Substituted nitrogen heterocycles as TRMP8 modulators

Abstract

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

Description

Technical Field

[0001] The present invention relates to a specific class of compounds capable of activating TRPM8 ion channels. The present invention also relates to the use of said compounds for inducing a cooling sensation and to consumer products containing these compounds.

[0002] background

[0003] TRPM8 (transient receptor potential melastatin member 8, also known as Trp-p8 or MCR1) is activated by harmless cold and therefore plays an important role as a temperature sensor. The channel is widely distributed in different tissues (such as human skin and mucous membranes (such as oral mucosa, pharyngeal mucosa and nasal mucosa), male urogenital tract, lung epithelial cells and arterial myocytes). They are Ca 2+ A permeable, non-selective cation channel with a multimodal gating mechanism that is activated by harmless cold to low temperatures, membrane depolarization, and molecules called cooling agents (including natural and synthetic compounds). This receptor was first described as a cold receptor in 2002 in numerous publications.

[0004] The present invention is based on the discovery that a specific class of compounds can be used to drive a cooling response when contacting the TRPM8 receptor in vitro and in vivo.

[0005] Compounds that provide a cooling sensation have long played an important role in the flavor and fragrance industry, creating associations with freshness and cleanliness. Cooling compounds are widely used in a variety of products, such as food, tobacco products, beverages, dentifrices, mouthwashes, toothpastes, and toiletries. The cooling sensation they provide contributes to the appeal and acceptability of consumer products. In particular, oral care products, such as dentifrices and mouthwashes, are formulated with cooling agents because they provide a breath-freshening effect and a clean, cooling, and refreshed feeling in the mouth.

[0006] Numerous compounds have been described that provide a cooling sensation. The best-known naturally occurring compound is menthol, particularly L-menthol. Among synthetic compounds that provide a cooling sensation, many are derivatives of menthol or are structurally related to menthol, containing a cyclohexane moiety and derivatized with functional groups including carboxamides, ketals, esters, ethers, and alcohols.

[0007] Applicants have surprisingly discovered a new class of compounds that are structurally significantly different from hitherto known TRPM8 modulators. Surprisingly, the compounds described herein can provide long-lasting cooling to human skin and / or mucous membranes at very low concentrations.

[0008] Overview

[0009] In a first aspect, there is provided a compound of formula (I), a salt or a solvate thereof (particularly for providing a cooling sensation)

[0010]

[0011] in

[0012] n is 0 or 1;

[0013] R 1 Selected from

[0014] i) halogen,

[0015] ii) C6-C 10 Aryl,

[0016] iii) C5-C 10 mono- or bicyclic heteroaryl, wherein up to 2 C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen,

[0017] iv) C6-C 10 Aryl, substituted with up to four substituents independently selected from the group consisting of

[0018] Halogen; OH; C≡N; NO2; C1-C6 alkyl;

[0019] C1-C6 alkyl containing up to 5 halogen atoms;

[0020] C1-C3 alkyl containing up to 3 OH groups;

[0021] C2-C6 alkenyl;

[0022] C1-C6 alkoxy;

[0023] C1-C6 alkoxy containing up to 3 halogen atoms;

[0024] C1-C3 alkoxy C1-C3 alkyl;

[0025] C3-C7 cycloalkyl;

[0026] -C(O)R 10 , where R 10 Selected from C1-C3 alkyl;

[0027] -OC(O)R 11 , where R 11 Selected from H and C1-C3 alkyl;

[0028] -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl;

[0029] -(CH2) m N(R 13 )R 14 , where m is 0 or 1, R13 Selected from hydrogen, C1-C3 alkyl and -SO2R 15 , where R 15 is a C1-C3 alkyl group, and R 14 Selected from hydrogen, C1-C3 alkyl and -SO2R 16 , where R 16 is a C1-C3 alkyl group, or wherein R 13 and R 14 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0030] -SR 17 , where R 17 selected from hydrogen and C1-C3 alkyl; and

[0031] -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl;

[0032] Provided that when the aryl ring is substituted with two or more substituents, the two substituents may be taken together with the carbon atoms to which they are attached to form a ring,

[0033] and

[0034] v)C5-C 10 Mono- or bicyclic heteroaryl, wherein up to 2 C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, said heteroaryl being substituted by up to four substituents selected from the group consisting of

[0035] Halogen; OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl;

[0036] C1-C6 alkyl containing up to 5 halogen atoms;

[0037] C2-C6 alkenyl;

[0038] C1-C6 alkoxy;

[0039] C1-C6 alkoxy containing up to 3 halogen atoms;

[0040] C1-C3 alkoxy C1-C3 alkyl;

[0041] C3-C7 cycloalkyl;

[0042] -C(O)R 20 , where R 20 Selected from C1-C3 alkyl;

[0043] -OC(O)R 21 , where R 21 Selected from H and C1-C3 alkyl;

[0044] -C(O)OR 22 , where R 22 is selected from hydrogen and C1-C3 alkyl;

[0045] -(CH2) m N(R 23 )R 24 , where m is 0 or 1, R 23 Selected from hydrogen, C1-C3 alkyl and -SO2R 25 , where R 25 is a C1-C3 alkyl group, and R 24 Selected from hydrogen, C1-C3 alkyl and -SO2R 26 , where R 26 is a C1-C3 alkyl group, or wherein R 23 and R 24 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0046] -SR 27 , where R 27 selected from hydrogen and C1-C3 alkyl; and

[0047] -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl;

[0048] Y is a monocyclic or bicyclic unsaturated or aromatic heterocycle containing one, two, three or four heteroatoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally selected from 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 The group is mono-, di- or tri-substituted, wherein R 40 and R 41 independently selected from hydrogen and C1-C4 alkyl, and p is 0, 1 or 2;

[0049] A is a 5- to 7-membered heterocyclic ring, which optionally contains one additional heteroatom selected from oxygen and sulfur, wherein said heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =0;

[0050] Z is C, S or S(O); and

[0051] R 4 、R 5 and R 6 Together with the carbon atoms to which they are attached they form a hydrocarbon group optionally comprising up to five heteroatoms selected from O, N, S and F.

[0052] According to a second aspect, there is provided a method of modulating (in vitro and in vivo) transient receptor potential melastatin member 8 (TRPM8), the method comprising contacting the receptor with a compound of formula (I) or a salt or solvate thereof.

[0053] In a third aspect, there is provided a method of inducing a cooling sensation in a human or animal, the method comprising contacting the human or animal with a compound of formula (I) or a salt or solvate thereof.

[0054] In a fourth aspect, there is provided a consumer product, in particular a consumer product that comes into contact with human skin and / or mucous membranes, comprising a compound defined by formula (I) or a salt or solvate thereof.

[0055] In a fifth aspect, a composition comprising a cooling sensation is provided, wherein the composition comprises at least one compound of formula (I), a salt or solvate thereof and an additional cooling compound.

[0056] In a sixth aspect, there is provided a pharmaceutical composition comprising one or more compounds defined by formula (I) or a salt or solvate thereof.

[0057] The details, embodiments and preferences provided in connection with any particular one or more of the aspects of the present invention will be further described herein and are equally applicable to all aspects of the present invention. Unless otherwise indicated herein or clearly contradictory to the context, any combination of all possible variations of the embodiments, embodiments and preferences described herein are included in the present invention.

[0058] Details

[0059] The present invention is based, at least in part, on the surprising discovery of a new class of compounds that are structurally significantly different from hitherto known TRPM8 modulators and that are capable of activating TRPM8 ion channels, thereby leading to Ca 2+ The resulting electrical signals are ultimately perceived as a cooling sensation. Applicants have surprisingly discovered that the compounds described further herein can provide a long-lasting cooling effect on human skin and / or mucous membranes at very low concentrations.

[0060] Therefore, in a first aspect, there is provided a compound of formula (I), a salt or solvate thereof (particularly for providing a cooling sensation)

[0061]

[0062] in

[0063] n is 0 or 1;

[0064] R 1 Selected from

[0065] Halogens (including Br, Cl and F),

[0066] C6-C 10 Aryl (eg, phenyl or naphthyl), optionally substituted with up to four (eg, 1, 2, or 3) substituents independently selected from the group consisting of

[0067] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0068] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0069] C1-C3 alkyl containing up to 3 OH groups, for example CH2OH;

[0070] C2-C6 alkenyl, for example -CH=CH2;

[0071] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0072] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0073] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0074] -C(O)R 10 , where R 10 Selected from C1-C3 alkyl;

[0075] -OC(O)R 11 , where R 11 Selected from H and C1-C3 alkyl;

[0076] -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl;

[0077] -(CH2) m N(R 13 )R 14 , where m is 0 or 1, R 13 Selected from hydrogen, C1-C3 alkyl and -SO2R 15 , where R 15 is a C1-C3 alkyl group, and R14 Selected from hydrogen, C1-C3 alkyl and -SO2R 16 , where R 16 is a C1-C3 alkyl group, or wherein R 13 and R 14 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0078] -SR 17 , where R 17 selected from hydrogen and C1-C3 alkyl; and

[0079] -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl;

[0080] provided that when the aryl ring is substituted with two or more substituents, the two substituents may be taken together with the carbon atoms to which they are attached to form a ring, and

[0081] C5-C 10 Mono- or bicyclic heteroaryl, wherein up to 2 C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, said heteroaryl being optionally substituted by up to four (e.g. 1, 2 or 3) substituents selected from the group consisting of

[0082] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0083] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0084] C2-C6 alkenyl, for example -CH=CH2;

[0085] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0086] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0087] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0088] -C(O)R 20 , where R 20 Selected from C1-C3 alkyl;

[0089] -OC(O)R 21 , where R 21 Selected from H and C1-C3 alkyl;

[0090] -C(O)OR22 , where R 22 selected from hydrogen and C1-C3 alkyl);

[0091] -(CH2) m N(R 23 )R 24 , where m is 0 or 1, R 23 Selected from hydrogen, C1-C3 alkyl and -SO2R 25 , where R 25 is a C1-C3 alkyl group, and R 24 Selected from hydrogen, C1-C3 alkyl and -SO2R 26 , where R 26 is a C1-C3 alkyl group, or wherein R 23 and R 24 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0092] -SR 27 , where R 27 selected from hydrogen and C1-C3 alkyl; and

[0093] -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl;

[0094] Y is a monocyclic or bicyclic unsaturated or aromatic heterocycle containing one, two, three or four heteroatoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally selected from 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 The group is mono-, di- or trisubstituted, wherein R 40 and R 41 independently selected from hydrogen and C1-C4 alkyl (including ethyl and propyl), and p is 0, 1 or 2;

[0095] A is a 5- to 7-membered heterocyclic ring, which optionally contains one additional heteroatom selected from oxygen and sulfur, wherein said heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =0;

[0096] Z is C, S or S(O); and

[0097] R4 、R 5 and R 6 Together with the carbon atoms to which they are attached they form a hydrocarbyl group optionally comprising up to five (e.g. 1, 2, 3, 4) heteroatoms selected from O, N, S and F (preferably the hydrocarbyl group comprises 2 to 15 C atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms).

[0098] Non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein

[0099] R 4 is selected from hydrogen and methyl; and

[0100] R 5 Selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl;

[0101] 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, furanyl optionally substituted with methyl (e.g. 2-furanyl or 3-furanyl), C1-C6 fluoro-alkyl (e.g. pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl), and -NR 30 R 31 , where R 30 and R 31 independently selected from hydrogen and C1-C3 alkyl;

[0102] or

[0103] R 6 and R 5 Together with the carbon atoms to which they are attached, they form

[0104] a) Carbonyl (C=O) or vinyl (C=CR 32 R 33 , where R 32 and R 33 independently selected from H or C1-C3 alkyl); or

[0105] b) a 3- to 7-membered saturated or unsaturated ring containing up to 3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy; (e.g., R5 and R 6 Together with the carbon atom to which they are attached they form a thiadiazole or furyl group).

[0106] Further non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein Y is a 5-membered unsaturated heterocyclic ring containing one, two, three or four heteroatoms independently selected from nitrogen, sulfur and oxygen (e.g., Y is selected from imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, thiadiazole, pyrrole, furan, thiophene and isoxazole), or Y is benzimidazole.

[0107] Further non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein

[0108] Z is C;

[0109] R 1 Selected from C6-C 10 Aryl (eg, phenyl or naphthyl), optionally substituted with up to four (eg, 1, 2, or 3) substituents independently selected from the group consisting of

[0110] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0111] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0112] C1-C3 alkyl containing up to 3 OH groups, for example CH2OH;

[0113] C2-C6 alkenyl, for example -CH=CH2;

[0114] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0115] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0116] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0117] -C(O)R 10 , where R 10 Selected from C1-C3 alkyl;

[0118] -OC(O)R 11 , where R 11 Selected from H and C1-C3 alkyl;

[0119] -C(O)OR 12 , where R 12is selected from hydrogen and C1-C3 alkyl;

[0120] -(CH2) m N(R 13 )R 14 , where m is 0 or 1, R 13 Selected from hydrogen, C1-C3 alkyl and -SO2R 15 , where R 15 is a C1-C3 alkyl group, and R 14 Selected from hydrogen, C1-C3 alkyl and -SO2R 16 , where R 16 is a C1-C3 alkyl group, or wherein R 13 and R 14 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0121] -SR 17 , where R 17 selected from hydrogen and C1-C3 alkyl; and

[0122] -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl;

[0123] provided that when the aryl ring is substituted with two or more substituents, the two substituents may be taken together with the carbon atoms to which they are attached to form a ring, and

[0124] R 4 、R 5 and R 6Together with the carbon atoms to which they are attached, they form a hydrocarbyl group selected from the group consisting of: 3-thietan-2-yl, 2-methyl-3-thietan-2-yl, 3-thiapentan-2-yl, 4-thiapentan-2-yl, 2-thiapropan-1-yl, 2-methyl-3-thiapentan-2-yl, 3-oxo-3-thietan-2-yl, 3-oxo-2-methyl-3-thietan-2-yl, 3-oxo-3-thiapentan-2-yl, 4-oxo-4-thiapentan-2-yl, 2-oxo-2-thiapropan-1-yl, 3-oxo-2-methyl-3-thiapentan-2-yl, butan-2-yl, butan-3-pentan-2-yl, -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- 1-methyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl 1-methylfuran-3-yl)eth-1-yl, 2-(3-furan-2-yl)prop-2-yl, 1-(2-tetrahydrofuran-3-yl)eth-1-yl, 2-(2-tetrahydrofuran-2-yl)prop-2-yl, 1-(3-tetrahydrofuran-1-yl, 2-(3-tetrahydrofuran-2-yl)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-thietan-1-yl.

[0125] In addition, non-limiting examples are compounds of formula (Ia), salts or solvates thereof

[0126]

[0127] in

[0128] n is 0 or 1;

[0129] R 1 Selected from

[0130] Halogens (including Br, Cl, and F);

[0131] C6-C 10 Aryl (eg, phenyl or naphthyl), optionally substituted with up to four (eg, 1, 2, or 3) substituents independently selected from the group consisting of

[0132] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0133] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0134] C1-C3 alkyl containing up to 3 OH groups, for example CH2OH;

[0135] C2-C6 alkenyl, for example -CH=CH2;

[0136] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0137] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0138] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0139] -C(O)R 10 , where R 10 Selected from C1-C3 alkyl;

[0140] -OC(O)R 11 , where R 11 Selected from H and C1-C3 alkyl;

[0141] -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl;

[0142] -(CH2) m N(R 13 )R 14 , where m is 0 or 1, R 13 Selected from hydrogen, C1-C3 alkyl and -SO2R 15 , where R 15 is a C1-C3 alkyl group, and R 14 Selected from hydrogen, C1-C3 alkyl and -SO2R 16 , where R 16is a C1-C3 alkyl group, or wherein R 13 and R 14 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0143] -SR 17 , where R 17 selected from hydrogen and C1-C3 alkyl; and

[0144] -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl;

[0145] provided that when the aryl ring is substituted with two or more substituents, the two substituents may be taken together with the carbon atoms to which they are attached to form a ring, and

[0146] C5-C 10 Mono- or bicyclic heteroaryl, wherein up to 2 C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, said heteroaryl being optionally substituted by up to four (e.g. 1, 2 or 3) substituents selected from the group consisting of

[0147] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0148] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0149] C2-C6 alkenyl, for example -CH=CH2;

[0150] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0151] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0152] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0153] -C(O)R 20 , where R 20 Selected from C1-C3 alkyl;

[0154] -OC(O)R 21 , where R 21 Selected from H and C1-C3 alkyl;

[0155] -C(O)OR 22 , where R 22 selected from hydrogen and C1-C3 alkyl);

[0156] -(CH2) m N(R 23 )R 24 , where m is 0 or 1, R 23 Selected from hydrogen, C1-C3 alkyl and -SO2R 25 , where R 25 is a C1-C3 alkyl group, and R 24 Selected from hydrogen, C1-C3 alkyl and -SO2R 26 , where R 26 is a C1-C3 alkyl group, or wherein R 23 and R 24 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0157] -SR 27 , where R 27 selected from hydrogen and C1-C3 alkyl; and

[0158] -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl;

[0159] Y is a monocyclic or bicyclic unsaturated or aromatic heterocycle containing one, two, three or four heteroatoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally selected from 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 The group is mono-, di- or trisubstituted, wherein R 40 and R 41 independently selected from hydrogen and C1-C4 alkyl (including ethyl and propyl), and p is 0, 1 or 2;

[0160] Z is C, S or S(O); and

[0161] R 4 、R 5 and R 6 Together with the carbon atoms to which they are attached they form a hydrocarbyl group optionally comprising up to five (e.g. 1, 2, 3, 4) heteroatoms selected from O, N, S and F (preferably the hydrocarbyl group comprises 2 to 15 C atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms).

[0162] Further non-limiting examples are compounds of formula (Ia), salts or solvates thereof, wherein 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, furanyl optionally substituted with methyl (e.g. 2-furanyl or 3-furanyl), C1-C6 fluoro-alkyl (e.g. pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl), and -NR 30 R 31 , where R 30 and R 31 independently selected from hydrogen and C1-C3 alkyl; or

[0163] R 6 and R 5 Together with the carbon atoms to which they are attached, they form

[0164] a) Carbonyl (C=O) or vinyl (C=CR 32 R 33 , where R 32 and R 33 independently selected from H or C1-C3 alkyl); or

[0165] b) a 3- to 7-membered saturated or unsaturated ring containing up to 3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy; (e.g., R 5 and R 6 Together with the carbon atom to which they are attached they form a thiadiazole or furyl group).

[0166] Further non-limiting examples are compounds of formula (Ia), salts or solvates thereof, wherein Z is C and R 4 、R 5 and R 6Together with the carbon atoms to which they are attached, they form a hydrocarbyl group selected from the group consisting of: 3-thietan-2-yl, 2-methyl-3-thietan-2-yl, 3-thiapentan-2-yl, 4-thiapentan-2-yl, 2-thiapropan-1-yl, 2-methyl-3-thiapentan-2-yl, 3-oxo-3-thietan-2-yl, 3-oxo-2-methyl-3-thietan-2-yl, 3-oxo-3-thiapentan-2-yl, 4-oxo-4-thiapentan-2-yl, 2-oxo-2-thiapropan-1-yl, 3-oxo-2-methyl-3-thiapentan-2-yl, butan-2-yl, butan-3-pentan-2-yl, -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- 1-methyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl 1-methylfuran-3-yl)eth-1-yl, 2-(3-furan-2-yl)prop-2-yl, 1-(2-tetrahydrofuran-3-yl)eth-1-yl, 2-(2-tetrahydrofuran-2-yl)prop-2-yl, 1-(3-tetrahydrofuran-1-yl, 2-(3-tetrahydrofuran-2-yl)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-thietan-1-yl.

[0167] Further non-limiting examples are compounds of formula (Ib), salts or solvates thereof

[0168]

[0169] in

[0170] n is 0 or 1;

[0171] R 1 Selected from

[0172] Halogens (including Br, Cl and F),

[0173] C6-C 10 Aryl (eg, phenyl or naphthyl), optionally substituted with up to four (eg, 1, 2, or 3) substituents independently selected from the group consisting of

[0174] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0175] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0176] C1-C3 alkyl containing up to 3 OH groups, for example CH2OH;

[0177] C2-C6 alkenyl, for example -CH=CH2;

[0178] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0179] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0180] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0181] -C(O)R 10 , where R 10 Selected from C1-C3 alkyl;

[0182] -OC(O)R 11 , where R 11 Selected from H and C1-C3 alkyl;

[0183] -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl;

[0184] -(CH2) m N(R 13 )R 14 , where m is 0 or 1, R 13 Selected from hydrogen, C1-C3 alkyl and -SO2R 15 , where R 15 is a C1-C3 alkyl group, and R 14 Selected from hydrogen, C1-C3 alkyl and -SO2R 16 , where R 16is a C1-C3 alkyl group, or wherein R 13 and R 14 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0185] -SR 17 , where R 17 selected from hydrogen and C1-C3 alkyl; and

[0186] -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl;

[0187] provided that when the aryl ring is substituted with two or more substituents, the two substituents may be taken together with the carbon atoms to which they are attached to form a ring, and

[0188] C5-C 10 Mono- or bicyclic heteroaryl, wherein up to 2 C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, said heteroaryl being optionally substituted by up to four (e.g. 1, 2 or 3) substituents selected from the group consisting of

[0189] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0190] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0191] C2-C6 alkenyl, for example -CH=CH2;

[0192] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0193] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0194] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0195] -C(O)R 20 , where R 20 Selected from C1-C3 alkyl;

[0196] -OC(O)R 21 , where R 21 Selected from H and C1-C3 alkyl;

[0197] -C(O)OR 22 , where R 22 selected from hydrogen and C1-C3 alkyl);

[0198] -(CH2) m N(R 23 )R 24 , where m is 0 or 1, R 23 Selected from hydrogen, C1-C3 alkyl and -SO2R 25 , where R 25 is a C1-C3 alkyl group, and R 24 Selected from hydrogen, C1-C3 alkyl and -SO2R 26 , where R 26 is a C1-C3 alkyl group, or wherein R 23 and R 24 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0199] -SR 27 , where R 27 selected from hydrogen and C1-C3 alkyl; and

[0200] -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl;

[0201] A is a 5- to 7-membered heterocyclic ring, which optionally contains one additional heteroatom selected from oxygen and sulfur, wherein said heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =0;

[0202] Z is C, S or S(O);

[0203] R 4 、R 5 and R 6 together with the carbon atoms to which they are attached form a hydrocarbyl group optionally comprising up to five (e.g. 1, 2, 3, 4) heteroatoms selected from O, N, S and F (preferably the hydrocarbyl group comprises 2 to 15 C atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms);

[0204] X 1 is NH, O or S; and

[0205] X 2 and X 3 are independently selected from C, N and O, provided that X 2 or X 3 Not C.

[0206] Further non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein

[0207] R 1 Selected from

[0208] Halogens (including Br, Cl and F),

[0209] C6-C 10 Aryl (eg, phenyl or naphthyl), optionally substituted with up to four (eg, 1, 2, or 3) substituents independently selected from the group consisting of

[0210] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0211] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0212] C1-C3 alkyl containing up to 3 OH groups, for example CH2OH;

[0213] C2-C6 alkenyl, for example -CH=CH2;

[0214] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0215] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0216] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0217] -C(O)R 10 , where R 10 Selected from C1-C3 alkyl;

[0218] -OC(O)R 11 , where R 11 Selected from H and C1-C3 alkyl;

[0219] -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl;

[0220] -(CH2) m N(R 13 )R 14 , where m is 0 or 1, R 13 Selected from hydrogen, C1-C3 alkyl and -SO2R 15 , where R 15 is a C1-C3 alkyl group, and R 14 Selected from hydrogen, C1-C3 alkyl and -SO2R 16 , where R 16 is a C1-C3 alkyl group, or wherein R 13 and R 14 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0221] -SR 17 , where R 17 selected from hydrogen and C1-C3 alkyl; and

[0222] -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl;

[0223] provided that when the aryl ring is substituted with two or more substituents, the two substituents may be taken together with the carbon atoms to which they are attached to form a ring, and

[0224] C5-C 10 Mono- or bicyclic heteroaryl, wherein up to 2 C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, said heteroaryl being optionally substituted by up to four (e.g. 1, 2 or 3) substituents selected from the group consisting of

[0225] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0226] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0227] C2-C6 alkenyl, for example -CH=CH2;

[0228] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0229] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0230] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0231] -C(O)R 20 , where R 20 Selected from C1-C3 alkyl;

[0232] -OC(O)R 21 , where R 21 Selected from H and C1-C3 alkyl;

[0233] -C(O)OR 22 , where R 22 selected from hydrogen and C1-C3 alkyl);

[0234] -(CH2) m N(R 23 )R 24 , where m is 0 or 1, R 23Selected from hydrogen, C1-C3 alkyl and -SO2R 25 , where R 25 is a C1-C3 alkyl group, and R 24 Selected from hydrogen, C1-C3 alkyl and -SO2R 26 , where R 26 is a C1-C3 alkyl group, or wherein R 23 and R 24 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0235] -SR 27 , where R 27 selected from hydrogen and C1-C3 alkyl; and

[0236] -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl;

[0237] and

[0238] R 4 、R 5 and R 6Together with the carbon atoms to which they are attached, they form a hydrocarbyl group selected from the group consisting of: 3-thietan-2-yl, 2-methyl-3-thietan-2-yl, 3-thiapentan-2-yl, 4-thiapentan-2-yl, 2-thiapropan-1-yl, 2-methyl-3-thiapentan-2-yl, 3-oxo-3-thietan-2-yl, 3-oxo-2-methyl-3-thietan-2-yl, 3-oxo-3-thiapentan-2-yl, 4-oxo-4-thiapentan-2-yl, 2-oxo-2-thiapropan-1-yl, 3-oxo-2-methyl-3-thiapentan-2-yl, butan-2-yl, butan-3-pentan-2-yl, -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- 1-methyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl 1-methylfuran-3-yl)eth-1-yl, 2-(3-furan-2-yl)prop-2-yl, 1-(2-tetrahydrofuran-3-yl)eth-1-yl, 2-(2-tetrahydrofuran-2-yl)prop-2-yl, 1-(3-tetrahydrofuran-1-yl, 2-(3-tetrahydrofuran-2-yl)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-thietan-1-yl.

[0239] Further non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein Z is C.

[0240] Further non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein Z is C, R 4 is selected from hydrogen and methyl; R 5is 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, furanyl optionally substituted with methyl (e.g. 2-furanyl or 3-furanyl), C1-C6 fluoro-alkyl (e.g. pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl), and -NR 30 R 31 , where R 30 and R 31 independently selected from hydrogen and C1-C3 alkyl; or

[0241] R 6 and R 5 Together with the carbon atoms to which they are attached, they form

[0242] a) Carbonyl (C=O) or vinyl (C=CR 32 R 33 , where R 32 and R 33 independently selected from H or C1-C3 alkyl); or

[0243] b) a 3- to 7-membered saturated or unsaturated ring containing up to 3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy; (e.g., R 5 and R 6 Together with the carbon atom to which they are attached they form a thiadiazole or furyl group).

[0244] Further non-limiting examples are compounds of formula (Ic), salts or solvates thereof

[0245]

[0246] in

[0247] n is 0 or 1;

[0248] R 1 Selected from

[0249] Halogens (including Br, Cl and F),

[0250] C6-C 10Aryl (eg, phenyl or naphthyl), optionally substituted with up to four (eg, 1, 2, or 3) substituents independently selected from the group consisting of

[0251] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0252] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0253] C1-C3 alkyl containing up to 3 OH groups, for example CH2OH;

[0254] C2-C6 alkenyl, for example -CH=CH2;

[0255] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0256] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0257] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0258] -C(O)R 10 , where R 10 Selected from C1-C3 alkyl;

[0259] -OC(O)R 11 , where R 11 Selected from H and C1-C3 alkyl;

[0260] -C(O)OR 12 , where R 12 is selected from hydrogen and C1-C3 alkyl;

[0261] -(CH2) m N(R 13 )R 14 , where m is 0 or 1, R 13 Selected from hydrogen, C1-C3 alkyl and -SO2R 15 , where R 15 is a C1-C3 alkyl group, and R 14 Selected from hydrogen, C1-C3 alkyl and -SO2R 16 , where R 16 is a C1-C3 alkyl group, or wherein R 13 and R 14 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0262] -SR 17, where R 17 selected from hydrogen and C1-C3 alkyl; and

[0263] -S(O)2R 18 , where R 18 is selected from hydrogen and C1-C3 alkyl;

[0264] provided that when the aryl ring is substituted with two or more substituents, the two substituents may be taken together with the carbon atoms to which they are attached to form a ring, and

[0265] C5-C 10 Mono- or bicyclic heteroaryl, wherein up to 2 C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, said heteroaryl being optionally substituted by up to four (e.g. 1, 2 or 3) substituents selected from the group consisting of

[0266] Halogen (including F, Cl, Br); OH (hydroxyl); C≡N (cyano); NO2 (nitro);

[0267] C1-C6 alkyl, which optionally contains up to 5 halogen atoms (e.g. F), such as CH3, CF3 or CHF2;

[0268] C2-C6 alkenyl, for example -CH=CH2;

[0269] C1-C6 alkoxy, which optionally contains up to 3 halogen atoms (e.g. F), for example OCH3, OCH3, OCF3;

[0270] C1-C3 alkoxy C1-C3 alkyl, for example 2-methoxy-ethyl;

[0271] C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl;

[0272] -C(O)R 20 , where R 20 Selected from C1-C3 alkyl;

[0273] -OC(O)R 21 , where R 21 Selected from H and C1-C3 alkyl;

[0274] -C(O)OR 22 , where R 22 selected from hydrogen and C1-C3 alkyl);

[0275] -(CH2) m N(R 23 )R 24 , where m is 0 or 1, R 23 Selected from hydrogen, C1-C3 alkyl and -SO2R 25 , where R25 is a C1-C3 alkyl group, and R 24 Selected from hydrogen, C1-C3 alkyl and -SO2R 26 , where R 26 is a C1-C3 alkyl group, or wherein R 23 and R 24 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0276] -SR 27 , where R 27 selected from hydrogen and C1-C3 alkyl; and

[0277] -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl;

[0278] Z is C, S or S(O); and

[0279] R 4 、R 5 and R 6 together with the carbon atoms to which they are attached form a hydrocarbyl group optionally comprising up to five (e.g. 1, 2, 3, 4) heteroatoms selected from O, N, S and F (preferably the hydrocarbyl group comprises 2 to 15 C atoms (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms);

[0280] X 1 is NH or O; and

[0281] X 2 and X 3 are independently selected from C, N and O, provided that X 2 or X 3 Not C.

[0282] Further non-limiting examples are compounds of formula (Ic), salts or solvates thereof, wherein Z is C.

[0283] Further non-limiting examples are compounds of formula (Ic), salts or solvates thereof, wherein Z is C,

[0284] R 4 is selected from hydrogen and methyl;

[0285] R 5 is selected from hydrogen, C1-C2 alkyl and C2-C3 alkenyl; and

[0286] 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, furanyl optionally substituted with methyl (e.g. 2-furanyl or 3-furanyl), C1-C6 fluoro-alkyl (e.g. pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl), and -NR 30 R 31 , where R 30 and R 31 independently selected from hydrogen and C1-C3 alkyl;

[0287] or

[0288] R 6 and R 5 Together with the carbon atoms to which they are attached, they form

[0289] a) Carbonyl (C=O) or vinyl (C=CR 32 R 33 , where R 32 and R 33 independently selected from H or C1-C3 alkyl); or

[0290] b) a 3- to 7-membered saturated or unsaturated ring containing up to 3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy; (e.g., R 5 and R 6 Together with the carbon atom to which they are attached they form a thiadiazole or furyl group).

[0291] Further non-limiting examples are compounds of formula (Ic), salts or solvates thereof, 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 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, furanyl optionally substituted with methyl (e.g. 2-furanyl or 3-furanyl), C1-C6 fluoro-alkyl (e.g. pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl) and -NR 30 R 31 , where R 30 and R 31 Independently selected from hydrogen and C1-C3 alkyl.

[0292] Further non-limiting examples are compounds of formula (Ic) wherein Z is C and R 4 、R 5 and R 6Together with the carbon atoms to which they are attached, they form a hydrocarbyl group selected from the group consisting of: 3-thietan-2-yl, 2-methyl-3-thietan-2-yl, 3-thiapentan-2-yl, 4-thiapentan-2-yl, 2-thiapropan-1-yl, 2-methyl-3-thiapentan-2-yl, 3-oxo-3-thietan-2-yl, 3-oxo-2-methyl-3-thietan-2-yl, 3-oxo-3-thiapentan-2-yl, 4-oxo-4-thiapentan-2-yl, 2-oxo-2-thiapropan-1-yl, 3-oxo-2-methyl-3-thiapentan-2-yl, butan-2-yl, butan-3-pentan-2-yl, -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- 1-methyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl, 1-methylcyclopropyl 1-methylfuran-3-yl)eth-1-yl, 2-(3-furan-2-yl)prop-2-yl, 1-(2-tetrahydrofuran-3-yl)eth-1-yl, 2-(2-tetrahydrofuran-2-yl)prop-2-yl, 1-(3-tetrahydrofuran-1-yl, 2-(3-tetrahydrofuran-2-yl)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-thietan-1-yl.

[0293] Further non-limiting examples are compounds of formula (I), (Ia), (Ib) and (Ic) wherein n is 0.

[0294] Further non-limiting examples are compounds of formula (I), (Ia), (Ib) and (Ic) wherein R 1 It is p-methyl-phenyl.

[0295] Further non-limiting examples are compounds of formula (I), (Ia), (Ib) and (Ic) wherein n is 0 and R 1 It is p-methyl-phenyl.

[0296] Further non-limiting examples are compounds of formula (I), (Ia), (Ib) and (Ic) wherein Z is C, n is 0, and R 1 It is p-methyl-phenyl.

[0297] Further non-limiting examples are compounds of formula (I), (Ia), (Ib) and (Ic) wherein n is 0, 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 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.

[0298] Further non-limiting examples are compounds of formula (I), (Ia) or (Ib) selected from the group consisting of:

[0299] (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(1,2,3-thiadiazol-5-yl)methanone,

[0300] (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(thietan-3-yl)methanone,

[0301] (2,2-dimethylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0302] (2-ethoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0303] (2-methoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0304] (2-Methylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0305] (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0306] (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0307] (E)-1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-2-en-1-one,

[0308] (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one,

[0309] (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pent-3-en-1-one,

[0310] (R)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0311] (S)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0312] (S)-2-(methylthio)-1-((S)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0313] (S)-2-methyl-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0314] (tetrahydrofuran-3-yl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0315] 1-(2-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0316] 1-(2-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0317] 1-(2-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0318] 1-(2-(4-(2,3-dihydrobenzofuran-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0319] 1-(2-(4-(2,3-dihydrobenzofuran-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0320] 1-(2-(4-(2,5-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0321] 1-(2-(4-(2-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0322] 1-(2-(4-(2-cyclopropyloxazol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0323] 1-(2-(4-(2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0324] 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0325] 1-(2-(4-(3-((dimethylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0326] 1-(2-(4-(3,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0327] 1-(2-(4-(3,5-dimethylisoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0328] 1-(2-(4-(3-chloro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0329] 1-(2-(4-(3-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0330] 1-(2-(4-(4-((1,1-dioxothiomorpholino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0331] 1-(2-(4-(4-(1-hydroxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0332] 1-(2-(4-(4-(difluoromethoxy)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0333] 1-(2-(4-(4-(difluoromethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0334] 1-(2-(4-(4-(methylsulfonyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0335] 1-(2-(4-(4-(tert-butyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0336] 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0337] 1-(2-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0338] 1-(2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0339] 1-(2-(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0340] 1-(2-(4-(4-isopropylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0341] 1-(2-(4-(4-methyl-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0342] 1-(2-(4-(5-((dimethylamino)methyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0343] 1-(2-(4-(5-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0344] 1-(2-(4-(5-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0345] 1-(2-(4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0346] 1-(2-(4-(Benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0347] 1-(2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0348] 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-((trifluoromethyl)thio)ethan-1-one,

[0349] 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0350] 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-dien-1-one,

[0351] 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one,

[0352] 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0353] 1-(2-(5-(2,3-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0354] 1-(2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0355] 1-(2-(5-(2,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0356] 1-(2-(5-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0357] 1-(2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0358] 1-(2-(5-(2-methoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0359] 1-(2-(5-(3-(methylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0360] 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0361] 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-3-en-1-one,

[0362] 1-(2-(5-(3,4-dimethoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0363] 1-(2-(5-(3,4-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0364] 1-(2-(5-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0365] 1-(2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0366] 1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0367] 1-(2-(5-(3-methylisothiazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0368] 1-(2-(5-(3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0369] 1-(2-(5-(4-((methylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0370] 1-(2-(5-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0371] 1-(2-(5-(4-(aminomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0372] 1-(2-(5-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0373] 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0374] 1-(2-(5-(4-acetylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0375] 1-(2-(5-(4-aminophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0376] 1-(2-(5-(4-chloro-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0377] 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0378] 1-(2-(5-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0379] 1-(2-(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0380] 1-(2-(5-(4-methoxy-2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0381] 1-(2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0382] 1-(2-(5-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0383] 1-(2-(5-(5-(methoxymethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0384] 1-(2-(5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0385] 1-(2-(5-(Benzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0386] 1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0387] 1-(2-(5-benzyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0388] 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0389] 2-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile,

[0390] 2-(2-(4-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile,

[0391] 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0392] 2-(allylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0393] 2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0394] 2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0395] 2-(ethylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0396] 2-(Furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one,

[0397] 2-(furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0398] 2-(Furan-3-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one,

[0399] 2-(furan-3-yl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0400] 2-(methylamino)-N-(4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetamide,

[0401] 2-(methylsulfinyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0402] 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one,

[0403] 2-(methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0404] 2-(methylthio)-1-(2-(2-(p-tolyl)-2H-tetrazol-5-yl)piperidin-1-yl)propan-1-one,

[0405] 2-(methylthio)-1-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)propan-1-one,

[0406] 2-(methylthio)-1-(2-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0407] 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0408] 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0409] 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0410] 2-(methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0411] 2-(methylthio)-1-(2-(4-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0412] 2-(methylthio)-1-(2-(4-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0413] 2-(methylthio)-1-(2-(4-(pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0414] 2-(methylthio)-1-(2-(4-(pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0415] 2-(methylthio)-1-(2-(4-(pyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0416] 2-(methylthio)-1-(2-(4-(quinoxalin-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0417] 2-(methylthio)-1-(2-(4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0418] 2-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one,

[0419] 2-(methylthio)-1-(2-(5-(2-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0420] 2-(methylthio)-1-(2-(5-(2,3,4-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0421] 2-(methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0422] 2-(methylthio)-1-(2-(5-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0423] 2-(methylthio)-1-(2-(5-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0424] 2-(methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0425] 2-(methylthio)-1-(2-(5-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0426] 2-(methylthio)-1-(2-(5-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0427] 2-(methylthio)-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0428] 2-(methylthio)-1-(2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one,

[0429] 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)azepan-1-yl)propan-1-one,

[0430] 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0431] 2-(methylthio)-1-(2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one,

[0432] 2-(methylthio)-1-(2-(5-(p-tolyl)isoxazol-3-yl)piperidin-1-yl)propan-1-one,

[0433] 2-(methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one,

[0434] 2-(methylthio)-1-(2-(5-(p-tolyl)thiazol-2-yl)piperidin-1-yl)propan-1-one,

[0435] 2-(methylthio)-1-(2-(5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0436] 2-(methylthio)-1-(2-(5-phenyl-1H-imidazol-2-yl)pyrrolidin-1-yl)propan-1-one,

[0437] 2-(methylthio)-1-(2-(5-phenyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one,

[0438] 2-(methylthio)-1-(2-(5-phenyloxazol-2-yl)piperidin-1-yl)propan-1-one,

[0439] 2-(methylthio)-1-(4-(5-(p-tolyl)-1H-imidazol-2-yl)thiazolidin-3-yl)propan-1-one,

[0440] 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one,

[0441] 2,2,3-trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0442] 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one,

[0443] 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0444] 2,3-dimethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0445] 2,3-dimethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0446] 2,5-difluoro-4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile,

[0447] 2-amino-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0448] 2-cyclobutyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0449] 2-cyclopentyl-2-ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one,

[0450] 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one,

[0451] 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0452] 2-cyclopropyl-2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one,

[0453] 2-ethoxy-1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0454] 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one,

[0455] 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0456] 2-fluoro-4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile,

[0457] 2-mercapto-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0458] 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0459] 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0460] 2-methoxy-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0461] 2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0462] 2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0463] 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one,

[0464] 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0465] 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butane-1,3-dione,

[0466] 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pentan-1-one,

[0467] 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)prop-2-en-1-one,

[0468] 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0469] 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0470] 2-methyl-3-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0471] 2-methylene-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0472] 3-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile,

[0473] 3,3,3-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0474] 3,3,4,4,4-pentafluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0475] 3,3-difluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0476] 3-fluoro-4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile,

[0477] 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one,

[0478] 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0479] 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile,

[0480] 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde,

[0481] 4,4,4-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0482] Bicyclo[1.1.1]pentan-1-yl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0483] Cyclobutyl(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0484] Cyclopentyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0485] Cyclopropyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0486] 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid methyl ester,

[0487] N-(2-hydroxyethyl)-4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)benzenesulfonamide,

[0488] 2-(methylthio)-1-(2-(5-(3-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0489] N-(4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methanesulfonamide,

[0490] 2-(methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0491] 1-(sec-butylsulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0492] 1-(sec-butylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0493] 1-(isopropylsulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0494] 1-(isopropylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0495] 1-((1-(methylthio)ethyl)sulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0496] 1-((1-(methylthio)ethyl)sulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0497] 1-((2-(methylthio)propan-2-yl)sulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0498] 1-((2-(methylthio)propan-2-yl)sulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0499] 1-(But-3-en-2-ylsulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0500] 1-(But-3-en-2-ylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0501] 1-(pent-3-en-2-ylsulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0502] 1-(pent-3-en-2-ylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0503] 1-((2-methylbut-3-en-2-yl)sulfinyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0504] 1-((2-methylbut-3-en-2-yl)sulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0505] 1-(2-(5-(4-(Hydroxymethyl)-phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0506] 2-(methylsulfonyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one,

[0507] 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0508] 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0509] 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0510] 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0511] 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one,

[0512] 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one,

[0513] 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one,

[0514] 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0515] 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0516] 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one,

[0517] 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0518] 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0519] 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfonyl)propan-1-one,

[0520] 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)-propan-1-one,

[0521] 1-(4-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one,

[0522] 1-(5-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one,

[0523] 1-(2-hydroxy-6-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one,

[0524] 1-(3-hydroxy-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylsulfinyl)propan-1-one,

[0525] 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0526] 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0527] 1-(4-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0528] 1-(3-hydroxy-2-(5-(4-(hydroxymethyl)-phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one,

[0529] 1-(2-hydroxy-6-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0530] 1-(5-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0531] 1-(4-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0532] 1-(3-hydroxy-2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0533] 4-(2-(1-(2-methylbutyryl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde,

[0534] 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid,

[0535] 4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid,

[0536] (2,2-dimethylcyclopropyl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone,

[0537] 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0538] 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0539] 2-(4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile,

[0540] 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile,

[0541] 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile,

[0542] 2,3-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0543] 2-methyl-1-(2-(5-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0544] 2-methyl-1-(2-(5-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0545] 1-(2-(5-(4-(hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one,

[0546] 1-(isopropylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0547] 1-(sec-butylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine,

[0548] 2-methyl-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one,

[0549] 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperazin-1-yl)propan-1-one,

[0550] 2-(methylthio)-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one, and

[0551] 2-methyl-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)butan-1-one.

[0552] Compounds defined by formula (I), which include compounds of formula (Ia), (Ib), and (Ic), contain several chiral centers (two of which are represented by * in the respective formulas) and can therefore exist as mixtures of stereoisomers, or they can be resolved into isomerically pure forms. Resolving stereoisomers increases the complexity of manufacturing and purification of these compounds, and simply for economic reasons, it is preferred to use these compounds as mixtures of their stereoisomers. However, if it is necessary to prepare individual stereoisomers, this can be achieved according to methods known in the art, such as preparative HPLC and GC, crystallization, or stereoselective synthesis. Compounds defined by formula (I), which include compounds of formula (Ia), (Ib), and (Ic), can also exist in various tautomeric forms, including enol-keto forms, lactam-lactim forms, amide-imidic acid forms, amine-imine forms, and 1H-imidazole-3H-imidazole forms. Therefore, the chemical structures described herein include all possible stereoisomers and tautomeric forms of the compounds shown.

[0553] It should also be noted that the compounds defined by formula (I), which include compounds of formula (Ia), (Ib), and (Ic), can exist in unsolvated forms as well as solvated forms (including hydrated forms), and as N-oxides. Generally, the compounds can be hydrated, solvated, or N-oxides. Certain compounds can exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to fall within the scope of the present invention.

[0554] "Solvate" refers to a compound formed by solvation (the combination of solvent molecules with molecules or ions of a solute), or an aggregate consisting of solute ions or molecules, i.e., a compound defined by formula (I) (which includes compounds of formula (Ia), (Ib), and (Ic)), and one or more solvent molecules. When water is the solvent, the corresponding solvate is a "hydrate." Other suitable solvents may include, but are not limited to, acetone, acetonitrile, benzene, cyclohexane, dihydrolevoglucosenone, methyl-tetrahydrofuran, pentanediol, 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.

[0555] "Salt" refers to a salt of a compound defined by formula (I) (which includes compounds of formula (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, etc.; or with organic acids such as amino acids, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid (1) when the parent compound is formed by reacting the acidic proton with a metal ion such as an alkali metal ion, an alkaline earth ion or an aluminum ion; or (2) when the 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 when the acidic proton is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine or the like.

[0556] The compounds defined by formula (I), which includes compounds of formula (Ia), (Ib) and (Ic), are "TRPM8 agonists," meaning that they have an effect on the cellular Ca2+ signaling pathway of the TRPM8 channel. 2+ Ion permeability has an agonistic effect. Thus, a "TRPM8 agonist" refers to any compound that, when in contact with the TRPM8 receptor, produces an increase in fluorescence relative to background 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 section.

[0557] Thus, in a second aspect there is provided a method of modulating (in vitro and in vivo) transient receptor potential melastatin member 8 (TRPM8) comprising contacting the receptor with a compound of formula (I) or a salt or solvate thereof.

[0558] In certain embodiments of the second aspect of the invention, the method of modulation is an in vitro method.

[0559] In a third aspect, a non-medical method of inducing a cooling sensation in a human or animal is provided, the method comprising contacting the human or animal with a compound of formula (I) (which includes compounds of formula (Ia), (Ib) and (Ic)) or a salt or solvate thereof.

[0560] In certain embodiments, the method is a method of achieving 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 a salt or solvate thereof.

[0561] Compounds of formula (I), including compounds of formula (Ia), (Ib), and (Ic), can be administered directly or as a solution or suspension containing an effective amount of the compound of formula (I). The effective amount depends, among other things, on the target TRPM8 region of the human body and on the cooling effect of the compound or compound mixture.

[0562] In a fourth aspect, there is provided a consumer product comprising a compound defined by formula (I), which includes compounds of formula (Ia), (Ib) and (Ic), particularly a consumer product that comes into contact with human skin and / or mucous membranes.

[0563] Consumer products that come into contact with mucous membranes include, but are not limited to, food, beverages, chewing gum, tobacco and tobacco substitute products, dental care products, personal care products including lip care products, and sexual health and intimate care products.

[0564] In certain embodiments, the dental care product is an oral care product, a tooth care product, a denture cleanser, a denture adhesive, or the like.

[0565] In certain embodiments, the food product is an iced consumable, such as ice cream, sorbet; confectionery, such as candy and chocolate; food containing mint or mint flavoring, sauces, dairy products, such as milk drinks and yogurt; and snacks.

[0566] In certain embodiments, the tobacco substitute product is a liquid or solid suitable for electronic consumption, such as a liquid for an electronic cigarette.

[0567] In certain embodiments, personal care products that contact mucous membranes are lip balms, nasal sprays, and eye drops.

[0568] Consumer products that come into contact with human skin include, but are not limited to, cosmetics. In certain embodiments, cosmetics are skin care products, particularly bath products, skin washes and cleansing products, skin care products, eye makeup, nail care products, foot care products, and the like. In certain embodiments, cosmetics are products with special effects, particularly sunscreens, insect repellents, tanning products, pigment removal products, deodorants, antiperspirants, depilatories, and shaving products. In certain embodiments, cosmetics are hair care products, particularly shampoos, hair conditioning products, hair styling products, hair styling products, and hair coloring products, as well as scalp care products, such as scalp cooling shampoos and lotions.

[0569] In certain 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 domestic spaces (rooms, refrigerators, cabinets, shoes or cars) and / or public places (lobbies, hotels, shopping malls, etc....).

[0570] The consumer product can be in any physical form, such as solid, semi-solid, plaster, solution, suspension, lotion, emulsion, foam, gel, paste or a combination thereof. The physical form of the consumer product that is suitable for depends largely on the specific role that this consumer product should meet, such as cleaning, softening, nursing, cooling etc.

[0571] In certain embodiments, the consumer products that come into contact with human skin are fabric care products (e.g., fabric cleaners, fabric conditioners (including tumble dryer sheets), and fragrance enhancers (liquid or solid) that are applied to fabric in a first step, e.g., when the fabric is washed, and the treated fabric is subsequently contacted with human skin.

[0572] The use level of the compounds of the present invention (compounds defined by formula (I), including compounds of formula (Ia), (Ib), and (Ic)) depends, among other things, on the target TRPM8 area of ​​the body and also on the cooling efficacy of the compound or compound mixture. For example, in cavity applications of the compounds of the present invention, such as dentifrices, dental floss, chewing gum, or whitening strips, the use level can be from about 0.00001% (0.01 ppm) to about 0.1% (1000 ppm); from about 0.00005% (0.5 ppm) to about 0.1% (1000 ppm); from about 0.0001% (1 ppm) to about 0.05% (500 ppm); or from about 0.001% (10 ppm) to about 0.01% (100 ppm), by weight of the composition. When the compounds of the present invention are used in mouthwashes, usage levels 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, levels may be from about 0.001% (10 ppm) to about 0.5% (5000 ppm) by weight of the composition or from about 0.01% (100 ppm) to about 0.4% (4000 ppm) by weight of the composition.

[0573] The cooling effect (intensity) of a compound is determined by its EC 50 Value definition. EC 50 EC (half-maximal effective concentration) is the concentration of a compound that elicits a response halfway between baseline and maximum after a specified exposure time. It is often used as a measure of potency. 50It is a measure of concentration expressed in μM (μmolar) units, where 1 μM is equivalent to 1 μmol / L.

[0574] EC 50 Compounds at 10 μM or lower are perceived by humans as cooling. 50 The lower the value, the higher the cooling effect. For example, EC 50 Compounds with values ​​around 0.1 μM were considered to be strong cooling compounds.

[0575] However, the cooling properties of a compound depend not only on its strength (potency; EC 50 ), and also its duration, i.e. the period of time (in minutes) during which the cooling effect is perceived. The duration can vary from a few seconds after rinsing to hours or even days. In the case of oral care products, the preferred "long-lasting" effect is usually between 20 minutes and 3 hours after rinsing.

[0576] Compounds defined by formula (I), which include compounds of formula (Ia), (Ib), and (Ic), are generally well soluble in water at the desired concentration. However, to increase solubility, specific isomers may be used instead of isomer mixtures. As is well known to those skilled in the art, cis / trans isomers and / or diastereomers may have different solubilities, and therefore mixtures of isomers or individual isomers may be selected for use in consumer products, depending on the desired cooling effect.

[0577] Compounds of formula (I), which include compounds of formula (Ia), (Ib), and (Ic), are very effective at relatively low concentrations. Therefore, it is preferred to prepare a stock solution that is further diluted before mixing with the consumer product. Particularly suitable solvents, in addition to water, are triacetin and propylene glycol. Acetone, benzyl alcohol, dihydrolevulinone, 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 may also be mentioned as suitable solvents for compounds of formula (I), which include compounds of formula (Ia), (Ib), and (Ic). However, other solvent systems containing surfactants may also be used.

[0578] In order to improve the cooling effect of the compounds as defined herein by formula (I), which includes compounds of formula (Ia), (Ib) and (Ic), the compounds, their salts or solvates 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.

[0579] These compounds are known to modulate the concentration of these ions in the extracellular space, thereby affecting the response of the TRPM8 ion channel, leading to changes in the perceived cooling effect.

[0580] According to Kizilbash et al. (WO2019 / 121193A1), both cooling intensity and flavor intensity can be enhanced when combined with agents having properties that enhance the effect. Therefore, the compound defined herein by formula (I) can be combined in a particular embodiment with an enhancer disclosed in WO2019 / 121193, which is incorporated by reference, particularly with respect to synergists.

[0581] As a further enhancer, mention may be made of N-lactylethanolamine (2-hydroxy-N-(2-hydroxyethyl)propionamide; CAS 5422-34-4), which is known as an enhancer for cooling agents, for example from PCT International Publication WO 2008 / 107137, which is incorporated by reference, in particular with regard to the cooling enhancer defined by formula (I).

[0582] Compounds of formula (I), which include compounds of formula (Ia), (Ib), and (Ic), may be used in combination with other cooling compounds known in the art.

[0583] Thus, in a fifth aspect there is provided a composition comprising a cooling sensation, wherein the composition comprises at least one compound of formula (I), a salt or solvate thereof and a further cooling compound.

[0584] In a specific embodiment, the compounds of formula (I) (which include compounds of formula (Ia), (Ib) and (Ic)) can be combined with menthol (e.g., in the form of peppermint oil and / or spearmint oil), menthone, p-menthanecarboxamide, N-2,3-trimethyl-2-isopropyl-butyramide (WS-23), menthyl lactate ( ML), Menthone Glyceryl Acetal ( MGA), 3-(1-menthoxy)-propane-1,2-diol (TK-10), p-menthane-3,8-diol (known as Coolact38D), isopulegol (known as Coolact P), monomenthyl succinate ( ), monomenthyl glutarate, o-menthylglycerol, menthyl N,N-dimethylsuccinamate, 2-(sec-butyl)cyclohexan-1-one (menthone), 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-2,6-dimethoxyphenoxy)-1-((2-isopropyl-5-methylcyclohexyl)oxy)propyl)- 2-Methoxyphenol (including 4-(2-(4-allyl-2,6-dimethylphenoxy)-1-(((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol) and 4-(2-(4-allyl-2,6-dimethylphenoxy)-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.

[0585] Examples of p-menthanecarboxamides include compounds such as 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 190) and (1R,2S,5R)-N-((S)-2-((R)-2-aminopropionylamino)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide.

[0586] To achieve more than just a cooling effect, the compounds of formula (I) (which includes compounds of formula (Ia), (Ib) and (Ic)), their salts or solvates may be combined with other active substances, such as flavors, fragrances and sweeteners.

[0587] Examples of flavor ingredients include natural flavors, artificial flavors, spices, seasonings, etc. Exemplary flavor ingredients include synthetic flavor oils and flavoring fragrances and / or oils, oleoresins, essential oils and distillates, and combinations comprising at least one of the foregoing.

[0588] Spice 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, cypress leaf oil, nutmeg oil, allspice, sage oil, mace, bitter almond oil, and cassia bark oil. Useful flavoring agents include artificial, natural and synthetic fruit flavors, such as vanilla, and citrus oils, including lemon, orange, lime, grapefruit, yuzu, sudachi, and fruit essential oils, including apple, pear, peach, grape, raspberry, blackberry, gooseberry, blueberry, strawberry, cherry, plum, prune, raisin, cola, guarana, orange blossom, pineapple, apricot, banana, melon, apricot, cherry, tropical fruit, mango, mangosteen, pomegranate, papaya, etc.

[0589] Additional exemplary flavors imparted by the flavor 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 Japanese mint flavor; spicy flavor, such as asafoetida 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 seed flavor, sassafras flavor, savory flavor, Sichuan pepper flavor, and perilla flavor. , juniper berry essence, ginger essence, star anise essence, horseradish essence, thyme essence, tarragon essence, dill essence, chili flavor, nutmeg essence, basil flavor, parsley flavor, marjoram flavor, rosemary flavor, bay leaf flavor and wasabi (Japanese horseradish) flavor; nut flavors such as almond flavor, hazelnut flavor, macadamia flavor, peanut flavor, pecan flavor, pistachio flavor and walnut flavor; wine flavors such as wine flavor, whiskey flavor, brandy flavor, rum flavor, gin flavor and liqueur flavor; flower flavors; and vegetable flavors such as onion flavor, garlic flavor, cabbage flavor, carrot flavor, celery flavor, mushroom flavor and tomato flavor.

[0590] Generally any flavor or food additive (including food coloring) may be used, such as those described in "Essential guide to food additives," third edition, 2008, pp. 101-321, provided by Leatherhead Food International Ltd. (ISBN: 978-1-905224-50-0), which publication is incorporated herein by reference.

[0591] In a specific embodiment, the compound of formula (I) (which includes compounds of formula (Ia), (Ib) and (Ic)) can be combined with anethole, levomenthol, levocarvone, ethyl maltol, vanillin, eucalyptol, eugenol, racemic menthol, cis-3-hexenol, linalool, mint oil (e.g., peppermint arvensis oil), peppermint piperita oil, oil), spearmint natural oil, spearmint Scotch oil), methylcyclopentenolone (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, ethylionone, linalyl acetate, decanal, cis-jasmone, ethyl hexanoate, melonal (2,6-dimethylhept-5-enal), citronellol, ethyl acetoacetate, nutmeg oil and clove oil or a mixture thereof.

[0592] In a specific embodiment, the compound of formula (I) is selected from 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-(methyl 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 a mixture thereof.

[0593] 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 glycosides, naringin dihydrochalcone, mogroside V, monk fruit extract, rubusoside, rubusoside extract, glycyphyllin, isomogroside V, mogroside IV, siamenoside I, neomogroside, mukurozioside IIb, (+)-hernandulcin, 4β-hydroxyhernandulcin, baiyunoside, phlomisoside I I), bryodulcoside, bryosidebryonoside, abrusosides AE, cyclocarioside A, cyclocaryoside I, albiziasaponins AE, glycyrrhizin, araboglycyrrhizin, periandrins IV, pterocaryosides A and B, osladin, polypodosides A and B, telosmoside A8-18, phyllodulcin, huangqioside Eneoastilbin, 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 sweet enhancers and sweeteners. When used as sweet enhancers, they are typically used in amounts below their sweetness detection threshold.

[0594] In certain embodiments, the compounds of Formula (I) may be combined with additional ingredients that together involve an orally acceptable carrier material.

[0595] In some aspects, orally acceptable carriers can include one or more compatible solid or liquid excipients or diluents suitable for topical oral administration. As used herein, "compatible" means that the components of the composition can be mixed without interacting in a manner that significantly reduces stability and / or efficacy. The carrier can include the common and conventional components of dentifrice, non-abrasive gel, subgingival gel, mouthwash or rinse, oral spray, chewing gum, lozenge and mint. The selection of the carrier used depends essentially on the manner in which the composition is introduced into the oral cavity. Carrier materials for toothpaste, tooth gel, etc. include abrasive materials, foaming agents, adhesives, humectants, flavorings and sweeteners, etc., as disclosed in, for example, U.S. Patent No. 3,988,433 to Benedict. Carrier materials for dual-phase dentifrice formulations are disclosed in U.S. Patents Nos. 5,213,790; 5,145,666, and 5,281,410, all issued to Lukacovic et al., and U.S. Patents Nos. 4,849,213 and 4,528,180 issued to Schaeffer. Carrier materials for mouthwashes, rinses, or oral sprays typically include water, flavorings, and sweeteners, as disclosed, for example, in U.S. Patent No. 3,988,433 issued to Benedict. Carrier materials for lozenges typically include a candy base; chewing gum carrier materials include gum base, flavorings, and sweeteners, as disclosed, for example, in U.S. Patent No. 4,083,955 issued to Grabenstetter et al. Pouch carrier materials typically include a pouch, flavorings, and sweeteners. For subgingival gels used to deliver active substances into or around the periodontal pocket, a "subgingival gel carrier" is selected, as described, for example, in U.S. Patent Nos. 5,198,220 and 5,242,910, both to Damani. Carriers suitable for preparing the compositions of the present disclosure are well known in the art. Their selection will depend on secondary considerations such as taste, cost, and shelf stability.

[0596] Other suitable types of orally acceptable carrier materials or excipients are listed in WO 2010 / 059289, in particular pages 17-31, which is incorporated by reference.

[0597] Scientific literature indicates that activation of TRPM8 channels may be helpful in treating most TRPM8-mediated pathological symptoms (J. Med. Chem. 2016, 59 (22), 10006-10029). Therefore, it is envisioned that compounds of formula (I) may also be suitable for treating prostate cancer, bladder weakness, inflammation or pain, including contacting a patient with one or more compounds of formula (I) as defined herein. It is also envisioned that compounds of formula (I) as defined herein may be suitable for relieving symptoms of cough and cold, irritation, sore throat or hoarseness, and treating dysphagia (Int. J. Mol. Sci. 2018, 19, 4113).

[0598] Thus, in a sixth aspect there is provided a pharmaceutical composition comprising one or more compounds defined by formula (I) (which includes compounds of formula (Ia), (Ib) and (Ic)) or a salt or solvate thereof.

[0599] Depending on the specific treatment regimen contemplated, pharmaceutical compositions comprising one or more compounds of formula (I) may be administered parenterally, topically, orally or topically.The pharmaceutical compositions may be liquids, suspensions or solid formulations.

[0600] In certain embodiments, the pharmaceutical composition is a nasal spray, a topical cream, a skin spray, a throat spray, or eye drops.

[0601] While some compounds are known per se from the literature, other compounds falling within the definition of formula (I) as defined above are not described in the literature and are therefore novel per se.

[0602] Therefore, in another aspect of the present invention there is provided a compound of formula (Ib)

[0603]

[0604] in

[0605] n is 0 or 1;

[0606] R 1 Selected from

[0607] i) C6 aryl or heteroaryl, wherein up to 2 C atoms are replaced by N atoms, said aryl or heteroaryl being substituted by 1-4 (e.g. 2 or 3) substituents selected from the group consisting of

[0608] Halogen; OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl;

[0609] C1-C6 alkyl containing up to 5 halogen atoms;

[0610] C2-C6 alkenyl;

[0611] C1-C6 alkoxy;

[0612] C1-C6 alkoxy containing up to 3 halogen atoms;

[0613] C1-C3 alkoxy C1-C3 alkyl;

[0614] C3-C7 cycloalkyl;

[0615] -C(O)R 20 , where R 20 Selected from C1-C3 alkyl;

[0616] -OC(O)R 21 , where R 21 Selected from H and C1-C3 alkyl;

[0617] -C(O)OR 22 , where R 22 is selected from hydrogen and C1-C3 alkyl;

[0618] -(CH2) m N(R 23 )R 24 , where m is 0 or 1, R 23 Selected from hydrogen, C1-C3 alkyl and -SO2R 25 , where R 25 is a C1-C3 alkyl group, and R 24 Selected from hydrogen, C1-C3 alkyl and -SO2R 26 , where R 26 is a C1-C3 alkyl group, or wherein R 23 and R 24 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0619] -SR 27 , where R 27 selected from hydrogen and C1-C3 alkyl; and

[0620] -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl;

[0621] The condition is relative to R 1 With respect to the rest of formula (Ib), a substituent is attached to the para position (e.g. R 1 is p-tolyl); and

[0622] ii) thiophene, which is substituted with up to three substituents selected from the group consisting of

[0623] Halogen; OH (hydroxyl); C≡N (cyano); NO2 (nitro); C1-C6 alkyl;

[0624] C1-C6 alkyl containing up to 5 halogen atoms;

[0625] C2-C6 alkenyl;

[0626] C1-C6 alkoxy;

[0627] C1-C6 alkoxy containing up to 3 halogen atoms;

[0628] C1-C3 alkoxy C1-C3 alkyl;

[0629] C3-C7 cycloalkyl;

[0630] -C(O)R 20 , where R 20 Selected from C1-C3 alkyl;

[0631] -OC(O)R 21 , where R 21 Selected from H and C1-C3 alkyl;

[0632] -C(O)OR 22 , where R 22 is selected from hydrogen and C1-C3 alkyl;

[0633] -(CH2) m N(R 23 )R 24 , where m is 0 or 1, R 23 Selected from hydrogen, C1-C3 alkyl and -SO2R 25 , where R 25 is a C1-C3 alkyl group, and R 24 Selected from hydrogen, C1-C3 alkyl and -SO2R 26 , where R 26 is a C1-C3 alkyl group, or wherein R 23 and R 24 Together with the nitrogen atom to which they are attached, they form morpholine, thiomorpholine or 1,1-dioxothiomorpholine;

[0634] -SR 27 , where R 27 selected from hydrogen and C1-C3 alkyl; and

[0635] -S(O)2R 28 , where R 28 is selected from hydrogen and C1-C3 alkyl;

[0636] A is a 5- to 7-membered heterocyclic ring, which optionally contains one additional heteroatom selected from oxygen and sulfur, wherein said heterocyclic ring A is optionally substituted by one or two groups selected from -OH and =0;

[0637] Z is C, S or S(O);

[0638] X 1 is NH, O or S;

[0639] X 2 and X 3 are independently selected from C, N and O, provided that X 2 or X 3 Not for C;

[0640] R 4 is selected from hydrogen and methyl;

[0641] R 5 Selected from hydrogen, C1-C2 alkyl, C2-C3 alkenyl;

[0642] 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, furanyl optionally substituted with methyl (e.g. 2-furanyl or 3-furanyl), C1-C6 fluoro-alkyl (e.g. pentafluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl), and -NR 30 R 31 , where R 30 and R 31 independently selected from hydrogen and C1-C3 alkyl;

[0643] or

[0644] R 6 and R 5 Together with the carbon atom to which they are attached, they form carbonyl (C=O), vinyl (C=CR 32 R 33 , where R 32 and R 33 independently selected from H or C1-C3 alkyl) or 2,2-dimethylcyclopropyl;

[0645] The condition is R 5 and R 6Together with the carbon atoms to which they are attached, they contain at least 4 C atoms (e.g. 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms), wherein one of the C atoms is optionally replaced by a heteroatom selected from S and N.

[0646] The compounds of formula (I) can 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, a sulfonyl halide or a sulfinyl halide (for example, the halide is a chloride, a bromide or a fluoride) (3a), the reaction can be carried out in the presence of a base such as an organic base (for example, triethylamine, diisopropylethylamine) or an inorganic base (for example, potassium carbonate, potassium phosphate, sodium bicarbonate, sodium hydroxide) in a suitable solvent (for example, dichloromethane, water, dioxane, N,N-dimethylformamide, tetrahydrofuran) or in the absence of a solvent. When the reaction partner is a carboxylic acid 3b, the reaction can be carried out in a suitable solvent such as N,N-dimethylformamide or dichloromethane with the help of an amide coupling agent (e.g., dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or EDCI) or its hydrochloride 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl)), a nucleophilic mediator (e.g., 4-dimethylaminopyridine (DMAP), 1-hydroxy-benzotriazole (HOBt)) and an organic base (e.g., triethylamine, diisopropylethylamine). In some cases, the amide coupling agent and the 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-oxo hexafluorophosphate (HATU) or N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU). Other conditions for amine 2 functionalization known to those skilled in the art of organic synthesis can be used.

[0647]

[0648] Secondary amines 2 can be prepared by deprotecting their carbamate protected forms (4). When the carbamate is tert-butyl carbamate (PG = Boc group = tert-butyloxycarbonyl), such deprotection can be accomplished 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), such deprotection can be accomplished by hydrogenating the benzyl group by exposing 4 to hydrogen (usually at ambient pressure, but sometimes at higher pressures) in the presence of a hydrogenation catalyst such as palladium on carbon and a suitable solvent such as tetrahydrofuran, ethyl acetate, ethanol, or methanol. Other conditions for deprotection of carbamates 4 known to those skilled in the art of organic synthesis can be used. It must be noted that it may not be necessary to use a protecting group for the secondary amine, as it may be orthogonal to other functional groups present in the compound and can be prepared directly in unprotected form. Protection is explicitly mentioned here because it provides a more generally applicable synthetic approach.

[0649]

[0650] Preparation of 4 can be accomplished by a cross-coupling reaction (e.g., Suzuki cross-coupling) of a heterocyclic halide 5 and an organometallic compound such as an organoboron compound of type 6 (note that -B(pin) is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane) or a similar organotin, organozinc, or organomagnesium compound. This is typically accomplished by reacting compounds 5 and 6 or the like in the presence of a transition metal catalyst (typically a palladium or nickel catalyst) such as palladium acetate or tris(dibenzylideneacetone)-dipalladium (Pd2(dba)3), typically in combination with a suitable ligand (typically a phosphine ligand such as triphenylphosphine, 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) or 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) 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 typically carried out at an elevated temperature (e.g., 80° C. or 100° C.) under an atmosphere of an inert gas such as nitrogen or argon. Other conditions known to those skilled in the art of organic synthesis for the cross-coupling of halide 5 with organometallic compound 6 or the like may be used.

[0651]

[0652] Halides of type 5 can be prepared by halogenation of heterocycle Y. This is typically accomplished 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 may result in over-halogenation, producing, for example, a compound with 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 in a suitable solvent (e.g., ethanol / water mixture) at elevated temperature (e.g., 100°C).

[0653]

[0654] The formation of heterocycle Y in compounds 6 and 4 can be achieved in a variety of ways using synthetic strategies known to those skilled in the art.

[0655] For example, imidazole 7 can be prepared by the reaction of aldehyde 8 with a C2 building block in a suitable oxidation state, such as glyoxal and an ammonia source, such as aqueous ammonia solution. The reaction is carried out in a suitable solvent such as methanol and at a suitable temperature, such as, but not limited to, ambient temperature. Those skilled in the art will recognize that extending the C2 building block to various 1,2-dicarbonyl compounds allows the preparation method to produce more types of substituted imidazoles (wherein Y is imidazole).

[0656]

[0657] Oxazoles of type 9 can be prepared in two steps starting from the formation of an amide bond between a carboxylic acid 10 and a suitable primary amine 11 (which can be used as a salt such as the hydrochloride) under conditions similar to those described for the preparation of (I) from 3b above. The resulting amide intermediate can then be subjected to a dehydration condensation reaction by reacting it with a dehydrating agent such as phosphorus oxychloride (POCl3) or sulfuric acid at elevated temperatures (e.g., 80°C-100°C) in a suitable solvent such as MeCN.

[0658]

[0659] Furthermore, the amide intermediate prepared by coupling carboxylic acid 10 and amine 11 can be directly converted to imidazole 4 by exposing it to an ammonia source such as ammonium acetate or ammonium carbonate, optionally catalyzed by an acid additive such as acetic acid or propionic acid, at elevated temperature (e.g., 100° C., 140° C., or 160° C.) in a suitable solvent such as toluene or xylene.

[0660] Oxadiazoles of type 12 can be prepared in two steps, starting from the formation of an amide bond from a carboxylic acid 10 and a suitable hydrazide 13 (which can be used as a salt such as the hydrochloride) under conditions similar to those described above for the preparation of (I) from 3b. The resulting intermediate can then be subjected to a dehydration condensation by reacting it with a dehydrating agent such as p-toluenesulfonyl chloride (TsCl), typically in combination with a base (e.g., an amine base such as triethylamine or diisopropylethylamine) in a suitable solvent such as acetonitrile at a suitable temperature (e.g., 0°C or room temperature).

[0661]

[0662] Isoxazole 14 can be prepared by a 1,3-dipolar cycloaddition between alkyne 15 and a nitrile oxide obtained from aldehyde 8. Aldehyde 8 is typically first reacted with hydroxylamine, either as a free base or as a salt thereof, such as the hydrochloride, in which case a base, such as 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, such as 0°C to room temperature. The resulting oxime 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, such as 40°C or room temperature. The resulting intermediate can then be exposed to a base, such as an organic base, such as triethylamine or diisopropylethylamine, or an inorganic base, in a suitable solvent, such as dichloromethane or tetrahydrofuran, and reacted in the presence of alkyne 15.

[0663]

[0664] Triazole 16 can be prepared by reacting nitrile 17 with a suitable hydrazide 13 (which can be used as a salt, e.g., the hydrochloride salt) in the presence of a base, e.g., an inorganic base such as potassium carbonate or sodium carbonate, in a suitable solvent, e.g., ethanol or butanol, typically at elevated temperature (e.g., 70°C or 120°C).

[0665]

[0666] Thiazoles of type 18 can be prepared in a similar manner to oxazoles of type 9, but by subjecting the intermediate formed from acid 10 and amine 11 to a sulfur source such as 2,4-bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiadiphosphane (Lawesson's reagent) or 2,4-bis(p-tolylthio)-1,3,2,4-dithiadiphosphane 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).

[0667]

[0668] Nitriles 17 can be prepared from aldehydes 8 by condensing them with hydroxylamine, which can be used as its salt, such as the hydrochloride, in a suitable solvent, such as a mixture of water and ethanol or a mixture of water and methanol, at a suitable temperature, such as 0° C. to room temperature, in which case a base, such as an inorganic base such as sodium carbonate or potassium carbonate, is added. The resulting oxime can then be dehydrated, for example, by reaction with catalytic copper(II) acetate at elevated temperature (e.g., 70° C. or 80° C.) in a suitable solvent (e.g., acetonitrile). Other conditions known to those skilled in the art of organic synthesis for converting aldehydes 8 to nitrile 17 can be used.

[0669] Aldehydes of type 8 can be prepared from acids of type 10 by selective reduction. This is typically accomplished in a two- or three-step protocol by first reacting the acid 10 with an activating agent such as thionyl chloride, oxalyl chloride (with catalytic N,N-dimethylformamide added), or carbonyldiimidazole in a suitable solvent such as, but not limited to, dichloromethane or tetrahydrofuran, or neat, at a suitable temperature (0°C to 100°C, depending on the activating agent). The activated acid is then exposed to N,O-dimethylhydroxylamine (optionally in the form of a salt thereof, such as the hydrochloride salt), in the same step or in a separate step, in a suitable solvent such as dichloromethane or tetrahydrofuran, and optionally in the presence of a base, such as 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 amide thus obtained 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).

[0670] Hydrazide 13 can be prepared from simple ester 19 by reaction with a hydrazine source such as hydrazine monohydrate in a suitable solvent such as ethanol or methanol at a suitable temperature (eg, 70°C or 80°C).

[0671]

[0672] It must be added that a different order of steps is also possible and in some cases advantageous. For example, the amide formation described for forming (I) (i.e., forming the NZ bond) can be performed first, followed by the step for installing the aromatic heterocycle Y. As will be understood by those skilled in the art, this also eliminates the need for a protecting group for the secondary amine.

[0673] Furthermore, it has to be mentioned that certain sensitive functional groups may be carried through the preparation sequence in protected or masked form and removed at the end of the synthetic sequence by standard methods known to those skilled in the art.

[0674] In the above reaction scheme described in formula 2-19, the parameters A, Y, Z, n, R 1 、R4 、R 5 and R 6 has the same meaning as defined in formula (I) (which includes compounds of formula (Ia), (Ib) and (Ic)).

[0675] The present invention will now be further described with reference to the following non-limiting examples. These examples are for illustrative purposes only, and it is to be understood that variations and modifications may be made by those skilled in the art. Example

[0676] Example 1: tert-Butyl 2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate

[0677] 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 (40% in water, 25.9 g, 178 mmol) in methanol (100 mL) was added dropwise ammonia solution (25% in water, 17.0 g, 249 mmol) at 0°C. The solution was allowed to warm to room temperature and stirred at rt for 16 h. The solution was then concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate (100 mL*3). Any precipitate was removed by filtration, and the organic phase was washed with saturated aqueous NaHCO3 (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).

[0678] 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) at 0°C over 10 minutes. The mixture was stirred at 0°C for an additional 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 dark 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).

[0679] 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 Na2SO3 (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 CH2Cl2 (200 mL) and H2O (200 mL). The aqueous layer was extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography to give tert-butyl 2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (23.0 g, yield: 93%) as a white solid. GC / MS (EI): m / z (%): 329 (3) [M + ],331(3)[M + ], 275(10), 273(10), 258(9), 256(9), 230(20), 228(20), 214(26), 212(26). 175(100), 173(100), 162(9), 160(9), 93(8), 57(44).

[0680] Example 2: 1-(2-(5-(2-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0681] 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-dichloropalladium(II) 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. Completion of the reaction 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*3). The combined organic layers were washed once with brine (30 mL), dried over MgSO 4 , filtered, and concentrated. The crude oil was purified by silica gel chromatography (hexane:MTBE=5:1) to give 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).

[0682] 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 room temperature 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 EA (ethyl acetate) (40 mL*3) was added for extraction. The organic phase was concentrated to obtain 2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)piperidine as a light yellow oil (111 mg, 0.925 mmol).

[0683] b) To a solution of 2-(methylthio)propanoic acid (111 mg, 0.925 mmol) in dichloromethane (20 mL) were 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 room temperature for 0.5 h. 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 then added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered, the solvent was removed 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). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.19, 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). 13C 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), 28 .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.

[0684] Example 3: 1-(2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0685] Prepared by a similar method as 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)propionic acid, the title product was obtained 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). 1 HNMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.52-12.03 (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). 13C 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), 14 8.1(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), 38 .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.

[0686] Example 4: 3-Fluoro-4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile

[0687] Prepared by a similar method as 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)propionic acid, the title product was obtained as a white solid. GC / MS (EI): m / z (%): 372 (9) [M + ],357(10),326(6),297(11),269(100),75(16). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.49, 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.

[0688] Example 5: 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0689] Prepared by a similar method as described in Example 2 using tert-butyl 2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-chlorophenyl)boronic acid and 2-(methylthio)propionic acid, the title product was obtained as a white solid. GC / MS (EI): m / z (%): 363 (8) [M + ],348(5),317(4),288(10),260(100),233(9),75(11). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.21, 12.14, 11.92 (brs, 1H), 7.91-7.74 (m, 2H), 7.73-7.57 (m, 1H), 7.52-7.27 (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 CNMR (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.

[0690] Example 6: 1-(2-(5-(3,4-dimethoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0691] Prepared following a similar procedure as 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)propionic acid to give the title product as a white solid.

[0692] 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.

[0693] Example 7: 1-(2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0694] Prepared by a similar method as 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)propionic acid, the title product was obtained 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 HNMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.10-11.88 (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.

[0695] Example 8: 2-(Methylthio)-1-(2-(5-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0696] Prepared following a similar procedure as described in Example 2 using tert-butyl 2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (3-trifluoromethylphenyl)boronic acid and 2-(methylthio)propionic acid to give the title product as a white solid.

[0697] 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.26, 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).

[0698] 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), 12 0.3(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.

[0699] Example 9: 1-(2-(5-(3,4-dimethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0700] Prepared by a similar method as 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)propionic acid, the title product was obtained 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.05-11.75 (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.

[0701] Example 10: 1-(2-(5-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0702] Prepared by a similar method as 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)propionic acid, the title product was obtained 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). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 11.86-11.63 (m, 1H), 7.80-6.92 (m, 3H), 6.69 (d, J=8.4 Hz, 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.

[0703] Example 11: 1-(2-(5-(4-chloro-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0704] Prepared by a similar method as 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)propionic acid, the title product was obtained 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.22, 12.15, 12.01 (brs, 1H), 7.81-7.41 (m, 4H), 5.80-5.43 (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 peak) 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), 116. 5.4(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.

[0705] Example 12: 1-(2-(5-(4-acetylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0706] Prepared by a similar method as described in Example 2 using tert-butyl 2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-acetylphenyl)boronic acid and 2-(methylthio)propionic acid, the title product was obtained 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 HNMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.27, 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.

[0707] Example 13: 2-(Ethylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0708] Prepared following a similar procedure as described in Example 2 using tert-butyl 2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-methylphenyl)boronic acid and 2-(ethylthio)propionic acid to give the title product as a white solid.

[0709] 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.02, 11.79 (brs, 1H), 7.65 (d, J = 6.6 Hz, 2H), 7.49 (s, 1H), 7.14 (d, J = 7.2 Hz, 2H), 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.

[0710] Example 14: (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one

[0711] Prepared by a similar method as 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, the title product was obtained 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). 1HNMR (300 MHz, DMSO-d6, mixture of tautomers) δ 12.08, 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.

[0712] Example 15: 2-methylene-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0713] Prepared by a similar method as 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, the title product was obtained as a light 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 (300 MHz, DMSO-d6, mixture of tautomers) δ 12.11-11.86 (m, 1H), 7.72-7.01 (m, 5H), 5.76-5.05 (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 (75 MHz, DMSO-d6, mixture of tautomers) δ 171.1 (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.

[0714] Example 16: 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0715] Prepared by a similar method as 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)propionic acid, the title product was obtained 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.

[0716] Example 17: 2-(Methylthio)-1-(2-(5-(4-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0717] Prepared by a similar method as described in Example 2 using tert-butyl 2-(5-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate, (4-nitrophenyl)boronic acid and 2-(methylthio)propionic acid, the title product was obtained as a light 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.

[0718] Example 18: 1-(2-(5-(4-aminophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0719] 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 carbon) (10 wt %) (48.1 mg, 0.048 mmol) under a nitrogen atmosphere, and the mixture was purged with hydrogen and allowed to react overnight at room temperature under a hydrogen atmosphere (1 bar). The resulting mixture was purged with nitrogen, filtered through 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). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 11.80-11.57 (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). 13C 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.

[0720] Example 19: 2-(Methylthio)-1-(2-(5-(2,4,5-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0721] Prepared by a similar method as 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)propionic acid, the title product was obtained 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). 1 HNMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.37-11.82 (m, 1H), 8.00-7.76 (m, 1H), 7.67-7.28 (m, 2H), 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.

[0722] Example 20: 1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-3-en-1-one

[0723] Prepared by a similar method as 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, the title product was obtained as a light yellow solid. GC / MS (EI, mixture of stereoisomers in a ratio of 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.21-1.94 (brs, 1H), 7.73-7.58 (m, 3H), 7.39-7.33 (m, 1H), 5.92-5.77 (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). 13 C 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), 11 8.0(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.

[0724] Example 21: (E)-1-(2-(5-(3,4-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbut-2-en-1-one

[0725] Obtained as an isomerization by-product in the final step of the preparation of Example 20 according to the general method of Example 2. The title product was obtained as a light 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 (300 MHz, DMSO-d6, mixture of tautomers) δ 12.2-12.0 (m, 1H), 7.77-7.33 (m, 4H), 5.66-5.46 (m, 2H), 4.77-2.89 (m, 2H), 2.35-2.20 (m, 1H), 1.76-1.32 (m, 11H) ppm.

[0726] Example 22: 1-(2-(5-(2,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0727] 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 room temperature for 16 h. After the solution was cooled to 5° C., dilute NaHCO 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.

[0728] b) To a solution of 2-(methylthio)propanoic acid (2.51 g, 20.86 mmol) in dichloromethane (150 mL) were added 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) at 0-5° C., and the mixture was stirred at room temperature for 0.5 h. 2-(5-bromo-1H-imidazol-2-yl)piperidine (5.00 g, 17.38 mmol) and DIPEA (6.07 mL, 34.80 mmol) were then added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered, the solvent was removed 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). 1 H 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).

[0729] Example 22b: 1-(2-(5-(2,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0730] 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-dichloropalladium(II) dichloromethane complex (74 mg, 0.090 mmol) in tetrahydrofuran (6 mL) and water (1.2 mL) was stirred and refluxed for 16 h under an argon atmosphere. 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 light yellow solid. GC / MS (EI): m / z (%): 365 (9) [M + ],350(5),319(8),290(13),262(100),235(12),75(13). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.34, 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.

[0731] Example 23: 1-(2-(5-(2,3-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0732] Following the general procedure as 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) were reacted in tetrahydrofuran (6 mL) and water (1.2 mL) to give the title product (100 mg, yield: 61%) as a light 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.39, 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). 13 CNMR (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.

[0733] Example 24: 2-(Methylthio)-1-(2-(5-(2,3,4-trifluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0734] Following the general procedure as described in Example 22b: 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) were reacted in tetrahydrofuran (6 mL) and water (1.2 mL) to give the title product (95 mg, yield: 41%) as a light yellow solid. GC / MS (EI): m / z (%): 383 (8) [M + ],368(5),337(7),308(11),280(100),225(28),75(13). 1 HNMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) 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). 13C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.4 (q), 170.1 (q), 150.4 (q), 150.3 (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), 1 37.9(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.

[0735] Example 25: 1-(2-(5-(Benzo[d][1,3]dioxol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0736] Following the general procedure as described in Example 22b, 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) were reacted in tetrahydrofuran (6 mL) and water (1.2 mL) to afford the title product (81 mg, yield: 36%) as a light yellow solid. GC / MS (EI): m / z (%): 373 (10) [M + ],358(5),327(2),298(6),270(100),243(11),75(9). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 11.98-11.76 (m, 1H), 7.57-7.39 (m, 1H), 7.35-7.11 (m, 2H), 6.88 (d, J = 7.8 Hz, 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 = 6.5 Hz, 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.

[0737] Example 26: 1-(2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0738] Following the general procedure as described in Example 22b: 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) were reacted to give 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). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 11.96, 11.74 (brs, 1H), 7.76-7.42 (m, 3H), 6.91 (d, J = 7.9 Hz, 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 = 6.6 Hz, 3H). 13 C NMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers, main peaks) δ170.2(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.

[0739] Example 27: 2-(Methylthio)-1-(2-(5-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0740] Following the general procedure as described in Example 22b, 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) were reacted in tetrahydrofuran (6 mL) and water (1.2 mL) to give the title product (95 mg, yield: 38%) as a light yellow solid. GC / MS (EI): m / z (%): 413 (9) [M + ],398(5),367(4),338(9),310(100),281(19),75(14). 1HNMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.16, 11.94 (brs, 1H), 8.05-7.72 (m, 2H), 7.65 (t, J = 8.2 Hz, 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 = 6.6 Hz, 3H). 13 C 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.

[0741] Example 28: 2-Fluoro-4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile

[0742] Following the general procedure as described in Example 22b: 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) were reacted in tetrahydrofuran (6 mL) and water (1 mL) to give 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.42, 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 = 6.5 Hz, 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) 2 8.0(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.

[0743] Example 29: 2-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzonitrile

[0744] Following the general procedure as 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-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) were reacted in tetrahydrofuran (6 mL) and water (1 mL) to give 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 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) 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 CNMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.8 (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.

[0745] Example 30: 2-(Methylthio)-1-(2-(5-(3-nitrophenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0746] Following the general procedure as described in Example 22b, 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) were reacted in tetrahydrofuran (6 mL) and water (1 mL) to give the title product (90 mg, yield: 40%) as a light 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.31, 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). 13 C 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). (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.

[0747] Example 31: 2-(Methylthio)-1-(2-(5-(2-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0748] Following the general procedure as 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-(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) were reacted in tetrahydrofuran (6 mL) and water (1 mL) to give 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). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) 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). 13CNMR (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.4 (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.

[0749] Example 32: 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde

[0750] Following the general procedure as described in Example 22b, 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) were reacted in tetrahydrofuran (10 mL) and water (1.5 mL) to give 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). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.29, 12.09 (s, 1H), 9.95 (s, 1H), 8.00 (d, J = 7.9 Hz, 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 = 6.5 Hz, 3H). 13 C 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.

[0751] Example 33: 1-(2-(5-(4-(Aminomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0752] To a solution of 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde (300 mg, 0.839 mmol) in methanol (10 mL) was added 25% aqueous ammonium hydroxide solution (1176 mg, 8.390 mmol), and the mixture was stirred at room temperature for 24 h under an argon atmosphere. The mixture was then treated with NaBH4 (32 mg, 0.839 mmol) at 10 ° C. and stirred at room temperature for 6 h. The mixture was filtered, the solvent was removed 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 light yellow solid. 1HNMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.11-11.80 (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.

[0753] Example 34: 1-(2-(5-(4-((methylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0754] 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 methylamine hydrochloride (378 mg, 5.59 mmol) and triethylamine (566 mg, 5.59 mmol), and the mixture was stirred at room temperature under an argon atmosphere for 24 h. The mixture was then treated with NaBH4 (21 mg, 0.559 mmol) at 10°C and stirred at room temperature for 6 h. The mixture was filtered, the solvent was removed, and purification was performed 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 light yellow solid. GC / MS(EI): m / z(%): 370(3)[M-2] +, 355(5), 295(10), 267(100), 240(11), 212(12), 75(40). 1 H 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.

[0755] Example 35: Methyl 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoate

[0756] Following the general procedure as described in Example 22b, 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) were reacted in tetrahydrofuran (10 mL) and water (1.5 mL) to give 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 HNMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) 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 (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 170.7 (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.

[0757] Example 36: 2-(Furan-2-yl)-1-(2-(5-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one

[0758] To a solution of 2-(5-phenylimidazol-2-yl)piperidine (200 mg, 0.88 mmol) in dichloromethane (2 mL) were added HOBt (162 mg, 1.056 mmol, 1.2 eq) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (202 mg, 1.056 mmol, 1.2 eq) 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 eq) and N,N-diisopropylethylamine (114 mg, 0.88 mmol, 1 eq), and the resulting mixture was stirred at room temperature for 16 h. The mixture was filtered and the solvent removed and the crude product was purified by silica gel chromatography (EtOAc in heptane gradient) 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, 70 eV): 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 (400 MHz, DMSO, mixture of stereoisomers and tautomers) δ 12.16, 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 = 6.9 Hz, 1H).

[0759] Example 37: 2-(Methylthio)-1-(2-(5-phenylimidazol-2-yl)piperidin-1-yl)propan-1-one

[0760] Prepared in the same manner as Example 36 using 2-(5-phenylimidazol-2-yl)piperidine and 2-(methylthio)propionic acid. The title compound was obtained as a white solid. MS (EI, 70 eV): 329 (2, [M] +·), 227 (16), 226 (100), 199 (13), 171 (25), 170 (12), 75 (69), 56 (16), 55 (15), 47 (19), 41 (19). 1H NMR (400 MHz, DMSO, mixture of stereoisomers and tautomers) δ 12.14, 12.05, 11.82 (brs, 1H), 7.82-7.71 (m, 2H), 7.69-7.50 (m, 1H), 7.45-7.28 (m, 2H), 7.27-7.11 (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.

[0761] Example 38: 2-(Methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0762] 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 container was opened and the contents were poured into aqueous NaHCO3 (50 mL), extracted with EtOAc (2 x 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 flash column chromatography on silica gel eluting with a gradient of EtOAc in heptane to give tert-butyl 2-(5-(p-tolyl)imidazol-2-yl)piperidine-1-carboxylate (314 mg, 0.920 mmol, 76% yield) as a white solid. MS (EI, 70 eV): 341 (4, [M]+·), 285 (11), 268 (3), 240 (30), 185 (100), 172 (16), 91 (6), 57 (99). 1H NMR (DMSO-d6, 400 MHz, mixture of rotamers and tautomers): δ 11.66-12.09 (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 = 12.1 Hz, 1H), 3.05 (br t, J = 10.9 Hz, 1H), 2.28 (s, 3H), 2.18-2.25 (m, 1H), 1.65-1.78 (m, 1H), 1.22-1.63 (m, 13H) ppm. 13 C NMR (75 MHz, DMSO, mixture of tautomers) δ 155.1 (q), 147.5 (q), 140.2 (q), 135.3 (q), 132.7 (q), 129.4 (t), 124.6 (t), 112.5 (t), 79.3 (q), 63.3 (d), 49.7 (t), 41.2 (d), 28.5 (s), 28.4 (d), 26.8 (d), 25.3 (d), 21.2 (s), 19.9 (d) ppm.

[0763]

[0266] 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 dropwise with 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. The mixture was then extracted with dichloromethane (3 x 20 mL), dried over MgSO4 and concentrated under reduced pressure to afford 2-(5-(p-tolyl)imidazol-2-yl)piperidine (160 mg, 0.664 mmol, 74% yield) as a light 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). 1H 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).

[0764] Example 38c: 2-(methylthio)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one: Prepared in the same manner as Example 36 using 2-(5-(p-tolyl)imidazol-2-yl)piperidine and 2-(methylthio)propionic 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, 70 eV): 343 (2, [M]+·), 241 (17), 240 (100), 213 (13), 185 (18), 184 (9), 75 (55), 56 (11), 55 (9), 47 (10), 41 (11). 1 H NMR (400 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.07, 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.

[0765] Example 39: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one

[0766] To a solution of 2-methylbut-3-enoic acid (0.597 g, 5.97 mmol) in dichloromethane (100 mL) were 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 room temperature for 0.5 h. 2-(5-(p-Tolyl)-1H-imidazol-2-yl)piperidine (1.2 g, 4.97 mmol) and DIPEA (1.563 ml, 8.95 mmol) were then added, and the mixture was stirred at room temperature for 16 h. The suspension was filtered and the solvent was removed. 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). Isomer 2: m / z(%): 323(2) [M +], 268(5), 240(100), 211(6), 172(81), 117(7), 84(2), 55(10). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) 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 (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 172.7 (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.

[0767] Example 40: 2,2-Dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one

[0768] Following the general procedure as described in Example 39: 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) were reacted in dichloromethane (30 mL) to give 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 HNMR (300 MHz, DMSO-d6, mixture of tautomers) δ 12.04-11.70 (m, 1H), 7.83-7.51 (m, 2H), 7.51-7.37 (m, 1H), 7.32-7.00 (m, 2H), 6.23-6.10 (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 (75 MHz, DMSO-d6, mixture of tautomers) δ 174.1 (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.

[0769] Example 41: 2,2-Dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0770] 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 through celite and evaporated to give a 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 (300 MHz, DMSO-d6, mixture of tautomers) δ 12.02, 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 = 7.2 Hz, 3H). 13 C NMR (75 MHz, DMSO-d6, mixture of tautomers) δ 175.3 (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.

[0771] Example 42: 2,2,3-Trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one

[0772] Following the general procedure as described in Example 39, 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) were reacted in dichloromethane (30 mL) to give 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 (300 MHz, DMSO-d6, mixture of tautomers) δ 12.04-11.71 (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 (75 MHz, DMSO-d6, mixture of tautomers) δ 174.1 (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.

[0773] Example 43: 2,2,3-Trimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0774] Following the general procedure as described in Example 41: 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) was catalyzed by 10% Pd / C (57 mg) in ethyl acetate (20 ml) under hydrogen atmosphere to give 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 (300 MHz, DMSO-d6, mixture of tautomers) δ 12.00, 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 (75 MHz, DMSO-d6, mixture of tautomers) δ 176.0 (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.

[0775] Example 44: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)prop-2-en-1-one

[0776] Following the general procedure as described in Example 39, 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) were reacted in dichloromethane (30 mL) to give 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 (300 MHz, DMSO-d6, mixture of tautomers) δ 12.15-11.91 (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 (75 MHz, DMSO-d6, mixture of tautomers) δ 171.4 (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.

[0777] Example 45: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0778] Following the general procedure described in Example 41, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one (350 mg, 1.082 mmol) was catalytically hydrogenated with 10% Pd / C (216 mg, 0.216 mmol) in ethyl acetate (20 ml) under a hydrogen atmosphere to afford 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 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) 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 (75 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 175.4 (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.

[0779] Example 46: 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0780] Following the general procedure as described in Example 39, 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) were reacted in dichloromethane (30 mL) to give 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 (300 MHz, DMSO-d6, mixture of tautomers) δ 12.06, 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 (75 MHz, DMSO-d6, mixture of tautomers) δ 171.1 (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.

[0781] Example 47: 2-(Allylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0782] Following the general procedure as described in Example 39, 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) were reacted in dichloromethane (30 mL) to give the title product (193 mg, yield: 42%) as a white solid. GC / MS (EI, mixture of stereoisomers in a ratio of 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.02, 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.

[0783] Example 48: (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pent-2-en-1-one

[0784] Following the general procedure as described in Example 39, (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) were reacted in dichloromethane (50 mL) to give 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).

[0785] Example 49: 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pentan-1-one

[0786] Following the general procedure as 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 by 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 in a ratio of 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.09-11.75 (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). 13 C 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.

[0787] Example 50: 2-Methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butane-1,3-dione

[0788] Following the general procedure as described in Example 39: 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) were reacted in dichloromethane (50 mL) to give 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). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 11.94, 11.78 (brs, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.42 (s, 1H), 7.14 (d, J = 7.5 Hz, 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.

[0789] Example 51: 1-(2-(5-benzyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0790] Prepared by a similar method as 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)propionic acid, the title product was obtained as a light 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).

[0791] Example 52: 2-Methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0792] Following the general procedure as described in Example 39, 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) were reacted in dichloromethane (30 mL) to give 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). 1 H NMR (300 MHz, DMSO-d6, mixture of tautomers) δ 11.94-11.72 (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 (75 MHz, DMSO-d6, mixture of tautomers) δ 175.8 (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.

[0793] Example 53: 1-(2-(5-(p-Tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0794] Following the general procedure as described in Example 39, 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) were reacted in dichloromethane (30 mL) to give the title product (239 mg, yield: 65%) as a light yellow solid. GC / MS (EI): m / z (%): 297 (10) [M + ],268(1),240(100),185(13),103(3),57(10). 1 H NMR (300 MHz, DMSO-d6, mixture of tautomers) δ 11.97, 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 (75 MHz, DMSO-d6, mixture of tautomers) δ 172.7 (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), 112.6 (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.

[0795] Example 54: 2-(Furan-3-yl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0796] Following the general procedure as described in Example 39, 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) were reacted in dichloromethane (30 mL) to give the title product (565 mg, yield: 57%) as a white solid. GC / MS (EI, mixture of stereoisomers in a ratio of 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.10-11.79 (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). 13 C 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), 1 24.6(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.

[0797] Example 55: Cyclopropyl(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone

[0798] Following the general procedure as described in Example 39, 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) were reacted in dichloromethane (30 mL) to give 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 (300 MHz, DMSO-d6, mixture of tautomers) δ 11.94-11.73 (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 (75 MHz, DMSO-d6, mixture of tautomers) δ 174.7 (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.

[0799] Example 56: (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0800] Following the general procedure as described in Example 39, (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) were reacted in dichloromethane (100 mL) to give 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.03-11.71 (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), 12 4.6(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), 2 7.2(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.

[0801] Example 57: (E)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)pent-3-en-1-one

[0802] Following the general procedure as described in Example 39: (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) were reacted in dichloromethane (30 mL) to give the title product (460 mg, yield: 69%) as a white solid. GC / MS (EI, mixture of stereoisomers in a ratio of 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). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.03-11.75 (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.

[0803] Example 58: 2-methoxy-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0804] Following the general procedure as described in Example 39, 2-methoxypropionic 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) were reacted in dichloromethane (30 mL) to give 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). 13 CNMR (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.

[0805] Example 59: 2-(Methylthio)-1-(2-(5-(5-methylthiophen-2-yl)imidazol-2-yl)piperidin-1-yl)propan-1-one

[0806] Following a similar procedure as 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)propionic acid, the title product was obtained as a white solid. MS (EI, 70 eV): 349 (3, [M] + ·), 247 (16), 246 (100), 219 (13), 191 (16), 84 (13), 75 (69), 56 (16), 55 (14), 47 (17), 41 (17).

[0807] Example 60: 2-(Methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)imidazol-2-yl)piperidin-1-yl)propan-1-one

[0808] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-(trifluoromethyl)phenyl)boronic acid and 2-(methylthio)propanoic acid to give 2-(methylthio)-1-(2-(5-(4-(trifluoromethyl)phenyl)imidazol-2-yl)piperidin-1-yl)propan-1-one as a white solid. MS (EI, 70 eV): 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).

[0809] Example 61: 2-(Methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one

[0810] 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) was added 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) at 0°C. The reaction mixture was stirred at room temperature overnight, diluted with water (300 ml) and extracted with ethyl acetate (100 ml x 3). The organic layer that merges is washed with water (100ml × 3) and salt solution (150ml).With it at Na SO Lower drying and under reduced pressure concentrate.The crude product is purified by flash column chromatography, uses silica gel (230-400 mesh), uses EtOAc / petroleum ether (0-25%) as eluent, obtains 2-((2-oxo-2-(p-tolyl) ethyl) formamyl) piperidine-1-benzyl formate (8.0g, 50%), is yellow liquid.LC-MS(ESI+): 395(100,[M+H]+).

[0811] Example 61b: 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 POCl (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 aqueous sodium bicarbonate. 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). Dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography using silica gel (230-400 mesh) and EtOAc / petroleum ether (0-25%) as eluent to afford benzyl 2-(5-(p-tolyl)oxazol-2-yl)piperidine-1-carboxylate (4.5 g, 63%) as a light yellow liquid. LC-MS (ESI+): 377 (100, [M+H]+).

[0812] 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) was added 10% Pd / C (0.45 g, 10 mol%) and stirred at RT 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 x 3). The combined organic layers were washed with water (50 ml x 3) and brine (50 ml). Drying under Na2SO4 and concentration under reduced pressure gave 2-(piperidin-2-yl)-5-(p-tolyl)oxazole (2.5 g, 63%) as a liquid. LC-MS(ESI+): 243(100, [M+H]+). 13 C 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.

[0813] Example 61d: 2-(Methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one: Prepared according to the general procedure described in Example 39 from 2-(piperidin-2-yl)-5-(p-tolyl)oxazole and 2-(methylthio)propanoic acid to give 2-(methylthio)-1-(2-(5-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one as a white solid. MS (EI, 70 eV): 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 (400 MHz, DMSO, mixture of stereoisomers and tautomers) δ 7.64-7.50 (m, 3H), 7.28 (d, J=7.9 Hz, 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).

[0814] Example 62: 2-(Methylthio)-1-(2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one

[0815] 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 room temperature overnight, diluted with water (15 ml) and extracted with ethyl acetate (25 ml x 3). The combined organic layers were washed with water (15 ml x 3) and brine (15 ml). It was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 8% methanol in DCM (dichloromethane) as eluent to give tert-butyl 2-(2-(4-methylbenzoyl)hydrazine-1-carbonyl)piperidine-1-carboxylate as a light yellow gummy solid (3.0 g). LC-MS (ESI-): 360 (100, [MH]-).

[0816] 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 room temperature overnight and quenched with saturated aqueous K2CO3 solution (50 ml). The reaction mixture was concentrated under reduced pressure, diluted with water (30 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with water (50 ml) and brine (50 ml). It was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 20% ​​ethyl acetate in petroleum ether as eluent to give tert-butyl 2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate as a yellow low melting point solid (3.5 g). LC-MS (ESI+): 344 (57, [M+H]+), 288 (100), 244 (28). 13C 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.

[0817] Example 62c: 2-(Piperidin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole: Prepared in analogy to Example 38b, 2-(piperidin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole was obtained from tert-butyl 2-(5-(p-tolyl)-1,3,4-oxadiazole-2-yl)piperidine-1-carboxylate as a yellow oil, which was used without further purification.

[0818] Example 62d: 2-(Methylthio)-1-(2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one: Prepared analogously to Example 39, 2-(methylthio)-1-(2-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)propan-1-one was obtained from 2-(piperidin-2-yl)-5-(p-tolyl)-1,3,4-oxadiazole as a white solid. MS (EI, 70 eV): 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 (400 MHz, DMSO, mixture of stereoisomers and tautomers) δ 7.86 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.0 Hz, 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).

[0819] Example 63: 2-(Methylthio)-1-(4-(5-(p-tolyl)imidazol-2-yl)thiazolidin-3-yl)propan-1-one

[0820] Example 63a: 3-(2-(Methylthio)propionyl)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)propionyl chloride (2.301 g, 16.60 mmol) in dichloromethane (10 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was poured onto ice-cold 1 M HCl (100 mL), extracted with dichloromethane (2 x 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]-).

[0821] Example 63b: 2-Oxo-2-(p-tolyl)ethyl 3-(2-(methylthio)propionyl)thiazolidine-4-carboxylate: A solution of crude 3-(2-(methylthio)propionyl)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 overnight and then poured into water (100 mL), extracted with EtOAc (2 x 100 mL), washed with 1 M HCl (50 mL), saturated aqueous NaHCO 3 solution (50 mL), water (50 mL), brine (50 mL), dried over MgSO 4 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. MS (EI, 70 eV): 367 (1, [M] +·), 264 (21), 234 (37), 119 (47), 91 (30), 75 (100).

[0822] 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 using an EtOAc / heptane gradient to afford 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 light yellow oil. MS (EI, 70 eV): 347 (11, [M] + ·), 332 (4), 301 (14), 244 (59), 217 (33), 185 (100), 184 (94), 103 (17), 91 (15), 75 (59), 28 (23). 1 HNMR (400 MHz, CDCl3, mixture of stereoisomers and tautomers) δ 10.33, 10.03, 9.87 (brs, 1H), 7.51 (d, J = 112.3 Hz, 2H), 7.19 (d, J = 9.2 Hz, 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).

[0823] Example 64: 2-(Methylthio)-1-((S)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one

[0824] 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 1M HCl (100 mL) solution, extracted twice with CH Cl (50 mL), washed with water (50 mL), dried over MgSO and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using an EtOAc / heptane gradient to give (S)-tert-butyl 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).

[0825] 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 x 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 afford (S)-tert-butyl 2-(5-(p-tolyl)imidazol-2-yl)piperidine-1-carboxylate (1.03 g, 3.02 mmol, 27% yield) as a white solid. MS (EI, 70 eV): 341 (4, [M] + ·), 285 (12), 268 (4), 240 (23), 185 (85), 91 (6), 57 (100).

[0826] Example 64c: (S)-2-(5-(p-Tolyl)imidazol-2-yl)piperidine: Prepared in the same manner as Example 38b, (S)-2-(5-(p-Tolyl)imidazol-2-yl)piperidine was obtained from (S)-2-(5-(p-Tolyl)imidazol-2-yl)piperidine-1-carboxylate as an orange solid, which was used in the next step without further purification.

[0827] 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 Example 36, 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) was obtained from (S)-2-(5-(p-tolyl)imidazol-2-yl)piperidine (0.40 g, 1.66 mmol) and racemic 2-(methylthio)propionic acid (0.20 g, 1.66 mmol) 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). 1H NMR (400 MHz, DMSO, mixture of stereoisomers and tautomers) δ 12.07, 12.02, 11.99, 11.95 (brs, 1H), 7.65 (dd, J=8.0, 2.8 Hz, 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). 13 C 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), 113.7 (t). 2.5(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).

[0828] Example 65: 2-(Methylsulfonyl)-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one

[0829] 2-(Methylsulfanyl)-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 product was purified by silica gel column chromatography using an EtOAc / heptane gradient to afford 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 light yellow foam. HRMS (ESI+): calculated value C 19 H 26 O3N3S[M+H]+: 376.1689; found: 376.1696.

[0830] Example 66: 2-(Methylsulfinyl)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0831] 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). Purified by silica gel column chromatography eluting with a gradient of EtOAc in heptane to afford 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 light yellow film. HRMS (ESI+): Calculated C 19 H 26 O2N3S[M+H]+: 360.1740; found: 360.1746.

[0832] Example 67: (S)-2-(Methylthio)-1-((R)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one

[0833] Example 67a: (S)-2-(Methylthio)propanoic acid: (S)-2-Mercaptopropionic 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. Methyl iodide (10.0 g, 71 mmol) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 4 hours. The mixture was poured into 2N 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 light yellow oil. GC / MS (EI): m / z (%): 120 (59) [M + ],105(1),91(1),87(1),75(100),59(15),55(6).

[0834] Example 67b: (R)-2-(5-(p-Tolyl)imidazol-2-yl)piperidine: Prepared in the same manner as Example 64, but starting from (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid and using (S)-2-(methylthio)propanoic acid in the last step, (S)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one was obtained as an off-white solid. MS (EI, 70 eV): 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 (400 MHz, DMSO-d6, mixture of rotamers and tautomers) δ 11.95 (brs, 1H), 7.63 (d, J = 8.0 Hz, 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.

[0835] Example 68: 2-(Methylthio)-1-(2-(5-(p-tolyl)isoxazol-3-yl)piperidin-1-yl)propan-1-one

[0836] Example 68a: (E)-2-((hydroxyimino)methyl)piperidine-1-carboxylic acid tert-butyl ester: 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. The mixture was stirred at 0°C for 30 minutes and then stirred at room temperature overnight. The mixture was concentrated under reduced pressure to half its volume and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (20 ml), dried over NaSO 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.

[0837] 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 portionwise N-chlorosuccinimide (2.73 g, 17.8 mmol) at room temperature. The reaction mixture was stirred at 40° C. for 1 h. It was cooled to room temperature, diluted with ethyl acetate (150 ml), washed with water (50 ml) and brine (50 ml). The organic layer was dried over 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.

[0838] Example 68c: tert-Butyl 2-(5-(p-tolyl)isoxazol-3-yl)piperidine-1-carboxylate: To a stirred solution of (Z)-tert-butyl 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 minutes, the mixture was warmed to room temperature and stirred at room temperature for 3 days. The reaction mixture was concentrated, diluted with ethyl acetate (200 ml) and washed with water (30 ml x 2). It was washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography using 20% ​​ethyl acetate in petroleum ether as 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). 13C 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.

[0839] Example 68d: 3-(Piperidin-2-yl)-5-(p-tolyl)isoxazole: Prepared in a manner similar 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.

[0840] Example 68e: 2-(Methylthio)-1-(2-(5-(p-tolyl)isoxazol-3-yl)piperidin-1-yl)propan-1-one: Prepared analogously to Example 36 using 3-(piperidin-2-yl)-5-(p-tolyl)isoxazole and 2-(methylthio)propionic 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, 70 eV): 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 (400 MHz, DMSO, mixture of stereoisomers and tautomers) δ 7.85-7.66 (m, 2H), 7.34 (d, J = 7.9 Hz, 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 = 5.3 Hz, 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.

[0841] Example 69: (R)-2-(Methylthio)-1-((R)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one

[0842] Example 69a: (R)-2-(Methylthio)propionic acid: Prepared as described in Example 67a, (R)-2-(Methylthio)propionic acid was obtained from (R)-2-mercaptopropionic acid as a colorless oil. GC / MS (EI): m / z (%): 120 (62) [M + ].

[0843] 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 Example 64, but starting from (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid and using (R)-2-(methylthio)propionic acid in the last step, (R)-2-(methylthio)-1-((R)-2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one was obtained 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 (400 MHz, DMSO-d6, mixture of rotamers and tautomers) δ 11.98, 11.75 (brs, 1H), 7.64 (d, J = 6.5 Hz, 2H), 7.48 (s, 1H), 7.14 (d, J = 7.0 Hz, 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. 13C 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), 43 .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.

[0844] Example 70: 2-Mercapto-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one

[0845] Example 70a: 1-(2-(5-(p-Tolyl)imidazol-2-yl)piperidin-1-yl)-2-(tritylthio)propan-1-one: Prepared in the same manner as 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, 70 eV): 328(4), 268(2), 243(92), 240(36), 165(100), 78(40).

[0846] 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 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 product was purified by flash column chromatography on silica gel using a gradient elution mixture of heptane and 80% EtOAc, 10% hexanes, 9% EtOH, and 1% Et3N to afford 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, 70 eV): 329 (3, [M]+·), 296 (1), 268 (6), 240 (83), 61 (100).

[0847] Example 71: 2-(Methylthio)-1-((R)-2-(5-phenylimidazol-2-yl)pyrrolidin-1-yl)propan-1-one

[0848] Prepared analogously to Example 36 from (R)-5-phenyl-2-(pyrrolidin-2-yl)-1H-imidazole dihydrochloride and 2-(methylthio)propanoic acid using two additional molar equivalents of N,N-diisopropylethylamine, 2-(methylthio)-1-((R)-2-(5-phenylimidazol-2-yl)pyrrolidin-1-yl)propan-1-one was obtained as an orange solid. MS (EI, 70 eV): 315 (3, [M] + ·), 300 (5), 269 (4), 240 (4), 212 (36), 172 (19), 77 (13), 75 (100), 47 (32).

[0849] Example 72: 2-amino-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-1-one

[0850] Example 72a: tert-Butyl (1-oxo-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-2-yl)carbamate: Prepared similarly to Example 36, tert-butyl (1-oxo-1-(2-(5-(p-tolyl)imidazol-2-yl)piperidin-1-yl)propan-2-yl)carbamate was obtained from 2-(5-(p-tolyl)imidazol-2-yl)piperidine and (tert-butoxycarbonyl)alanine as a white solid which was used in the next step without further purification.

[0851] 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 2M NaOH (20 mL), extracted with dichloromethane (2×30 mL), dried over MgSO 4 , and concentrated under reduced pressure to afford 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, 70 eV): 312 (3, [M] + ·), 240 (41), 44 (100).

[0852] Example 73: 2,5-difluoro-4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile

[0853] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-cyano-2,5-difluorophenyl)boronic acid and 2-(methylthio)propionic acid to give 2,5-difluoro-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)imidazol-4-yl)benzonitrile as a yellow film. HRMS (ESI+): Calcd. C 19 H 20 F2N4OS[M+H]+: 391.1399; found: 391.1395.

[0854] Example 74: (2-(4-phenylimidazol-2-yl)piperidin-1-yl)(1,2,3-thiadiazol-5-yl)methanone

[0855] Prepared similarly to Example 36, (2-(4-phenylimidazol-2-yl)piperidin-1-yl)(1,2,3-thiadiazol-5-yl)methanone was obtained from 2-(5-phenylimidazol-2-yl)piperidine and 1,2,3-thiadiazole-5-carboxylic acid as a light yellow solid. HRMS (ESI+): calculated value C 17 H 17 N5OS[M+H]+: 340.1227; found: 340.1223.

[0856] Example 75: 2-(Furan-3-yl)-1-(2-(4-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one

[0857] Prepared analogously to Example 36, 2-(5-phenylimidazol-2-yl)piperidine and 3-furanacetic acid gave 2-(furan-3-yl)-1-(2-(4-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one as a light yellow solid. HRMS (ESI+): calculated value C 20 H 21 N3O2[M+H]+: 336.1707; found: 336.1699.

[0858] Example 76: (Tetrahydrofuran-3-yl)(2-(4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone

[0859] Prepared similarly to Example 36, (tetrahydrofuran-3-yl)(2-(4-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone was obtained from 2-(5-(p-tolyl)imidazol-2-yl)piperidine and tetrahydrofuran-3-carboxylic acid as a light yellow oil. HRMS (ESI+): calculated value C 20 H 25 N3O2[M+H]+: 340.2020; measured value: 340.2013.

[0860] Example 77: 3,3-Difluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0861] Prepared similarly to Example 36 from 2-(5-phenylimidazol-2-yl)piperidine and 3,3-difluorobutyric acid to give 3,3-difluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one as a white solid. HRMS (ESI+): calculated value C 18 H 21 F2N3O[M+H]+: 334.1725; found: 334.1720.

[0862] Example 78: Cyclobutyl(2-(5-(3-fluorophenyl)imidazol-2-yl)piperidin-1-yl)methanone

[0863] Prepared similarly to Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidin-1-yl)methanone, (3-fluorophenyl)boronic acid, and cyclobutanecarboxylic acid as a pale yellow film. HRMS (ESI+): Calcd. C 19 H 22 FN3O[M+H]+: 328.1820; found: 328.1814.

[0864] Example 79: 1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0865] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (3-fluorophenyl)boronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 18 H 22 FN3OS[M+H]+: 348.1540; found: 348.1532.

[0866] Example 80: 3-Methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0867] Prepared analogously to Example 36, 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one was obtained from 2-(5-phenylimidazol-2-yl)piperidine and 3-methylbutanoic acid as a white solid. HRMS (ESI+): calculated value C 19 H 25 N3O[M+H]+: 312.2070; found: 312.2064.

[0868] Example 81: 3-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile

[0869] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (3-cyanophenyl)boronic acid, and 2-(methylthio)propionic acid to provide 3-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile as a light yellow film. HRMS (ESI+): Calcd. C 19 H 22 N4OS[M+H]+: 355.1587; found: 355.1581.

[0870] Example 82: 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile

[0871] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-cyanophenyl)boronic acid, and 2-(methylthio)propionic acid to provide 4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile as a yellow film. HRMS (ESI+): Calcd. C 19 H 22 N4OS[M+H]+: 355.1587; found: 355.1581.

[0872] Example 83: 2-(Methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one

[0873] Prepared similarly to Example 36, 2-(5-phenylimidazol-2-yl)piperidin-1-yl)ethan-1-one was obtained from 2-(5-phenylimidazol-2-yl)piperidine and 2-(methylsulfonyl)acetic acid as a light yellow oil. HRMS (ESI+): calculated value C 17 H 21 N3O3S[M+H]+: 348.1376; found: 348.1370.

[0874] Example 84: 2-Cyclopropyl-2-ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one

[0875] Prepared similarly to Example 36, 2-cyclopentyl-2-ethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one was obtained from 2-(5-phenylimidazol-2-yl)piperidine and 2-cyclopentyl-2-ethoxyacetic acid as a light yellow oil. HRMS (ESI+): calculated value C 23 H 31N3O2[M+H]+: 382.2489; found: 382.2481.

[0876] Example 85: 2-Methyl-3-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0877] Prepared similarly to Example 36, 2-methyl-3-(methylthio)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one was obtained from 2-(5-phenylimidazol-2-yl)piperidine and 2-methyl-3-(methylthio)propanoic acid as a yellow oil. HRMS (ESI+): calculated value C 19 H 25 N3OS[M+H]+: 344.1791; found: 344.1786.

[0878] Example 86: 2-(Methylthio)-1-(2-(4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0879] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 3-thienylboronic acid, and 2-(methylthio)propionic acid to provide 2-(methylthio)-1-(2-(4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a yellow film. HRMS (ESI+): Calcd. C 16 H 21 N3OS2[M+H]+: 336.1199; found: 336.1192.

[0880] Example 87: 1-(2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0881] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-fluorophenylboronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS (ESI+): Calcd. C 18 H 22 FN3OS[M+H]+: 348.1540; found: 348.1533.

[0882] Example 88: 2-(Methylsulfonyl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0883] Prepared similarly to Example 36, 2-(5-phenylimidazol-2-yl)piperidin-1-yl)propan-1-one was obtained from 2-(5-phenylimidazol-2-yl)piperidine and 2-(methylsulfonyl)propionic acid as a white waxy solid. HRMS (ESI+): calculated value C 18 H 23 N3O3S[M+H]+: 362.1533; found: 362.1524.

[0884] Example 89: 2-(Methylthio)-1-(2-(4-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0885] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, o-tolylboronic acid, and 2-(methylthio)propionic acid to provide 2-(methylthio)-1-(2-(4-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a colorless film. HRMS (ESI+): Calcd. C 19 H 25 N3OS[M+H]+: 344.1791; found: 344.1786.

[0886] Example 90: 2-(Methylthio)-1-(2-(4-(pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0887] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-pyridylboronic acid, and 2-(methylthio)propionic acid to provide 2-(methylthio)-1-(2-(4-(pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 17 H 22 N4OS[M+H]+: 331.1587; found: 331.1582.

[0888] Example 91: 1-(2-(4-(2-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0889] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-chlorophenylboronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(2-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 18 H 22 ClN3OS[M+H]+: 364.1245; found: 364.1238.

[0890] Example 92: 1-(2-(4-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0891] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-ethylphenylboronic acid, and 2-(methylthio)propionic acid to provide 1-(2-(4-(4-ethylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 20 H 27 N3OS[M+H]+: 358.1948; found: 358.1942.

[0892] Example 93: 1-(2-(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0893] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-hydroxyphenylboronic acid, and 2-(methylthio)propionic acid to provide 1-(2-(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 18 H 23 N3O2S[M+H]+: 346.1584; found: 346.1578.

[0894] Example 94: 2-(Methylthio)-1-(2-(4-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0895] Prepared similarly to that described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, m-tolylboronic acid, and 2-(methylthio)propionic acid to provide 2-(methylthio)-1-(2-(4-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 19 H 25 N3OS[M+H]+: 344.1791; found: 344.1786.

[0896] Example 95: 1-(2-(4-(2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0897] Prepared according to a similar method as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-fluorophenylboronic acid and 2-(methylthio)propanoic acid to provide 1-(2-(4-(2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow oil. HRMS (ESI+): calculated value C 18 H 22 FN3OS[M+H]+: 348.1540; found: 348.1535.

[0898] Example 96: 2-Methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0899] Prepared analogously to Example 36, 2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one was obtained from 2-(5-phenylimidazol-2-yl)piperidine and isobutyric acid as a white solid. HRMS (ESI+): calculated value C 18 H 23 N3O[M+H]+: 298.1914; found: 298.191.

[0900] Example 97: 2-Methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0901] Prepared similarly to Example 36, 2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one was obtained from 2-(5-phenylimidazol-2-yl)piperidine 2-methoxypropanoic acid as a white solid. HRMS (ESI+): calculated value C 18 H 23 N3O2[M+H]+: 314.1863; found: 314.1859.

[0902] Example 98: 3,3,4,4,4-Pentafluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0903] Prepared similarly to Example 36, 3,3,4,4,4-pentafluoro-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one was obtained from 2-(5-phenylimidazol-2-yl)piperidine-3,3,4,4,4-pentafluorobutyric acid as a light yellow film. HRMS (ESI+): calculated value C 18 H 18 F5N3O[M+H]+: 388.1443; found: 388.1439.

[0904] Example 99: N-(4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methanesulfonamide

[0905] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-(methylsulfonylamino)phenyl)boronic acid and 2-(methylthio)propionic acid to provide N-(4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)phenyl)methanesulfonamide as a light yellow wax. HRMS (ESI+): Calcd. C 19 H 26 N4O3S2[M+H]+: 423.1519; found: 423.1515.

[0906] Example 100: 1-(2-(4-(4-methoxy-2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0907] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-methoxy-2-methylphenylboronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-methoxy-2-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 20 H 27 N3O2S[M+H]+: 374.1897; found: 374.1894.

[0908] Example 101: 2-(Methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0909] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (5-methylfuran-3-yl)boronic acid and 2-(methylthio)propanoic acid to provide 2-(methylthio)-1-(2-(4-(5-methylthiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 17 H 23 N3OS2[M+H]+: 350.1355; found: 350.1352.

[0910] Example 102: 1-(2-(4-(5-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0911] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 5-methylpyridine-3-boronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(5-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 18 H 24 N4OS[M+H]+: 345.1744; found: 345.1743.

[0912] Example 103: 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0913] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-hydroxyphenylboronic acid, and 2-(methylthio)propionic acid to provide 1-(2-(4-(2-hydroxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a yellow film. HRMS (ESI+): Calcd. C 18 H 23 N3O2S[M+H]+: 346.1584; found: 346.1584.

[0914] Example 104: 1-(2-(4-(3,5-difluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0915] Prepared by a similar procedure as described in Example 38 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+): Calcd. C 18 H 21 F2N3OS[M+H]+: 366.1446; found: 366.1446.

[0916] Example 105: 1-(2-(4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0917] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 6-methylpyridine-3-boronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 18 H 24 N4OS[M+H]+: 345.1744; found: 345.1744.

[0918] Example 106: 1-(2-(4-(5-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0919] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 5-methyl-2-furanboronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(5-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 17 H 23 N3O2S[M+H]+: 334.1584; found: 334.1583.

[0920] Example 107: 1-(2-(4-(4-methyl-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0921] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, [4-methyl-3-(trifluoromethyl)phenyl]boronic acid and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-methyl-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 20 H 24 F3N3OS[M+H]+: 412.1665; found: 412.1665.

[0922] Example 108: 1-(2-(4-(2-methoxypyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0923] Prepared according to a similar method as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-methoxypyrimidine-5-boronic acid and 2-(methylthio)propanoic acid 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+): calculated value C 17 H 23 N5O2S[M+H]+: 362.1645; found: 362.1642.

[0924] Example 109: 1-(2-(4-(Benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0925] Prepared by a similar procedure as described in Example 38 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+): Calcd. C 20 H 23 N3OS2[M+H]+: 386.1355; found: 386.1353.

[0926] Example 110: 1-(2-(4-(2,3-dihydrobenzofuran-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0927] Prepared by a similar method as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (2,3-dihydrobenzofuran-6-yl)boronic acid and 2-(methylthio)propanoic acid to provide 1-(2-(4-(2,3-dihydrobenzofuran-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 20 H 25 N3O2S[M+H]+: 372.1740; found: 372.1737.

[0928] Example 111: 2-(Methylthio)-1-(2-(4-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0929] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-vinylphenylboronic acid, and 2-(methylthio)propionic acid to provide 2-(methylthio)-1-(2-(4-(4-vinylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a white wax. HRMS (ESI+): Calcd. C 20 H 25 N3OS[M+H]+: 356.1791; found: 356.1788.

[0930] Example 112: 1-(2-(4-(3-((dimethylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0931] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 3-(N,N-dimethylaminomethyl)phenylboronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(3-((dimethylamino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 21 H 30 N4OS[M+H]+: 387.2213; found: 387.2208.

[0932] Example 113: 1-(2-(4-(4-isopropylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0933] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-isopropylphenylboronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-isopropylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 21 H 29 N3OS[M+H]+: 372.2104; found: 372.2101.

[0934] Example 114: 1-(2-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0935] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-cyclopropyl-2-fluorophenylboronic acid pinacol ester, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-cyclopropyl-2-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 21 H 26 FN3OS[M+H]+: 388.1853; found: 388.1847.

[0936] Example 115: 1-(2-(4-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0937] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2-fluoro-4-methoxyphenylboronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(2-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 19 H 24 FN3O2S[M+H]+: 378.1646; found: 378.1642.

[0938] Example 116: 1-(2-(4-(4-(methylsulfonyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0939] Prepared according to a similar method as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-(methylsulfonyl)phenylboronic acid and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-(methylsulfonyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a colorless wax. HRMS (ESI+): Calcd. C 19 H 25 N3O3S2[M+H]+: 408.1410; found: 408.1406.

[0940] Example 117: 1-(2-(4-(3,5-dimethylisoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0941] Prepared according to a similar method as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 3,5-dimethylisoxazol-4-yl-4-boronic acid and 2-(methylthio)propanoic acid to provide 1-(2-(4-(3,5-dimethylisoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow oil. HRMS (ESI+): calculated value C 17 H 24 N4O2S[M+H]+: 349.1693; found: 349.1689.

[0942] Example 118: 1-(2-(4-(2,3-dihydrobenzofuran-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0943] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 2,3-dihydro-1-benzofuran-5-ylboranediol and 2-(methylthio)propanoic acid to provide 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+): Calcd. C 20 H 25 N3O2S[M+H]+: 372.1740; found: 372.1736.

[0944] Example 119: 1-(2-(4-(3-methylfuran-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0945] Prepared according to a similar method as described in Example 38 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 to provide 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+): calculated value C 17 H 23 N3O2S[M+H]+: 334.1584; found: 334.1580.

[0946] Example 120: 1-(2-(4-(5-((dimethylamino)methyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0947] Prepared according to a similar procedure as described in Example 38 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 to provide 1-(2-(4-(5-((dimethylamino)methyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 19 H 28 N4OS2[M+H]+: 393.1777; found: 393.1772.

[0948] Example 121: 2-(Methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0949] Prepared according to a similar method as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, [5-(trifluoromethyl)thiophen-2-yl]boronic acid and 2-(methylthio)propanoic acid to provide 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)thiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow oil. HRMS (ESI+): Calcd. C 17 H 20 F3N3OS2[M+H]+: 404.1073; found: 404.1070.

[0950] Example 122: 1-(2-(4-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0951] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-methyl-2-(methylthio)-5-pyridinylboronic acid and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-methyl-6-(methylthio)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 19 H 26 N4OS2[M+H]+: 391.1621; found: 391.1616.

[0952] Example 123: 2-(Methylthio)-1-(2-(4-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0953] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 4-propylphenylboronic acid, and 2-(methylthio)propionic acid to provide 2-(methylthio)-1-(2-(4-(4-propylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 21 H 29 N3OS[M+H]+: 372.2104; found: 372.2101.

[0954] Example 124: 1-(2-(4-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0955] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, [4-(2-methoxyethyl)phenyl]boranediol and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-(2-methoxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 21 H 29 N3O2S[M+H]+: 388.2053; found: 388.2047.

[0956] Example 125: 1-(2-(4-(4-(difluoromethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0957] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, [4-(difluoromethyl)thiophen-3-yl]boronic acid and 2-(methylthio)propanoic acid to provide 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+): Calcd. C 17 H 21 F2N3OS2[M+H]+: 386.1167; found: 386.1162.

[0958] Example 126: 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0959] Prepared according to a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-cyclobutylphenyl)boronic acid and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-cyclobutylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow wax. HRMS (ESI+): Calcd. C 22 H 29 N3OS[M+H]+: 384.2104; found: 384.2100.

[0960] Example 127: 1-(2-(4-(3-chloro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0961] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 3-chloro-4-methylphenylboronic acid, and 2-(methylthio)propanoic acid to provide 1-(2-(4-(3-chloro-4-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 19 H 24 ClN3OS[M+H]+: 378.1401; found: 378.1397.

[0962] Example 128: 1-(2-(4-(4-((1,1-dioxothiomorpholino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[0963] Prepared according to a similar method as described in Example 38 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 to provide 1-(2-(4-(4-((1,1-dioxothiomorpholino)methyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): calculated value C 23 H 32 N4O3S2[M+H]+: 477.1989; found: 477.1990.

[0964] Example 129: 2-Cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0965] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-cyclopropylpropionic acid to provide 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as an off-white wax. HRMS (ESI+): Calcd. C 20 H 25 N3O[M+H]+: 324.2071; found: 324.2071.

[0966] Example 130: Cyclopropyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone

[0967] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and cyclopropanecarboxylic acid to provide cyclopropyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as an off-white wax. HRMS (ESI+): Calcd. C 18 H 21 N3O[M+H]+: 296.1758; found: 296.1759.

[0968] Example 131: (2R)-2-(Dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0969] Prepared by a similar procedure as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and dimethyl-D-alanine to provide (2R)-2-(dimethylamino)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow gum. HRMS (ESI+): Calcd. C 19 H 26 N4O[M+H]+: 327.2180; found: 327.2180.

[0970] Example 132: 3-Methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one

[0971] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 3-methylbut-2-enoic acid to provide 3-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one as a light yellow oil. HRMS (ESI+): calculated value C 19 H 23 N3O[M+H]+: 310.1914; found: 310.1916.

[0972] Example 133: Cyclopropyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone

[0973] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and cyclopentanecarboxylic acid to provide cyclopentyl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a light yellow oil. HRMS (ESI+): Calcd. 20 H 25 N3O[M+H]+: 324.2071; found: 324.2071.

[0974] Example 134: 2-(Furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0975] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-(furan-2-yl)propanoic acid to provide 2-(furan-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow oil. HRMS (ESI+): calculated value C 21 H 23 N3O2[M+H]+: 350.1863; found: 350.1861.

[0976] Example 135: 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one

[0977] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-ethylbut-2-enoic acid to provide 2-ethyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)but-2-en-1-one as a light yellow oil. HRMS (ESI+): calculated value C 20 H 25 N3O[M+H]+: 324.2071; found: 324.2070.

[0978] Example 136: 2-Methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0979] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-methoxybutyric 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+): Calcd. C 19 H 25 N3O2[M+H]+: 328.2020; measured value: 328.2019.

[0980] Example 137: 2-Cyclopropyl-2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one

[0981] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-cyclopropyl-2-methoxyacetic acid to provide 2-cyclopropyl-2-methoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one as a colorless film. HRMS (ESI+): Calcd. C 20 H 25 N3O2[M+H]+: 340.2020; measured value: 340.2020.

[0982] Example 138: 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0983] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and butyric acid to provide 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one as a light yellow oil. HRMS (ESI+): Calcd. 18 H 23 N3O[M+H]+: 298.1914; measured value: 298.1914.

[0984] Example 139: (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone

[0985] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 5-methyltetrahydrofuran-3-carboxylic acid to provide (5-methyltetrahydrofuran-3-yl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a light yellow film. HRMS (ESI+): Calcd. C 20 H 25 N3O2[M+H]+: 340.2020; measured value: 340.2019.

[0986] Example 140: 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0987] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and propionic acid to provide 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a white solid. HRMS (ESI+): Calcd. C 17 H 21 N3O[M+H]+: 284.1758; found: 284.1757.

[0988] Example 141: 3,3,3-Trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0989] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 3,3,3-trifluoro-2-methylpropanoic acid to provide 3,3,3-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a yellow film. HRMS (ESI+): Calcd. C 18 H 20 F3N3O[M+H]+: 352.1631; found: 352.1630.

[0990] Example 142: 4,4,4-Trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[0991] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 4,4,4-trifluoro-2-methylbutanoic acid to provide 4,4,4-trifluoro-2-methyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one as a yellow film. HRMS (ESI+): Calcd. C 19 H 22 F3N3O[M+H]+: 366.1788; found: 366.1787.

[0992] Example 143: (2,2-Dimethylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone

[0993] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2,2-dimethylcyclopropane-1-carboxylic acid to provide (2,2-dimethylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a light yellow film. HRMS (ESI+): Calcd. C 20 H 25 N3O[M+H]+: 324.2071; found: 324.2070.

[0994] Example 144: cis-2-(2-(4-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile

[0995] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and cis-2-cyanocyclopropane-1-carboxylic acid to provide cis-2-(2-(4-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)cyclopropane-1-carbonitrile as a yellow film. HRMS (ESI+): Calcd. 19 H 20 N4O[M+H]+: 321.1710; found: 321.1709.

[0996] Example 145: 2,3-Dimethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[0997] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2,3-dimethoxypropionic acid to provide 2,3-dimethoxy-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a yellow film. HRMS (ESI+): Calcd. 19 H 25 N3O3[M+H]+: 344.1969; found: 344.1968.

[0998] Example 146: 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-dien-1-one

[0999] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 3,5-hexadienoic acid to provide 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)hexa-3,5-dien-1-one as a yellow film. HRMS (ESI+): Calcd. C 20 H 23 N3O[M+H]+: 322.1914; measured value: 322.1913.

[1000] Example 147: 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[1001] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-(5-methylfuran-2-yl)propanoic acid to provide 2-(5-methylfuran-2-yl)-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 22 H 25 N3O2[M+H]+: 364.2020; observed value: 364.2017.

[1002] Example 148: (trans-2-methoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone

[1003] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and trans-2-methoxycyclopropane-1-carboxylic acid to provide (trans-2-methoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a yellow wax. HRMS (ESI+): Calcd. C 19 H 23N3O2[M+H]+: 326.1863; found: 326.1862.

[1004] Example 149: (2-Ethoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone

[1005] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-ethoxycyclopropane-1-carboxylic acid to provide (2-ethoxycyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a light yellow film. HRMS (ESI+): Calcd. C 20 H 25 N3O2[M+H]+: 340.2020; measured value: 340.2020.

[1006] Example 150: Bicyclo[1.1.1]pentan-1-yl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone

[1007] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and bicyclo[1.1.1]pentane-1-carboxylic acid to provide bicyclo[1.1.1]pentan-1-yl(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a white solid. HRMS (ESI+): Calcd. C 20 H 23 N3O[M+H]+: 322.1914; measured value: 322.1914.

[1008] Example 151: (2-Methylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone

[1009] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-methylcyclopropane-1-carboxylic acid to provide (2-methylcyclopropyl)(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)methanone as a white solid. HRMS (ESI+): Calcd. C 19 H 23 N3O[M+H]+: 310.1914; found: 310.1913.

[1010] Example 152: (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(thietan-3-yl)methanone

[1011] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and thietane-3-carboxylic acid to provide (2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)(thietan-3-yl)methanone as a light yellow solid. HRMS (ESI+): calculated value C 18 H 21 N3OS[M+H]+: 328.1478; found: 328.1478.

[1012] Example 153: 2-cyclobutyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[1013] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-cyclobutylpropionic acid to provide 2-cyclobutyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 21 H 27 N3O[M+H]+: 338.2227; found: 338.2226.

[1014] Example 154: 2-Cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one

[1015] Prepared by a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 2-cyclopropylacetic acid to provide 2-cyclopropyl-1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)ethan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 19 H 23 N3O[M+H]+: 310.1914; measured value: 310.1914.

[1016] Example 155: 1-(2-(4-(5-(methoxymethyl)thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1017] Prepared by a similar procedure as described in Example 38 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 to provide 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+): Calcd. C 18 H 25 N3O2S2[M+H]+: 380.1461; found: 380.1461.

[1018] Example 156: 1-(2-(4-(3-(methylamino)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1019] Prepared by a similar procedure as described in Example 38 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+): Calcd. C 19 H 26 N4OS[M+H]+: 359.1900; found: 359.1900.

[1020] Example 157: 1-(2-(4-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1021] Prepared by a similar procedure as described in Example 38 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 to provide 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+): Calcd. C 18 H 24 N4O2S[M+H]+: 361.1693; found: 361.1692.

[1022] Example 158: 2-(Methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[1023] Prepared by a similar procedure as described in Example 38 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 to provide 2-(methylthio)-1-(2-(4-(4-(morpholinomethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 23 H 32 N4O2S[M+H]+: 429.2319; found: 429.2321.

[1024] Example 159: 1-(2-(4-(4-(1-hydroxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1025] Prepared according to a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacan-2-yl)phenyl)ethan-1-ol and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-(1-hydroxyethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow wax. HRMS (ESI+): Calcd. C 20 H 27 N3O2S[M+H]+: 374.1897; found: 374.1899.

[1026] Example 160: 2-(Methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[1027] Prepared according to a similar method as described in Example 38 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 to provide 2-(methylthio)-1-(2-(4-(5-(trifluoromethyl)furan-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow film. HRMS (ESI+): calculated value C 17 H 20F3N3O2S[M+H]+: 388.1301; found: 388.1300.

[1028] Example 161: 2-(Methylthio)-1-(2-(4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[1029] Prepared according to a similar method as described in Example 38 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 to provide 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+): calculated value C 16 H 20 F3N5OS[M+H]+: 388.1414; found: 388.1413.

[1030] Example 162: 2-(Methylthio)-1-(2-(4-(quinoxalin-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[1031] Prepared according to a similar method as described in Example 38 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 to provide 2-(methylthio)-1-(2-(4-(quinoxalin-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a yellow solid. HRMS (ESI+): Calcd. C 20 H 23 N5OS[M+H]+: 382.1696; found: 382.1696.

[1032] Example 163: 2-(Methylthio)-1-(2-(4-(pyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one

[1033] Prepared by a similar procedure as described in Example 38 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 to provide 2-(methylthio)-1-(2-(4-(pyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 16 H 21 N5OS[M+H]+: 332.1540; found: 332.1540.

[1034] Example 164: 1-(2-(4-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1035] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (3-fluoro-4-(methoxymethyl)phenyl)boronic acid and 2-(methylthio)propanoic acid to provide 1-(2-(4-(3-fluoro-4-(methoxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 20 H 26 FN3O2S[M+H]+: 392.1803; found: 392.1803.

[1036] Example 165: 1-(2-(4-(4-(difluoromethoxy)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1037] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-(difluoromethoxy)-3-fluorophenyl)boronic acid and 2-(methylthio)propanoic acid to provide 1-(2-(4-(4-(difluoromethoxy)-3-fluorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): Calcd. C 19 H 22 F3N3O2S[M+H]+: 414.1458; found: 414.1460.

[1038] Example 166: N-(2-hydroxyethyl)-4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)benzenesulfonamide

[1039] Prepared by a similar procedure as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (4-(N-(2-hydroxyethyl)sulfamoyl)phenyl)boronic acid and 2-(methylthio)propanoic acid to provide N-(2-hydroxyethyl)-4-(2-(1-(2-(methylthio)propanoyl)piperidin-2-yl)-1H-imidazol-4-yl)benzenesulfonamide as a light yellow film. HRMS (ESI+): Calcd. C 20 H 28 N4O4S2[M+H]+: 453.1625; found: 453.1625.

[1040] Example 167: 1-(2-(4-(2-cyclopropyloxazol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1041] Prepared according to a similar method as described in Example 38 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 to provide 1-(2-(4-(2-cyclopropyloxazol-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): calculated value C 18 H 24 N4O2S[M+H]+: 361.1693; found: 361.1692.

[1042] Example 168: 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one

[1043] Prepared according to a similar method as described in Example 36 from 2-(4-phenyl-1H-imidazol-2-yl)piperidine and 4-pentenoic acid to provide 1-(2-(4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pent-4-en-1-one as a light yellow solid. HRMS (ESI+): calculated value C 19 H 23 N3O[M+H]+: 310.1914; measured value: 310.1914.

[1044] 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

[1045] Following a similar procedure as described in Example 38, 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 light yellow film. HRMS (ESI+): Calcd. C 19 H 21 F2N3O3S[M+H]+: 410.1345; found: 410.1346.

[1046] Example 170: 1-(2-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1047] Prepared according to a similar method as described in Example 38 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 to provide 1-(2-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one as a light yellow film. HRMS (ESI+): calculated value C 16 H 23 N5OS[M+H]+: 334.1696; found: 334.1696.

[1048] Example 171: 2-(Methylthio)-1-(2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one

[1049]

[0266] Example 171a: tert-Butyl 2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate: In a 100 mL round-bottom flask were added 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. 1 N 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 silica gel column chromatography 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.

[1050] 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 room temperature for 6 h. After the solution was cooled to 5°C, a dilute NaHCO3 solution was added, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phase was concentrated to give 2-(5-(p-tolyl)-4H-1,2,4-triazol-3-yl)piperidine as a yellow solid.

[1051] b) To a solution of 2-(methylthio)propanoic acid (200 mg, 1.73 mmol) in dichloromethane (50 mL) were 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 room temperature for 0.5 h. 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 then added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered, the solvent was removed 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). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 14.24-13.80 (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). 13C 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.

[1052] Example 172: 1-(2-(5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1053] Prepared in a manner similar to Example 171 from tert-butyl 2-cyanopiperidine-1-carboxylate, 4-fluorobenzohydrazide and 2-(methylthio)propionic acid to give 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).

[1054] Example 173: 2-(Methylthio)-1-(2-(5-phenyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)propan-1-one

[1055] Prepared in a manner similar to Example 171, the title product was obtained from tert-butyl 2-cyanopiperidine-1-carboxylate, phenylhydrazine and 2-(methylthio)propionic acid 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).

[1056] Example 174: 2-(Methylthio)-1-(2-(5-phenyloxazol-2-yl)piperidin-1-yl)propan-1-one

[1057] 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), EDC (5.0 g, 26.2 mmol) in dichloromethane (50 mL) were 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 room temperature for 16 h. The mixture was filtered and the solvent was removed, 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 light yellow solid.

[1058] 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) was added sulfuric acid (14.2 g, 144.0 mmol) under an ice bath, and the mixture was stirred at 100° C. for 1 h. After the solution was cooled to room temperature, a diluted NaHCO3 solution was added, and the organic phase was extracted with ethyl acetate (50 mL*3) and 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 light 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).

[1059] 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) were 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 room temperature for 0.5 h. 5-Phenyl-2-(piperidin-2-yl)oxazole (1000 mg, 4.38 mmol) and DIPEA (1.53 mL, 8.76 mmol) were then added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered, the solvent was removed, and the residue was purified by silica gel chromatography (hexane:MTBE=50:1) to a crude product as a light yellow oil. The oil was distilled by 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, CDCl3, 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.

[1060] Example 175: 1-(2-(4-methyl-5-phenyl-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1061] 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 minutes, then NH4OAc (1.8 g, 23.44 mmol) was added, followed by 1-phenylpropane-1,2-dione (0.69 mg, 4.69 mmol), and the mixture was heated to 60-65°C and stirred overnight. After the solution was cooled to room temperature, a diluted NaHCO3 solution was added, extracted with ethyl acetate (50 mL*3), and the organic phase was concentrated. The residue was purified by column chromatography (hexane:MTBE=3:1) to give 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).

[1062] 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 room temperature for 0.5 h. 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 then added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered, the solvent was removed 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). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 11.81-11.59 (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). 13 C 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), 4 6.6(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), 25 .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.

[1063] Example 176: 1-(2-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one

[1064] 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 benzene-1,2-diamine (1014 mg, 9.38 mmol) dropwise 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 x 150 mL). Any precipitate was removed by filtration, and the organic phase was washed with concentrated aqueous NaHCO3 (2 x 100 mL) and brine (2 x 100 mL). The solution was then concentrated under reduced pressure to afford 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).

[1065] 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 room temperature for 6 h. After the solution was cooled to 5° C., dilute NaHCO solution was added, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phase was concentrated to give 2-(piperidin-2-yl)-1H-benzo[d]imidazole as a white solid (260 mg, yield: 78%).

[1066] b) To a solution of 2-(methylthio)propanoic acid (179 mg, 1.491 mmol) in dichloromethane (30 mL) were added HOBt (304 mg, 1.987 mmol) and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (309 mg, 1.987 mmol) at 0-5° C., and the mixture was stirred at room temperature for 0.5 h. 2-(piperidin-2-yl)-1H-benzo[d]imidazole (200 mg, 0.994 mmol) and DIPEA (0.434 ml, 2.484 mmol) were then added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the solvent was removed 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.39, 12.16 (brs, 1H), 7.60-7.44 (m, 2H), 7.16-7.15 (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.

[1067] Example 177: (S)-2-Methyl-1-((R)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[1068] Prepared by a method similar to Example 39: (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) to give 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). 1H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.0, 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.

[1069] Example 178: 2-(Methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)azepan-1-yl)propan-1-one

[1070] Prepared in a manner similar to Example 64 from 1-(tert-butoxycarbonyl)-azepane-2-carboxylic acid, 2-amino-1-(p-tolyl)ethan-1-one hydrochloride, and 2-(methylthio)propionic acid to give 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). 13C 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, 4 2.3, 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, 25 .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.

[1071] Example 179: (2,2-Dimethylcyclopropyl)(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)methanone

[1072] Prepared in a similar manner as described in Example 39 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 to give 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). 1 H NMR (400 MHz, DMSO-d6, 25°C, mixture of stereoisomers): δ = 11.52-12.19 (m, 1H), 7.08-7.72 (m, 5H), 5.24-6.02 (m, 1H), 3.83-4.56 (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 = 10.8 Hz, 3H), 0.87-1.08 (m, 4H), 0.61-0.77 ppm (m, 1H).

[1073] Example 180: 1-(2-(5-Bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one

[1074] Prepared by a similar procedure as described in Example 22a using 2-methylbutanoic acid instead of 2-(methylthio)propionic 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 7.23-7.15 (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.

[1075] Example 181: 1-(2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one

[1076] Prepared in a similar manner as described in Example 22b from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and 4-chlorophenylboronic acid to give the title product as a white solid. GC / MS (EI): m / z (%): 345 (11) [M + ],330(1),260(100). 1 HNMR (400 MHz, chloroform-d, 25°C, mixture of stereoisomers): δ = 9.83-10.84 (m, 1H), 7.37-7.79 (m, 2H), 7.32 (d, J = 8.6 Hz, 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), 0.80-1.00 ppm (m, 3H).

[1077] Example 182: 2-(4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile

[1078] Prepared in a similar manner as described in Example 22b from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-(methylthio)propan-1-one and (4-(cyanomethyl)phenyl)boronic acid 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). 1 H NMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.26-11.85 (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.

[1079] Example 183: 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile

[1080] Prepared in a similar manner as described in Example 22b from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and (4-(cyanomethyl)phenyl)boronic acid to give the title product 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). 1 HNMR (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.20-11.75 (m, 1H), 7.80-7.69 (m, 2H), 7.68-7.52 (m, 1H), 7.43-7.27 (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.

[1081] Example 184: 2-(4-(2-(1-(2-methylbutanoyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile

[1082] Prepared in a similar manner as described in Example 22b from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and 4-cyanophenylboronic acid to give the title product 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 (400 MHz, DMSO-d6, 25°C, mixture of stereoisomers): δ = 7.93-8.11 (m, 3H), 7.88 (br t, J = 8.3 Hz, 2H), 5.87 (br d, J = 14.9 Hz, 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), 0.87 ppm (br t, J = 7.5 Hz, 3H).

[1083] Example 185: 2,3-Dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[1084] Prepared by a similar procedure as described in Example 39 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 to give 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 (400 MHz, DMSO-d6, 25°C, 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 = 8.6 Hz, 1H), 2.24-2.38 (m, 3H), 1.48-1.91 (m, 5H), 1.23-1.35 (m, 4H), 0.78-1.08 ppm (m, 9H).

[1085] Example 186: 2-Methyl-1-(2-(5-(o-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[1086] Prepared in a similar manner as described in Example 22b from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and o-tolylboronic acid to give 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 (300 MHz, DMSO-d6, mixture of stereoisomers and tautomers) δ 12.08-11.72 (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.

[1087] Example 187: 2-Methyl-1-(2-(5-(m-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[1088] Prepared in a similar manner as described in Example 22b from 1-(2-(5-bromo-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one and m-tolylboronic acid to give 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). 1 H 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.

[1089] Example 188: 1-(2-(5-(4-(Hydroxymethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-2-methylbutan-1-one

[1090] Prepared according to a similar method as described in Example 38 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 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 (500 MHz, DMSO-d6, 140°C, 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 = 0.6 Hz, 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), 0.84-0.93ppm (m, 3H). 13 C NMR (126 MHz, DMSO-d6, 140°C, mixture of stereoisomers): δ = 175.6, 175.6, 140.8, 127.4, 127.1, 124.7, 119.5, 110.0, 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, 11.6 ppm.

[1091] Example 189: 1-(Isopropylsulfonyl)-2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine

[1092] 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 minutes 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) for 5 minutes. The mixture was allowed to reach room temperature and then poured into an ice-cold 2 M HCl solution (50 mL), extracted with DCM (3 x 20 mL), washed with water (20 mL), brine (20 mL), dried over MgSO , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with a heptane gradient containing 1-50% of a mixture of 80% EtOAc, 10% hexanes, 9% EtOH, and 1% Et3N) to afford 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). 1 H 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 (brdd, J=8.7, 4.5Hz, 1 H), 2.93-3.04(m, 1H), 2.56-2.70(m, 1H), 2.32(s, 4H), 1.78-1.99(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 (101MHz, DMSO-d6, 25°C): Shift=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, 14.1ppm.

[1093] Example 190: 1-(sec-Butylsulfonyl)-2-(5-(p-Tolyl)-1H-imidazol-2-yl)piperidine

[1094] 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 eq). The mixture was stirred at -78 ° C for 15 minutes and then slowly treated with a solution of butane-2-sulfonyl chloride (0.107 g, 0.68 mmol, 1.1 eq) in THF (1 mL) over 5 minutes. The mixture was allowed to reach room temperature and then poured into an ice-cold 2M HCl solution (50 mL), extracted with DCM (3 x 20 mL), washed with water (20 mL), brine (20 mL), dried over MgSO , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluting with a heptane gradient containing 1-50% of a mixture of 80% EtOAc, 10% hexanes, 9% EtOH, and 1% Et3N) to afford 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 (400 MHz, DMSO-d6, 25°C, mixture of stereoisomers): δ = 7.87-8.04 (m, 1H), 7.71-7.82 (m, 2H), 7.17-7.26 (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).

[1095] Example 191: 2-Methyl-1-(2-(5-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one

[1096] Prepared in a similar manner as described in Example 38 from tert-butyl 2-(5-bromoimidazol-2-yl)piperidine-1-carboxylate, (5-methylthiophen-2-yl)boronic acid and 2-methylbutanoic acid 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 (400 MHz, DMSO-d6, 25°C, 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).

[1097] Example 192: 2-(Methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperazin-1-yl)propan-1-one

[1098] Example 192a: 4-(tert-Butoxycarbonyl)-1-(2-(methylthio)propionyl)piperazine-2-carboxylic acid: NaOH (1.39 g, 34.7 mmol) and water (29 mL) were charged to a flask and the mixture was stirred. Once completely dissolved, 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 minutes. The resulting mixture was treated dropwise with 2-(methylthio)propionyl chloride (2.41 g, 17.8 mmol) at 5°C and stirred for 4 hours at 5°C. The mixture was then poured into ice-cold 1 M HCl solution (100 mL) and extracted with EtOAc (3 x 70 mL), washed with water (70 mL), brine (70 mL), dried over MgSO4 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. DIP-MS (EI): m / z (%): 276 (2) [M + -isobutylene], 259(1), 230(10), 75(53), 57(100).

[1099] Example 192b: 1-(tert-Butyl)3-(2-oxo-2-(p-tolyl)ethyl)4-(2-(methylthio)propionyl)piperazine-1,3-dicarboxylate: A solution of 4-(tert-butoxycarbonyl)-1-(2-(methylthio)propionyl)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 room temperature for 1 h. The mixture was then poured into ice-cold 1 M HCl solution (100 mL) and extracted with EtOAc (3 x 70 mL), washed with water (70 mL), brine (70 mL), dried over MgSO4, and concentrated. The crude product was then purified by flash column chromatography on silica gel eluting with a gradient of 7-60% EtOAc / 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).

[1100] 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 refluxed for 2 h. The mixture was then poured into ice-cold 1 M HCl solution (100 mL) and extracted with EtOAc (3 x 70 mL), washed with water (70 mL), brine (70 mL), dried over MgSO4 and concentrated. The crude product was then purified by flash column chromatography on silica gel eluting with a gradient of 7-60% EtOAc / heptane to afford 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).

[1101] 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 time TLC indicated the reaction was complete. The mixture was then poured into ice water (50 mL) and treated with 2M NaOH solution until a basic pH was observed, extracted with DCM (3 x 50 mL), dried over MgSO4 and concentrated. The crude product 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 fractions containing the product were collected and washed with water to remove AcOH, dried over MgSO4, filtered, and concentrated to afford 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).

[1102] Example 193: 2-(Methylthio)-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)propan-1-one

[1103] 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)propionyl chloride, 2-bromo-1-(p-tolyl)ethan-1-one and ammonium acetate in the order described in Example 63, it was isolated as a minor by-product (yellow solid). 1 H NMR (500 MHz, chloroform-d, 25° C., mixture of stereoisomers): δ = 7.82 (s, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.11 (brd, J = 4.0 Hz, 1H), 3.98 (br d, J = 13.1 Hz, 1H), 3.74 (q, J = 6.9 Hz, 1H), 3.26-3.39 (m, 1H), 2.46 (br d, J = 13.1 Hz, 1H), 2.38 (s, 3H), 2.01-2.19 (m, 3H), 1.66-1.89 (m, 5H), 1.56 ppm (d, J = 6.7 Hz, 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.

[1104] Example 194: 2-Methyl-1-(2-(4-(p-tolyl)oxazol-2-yl)piperidin-1-yl)butan-1-one

[1105] 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 in the order described in Example 63, it was isolated as a minor by-product (red oil). GC / MS (EI): m / z (%): 326 (8) [M + ], 269(1), 241(92), 186(10), 84(100), 57(44). 1H NMR (600 MHz, BENZENE-d6, 25°C, mixture of stereoisomers): δ = 7.71-7.80 (m, ...

Claims

1. A compound of formula (Ic) or a salt thereof (Ic) in n is 0 or 1; R 1 Selected from C6-C 10 Aryl; C6-C 10 Aryl, which is substituted with up to four substituents independently selected from the group consisting of Halogen; OH; C≡N; NO2; C1-C6 alkyl; C1-C6 alkyl containing up to 5 halogen atoms; C1-C3 alkyl containing up to 3 OH groups; C2-C6 alkenyl; C1-C6 alkoxy; C1-C6 alkoxy containing up to 3 halogen atoms; C1-C3 alkoxy C1-C3 alkyl; C3-C7 cycloalkyl; -C(O)R 10 , where R 10 Selected from C1-C3 alkyl; -OC(O)R 11 , where R 11 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, R 13 Selected from hydrogen, C1-C3 alkyl and -SO2R 15 , where R 15 is a C1-C3 alkyl group, and R 14 Selected from hydrogen, C1-C3 alkyl and -SO2R 16 , where R 16 is C1-C3 alkyl, or wherein R 13 and R 14 Together with the N atom to which they are attached they 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 the aryl ring is substituted with two or more substituents, the two substituents may be taken together with the carbon atoms to which they are attached to form a ring, and C5-C 10 A mono- or bicyclic heteroaryl group in which up to 2 C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, said heteroaryl group being optionally substituted by up to four substituents selected from the group consisting of Halogen; OH; C≡N; NO2; C1-C6 alkyl; C1-C6 alkyl containing up to 5 halogen atoms; C2-C6 alkenyl; C1-C6 alkoxy; C1-C6 alkoxy containing up to 3 halogen atoms; C1-C3 alkoxy C1-C3 alkyl; C3-C7 cycloalkyl; -C(O)R 20 , where R 20 Selected from C1-C3 alkyl; -OC(O)R 21 , where R 21 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, R 23 Selected from hydrogen, C1-C3 alkyl and -SO2R 25 , where R 25 is a C1-C3 alkyl group, and R 24 Selected from hydrogen, C1-C3 alkyl and -SO2R 26 , where R 26 is C1-C3 alkyl, or wherein R 23 and R 24 Together with the N atom to which they are attached they 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; Z is C; and 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, furanyl optionally substituted by methyl, C1-C6 fluoro-alkyl and -NR 30 R 31 , where R 30 and R 31 independently selected from hydrogen and C1-C3 alkyl; or R 6 and R 5 Together with the carbon atoms to which they are attached, they form a) Carbonyl (C=O) or vinyl (C=CR 32 R 33 , where R 32 and R 33 independently selected from H or C1-C3 alkyl); or b) a 3- to 7-membered saturated or unsaturated ring containing up to 3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the ring is optionally substituted with one or two groups independently selected from C1-C3 alkyl, C1-C3 alkoxy; X 1 is NH or O; and X 2 and X 3 are independently selected from C, N and O, provided that X 2 or X 3 Not for C.

2. The compound according to claim 1, wherein the compound is selected from: (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)-1H-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, 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-dioxothiomorpholino)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-(methylsulfonyl)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-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, 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-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)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-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-methylisothiazol-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)piperidin-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)propionyl)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)propionyl)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-tetrazolyl-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-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-(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-(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)-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)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)propan-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)piperidin-1-yl)propan-1-one, 2-(Methylthio)-1-(2-(5-phenyloxazol-2-yl)piperidin-1-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)propionyl)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, 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-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)propionyl)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)propionyl)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)propionyl)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)propionyl)piperidin-2-yl)-1H-imidazol-4-yl)benzonitrile, 4-(2-(1-(2-(methylthio)propionyl)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, 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid methyl ester, N-(2-hydroxyethyl)-4-(2-(1-(2-(methylthio)propionyl)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)propionyl)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-(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, 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, 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-methylbutyryl)piperidin-2-yl)-1H-imidazol-5-yl)benzaldehyde, 4-(2-(1-(2-(methylthio)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)benzoic acid, 4-(2-(1-(2-methylbutyryl)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)propionyl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1-(2-methylbutyryl)piperidin-2-yl)-1H-imidazol-5-yl)phenyl)acetonitrile, 2-(4-(2-(1-(2-methylbutyryl)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)pent-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)piperidin-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.

3. Consumer product comprising one or more compounds of formula (Ic) as defined in any one of claims 1 to 2.

4. Use of a compound of formula (Ic) as defined in any one of claims 1 to 2 for the preparation of a composition for providing a cooling sensation.

5. A composition providing a cooling sensation, wherein the composition comprises a compound of formula (Ic) as defined in any one of claims 1 to 2.

6. A composition according to claim 5 comprising at least one compound of formula (Ic) or a salt thereof and a further cooling compound.

7. A composition according to claim 6, wherein the additional cooling compound is selected from menthol, menthone, p-menthanecarboxamide, N-2,3-trimethyl-2-isopropylbutyramide, menthyl lactate, menthone glycerol acetal, 3-(1-menthoxy)-propane-1,2-diol, p-menthane-3,8-diol, isopulegol, monomenthyl succinate, monomenthyl glutarate, o-menthylglycerol, N,N-dimethylsuccinamate menthyl, 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]dioxol-5-yl)-N,N-diphenylacrylamide, 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.

8. A non-medical method of modulating transient receptor potential channel melastatin member 8 agonist (TRPM8 agonist) comprising contacting said receptor with a compound of formula (Ic) as defined in any one of claims 1 to 2 or a salt thereof.

9. A non-medical method of inducing a cooling sensation in a human or animal, comprising contacting the human or animal with a compound of formula (Ic) or a salt thereof as defined in any one of claims 1 to 2.

10. A method of achieving a cooling effect on the skin or mucous membranes comprising contacting the skin or mucous membranes with a product comprising one or more compounds of formula (Ic) as defined in any one of claims 1 to 2.

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