value for NO[M+H]+: 324.2071; Found: 324.2070.

[0271] Example 144: cis-2-(2-(4-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and cis-2-cyanocyclopropane-1-carboxylic acid provided cis-2-(2-(4-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile as a yellow film. HRMS(ESI+):C 19 H 20 Calculated value for NO[M+H]: 321.1710; Found: 321.1709.

[0272] Example 145: 2,3-Dimethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 36, 2,3-dimethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one was prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2,3-dimethoxypropanoic acid to provide a yellow film. HRMS(ESI+):C 19 H 25 Theoretical value for N3O3[M+H]+: 344.1969; Measured value: 344.1968.

[0273] Example 146: 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-dien-1-one Following a procedure similar to that described in Example 36, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-dien-1-one was prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 3,5-hexadienoic acid to provide a yellow film. HRMS(ESI+):C 20 H 23 Theoretical value for NO[M+H]+: 322.1914; Measured value: 322.1913.

[0274] Example 147: 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-(5-methylfuran-2-yl)propanoic acid provided 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow film. HRMS(ESI+):C 22 H 25 Theoretical value for N3O2[M+H]+: 364.2020; Measured value: 364.2017.

[0275] Example 148: (trans-2-Methoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and trans-2-methoxycyclopropane-1-carboxylic acid provided (trans-2-methoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a yellow wax. HRMS(ESI+):C 19 H 23 Theoretical value for N3O2[M+H]+: 326.1863; Measured value: 326.1862.

[0276] Example 149: (2-Ethoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-ethoxycyclopropane-1-carboxylic acid provided (2-ethoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a pale yellow film. HRMS(ESI+):C 20 H 25 Theoretical value for N3O2[M+H]+: 340.2020; Measured value: 340.2020.

[0277] Example 150: Bicyclo[1.1.1]pentan-1-yl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and bicyclo[1.1.1]pentane-1-carboxylic acid provided bicyclo[1.1.1]pentan-1-yl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a white solid. HRMS(ESI+):C 20 H 23 Theoretical value for NO[M+H]+: 322.1914; Found: 322.1914.

[0278] Example 151: (2-Methylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone Prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-methylcyclopropane-1-carboxylic acid following a procedure similar to that described in Example 36, provided (2-methylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a white solid. HRMS(ESI+):C 19 H 23 Theoretical value for NO[M+H]+: 310.1914; Measured value: 310.1913.

[0279] Example 152: (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(thietan-3-yl)methanone Following a procedure similar to that described in Example 36, preparation from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and thietan-3-carboxylic acid provided (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(thietan-3-yl)methanone as a pale yellow solid. HRMS(ESI+):C 18 H 21 Calculated value for N3OS[M+H]+: 328.1478; Found: 328.1478.

[0280] Example 153: 2-Cyclobutyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 36, 2-cyclobutyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one was prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-cyclobutylpropanoic acid to provide a pale yellow film. HRMS(ESI+):C 21 H 27 Calculated value for NO[M+H]: 338.2227; Found: 338.2226.

[0281] Example 154: 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one Following a procedure similar to that described in Example 36, 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one was prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-cyclopropylacetic acid to provide a pale yellow film. HRMS(ESI+):C 19 H 23 Theoretical value for NO[M+H]+: 310.1914; Measured value: 310.1914.

[0282] Example 155: 1-(2-(4-(5-(methoxymethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-(5-(methoxymethyl)thiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-(methylthio)propanoic acid provided 1-(2-(4-(5-(methoxymethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS(ESI+):C 18 H 25 Theoretical value for N3O2S2[M+H]+: 380.1461; Found: 380.1461.

[0283] Example 156: 1-(2-(4-(3-(methylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, 1-(2-(4-(3-(methylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one was prepared from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(3-(methylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS(ESI+):C 19 H 26Calculated value for N4OS[M+H]+: 359.1900; Found: 359.1900.

[0284] Example 157: 1-(2-(4-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and 2-(methylthio)propanoic acid provided 1-(2-(4-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS(ESI+):C 18 H 24 Theoretical value for N4O2S[M+H]+: 361.1693; Found: 361.1692.

[0285] Example 158: 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow film. HRMS(ESI+):C 23 H 32 Theoretical value for N4O2S[M+H]+: 429.2319; Found: 429.2321.

[0286] Example 159: 1-(2-(4-(4-(1-hydroxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-(1-hydroxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow wax. HRMS(ESI+):C 20 H 27 Theoretical value for N3O2S[M+H]+: 374.1897; Measured value: 374.1899.

[0287] Example 160: 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4,4,5,5-tetramethyl-2-(5-(trifluoromethyl)furan-2-yl)-1,3,2-dioxaborolane, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow film. HRMS(ESI+):C 17 H 20 Theoretical value for F3N3O2S[M+H]+: 388.1301; Found: 388.1300.

[0288] Example 161: 2-(methylthio)-1-(2-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a yellow oil. HRMS(ESI+):C 16 H 20 Theoretical value for F3N5OS[M+H]+: 388.1414; Found: 388.1413.

[0289] Example 162: 2-(methylthio)-1-(2-(4-(quinoxalin-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(quinoxalin-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a yellow solid. HRMS(ESI+):C 20 H 23 Calculated value for N5OS[M+H]+: 382.1696; Found: 382.1696.

[0290] Example 163: 2-(methylthio)-1-(2-(4-(pyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, and 2-(methylthio)propanoic acid provided 2-(methylthio)-1-(2-(4-(pyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a pale yellow film. HRMS(ESI+):C 16 H 21 Theoretical value for N5OS[M+H]+: 332.1540; Found: 332.1540.

[0291] Example 164: 1-(2-(4-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (3-fluoro-4-(methoxymethyl)phenyl)boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 20 H 26 Calculated value for FN3O2S[M+H]+: 392.1803; Found: 392.1803.

[0292] Example 165: 1-(2-(4-(4-(difluoromethoxy)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-(difluoromethoxy)-3-fluorophenyl)boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(4-(difluoromethoxy)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 19 H 22 Theoretical value for F3N3O2S[M+H]+: 414.1458; Found: 414.1460.

[0293] Example 166: N-(2-hydroxyethyl)-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzenesulfonamide Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-(N-(2-hydroxyethyl)sulfamoyl)phenyl)boronic acid, and 2-(methylthio)propanoic acid provided N-(2-hydroxyethyl)-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzenesulfonamide as a pale yellow film. HRMS(ESI+):C 20 H 28 Theoretical value for N4O4S2[M+H]+: 453.1625; Found: 453.1625.

[0294] Example 167: 1-(2-(4-(2-cyclopropyloxazol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole, and 2-(methylthio)propanoic acid provided 1-(2-(4-(2-cyclopropyloxazol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 18 H 24 Theoretical value for N4O2S[M+H]+: 361.1693; Measured value: 361.1692.

[0295] Example 168: 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one Prepared from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 4-pentenoic acid following a procedure similar to that described in Example 36 to provide 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one as a pale yellow solid. HRMS(ESI+):C 19 H 23Theoretical value for NO[M+H]+: 310.1914; Measured value: 310.1914.

[0296] Example 169: 1-(2-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (2,2-difluorobenzo[d][1,3]dioxol-5-yl)boronic acid, and 2-(methylthio)propanoic acid provided 1-(2-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 19 H 21 Theoretical value for F2N3O3S[M+H]+: 410.1345; Found: 410.1346.

[0297] Example 170: 1-(2-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Following a procedure similar to that described in Example 38, preparation from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 2-(methylthio)propanoic acid provided 1-(2-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a pale yellow film. HRMS(ESI+):C 16 H 23 Calculated value for N5OS[M+H]+: 334.1696; Found: 334.1696.

[0298] Example 171: 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one Example 171a: tert-butyl-2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate: A 100 mL round-bottom flask was charged with tert-butyl-2-cyanopiperidine-1-carboxylate (19.6 g, 93.0 mmol) and 4-methylbenzohydrazide (7.0 g, 46.6 mmol) in butanol (350 mL). Potassium carbonate (3.2 g, 5.0 mmol) was added. The reaction was heated to reflux overnight. The solvent was removed and dissolved in dichloromethane. 1N HCl was added until pH = 6. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over MgSO4. The crude product was purified by column chromatography on silica gel to give tert-butyl-2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (7.5 g, yield: 47%) as a white solid. GC / MS(EI):m / z(%):342(1)[M + ],281(1),242(6),226(3),186(100),173(10),91(6). 1 H NMR(300MHz,CDCl3)δ14.17,13.84(brs,1H),7.96-7.88(m,2H),7.31-7.22(m,2H),5.54- 5.34(m,1H),4.02-3.91(m,1H),3.14-2.90(m,1H),2.48-2.29(m,4H),1.97-1.30(m,14H). 13 C NMR(75MHz,CDCl3)δ170.6(q),163.6(q),161.5(q),157.1(q),155.3(q),155.0(q), 140.1(q),138.5(q),129.9(t),129.4(t),129.3(q),126.4(t),126.2(t),125.2(q), 79.5(q),78.9(q),50.2(t),48.7(t),41.2(d),28.5(d),28.4(s),25.3(d),25.1(d),21.3(s),21.1(s),19.8(d)ppm.

[0299] Example 171b: 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one: a) To a solution of tert-butyl-2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (500 mg, 1.46 mmol) in dichloromethane (50 mL) was added 2,2,2-trifluoroacetic acid (1330 mg, 11.60 mmol) at 5 °C, and the mixture was stirred at rt for 6 h. After the solution was cooled to 5 °C, diluted NaHCO3 solution was added and extracted with ethyl acetate (50 mL*3), and the organic phase was concentrated to give 2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidine as a yellow solid.

[0300] b) To a solution of 2-(methylthio)propanoic acid (200 mg, 1.73 mmol) in dichloromethane (50 mL) was added HOBt (220 mg, 1.44 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (220 mg, 1.44 mmol) at 0-5°C, and the mixture was stirred at rt for 0.5 h. Then 2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidine (350 mg, 1.44 mmol) and DIPEA (0.50 mL, 2.89 mmol) were added, and the mixture was stirred at rt for 16 h. The mixture was filtered to remove the solvent, and purified by silica gel chromatography (hexane:MTBE=3:1) to give 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one (400 mg, yield: 80%) as a white solid. GC / MS(EI):m / z(%):344(3)[M + ],329(6),298(46),269(36),241(100),226(14),186(79). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ14.24-13.80(m,1H),7.91-7.80(m,2H),7.32-7.27(m, 2H),5.88-5.32(m,1H),4.51-2.92(m,3H),2.63-2.28(m,4H),2.09-2.01(m,3H),1.91-1.33(m,8H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.8 (q), 170.4 (q), 169.8 (q), 162.9 (q), 161.4 (q), 156.4 (q), 154.7 (q), 140.1 (q), 138.5 (q), 129.7 (t), 129.4 (t), 128.9 (q), 126.0 (t), 124.7 (q), 51.0 (t), 47.2 (t),46.1(t),43.0(d),42.7(d),38.4(d),37.6(t),37.3(t),29.1(d),28.1(d),27.8(d),27.7(d),25. 7(d),25.3(d),25.0(d),21.1(s),19.8(d),17.9(s),17.6(s),17.5(s),11.8(s),11.5(s),11.4(s)ppm.

[0301] Example 172: 1-(2-(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Prepared from tert-butyl-2-cyanopiperidine-1-carboxylate, 4-fluorobenzoic hydrazide, and 2-(methylthio)propanoic acid following a procedure similar to that in Example 171 to afford the title product as a white solid. GC / MS(EI):m / z(%):348(4)[M + ],333(5),302(70),273(40),245(100),230(17),190(84),84(63).

[0302] Example 173: 2-(methylthio)-1-(2-(5-phenyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one Prepared from tert-butyl-2-cyanopiperidine-1-carboxylate, benzhydrazide, and 2-(methylthio)propanoic acid following a procedure similar to Example 171 to afford the title product as a white solid. GC / MS(EI):m / z(%):330(3)[M + ],315(7),284(71),255(43),227(100),172(85),146(13),84(57).

[0303] Example 174: 2-(methylthio)-1-(2-(5-phenyloxazol-2-yl)piperidin-1-yl)propan-1-one Example 174a: tert-butyl-2-((2-oxo-2-phenylethyl)carbamoyl)piperidine-1-carboxylate: To a solution of 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (5.0 g, 21.8 mmol), HOBt (4.0 g, 26.2 mmol), and EDC (5.0 g, 26.2 mmol) in dichloromethane (50 mL) was added 2-amino-1-phenylethan-1-one hydrochloride (3.7 g, 21.8 mmol) and DIPEA (5.64 g, 43.6 mmol) at 0-5 °C, and the mixture was stirred at rt for 16 h. The mixture was filtered to remove the solvent, and the residue was purified by silica gel chromatography (hexane:MTBE=5:1) to give the product, tert-butyl-2-((2-oxo-2-phenylethyl)carbamoyl)piperidine-1-carboxylate (5.0 g, yield: 66%), as a pale yellow solid.

[0304] Example 174b: 5-phenyl-2-(piperidin-2-yl)oxazole: To a solution of tert-butyl-2-((2-oxo-2-phenylethyl)carbamoyl)piperidine-1-carboxylate (5.0 g, 14.4 mmol) in an ice bath was added sulfuric acid (14.2 g, 144.0 mmol), and the mixture was stirred at 100 °C for 1 h. After the solution was cooled to rt, diluted NaHCO solution was added, extracted with ethyl acetate (50 mL * 3), and the organic phase was concentrated. The residue was purified by silica gel column chromatography to give the product 5-phenyl-2-(piperidin-2-yl)oxazole (2.0 g, yield: 61%) as a pale yellow oil. GC / MS(EI):m / z(%):228(13)[M + ],207(10),199(4),185(14),172(100),159(16),123(13),115(5),102(10),85(15).

[0305] Example 174c: 2-(methylthio)-1-(2-(5-phenyloxazol-2-yl)piperidin-1-yl)propan-1-one: To a solution of 2-(methylthio)propanoic acid (520 mg, 4.38 mmol) in dichloromethane (50 mL) was added HOBt (670 mg, 4.38 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (680 mg, 4.38 mmol) at 0-5 °C, and the mixture was stirred at rt for 0.5 h. Then, 5-phenyl-2-(piperidin-2-yl)oxazole (1000 mg, 4.38 mmol) and DIPEA (1.53 mL, 8.76 mmol) were added, and the mixture was stirred at rt for 16 h. The mixture was filtered to remove the solvent, and the residue was purified by silica gel chromatography (hexane:MTBE=50:1) to afford the crude product as a pale yellow oil. The oil was distilled through a Kugelrohr (0.12 mbar, 110° C.) to give 2-(methylthio)-1-(2-(5-phenyloxazol-2-yl)piperidin-1-yl)propan-1-one (475 mg, yield: 33%) as a white solid. GC / MS(EI):m / z(%):330(9)[M +],315(1),255(8),227(100),75(13). 1 H NMR (300 MHz, CDCl, mixture of stereoisomers and tautomers) δ 7.60-7.26 (m, 6H), 6.15-6.14 (m, 1H), 4.02-3.97 (m, 1H), 3.77-3.70 (m, 1H), 3.46-3.25 (m, 1H), 2.46-2.42 (m, 1H), 2.10 (s, 3H), 1.94-1.53 ​​(m, 8H). 13 C NMR (75 MHz, CDCl3, mixture of stereoisomers and tautomers) δ 170.5(q), 162.0(q), 160.9(q), 151.5(q), 128.8(t), 128.4(t), 127.8(q), 124.1(t), 121.8(t), 47.5(t), 43.2(d), 37.8(t), 27.6(d), 25.4(d), 20.1(d), 17.3(s), 11.5(s) ppm.

[0306] Example 175: 1-(2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)-propan-1-one Example 175a: tert-butyl 2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate: A solution of tert-butyl 2-formylpiperidine-1-carboxylate (1.0 g, 4.69 mmol) and DABCO (0.040 mg, 0.32 mmol) in n-butanol (25 mL) was stirred for 10 min, then NHOAc (1.8 g, 23.44 mmol) was added, followed by 1-phenylpropane-1,2-dione (0.69 mg, 4.69 mmol). The mixture was heated to 60-65 °C and stirred overnight. After the solution was cooled to rt, diluted NaHCO solution was added, extracted with ethyl acetate (50 mL), and the organic phase was concentrated. The residue was purified by column chromatography (hexane:MTBE = 3:1) to afford the product, tert-butyl 2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate (1.0 g, yield: 63%), as a white solid. GC / MS(EI):m / z(%):341(8)[M+],285(14),240(35),185(100),172(18),159(6),117(6),103(8),73(18).

[0307] Example 175b: 1-(2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one: To a solution of 2-(methylthio)propanoic acid (300 mg, 2.48 mmol) in dichloromethane (50 mL) was added HOBt (380 mg, 2.48 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (380 mg, 2.48 mmol) at 0-5°C, and the mixture was stirred at rt for 0.5 h. Then, 2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate (500 mg, 2.07 mmol) and DIPEA (0.72 mL, 4.14 mmol) were added, and the mixture was stirred at rt for 16 h. The mixture was filtered to remove the solvent and purified by silica gel chromatography (hexane:MTBE=3:1) to give 1-(2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (500 mg, yield: 70%) as a white solid. GC / MS(EI):m / z(%):343(6)[M + ],328(5),268(9),240(100),213(12),185(12),159(4),103(6),75(10). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ11.81-11.59(m,1H),7.78-7.09(m,5H),5.76 -5.36(m,1H),4.59-3.04(m,3H),2.68-2.23(m,4H),2.05-2.00(m,3H),1.74-1.20(m,8H). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 169.6 (q), 144.2 (q), 143.9 (q), 135.8 (q), 134.8 (q), 134.7 (q), 128.5 (t), 128.2 (t), 125.7 (t), 125.6 (t), 125.2 (t), 123.0 (q), 122.5 (q), 51.0 (t), 46.6(t),46.3(t),42.7(d),42.5(d),38.3(d),37.1(t),36.9(t),28.2(d),27.7(d),27.4(d),2 5.7(d),25.3(d),25.0(d),19.8(d),19.6(d),17.9(s),17.5(s),17.4(s),11.5(s),11.1(s)ppm.

[0308] Example 176: 1-(2-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one Example 176a: tert-butyl 2-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate: To a solution of tert-butyl 2-formylpiperidine-1-carboxylate (1000 mg, 4.69 mmol) in methanol (50 ml) was added dropwise benzene-1,2-diamine (1014 mg, 9.38 mmol) at 0 °C. The solution was allowed to warm to room temperature and stirred for 16 h. The solution was concentrated under reduced pressure, and the resulting residue was extracted with EtOAc (2 * 150 mL). Any precipitate was removed by filtration, and the organic phase was washed with concentrated aqueous NaHCO3 (2 * 100 mL) and brine (2 * 100 mL). The solution was then concentrated under reduced pressure to give tert-butyl 2-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (450 mg, yield: 32%) as a yellow solid. GC / MS(EI):m / z(%):301(6)[M + ],245(6),228(7),200(20),184(12),145(100),119(7),92(3),57(13).

[0309] Example 176b: 1-(2-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one: a) To a solution of tert-butyl 2-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (500 mg, 1.493 mmol) in dichloromethane (50 mL) was added 2,2,2-trifluoroacetic acid (1362 mg, 11.94 mmol) at 5 °C, and the mixture was stirred at rt for 6 h. After the solution was cooled to 5 °C, diluted NaHCO3 solution was added, extracted with ethyl acetate (50 mL*3), and the organic phase was concentrated to give 2-(piperidin-2-yl)-1H-benzo[d]imidazole as a white solid (260 mg, yield: 78%).

[0310] b) To a solution of 2-(methylthio)propanoic acid (179 mg, 1.491 mmol) in dichloromethane (30 mL), HOBt (304 mg, 1.987 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (309 mg, 1.987 mmol) were added at 0-5°C, and the mixture was stirred at rt for 0.5 h. Then, 2-(piperidin-2-yl)-1H-benzo[d]imidazole (200 mg, 0.994 mmol) and DIPEA (0.434 mL, 2.484 mmol) were added, and the mixture was stirred at rt for 16 h. The mixture was filtered to remove the solvent and purified by silica gel chromatography (hexane:MTBE=3:1) to give 1-(2-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one (74 mg, yield: 24%) as a white solid. GC / MS (EI, mixture of stereoisomers, ratio 1:1): isomer 1: m / z (%): 303 (1) [M + ],288(5),257(42),228(29),200(100),173(10),158(7),145(41),75(12).Isomer 2:m / z(%):303(3)[M +],288(7),257(31),228(36),200(100),173(14),158(6),145(46),75(13). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.39,12.16(brs,1H),7.60-7.44(m,2H),7.16-7.1 5(m,2H),5.98-5.62(m,1H),4.55-3.00(m,3H),2.60-2.19(m,1H),2.05(s,3H),2.01-1.35(m,8H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.7 (q), 170.3 (q), 169.9 (q), 153.9 (q), 153.8 (q), 153.6 (q), 143.7 (q), 135.3 (q), 135.0 (q), 122.3 (t), 122.3 (t), 121.5 (t), 121.4 (t), 119.0 (t), 118.9 (t), 111.6 (t), 111.5 (t) ),52.2(t),47.8(t),47.5(t),43.4(d),43.3(d),38.4(t),37.3(t),37.3(t),28.5(d),28.0(d),27.9(d),25.9 (d),25.5(d),25.3(d),20.4(d),20.2(d),20.1(d),18.4(s),17.9(s),17.8(s),12.0(s),11.6(s),11.5(s)ppm.

[0311] Example 177: (S)-2-Methyl-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Prepared following a procedure similar to that in Example 39: reaction of (S)-2-methylbutanoic acid (0.84 mg, 8.20 mmol), HOBt (1.37 mg, 8.95 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (1.39 mg, 8.95 mmol), (R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (2.00 g, 7.46 mmol), and DIPEA (1.85 ml, 11.19 mmol) in dichloromethane (100 mL) gave the title product (1.65 g, yield: 68%) as a white solid. GC / MS(EI):m / z(%):325(5)[M + ],310(1),268(2),240(100),224(3),185(14),159(2),117(6),57(15). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.0,11.90,11.72(brs,1H),7.68-7.47(m,3H),7.21-7.12(m,2H),5.83-5.28(m,1H) ),4.49-2.74(m,3H),2.45-2.19(m,1H),2.29(s,3H),1.74-1.55(m,5H),1.37-1.33(m,2H),1.07-1.05(m,3H),0.89-0.78(m,3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 175.4 (q), 175.1 (q), 148.5 (q), 147.2 (q), 147.0 (q), 140.5 (q), 140.1 (q), 136.1 (q), 135.2 (q), 132.8 (q), 129.7 (t), 129.3 (t), 124.6 (t), 112.8 (t), 112. 6(t),51.4(t),46.9(t),46.7(t),42.6(d),38.5(d),36.8(t),36.5(t),29.1(d),28.4(d),27.2(d) ,26.9(d),26.3(d),25.3(d),21.2(s),20.3(d),20.1(d),18.4(s),17.3(s),12.2(s),12.0(s)ppm.

[0312] Example 178: 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)azepan-1-yl)propan-1-one In a procedure similar to Example 64, preparation from 1-(tert-butoxycarbonyl)-azepane-2-carboxylic acid, 2-amino-1-(p-tolyl)ethan-1-one hydrochloride and 2-(methylthio)propanoic acid gave 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)azepan-1-yl)propan-1-one as an off-white solid. GC / MS(EI):m / z(%):357(9)[M+ ],342(12),282(6),254(100). 13 C NMR (101 MHz, DMSO-d6, mixture of stereoisomers and tautomers): δ = 174.1, 172.7, 172.3, 171.1, 170.8, 170.0, 149.1, 135.4, 129.5, 129.4, 128.3, 127.3, 124.7, 124.7, 124.6, 124.6, 119.5, 110.2, 60.2, 55.1, 54.0, 51.9, 51.2, 44.0, 43.1, 42.3,41.7,41.7,38.6,37.3,36.9,33.7,33.3,32.8,31.7,31.1,29.5,29.3,29.3,29.0,28.9,28.8,28.5,2 5.4,25.1,24.9,24.9,22.6,21.2,18.6,18.4,18.2,17.5,17.1,14.5,14.4,13.8,13.2,12.6,11.7,11.2ppm.

[0313] Example 179: (2,2-Dimethylcyclopropyl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone Prepared from 2,2-dimethylcyclopropane-1-carboxylic acid, HOBt, 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine, 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, and DIPEA in dichloromethane following a procedure similar to that described in Example 39 to afford the title product as a white solid. GC / MS(EI):m / z(%):337(8)[M + ],322(1),268(1),240(100),185(33),97(6). 1H NMR (400MHz, DMSO-d6, 25℃, mixture of stereoisomers): δ=11.52-12.19(m,1H),7.08-7.72(m,5H),5.24-6.02(m,1H),3.83-4.5 6(m,1H),3.21-3.32(m,1H),2.15-2.47(m,4H),1.75-1.84(m,1H),1.46-1.74(m,4H),1.27-1.43(m,1H),1.19(br d,J=10.8Hz,3H),0.87-1.08(m,4H),0.61-0.77ppm(m,1H).

[0314] Example 180: 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one Prepared following a procedure similar to that described in Example 22a, using 2-methylbutanoic acid instead of 2-(methylthio)propanoic acid, the title product was obtained as a white solid. GC / MS(EI):m / z(%):315(5)[M+],313(5)[M + ],300(1),287(1),258(2),256(2),228(100),230(99),173(33),57(39). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ7.23-7.15(m,1H),5.74-5.24(m,1H),4.41-3.82(m,1H),3.29-3 .10(m,1H),2.81-2.60(m,1H),2.38-2.10(m,1H),1.77-1.18(m,8H),1.06-0.93(m,3H),0.90-0.70(m,3H)ppm.

[0315] Example 181: 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one Prepared from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and 4-chlorophenylboronic acid following a procedure similar to that described in Example 22b, the title product was obtained as a white solid. GC / MS(EI):m / z(%):345(11)[M + ],330(1),260(100). 1H NMR (400MHz, chloroform-d, 25℃, mixture of stereoisomers): δ=9.83-10.84(m,1H),7.37-7.79(m,2H),7.32(d,J=8.6Hz,2H),7.17(s,1H),5.32-5. 93(m,1H),3.72-4.76(m,1H),3.08-3.24(m,1H),2.20-2.78(m,4H),1.36-1.89(m,7H),1.04-1.23(m,3H),0.80-1.00ppm(m,3H).

[0316] Example 182: 2-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile Prepared from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one and (4-(cyanomethyl)phenyl)boronic acid following a procedure similar to that described in Example 22b to give the title product as a pale yellow waxy solid. GC / MS(EI):m / z(%):368(10)[M + ],353(7),322(4),293(10),265(100),238(8),210(18),75(18). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.26-11.85(m,1H),7.85-7.53(m ,3H),7.44-7.26(m,2H),5.86-5.39(m,1H),4.01(s,2H),4.45-1.30(m,15H)ppm.

[0317] Example 183: 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile Prepared from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and (4-(cyanomethyl)phenyl)boronic acid following a procedure similar to that described in Example 22b, the title product was obtained as a white solid. GC / MS(EI):m / z(%):350(7)[M + ],293(2),265(100),249(4),210(14),184(2),155(3),117(5),57(14). 1H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.20-11.75(m,1H),7.80-7.69(m,2H),7.68-7.52(m,1H),7.4 3-7.27(m,2H),5.89-5.28(m,1H),4.00(s,2H),4.52-2.20(m,3H),1.80-1.14(m,8H),1.11-0.71(m,6H)ppm.

[0318] Example 184: 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile Prepared from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and 4-cyanophenylboronic acid following a procedure similar to that described in Example 22b, the title product was obtained as a white solid. GC / MS(EI):m / z(%):336(7)[M + ],321(1),279(2),251(100),196(24),57(25). 1 H NMR (400MHz, DMSO-d6, 25℃, mixture of stereoisomers): δ=7.93-8.11(m,3H),7.88(br t,J=8.3Hz,2H),5.87(br d,J=14.9Hz,1H),3.97-5.59(m,9H),3.82-3.97(m,1H),3.15-3.43(m,1H),2.72- 2.92(m,1H),2.24-2.46(m,1H),1.23-1.87(m,7H),0.96-1.13(m,3H),0.87ppm(br t,J=7.5Hz,3H).

[0319] Example 185: 2,3-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Prepared from 2,3-dimethylbutanoic acid, HOBt, 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine, 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine, and DIPEA in dichloromethane following a procedure similar to that described in Example 39 to afford the title product as a white solid. GC / MS(EI):m / z(%):339(9)[M +],324(1),296(1),268(2),240(100),185(16). 1 H NMR (400MHz, DMSO-d6, 25℃, mixture of stereoisomers): δ=11.54-12.12(m,1H),7.08-7.71(m,5H),4.36-6.00(m,2H),3.82-3.99(m,1H),3.40-3.79(m,1H),2.65(br d,J=8.6Hz,1H),2.24-2.38(m,3H),1.48-1.91(m,5H),1.23-1.35(m,4H),0.78-1.08ppm(m,9H).

[0320] Example 186: 2-methyl-1-(2-(5-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one The title product was prepared from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and o-tolylboronic acid following a procedure similar to that described in Example 22b to afford the title product as a white solid. GC / MS(EI):m / z(%):325(10)[M + ],310(1),268(2),240(100),224(3),185(13),159(2),117(6),57(9). 1 H NMR (300MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ12.08-11.72(m,1H),7.86-6.96 (m,5H),5.94-5.26(m,1H),4.53-2.18(m,3H),2.45(s,3H),1.86-1.21(m,8H),1.10-0.72(m,6H)ppm.

[0321] Example 187: 2-methyl-1-(2-(5-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one The title product was prepared from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and m-tolylboronic acid following a procedure similar to that described in Example 22b to afford the title product as a white solid. GC / MS(EI):m / z(%):325(10)[M +],310(1),268(2),240(100),224(4),185(12),159(2),117(5),57(10). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.17-11.67 (m, 1H), 7.64-6.93 (m, 5H), 5.88-5.24 (m, 1H), 4.52-2.23 (m, 3H), 2.32 (s, 3H), 1.78-0.75 (m, 14H) ppm.

[0322] Example 188: 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one Prepared from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol, and 2-methylbutanoic acid following a procedure similar to that described in Example 38 to provide the title compound as a white solid. DIP-MS (EI): m / z (%): 341 (7) [M + ],284(2),256(100),201(13),57(51). 1 H NMR (500MHz, DMSO-d6, 140℃, mixture of stereoisomers): δ=7.90-8.01(m,1H),7.65-7.70(m,2H),7.36-7.55(m,1H),7.31(d,J=0.6Hz,2H),7.30(s,1H),5.65(br s,1H),3.96-4.16(m,1H),3.21-3.43(m,1H),2.92(br s,2H),2.78(dq,J=13.3,6.7Hz,3H),2.26-2.35(m,1H),1.59-1.87(m,5H),1.34-1.53(m,2H),1.08(dd,J=9.9,6.6Hz,3H),0.84-0.93 ppm(m,3H). 13C NMR (126MHz, DMSO-d6, 140℃, mixture of stereoisomers): δ=175.6,175.6,140.8,127.4,127.1,124.7,119.5,11 0.0,63.6,36.9,36.7,28.9,28.8,27.3,27.1,25.9,25.8,20.1,20.1,17.5,17.5,11.7,11.6ppm.

[0323] Example 189: 1-(Isopropylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine A solution of 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (0.25 g, 1.04 mmol) in THF (2 mL) was cooled to −78° C. and then treated dropwise with KHMDS (potassium hexamethyldisilazide) (1 M in THF, 1.14 mL, 1.14 mmol, 1.1 equiv.). The mixture was stirred at −78° C. for 15 min and then slowly treated with a solution of propane-2-sulfonyl chloride (0.16 g, 1.14 mmol, 1.1 equiv.) in THF (1 mL) over 5 min. Once the mixture reached room temperature, it was poured into ice-cold 2 M HCl solution (50 mL), extracted with DCM (3×20 mL), washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (gradient elution with heptane containing 1–50% of a mixture of 80% EtOAc, 10% hexane, 9% EtOH, 1% EtN) to give the title compound 1-(isopropylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (65 mg, 0.187 mmol, 18% yield) as an orange liquid. GC / MS(EI):m / z(%):347(2)[M + ],291(5),240(100),185(71),43(85). 1H NMR(400MHz,DMSO-d6,25℃):δ=7.91(s,1H),7.73-7.78(m,2H),7.21(d,J=7.8Hz,2H),4.40(dquin,J=13.6,6.7Hz,1H),4.13(br dd,J=8.7,4.5Hz,1H),2.93-3.04(m,1H),2.56-2.70(m,1H),2.32(s,4H),1.78-1.9 9(m,4H),1.47-1.59(m,2H),1.38(d,J=6.8Hz,3H),1.23ppm(dd,J=6.7,2.3Hz,4H). 13 C NMR (101 MHz, DMSO-d6, 25 °C): shifts = 138.6, 136.8, 129.5, 129.1, 124.9, 115.6, 59.7, 56.0, 53.4, 52.8, 46.0, 30.8, 24.0, 20.8, 16.6, 16.0, 15.1, 14.1 ppm.

[0324] Example 190: 1-(sec-butylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine A solution of 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (0.15 g, 0.62 mmol) in THF (2 mL) was cooled to −78° C. and then treated dropwise with KHMDS (potassium hexamethyldisilazide) (1 M in THF, 0.68 mL, 0.68 mmol, 1.1 equiv.). The mixture was stirred at −78° C. for 15 min and then slowly treated with a solution of butane-2-sulfonyl chloride (0.107 g, 0.68 mmol, 1.1 equiv.) in THF (1 mL) over 5 min. Once the mixture reached room temperature, it was poured into ice-cold 2 M HCl solution (50 mL), extracted with DCM (3×20 mL), washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (gradient elution with heptane containing 1–50% of a mixture of 80% EtOAc, 10% hexane, 9% EtOH, 1% EtN) to give the title compound 1-(sec-butylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine (95 mg, 0.62 mmol, 42% yield) as an orange liquid. GC / MS(EI):m / z(%):361(4)[M + ],305(6),240(100),185(77),57(24). 1 H NMR (400MHz, DMSO-d6, 25℃, mixture of stereoisomers): δ=7.87-8.04(m,1H),7.71-7.82(m,2H),7.1 7-7.26(m,2H),6.77-7.05(m,1H),6.65(s,1H),4.08-4.43(m,2H),2.93-3.14(m,1H), 2.78(dqd,J=9.3,6.8,4.2Hz,1H),2.56-2.70(m,1H),2.29-2.36(m,3H),1.77-2.04(m ,5H),1.31-1.77(m,7H),1.17-1.26(m,3H),1.07-1.16(m,1H),0.87-1.06ppm(m,4H).

[0325] Example 191: 2-methyl-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Prepared from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (5-methylthiophen-2-yl)boronic acid, and 2-methylbutanoic acid following a procedure similar to that described in Example 38 to provide the title compound as a white solid. GC / MS(EI):m / z(%): 331(8)[M + ],274(2),246(100),57(21). 1 H NMR (400MHz, DMSO-d6, 25℃, mixture of stereoisomers): δ=11.62-12.20(m,1H),7.24-7.37(m,1H),6.98(br d,J=3.2Hz,1H),6.61-6.79(m,1H),5.14-5.85(m,1H),3.78-4.51(m,1H),3.20-3.32(m,1H),2.64-2.85(m,1H), 2.41(s,3H),2.14-2.35(m,1H),1.47-1.77(m,5H),1.21-1.46(m,2H),0.97-1.09(m,3H),0.74-0.92ppm(m,3H).

[0326] Example 192: 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperazin-1-yl)propan-1-one Example 192a: 4-(tert-butoxycarbonyl)-1-(2-(methylthio)propanoyl)piperazine-2-carboxylic acid: A flask was charged with NaOH (1.39 g, 34.7 mmol) and water (29 mL), and the mixture was stirred. Upon complete dissolution, the solution was cooled to 5 °C and treated with 4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (4.0 g, 17.4 mmol) and stirred for 20 min. The resulting mixture was treated with 2-(methylthio)propanoyl chloride (2.41 g, 17.8 mmol) dropwise at 5 °C and stirred at 5 °C for 4 h. The mixture was then poured into ice-cold 1 M HCl solution (100 mL), extracted with EtOAc (3 × 70 mL), washed with water (70 mL), brine (70 mL), dried over MgSO and concentrated to give the title product 4-(tert-butoxycarbonyl)-1-(2-(methylthio)propanoyl)piperazine-2-carboxylic acid (4.4 g, 13.2 mmol, 76% yield) as a white solid, which was used in the next step without further purification. DIP-MS (EI): m / z (%): 276 (2) [M + -Isobutylene], 259(1), 230(10), 75(53), 57(100).

[0327] Example 192b: 1-(tert-butyl) 3-(2-oxo-2-(p-tolyl)ethyl) 4-(2-(methylthio)propanoyl)piperazine-1,3-dicarboxylate: A solution of 4-(tert-butoxycarbonyl)-1-(2-(methylthio)propanoyl)piperazine-2-carboxylic acid (4.4 g, 13.2 mmol) and triethylamine (2.03 mL, 14.6 mmol, 1.1 equiv) in DMF (40 mL) was treated with 2-bromo-1-(p-tolyl)ethan-1-one (2.96 g, 13.9 mmol) at 5° C., and the resulting mixture was stirred at rt for 1 h. The mixture was then poured into ice-cold 1 M HCl solution (100 mL), extracted with EtOAc (3×70 mL), washed with water (70 mL), brine (70 mL), dried over MgSO4, and concentrated. The crude material was then purified by flash column chromatography on silica gel eluting with a gradient of 7 to 60% EtOAc in heptane to give the title product 1-(tert-butyl)3-(2-oxo-2-(p-tolyl)ethyl) 4-(2-(methylthio)propanoyl)piperazine-1,3-dicarboxylate (5.1 g, 11.0 mmol, 83% yield) as a yellow liquid. DIP-MS (EI): m / z (%): 418 (2) [M + -SCH3],331(6),275(15),231(29),119(66),91(27),75(100),57(78).

[0328] Example 192c: tert-butyl 4-(2-(methylthio)propanoyl)-3-(5-(p-tolyl)-1H-imidazol-2-yl)piperazine-1-carboxylate: A mixture of 1-(tert-butyl) 3-(2-oxo-2-(p-tolyl)ethyl) 4-(2-(methylthio)propanoyl)piperazine-1,3-dicarboxylate (5.1 g, 11.0 mmol), ammonium acetate (6.77 g, 88 mmol), and acetic acid (0.791 g, 13.17 mmol) in xylene (50 mL) was stirred at reflux for 2 h. The mixture was then poured into ice-cold 1 M HCl solution (100 mL), extracted with EtOAc (3 × 70 mL), washed with water (70 mL), brine (70 mL), dried over MgSO4, and concentrated. The crude material was then purified by flash column chromatography on silica gel eluting with a gradient of 7 to 60% EtOAc in heptane to give the title product tert-butyl 4-(2-(methylthio)propanoyl)-3-(5-(p-tolyl)-1H-imidazol-2-yl)piperazine-1-carboxylate (1.1 g, 2.47 mmol, 23% yield) as a yellow solid. DIP-MS (EI): m / z (%): 444 (1) [M + ],429(1),341(1),285(6),241(5),103(3),75(44),57(100).

[0329] Example 192d: 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperazin-1-yl)propan-1-one: A solution of tert-butyl 4-(2-(methylthio)propanoyl)-3-(5-(p-tolyl)-1H-imidazol-2-yl)piperazine-1-carboxylate (1 g, 2.25 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (TFA) (1.4 mL, 18 mmol) at 5° C. The cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 3 h. A second portion of TFA (1.4 mL, 18 mmol) was added, and the reaction mixture was stirred at ambient temperature for 3 h, at which point TLC indicated completion of the reaction. The mixture was then poured into ice-water (50 mL), treated with 2 M NaOH solution until a basic pH was observed, extracted with DCM (3×50 mL), dried over MgSO4, and concentrated. The crude material was then purified by flash column chromatography on silica gel eluting with a mixture of DCM / EtOH / AcOH in a ratio of 7:2:1. The product-containing fractions were collected, washed with water to remove AcOH, dried over MgSO, filtered, and concentrated to give the title product 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperazin-1-yl)propan-1-one (0.75 g, 2.18 mmol, 97% yield) as a yellow solid. GC / MS(EI):m / z(%):344(49)[M + ],329(45),269(51),241(49),186(100),103(20),75(73). 1 H NMR(400MHz,DMSO-d6,25℃):δ=11.77(br s,1H),7.64(d,J=8.1Hz,2H),7.44(br s,1H),7.15(d,J=8.1Hz,2H),5.13-5.58(m,1H),3.73-3.99(m,2H),3.17-3.63(m,4H),2.59 -3.01(m,3H),2.30(s,3H),2.01-2.10(m,2H),1.95-2.01(m,2H),1.38ppm(d,J=6.8Hz,3H).

[0330] Example 193: 2-(methylthio)-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one When 2-(methylthio)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one was prepared from piperidine-2-carboxylic acid, 2-(methylthio)propanoyl chloride, 2-bromo-1-(p-tolyl)ethan-1-one, and ammonium acetate according to the sequence described in Example 63, it was isolated as a minor by-product (yellow solid). 1 H NMR (500MHz, chloroform-d, 25℃, mixture of stereoisomers): δ=7.82(s,1H),7.63(d,J=7.9Hz,2H),7.21(d,J=8.2Hz,2H),6.11(br d,J=4.0Hz,1H),3.98(br d,J=13.1Hz,1H),3.74(q,J=6.9Hz,1H),3.26-3.39(m,1H),2.46(br d,J=13.1Hz,1H),2.38(s,3H),2.01-2.19(m,3H),1.66-1.89(m,5H),1.56 ppm(d,J=6.7Hz,3H). 13 C NMR (126 MHz, chloroform-d, 25 °C, mixture of stereoisomers): δ = 170.6, 162.6, 140.8, 137.8, 133.1, 129.4, 128.3, 125.5, 47.4, 43.3, 37.9, 27.6, 25.5, 21.3, 20.0, 17.3, 11.6 ppm.

[0331] Example 194: 2-methyl-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)butan-1-one When 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one was prepared from piperidine-2-carboxylic acid, 2-methylbutanoyl chloride, 2-bromo-1-(p-tolyl)ethan-1-one, and ammonium acetate according to the sequence described in Example 63, it was isolated as a minor by-product (yellow-red). GC / MS(EI):m / z(%):326(8)[M + ],269(1),241(92),186(10),84(100),57(44). 1¹H NMR (600MHz, venzon-d6, 25℃, mixture of stereoisomorphs): δ = 7.71-7.80 (m, 1H), 7.51-7.59 (m, 2H), 7.11-7.17 (m, 2H), 5.19-6.11 (m, 1H), 3.80-4.67 (m, 1H), 3.16-3.27 (m, 1H), 2.64-2. 76(m,1H),2.32-2.64(m,2H),2.28-2.32(m,3H),1.58-1.84(m,6H),1.37-1.51(m,2 H),1.17-1.28(m,1H),1.07-1.15(m,4H),0.86-0.94(m,4H),0.76-0.85ppm(m,1H).

[0332] Example 1: Assay for TRPM8 modulators A HEK293 cell line stably expressing hTRPM8 was 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 assays of TRPM8 channel activation, cells were seeded at a density of 12,000 cells per well in Dulbecco's Modified Eagle's 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 five times with 100 μL assay buffer (in mM: 130 NaCl, 5 KCl, 10 HEPES, 2 CaCl, and 10 glucose, pH 7.4) and further incubated at room temperature for 30 min in the dark. Cells were then washed five times with 100 μL assay buffer, and calcium influx to serial dilutions of compounds of the present invention was measured on a Flexstation 3 (Molecular Devices). Receptor activation was initiated following the addition of 20 μL of a 10x concentrated ligand stock solution (also prepared in assay buffer). Fluorescence was continuously monitored for 15 seconds prior to and 105 seconds after ligand addition (120 seconds total). Maximal receptor activation was determined relative 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.

[0333] TRPM8 agonists exhibiting EC50 values ​​below 35 μM are presented in Table 1 below. Table 1: Table 1-1

[0334] Table 1-2

[0335] Table 1-3

[0336] Table 1-4

[0337] Table 1-5

[0338] Table 1-6

[0339] Table 1-7

[0340] Table 1-8

[0341] Table 1-9

[0342] Table 1-10

[0343] Table 1-11

[0344] [Table 1-12]

[0345] [Table 1-13]

[0346] Example 2: Sensory studies in aqueous solutions The compounds listed in Table 2 below were dissolved in propylene glycol at a concentration of 1 wt-%. Appropriate aliquots of these solutions were then dispensed into deionized water containing 0.5 wt-% Poloxamer 407 (a hydrophilic non-ionic surfactant, commercially available, for example, from Sigma-Aldrich) and 0.25 wt-% Cremaphor® RH40 (obtained from BASF) as solubilizers to obtain the desired final concentration of each compound of 10 ppm (parts per million).

[0347] A group of trained panelists evaluated aqueous solutions containing the test compounds by rapidly holding 20 mL of the solution in their mouths (for 60 seconds), then expectorating it, without rinsing their mouths between evaluations. Panelists rated and recorded cooling performance and other sensory and organoleptic attributes at different time points over a 2-hour period. Cooling performance was assessed on a scale of 0 to 10, with 0 being no effect and 10 being extremely freezing. The scales were averaged across all panelists, and cooling intensity was considered "none" (scale of 0), "low" (above 0, up to 1), "moderate" (above 1, up to 4), "strong" (above 4, up to 8), and "extremely freezing" (scale above 8). These are provided in Table 2. None of the tested compounds exhibited any statistically significant bitterness or negative organoleptic characteristics.

[0348] Table 2: [Table 2] M=moderate; S=strong; L=low

[0349] Example 3: Sensory study on model toothpaste The compounds listed in Table 3 were dissolved in propylene glycol. A or benzyl alcohol B The test compounds were dissolved at a concentration of 1 wt-% in the respective solvents indicated in Table 3. Appropriate aliquots of these solutions were then dispensed into model unflavored dentifrices to give the desired final concentration of 40 ppm (parts per million) of test compound, the recipe of which is given below (each ingredient was obtained from the supplier indicated in parentheses).

[0350] [Table 3]

[0351] A group of trained panelists evaluated dentifrices containing a compound of formula (I) by brushing their teeth with 1 g of the dentifrice for 60 seconds using a toothbrush, then spitting it out, without rinsing their mouths between evaluations. The panelists rated and recorded cooling performance and other sensory and organoleptic attributes at different time points over a 2-hour period. Cooling performance was assessed on a scale of 0 to 10, with 0 being ineffective and 10 being extremely freezing. The scales were averaged across all panelists, and cooling intensity was considered "none" (scale of 0), "low" (above 0, up to 1), "moderate" (above 1, up to 4), "strong" (above 4, up to 8), and "extremely freezing" (scale above 8). These are summarized in Table 3 below. None of the tested compounds exhibited any statistically significant bitterness or negative organoleptic characteristics.

[0352] Table 3: [Table 4] M=moderate; S=strong; L=low

Claims

1. A method of modulating transient receptor potential channel melastatin member 8 (TRPM8), comprising: coupling the receptor to a compound represented by formula (Ia): 【Chemistry 1】 During the ceremony n is 0 or 1; R 1 is selected from: I C 6 ~C 10 aryl, ii) C 5 ~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, iii) C 6 ~C 10 aryl, but independently Halogen;OH;C≡N;NO 2 ;C 1 ~C 6 alkyl; C containing 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 1 ~C 6 Alkoxy; C containing 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 is 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 (where R 15 is C 1 ~C 3 alkyl), and R 14 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 16 (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 to 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 alkyl) and substituted with up to four substituents selected from the group consisting of (However, when an aryl ring is substituted with two or more substituents, the two substituents, together with the carbon atoms to which they are attached, may form a cyclic ring.) and iv) C 5 ~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen; Halogen; OH (hydroxyl); C≡N(cyano); NO 2 (nitro); C 1 ~C 6 alkyl; C containing up to 5 halogen atoms 1 ~C 6 alkyl; C 2 ~C 6 Alkenyl; C 1 ~C 6 Alkoxy; C containing 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 is 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 (where R 25 is C 1 ~C 3 alkyl), and R 24 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 26 (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 to 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 alkyl) substituted with up to four substituents selected from the group consisting of: Y is a monocyclic, unsaturated or aromatic heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen, wherein the ring is optionally substituted with halogen, methyl, ethyl, -N(R 40 )R 41 , -CON(R 40 )R 41 , -[CR 40 R 41 ] p -C(O)OR 40 , -C(O)R 40 , and -SO 2 N(R 40 )R 41 (where R 40 and R 41 are independently hydrogen and C 1 ~C 4 alkyl, and p is 0, 1, or 2; Z is C; and R 4 , R 5 , and R 6 together with the carbon atom to which they are attached form a hydrocarbon group containing 2 to 15 C atoms (optionally containing up to 5 heteroatoms selected from O, N, S and F), The method (excluding a method for treating a human) comprising contacting a subject with a compound represented by the formula:

2. The compound of formula (Ia) (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(1,2,3-thiadiazol-5-yl)methanone, (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(thietan-3-yl)methanone, (2,2-dimethylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-ethoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-methoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-cyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-methylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (E)-1 -(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-2-en-1-one, (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one, (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pent-3-en-1-one, (R)-2-(methylthio)-1-((R)- ... (imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1-((S)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-methyl-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,(Tetrahydrofuran-3-yl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,3 -dihydrobenzofuran-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,3-dihydrobenzofuran-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,5-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-cyclopropyloxazol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, ...fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-((dimethylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3,5-dimethylisoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(4-(3-chloro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-((1,1-dioxidethiomorpholino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- (1-hydroxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(difluoromethoxy)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(difluoromethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(methylthio) 1-(2-(4-(4-(tert-butyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol- 2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-isopropylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(4-(4-methyl-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-((dimethylamino)methyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-methylpi 1-(2-(4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, methylthio)propan-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-((trifluoromethyl)thio)ethan-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-dien-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl) 1-(2-(5-(2,3-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(5-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-methoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-( 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-3-en-1-one, 1-(2-(5-(3,4-dimethoxyphenyl)-1H-imidazol-2 -yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidine-1 -yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-methoxyisothiazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(5-(4-((methylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(aminomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(dimethylamino)phenyl)-1H -imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-acetylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-aminophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-chloro-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine-1-yl)-2-(methylthio)propan-1-one Lysin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-methoxy-2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(5-(5-(methoxymethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(benzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(p-tolyl)- 1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(5-benzyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile, 2-(2-(4-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile, 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl -1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(allylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(ethylthio)-1-(2-(5-(p-tolyl) -1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(furan-3-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan-3-yl)-1-(2-(5-(p-, tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylamino)-N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetamide, 2-(methylsulfinyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl ) ethan-1-one, 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(2-(p-tolyl)-2H-tetrazol-5-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(1-(trifluoromethyl)-1H-pyra 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophene-2-yl)- -yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,2-(methylthio)-1-(2-(4-(pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(pyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(quinoxalin-6-yl)-1H-imidazol-2 -yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(methylthio)-1-(2-(5-(2-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5- (2,3,4-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-(trifluoromethoxy)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,2-(methylthio)-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)azepan-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one 1-propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)isoxazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)thiazol-2-yl)piperidin-1-yl)propane- 1-one, 2-(methylthio)-1-(2-(5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyl-1H-imidazol-2-yl)pyrrolidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyl-4H-1,2,4-triazol-3-yl)piperi ...oxazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyloxazol-2-yl)piperidin-1-yl)propan-1-one, o)-1-(4-(5-(p-tolyl)-1H-imidazol-2-yl)thiazolidin-3-yl)propan-1-one, 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one,2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,3-dimethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2,3-dimethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,5-difluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzo Nitrile, 2-amino-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-cyclobutyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-cyclopentyl-2-ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one 2-Cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Cyclopropyl-2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-Ethoxy-1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-ene -1-one, 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile, 2-mercapto-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,2-Methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Methoxy-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-Methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Methyl-1-(2-(5-(p- tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butane-1,3-dione, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pentan-1-one, 2-methyl-1-(2-(5-(p-tolyl)- 1H-imidazol-2-yl)piperidin-1-yl)prop-2-en-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-3-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methylene-1-( 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 3-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile, 3,3,3-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 3,3,4,4,4-pentafluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,3,3-Difluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 3-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile, 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one, 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 4-(2-(1-( 2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile, 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde, 4,4,4-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, bicyclo[1.1.1]pentan-1-yl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, cyclobutyl (2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, cyclopentyl (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, cyclopropyl (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, methyl 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoate, N-(2-hydroxyethyl)-4-(2-(1-(2-(methylthio)propanoyl) N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methane-sulfonamide, 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)benzenesulfonamide, 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methane-sulfonamide, 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,1-(2-(5-(4-(hydroxymethyl)-phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)- 1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl) -2-(methylsulfonyl)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio) propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(3-hydroxy, -2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)-propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)-propan-1-one, )piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(4-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one ) propan-1-one, 1-(3-hydroxy-2-(5-(4-(hydroxymethyl)-phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,1-(4-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(3-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde, 4-(2-(1-(2-(methylthio)propanoyl)piperidine) Lysin-2-yl)-1H-imidazol-5-yl)benzoic acid, 4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid, (2,2-dimethylcyclopropyl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(4-(2-(1-(2-(methylthio)propanoyl)piperidine) 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2,3-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5 -(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-methyl-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperazin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)butan-1-one, 2-(furan-2-yl)-1-(2-(5-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one, cyclopentyl(2-(5-(p -tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)penta-3-en-1-one, (tetrahydrofuran-3-yl)(2-(4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(4-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-methoxy- 2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-methoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2-(methylthio)-1-(2-(4-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(4-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidine-1 -yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2-(methylthio)-1-(2-(4-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(4-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(4-(5-(methoxymethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-(methylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, and 1-(2-(4-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2. The method of claim 1 (excluding methods for treating humans), selected from the group consisting of:

3. A composition for providing a cooling sensation, the composition comprising a compound represented by formula (Ia) 【Chemistry 2】 During the ceremony n is 0 or 1; R 1 is selected from: I C 6 ~C 10 aryl, ii) C 5 ~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, iii) C 6 ~C 10 aryl, but independently Halogen;OH;C≡N;NO 2 ;C 1 ~C 6 alkyl; C containing 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 1 ~C 6 Alkoxy; C containing 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 is 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 (where R 15 is C 1 ~C 3 alkyl), and R 14 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 16 (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 to 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 and substituted with up to four substituents selected from the group consisting of alkyl (However, when an aryl ring is substituted with two or more substituents, the two substituents, together with the carbon atoms to which they are attached, may form a cyclic ring.) and iv) C 5 ~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen; Halogen; OH (hydroxyl); C≡N (cyano); NO 2 (nitro); C 1 ~C 6 alkyl; C containing up to 5 halogen atoms 1 ~C 6 alkyl; C 2 ~C 6 Alkenyl; C 1 ~C 6 Alkoxy; C containing 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 is 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 (where R 25 is C 1 ~C 3 alkyl), and R 24 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 26 (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 to 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 alkyl) substituted with up to four substituents selected from the group consisting of: Y is a monocyclic, unsaturated or aromatic heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen, wherein the ring is optionally substituted with halogen, methyl, ethyl, -N(R 40 )R 41 , -CON(R 40 )R 41 , -[CR 40 R 41 ] p -C(O)OR 40 , -C(O)R 40 , and -SO 2 N(R 40 )R 41 (where R 40 and R 41 are independently hydrogen and C 1 ~C 4 alkyl, and p is 0, 1, or 2; Z is C; and R 4 , R 5 , and R 6 together with the carbon atom to which they are attached form a hydrocarbon group containing 2 to 15 C atoms (optionally containing up to 5 heteroatoms selected from O, N, S and F), The composition comprising a compound represented by the formula:

4. 4. The composition of claim 3, comprising at least one compound of formula (Ia), a salt or a solvate thereof, and a further cooling compound.

5. 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-dimethylsuccinamate, 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]dioxamethyl)-N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide, ...

5. The composition of claim 4, wherein the alkyl acrylate 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.

6. A consumer product for providing a cooling sensation, comprising the composition of any one of claims 3 to 5.

7. A pharmaceutical composition for providing a cooling sensation, comprising the composition according to any one of claims 3 to 5.

8. Formula (Ia) 【Transformation 3】 During the ceremony n is 0 or 1; R 1 is selected from: I C 6 ~C 10 aryl, ii) C 5 ~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, iii) C 6 ~C 10 aryl, but independently Halogen;OH;C≡N;NO 2 ;C 1 ~C 6 alkyl; C containing 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 1 ~C 6 Alkoxy; C containing 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 is 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 (where R 15 is C 1 ~C 3 alkyl), and R 14 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 16 (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 to 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 alkyl) and substituted with up to four substituents selected from the group consisting of (However, when an aryl ring is substituted with two or more substituents, the two substituents, together with the carbon atoms to which they are attached, may form a cyclic ring.) and iv) C 5 ~C 10 wherein up to two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen, and oxygen; Halogen; OH (hydroxyl); C≡N (cyano); NO 2 (nitro);C 1 ~C 6 alkyl; C containing up to 5 halogen atoms 1 ~C 6 alkyl; C 2 ~C 6 Alkenyl; C 1 ~C 6 Alkoxy; C containing 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 is 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 (where R 25 is C 1 ~C 3 alkyl), and R 24 is hydrogen, C 1 ~C 3 Alkyl, and -SO 2 R 26 (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 to 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 alkyl) substituted with up to four substituents selected from the group consisting of: Y is a monocyclic, unsaturated or aromatic heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen, wherein the ring is optionally substituted with halogen, methyl, ethyl, -N(R 40 )R 41 , -CON(R 40 )R 41 , -[CR 40 R 41 ] p -C(O)OR 40 , -C(O)R 40 , and -SO 2 N(R 40 )R 41 (where R 40 and R 41 are independently hydrogen and C 1 ~C 4 alkyl, and p is 0, 1, or 2; Z is C; and R 4 , R 5 , and R 6 together with the carbon atom to which they are attached form a hydrocarbon group containing 2 to 15 C atoms (optionally containing up to 5 heteroatoms selected from O, N, S and F), a compound represented by the formula: The compound is 【Chemistry 4】 is not the compound, salt or solvate thereof.

9. 9. The compound of formula (Ia), its salt or solvate, according to claim 8, wherein Y is a 5-membered unsaturated heterocyclic ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen, or Y is benzimidazole.

10. The compound is (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(1,2,3-thiadiazol-5-yl)methanone, (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(thietan-3-yl)methanone, (2,2-dimethylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-ethoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-methoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-cyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2-methylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, (E)-1 -(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-2-en-1-one, (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one, (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pent-3-en-1-one, (R)-2-(methylthio)-1-((R)- ... (imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-(methylthio)-1-((S)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, (S)-2-methyl-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,(Tetrahydrofuran-3-yl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,3 -dihydrobenzofuran-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,3-dihydrobenzofuran-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2,5-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-cyclopropyloxazol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, ...fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-((dimethylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3,5-dimethylisoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(4-(3-chloro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-((1,1-dioxidethiomorpholino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4- (1-hydroxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(difluoromethoxy)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(difluoromethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-(methylthio) 1-(2-(4-(4-(tert-butyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol- 2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-isopropylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(4-(4-methyl-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-((dimethylamino)methyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(5-methylpi 1-(2-(4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, methylthio)propan-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-((trifluoromethyl)thio)ethan-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-dien-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one, 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl) 1-(2-(5-(2,3-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(5-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(2-methoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-( 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-3-en-1-one, 1-(2-(5-(3,4-dimethoxyphenyl)-1H-imidazol-2 -yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3,4-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidine-1 -yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-methoxyisothiazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(5-(4-((methylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(aminomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(dimethylamino)phenyl)-1H -imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-acetylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-aminophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-chloro-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine-1-yl)-2-(methylthio)propan-1-one Lysin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-methoxy-2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(5-(5-(methoxymethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(benzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(5-(p-tolyl)- 1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(5-benzyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile, 2-(2-(4-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile, 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl -1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(allylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(ethylthio)-1-(2-(5-(p-tolyl) -1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(furan-3-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(furan-3-yl)-1-(2-(5-(p-, tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylamino)-N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetamide, 2-(methylsulfinyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl ) ethan-1-one, 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(2-(p-tolyl)-2H-tetrazol-5-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(1-(trifluoromethyl)-1H-pyra 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophene-2-yl)- -yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,2-(methylthio)-1-(2-(4-(pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(pyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(quinoxalin-6-yl)-1H-imidazol-2 -yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-(methylthio)-1-(2-(5-(2-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5- (2,3,4-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-(trifluoromethoxy)phenyl)-1 H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,2-(methylthio)-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)azepan-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one 1-propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)isoxazol-3-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)thiazol-2-yl)piperidin-1-yl)propane- 1-one, 2-(methylthio)-1-(2-(5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyl-1H-imidazol-2-yl)pyrrolidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyl-4H-1,2,4-triazol-3-yl)piperi ...oxazol-2-yl)piperidin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(5-phenyloxazol-2-yl)piperidin-1-yl)propan-1-one, o)-1-(4-(5-(p-tolyl)-1H-imidazol-2-yl)thiazolidin-3-yl)propan-1-one, 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one,2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,3-dimethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2,3-dimethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2,5-difluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzo Nitrile, 2-amino-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-cyclobutyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-cyclopentyl-2-ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one 2-Cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Cyclopropyl-2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one, 2-Ethoxy-1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-ene -1-one, 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile, 2-mercapto-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,2-Methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Methoxy-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-Methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-Methyl-1-(2-(5-(p- tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butane-1,3-dione, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pentan-1-one, 2-methyl-1-(2-(5-(p-tolyl)- 1H-imidazol-2-yl)piperidin-1-yl)prop-2-en-1-one, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-3-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methylene-1-( 2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 3-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile, 3,3,3-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 3,3,4,4,4-pentafluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,3,3-Difluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 3-fluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile, 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one, 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 4-(2-(1-( 2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile, 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde, 4,4,4-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, bicyclo[1.1.1]pentan-1-yl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, cyclobutyl (2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, cyclopentyl (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, cyclopropyl (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone, methyl 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoate, N-(2-hydroxyethyl)-4-(2-(1-(2-(methylthio)propanoyl) N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methane-sulfonamide, 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)benzenesulfonamide, 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methane-sulfonamide, 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,1-(2-(5-(4-(hydroxymethyl)-phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)- 1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl) -2-(methylsulfonyl)propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio) propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(3-hydroxy, -2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)-propan-1-one, 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)-propan-1-one, )piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one, 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(4-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one ) propan-1-one, 1-(3-hydroxy-2-(5-(4-(hydroxymethyl)-phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,1-(4-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 1-(3-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde, 4-(2-(1-(2-(methylthio)propanoyl)piperidine) Lysin-2-yl)-1H-imidazol-5-yl)benzoic acid, 4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid, (2,2-dimethylcyclopropyl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-(4-(2-(1-(2-(methylthio)propanoyl)piperidine) 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2,3-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5 -(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-methyl-1-(2-(5-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one, 2-methyl-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperazin-1-yl)propan-1-one, 2-(methylthio)-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)butan-1-one, 2-(furan-2-yl)-1-(2-(5-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one, cyclopentyl(2-(5-(p -tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)penta-3-en-1-one, (tetrahydrofuran-3-yl)(2-(4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone, 1-(2-(4-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-methoxy- 2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(2-methoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2-(methylthio)-1-(2-(4-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(4-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidine-1 -yl)-2-(methylthio)propan-1-one, 1-(2-(4-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 2-(methylthio)-1-(2-(4-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 1-(2-(4-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,1-(2-(4-(5-(methoxymethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(3-(methylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 1-(2-(4-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, and 1-(2-(4-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one, 9. The compound of claim 8, selected from the group consisting of:

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