Heterocyclic derivatives as TRMP8 antagonists

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 comprising 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 channels are widely distributed in different tissues (e.g. human skin and mucous membranes (e.g. oral, pharyngeal and nasal mucosa), male urogenital tract, lung epithelial cells and arterial myocytes). They are Ca 2+ Permeable, non-selective cation channel with a multimodal gating mechanism that is activated by innocuous cold to low temperatures, membrane depolarization, and molecules called cooling agents (including natural and synthetic compounds). The receptor was first described as a cold receptor in 2002 in a number of 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 to create associations with freshness and cleanliness. Cooling compounds are used in a wide variety of products, such as food, tobacco products, beverages, dentifrices, mouthwashes, toothpastes, and toiletries. The cooling sensation provided contributes to the attractiveness 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, cool, fresh sensation in the oral cavity.

[0006] A large number of compounds that provide a cooling sensation have been described. The best known natural compound is menthol, especially L-menthol. Of the synthetic compounds that provide a cooling sensation, many are derivatives of menthol or are structurally related to menthol and are derived with functional groups including carboxamides, ketals, esters, ethers and alcohols.

[0007] Applicants have surprisingly discovered a new class of compounds that differ significantly in structure from hitherto known TRPM8 modulators. It has surprisingly been found that this class of compounds, further 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, a method of modulating (in vitro and in vivo) transient receptor potential melastatin member 8 (TRPM8) is provided, the method comprising contacting the receptor with a compound of formula (I), or a salt or solvate thereof

[0010]

[0011] in

[0012] Ring A represents a phenyl ring, a cyclohexyl ring or a cyclohexenyl ring;

[0013] R 1 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl) and C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy, propoxy),

[0014] R 2 is connected to the 3, 4 or 5 position of ring A and is selected from hydrogen, halogen (such as F, Cl, Br, I), C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl, isopropyl), C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy) and C(O)OC 1 -C 3 -alkyl (e.g. C(O)OCH 3 ),

[0015] R 3 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C 2 -C 6 alkenyl (eg, vinyl), OH and =O, and R 4 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C 2 -C 6 alkenyl (e.g. vinyl) and OH, provided that R 3 and R 4 At least one of is hydrogen, or

[0016] R 3 and R 1 Together with the carbon atoms to which they are attached, they form a six-membered ring system (i.e., R 3 and R 1 The divalent residue -CH 2 -CH 2 -), and R 4For hydrogen,

[0017] R 5 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0018] R 6 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0019] m is 0 or 1,

[0020] p is 0 or 1,

[0021] W is selected from -CH 2 -, -O-, >C=O, -CH= and >NR 13 , where R 13 Selected from hydrogen and C 1 -C 3 Alkyl (e.g., methyl or isopropyl);

[0022] V is selected from >CH- and >N-,

[0023] Z is selected from -O-, >S=O, >CHR 12 、>NR 12 , where R 12 For hydrogen, C 1 -C 3 Alkyl, OH or CH 2 OH,

[0024] Y is attached to position 2 or 3 of ring A and is selected from C 4 -C 6 Alkyl (e.g. isobutyl),

[0025]

[0026] in

[0027] Ring B represents a phenyl, thiophene, furan or pyridine ring,

[0028] R 11 Selected from CN, halogen (such as F, Cl, Br, I), CH 2 CN、NO 2 NH 2 CF 3 、C(O)OC 2 H 5 , C 1 -C 3 Alkyl (such as methyl or ethyl), C 1 -C 3Alkoxy (e.g. methoxy or ethoxy), C 2 -C 3 alkenyl (e.g., vinyl or allyl) and OH, and n is an integer from 0 to 5 (including 1, 2, and 3), provided that if n>1, then R 11 can be the same or different, and

[0029] X is selected from -CH 2 -、-O-、>CH-CH 3 、>CH=CH 2 , >C=O and >CHOH.

[0030] According to a second 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.

[0031] In a third aspect, there is provided a consumer product, in particular a consumer product for contact with human skin and / or mucous membranes, comprising a compound defined by formula (I) or a salt or solvate thereof.

[0032] In a fourth 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 an additional cooling compound.

[0033] In a fifth aspect, there is provided a pharmaceutical composition comprising one or more compounds defined by formula (I) or a salt or solvate thereof.

[0034] In a sixth aspect, there is provided a compound of formula (I) or a salt or solvate thereof.

[0035] The details, embodiments and preferences provided in connection with any specific 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 specified 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.

[0036] Details

[0037] 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 are capable of activating TRPM8 ion channels, thereby leading to Ca 2+ The resulting electrical signals are ultimately perceived as a sensation of cold. Applicants have surprisingly discovered that the compounds described further herein can provide long-lasting cooling to human skin and / or mucous membranes at very low concentrations.

[0038] The compounds defined below by formula (I), which includes compounds of formula (Ia) and (Ib), are "TRPM8 agonists", which means that they have an effect on the cellular Ca2+ of the TRPM8 channel. 2+ Ion permeability has an agonistic effect. Thus, a "TRPM8 agonist" refers to any compound that, when in contact with a 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.

[0039] Thus, in a first 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

[0040]

[0041] in

[0042] Ring A represents a phenyl ring, a cyclohexyl ring or a cyclohexenyl ring;

[0043] R 1 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl) and C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy, propoxy),

[0044] R 2 is connected to the 3, 4 or 5 position of ring A and is selected from hydrogen, halogen (such as F, Cl, Br, I), C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl, isopropyl), C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy) and C(O)OC 1 -C 3 -alkyl (e.g. C(O)OCH 3 ),

[0045] R 3 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C 2 -C 6 alkenyl (eg, vinyl), OH and =O, and R 4 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C2 -C 6 alkenyl (e.g. vinyl) and OH, provided that R 3 and R 4 At least one of is hydrogen, or

[0046] R 3 and R 1 Together with the carbon atoms to which they are attached, they form a six-membered ring system (i.e., R 3 and R 1 The divalent residue -CH 2 -CH 2 -), and R 4 For hydrogen,

[0047] R 5 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0048] R 6 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0049] m is 0 or 1,

[0050] p is 0 or 1,

[0051] W is selected from -CH 2 -, -O-, >C=O, -CH= and >NR 13 , where R 13 Selected from hydrogen and C 1 -C 3 Alkyl (e.g., methyl or isopropyl);

[0052] V is selected from >CH- and >N-,

[0053] Z is selected from -O-, >S=O, >CHR 12 、>NR 12 , where R 12 For hydrogen, C 1 -C 3 Alkyl, OH or CH 2 OH,

[0054] Y is attached to position 2 or 3 of ring A and is selected from C 4 -C 6 Alkyl (e.g. isobutyl),

[0055]

[0056] in

[0057] Ring B represents a phenyl, thiophene, furan or pyridine ring,

[0058] R 11 Selected from CN, halogen (such as F, Cl, Br, I), CH 2 CN、NO 2 NH 2 CF 3 、C(O)OC 2 H 5 , C 1 -C 3 Alkyl (such as methyl or ethyl), C 1 -C 3 Alkoxy (e.g. methoxy or ethoxy), C 2 -C 3 alkenyl (e.g., vinyl or allyl) and OH, and n is an integer from 0 to 5 (including 1, 2, and 3), provided that if n>1, then R 11 can be the same or different, and

[0059] X is selected from -CH 2 -、-O-、>CH-CH 3 、>CH=CH 2 , >C=O and >CHOH.

[0060] Furthermore, non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein R 11 Selected from CN, halogen (such as F, Cl, Br, I), CH 2 CN、NO 2 NH 2 CF 3 and methyl.

[0061] Furthermore, non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein R 1 Selected from H and C 1 -C 3 Alkyl (including ethyl), and R 2 is selected from methyl, ethyl and halogen (eg Cl).

[0062] Furthermore, non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of them is hydrogen.

[0063] Furthermore, non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein R 1 Selected from H and C 1 -C3 Alkyl (including ethyl), R 2 is selected from methyl, ethyl and Cl, R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of them is hydrogen.

[0064] Furthermore, non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein R 5 and R 6 is selected from hydrogen and methyl, such as R 5 and R 6 At least one of them is hydrogen, or R 5 =R 6 For hydrogen.

[0065] Furthermore, non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein R 1 Selected from H and C 1 -C 3 Alkyl (including ethyl), R 2 is selected from methyl, ethyl and Cl, R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of is hydrogen, and R 5 and R 6 is selected from hydrogen and methyl, such as R 5 and R 6 At least one of them is hydrogen, or R 5 =R 6 For hydrogen.

[0066] Furthermore, non-limiting examples are compounds of formula (I), salts or solvates thereof, wherein X is selected from -CH 2 -and-O-.

[0067] In addition, non-limiting examples are compounds of formula (I), salts or solvates thereof, R 1 Selected from H and C 1 -C 3 Alkyl (including ethyl), R 2 is selected from methyl, ethyl and Cl, R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of them is hydrogen, R 5 and R 6 is selected from hydrogen and methyl, such as R 5 and R6 At least one of them is hydrogen, or R 5 =R 6 is hydrogen, and X is selected from -CH 2 -and-O-.

[0068] Non-limiting examples are compounds of formula (Ia), salts or solvates thereof,

[0069]

[0070] in

[0071] Ring A represents a phenyl ring, a cyclohexyl ring or a cyclohexenyl ring;

[0072] R 1 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl) and C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy, propoxy),

[0073] R 2 is selected from hydrogen, halogen (e.g. F, Cl, Br, I), C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl, isopropyl), C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy) and C(O)OC 1 -C 3 -alkyl (e.g. C(O)OCH 3 ),

[0074] R 3 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C 2 -C 6 alkenyl (eg, vinyl), OH and =O, and R 4 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C 2 -C 6 alkenyl (e.g. vinyl) and OH, provided that R 3 and R 4 At least one of is hydrogen, or

[0075] R 3 and R 1 Together with the carbon atoms to which they are attached, they form a six-membered ring system (i.e., R 3 and R 1 The divalent residue -CH 2-CH 2 -), and R 4 For hydrogen,

[0076] R 5 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0077] R 6 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0078] m is 0 or 1,

[0079] p is 0 or 1,

[0080] W is selected from -CH 2 -, -O-, >C=O, -CH= and >NR 13 , where R 13 Selected from hydrogen and C 1 -C 3 Alkyl (e.g., methyl or isopropyl);

[0081] V is selected from >CH- and >N-,

[0082] Z is selected from -O-, >S=O, >CHR 12 、>NR 12 , where R 12 For hydrogen, C 1 -C 3 Alkyl, OH,

[0083] Ring B represents a phenyl, thiophene, furan or pyridine ring,

[0084] R 11 Selected from CN, halogen (such as F, Cl, Br, I), CH 2 CN、NO 2 NH 2 CF 3 、C(O)OC 2 H 5 , C 1 -C 3 Alkyl (such as methyl or ethyl), C 1 -C 3 Alkoxy (e.g. methoxy or ethoxy), C 2 -C 3 alkenyl (e.g., vinyl or allyl) and OH, and n is an integer from 0 to 5 (including 1, 2, and 3), provided that if n>1, then R 11 can be the same or different, and

[0085] X is attached to the 2 or 3 position of ring A and is selected from -CH 2 -、-O-、>CH-CH 3 、>CH=CH 2 , >C=O and >CHOH.

[0086] Furthermore, non-limiting examples are compounds of formula (Ia), salts or solvates thereof, wherein R 11 Selected from CN, halogen (such as F, Cl, Br, I), CH 2 CN、NO 2 NH 2 CF 3 and methyl.

[0087] Furthermore, non-limiting examples are compounds of formula (Ia), salts or solvates thereof, wherein R 1 Selected from H and C 1 -C 3 Alkyl (including ethyl), and R 2 is selected from methyl, ethyl and halogen (eg Cl).

[0088] Furthermore, non-limiting examples are compounds of formula (Ia), salts or solvates thereof, wherein R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of them is hydrogen.

[0089] Furthermore, non-limiting examples are compounds of formula (Ia), salts or solvates thereof, wherein R 1 Selected from H and C 1 -C 3 Alkyl (including ethyl), R 2 is selected from methyl, ethyl and Cl, R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of them is hydrogen.

[0090] Furthermore, non-limiting examples are compounds of formula (Ia), salts or solvates thereof, wherein R 5 and R 6 is selected from hydrogen and methyl, such as R 5 and R 6 At least one of them is hydrogen, or R 5 =R 6 For hydrogen.

[0091] Furthermore, non-limiting examples are compounds of formula (Ia), salts or solvates thereof, wherein R 1Selected from H and C 1 -C 3 Alkyl (including ethyl), R 2 is selected from methyl, ethyl and Cl, R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of is hydrogen, and R 5 and R 6 is selected from hydrogen and methyl, such as R 5 and R 6 At least one of them is hydrogen, or R 5 =R 6 For hydrogen.

[0092] Furthermore, non-limiting examples are compounds of formula (Ia), salts or solvates thereof, wherein X is selected from -CH 2 -and-O-.

[0093] In addition, non-limiting examples are compounds of formula (Ia), salts or solvates thereof, R 1 Selected from H and C 1 -C 3 Alkyl (including ethyl), R 2 is selected from methyl, ethyl and Cl, R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of them is hydrogen, R 5 and R 6 is selected from hydrogen and methyl, such as R 5 and R 6 At least one of them is hydrogen, or R 5 =R 6 is hydrogen, and X is selected from -CH 2 -and-O-.

[0094] Furthermore, non-limiting examples are compounds of formula (Ib), salts or solvates thereof.

[0095]

[0096] in

[0097] R 1 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl) and C 1 -C 6 Alkoxy (e.g. methoxy),

[0098] R2 is selected from hydrogen, halogen (e.g. F, Cl, Br, I), C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl), C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy) and C(O)OC 1 -C 3 -alkyl (e.g. C(O)OCH 3 ),

[0099] R 3 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl), C 2 -C 6 alkenyl (eg, vinyl), OH and =O, and R 4 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl), C 2 -C 6 alkenyl (e.g. vinyl) and OH, provided that R 3 and R 4 At least one of is hydrogen, or

[0100] R 3 and R 1 Together with the carbon atoms to which they are attached, they form a six-membered ring system (i.e., R 3 and R 1 The divalent residue -CH 2 -CH 2 -), and R 4 For hydrogen,

[0101] R 5 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl),

[0102] R 6 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl),

[0103] m is 0 or 1,

[0104] p is 0 or 1,

[0105] W is selected from -CH 2 -, -O-, >C=O, -CH= and >NR 13 , where R 13 Selected from hydrogen and C 1 -C 3Alkyl (e.g., methyl or isopropyl);

[0106] V is selected from >CH- and >N-,

[0107] Z is selected from -O-, >S=O, >CHR 12 、>NR 12 , where R 12 For hydrogen, C 1 -C 3 Alkyl, OH or CH 2 OH,

[0108] R 11 Selected from CN, halogen (such as F, Cl, Br, I), CH 2 CN、NO 2 NH 2 CF 3 、C(O)OC 2 H 5 , C 1 -C 3 Alkyl (such as methyl or ethyl), C 1 -C 3 Alkoxy (e.g. methoxy or ethoxy), C 2 -C 3 alkenyl (e.g., vinyl or allyl) and OH, and n is an integer from 0 to 5 (including 1, 2, and 3), provided that if n>1, then R 11 can be the same or different, and

[0109] X is selected from -CH 2 -、-O-、>CH-CH 3 、>CH=CH 2 , >C=O and >CHOH.

[0110] Furthermore, non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein R 11 Selected from CN, halogen (such as F, Cl, Br, I), CH 2 CN、NO 2 NH 2 CF 3 and methyl.

[0111] Furthermore, non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein R 1 Selected from H and C 1 -C 3 Alkyl (including ethyl), and R 2 is selected from methyl, ethyl and halogen (eg Cl).

[0112] Furthermore, non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of them is hydrogen.

[0113] Furthermore, non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein R 1 Selected from H and C 1 -C 3 Alkyl (including ethyl), R 2 is selected from methyl, ethyl and Cl, R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of them is hydrogen.

[0114] Furthermore, non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein R 5 and R 6 is selected from hydrogen and methyl, such as R 5 and R 6 At least one of them is hydrogen, or R 5 =R 6 For hydrogen.

[0115] Furthermore, non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein R 1 Selected from H and C 1 -C 3 Alkyl (including ethyl), R 2 is selected from methyl, ethyl and Cl, R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of is hydrogen, and R 5 and R 6 is selected from hydrogen and methyl, such as R 5 and R 6 At least one of them is hydrogen, or R 5 =R 6 For hydrogen.

[0116] Furthermore, non-limiting examples are compounds of formula (Ib), salts or solvates thereof, wherein X is selected from -CH 2 -and-O-.

[0117] In addition, non-limiting examples are compounds of formula (Ib), salts or solvates thereof, R 1Selected from H and C 1 -C 3 Alkyl (including ethyl), R 2 is selected from methyl, ethyl and Cl, R 3 is selected from H, methyl, -OH and =O, and R 4 is selected from hydrogen and methyl, provided that R 3 and R 4 At least one of them is hydrogen, R 5 and R 6 is selected from hydrogen and methyl, such as R 5 and R 6 At least one of them is hydrogen, or R 5 =R 6 is hydrogen, and X is selected from -CH 2 -and-O-.

[0118] Further non-limiting examples are compounds of formula (I), (Ia) or (Ib) selected from

[0119] (1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperidin-4-yl)methanol,

[0120] (5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)(phenyl)methanol,

[0121] (5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)(phenyl)methanone,

[0122] (E)-1-(2-((6-benzylidene-2,4-dimethylcyclohex-1-en-1-yl)oxy)ethyl)-4-methylpiperazine,

[0123] (E)-1-(3-(2-benzyl-4-methylphenyl)allyl)-4-methylpiperazine,

[0124] 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine,

[0125] (E)-2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)cyclohexan-1-one,

[0126] (E)-2-(5-methyl-2-(2-morpholinoethoxy)benzylidene)cyclohexan-1-one,

[0127] 2-(3,5-dimethyl-2-(2-morpholinopropoxy)benzyl)benzonitrile,

[0128] 2-(3,5-dimethyl-2-((1-morpholinoprop-2-yl)oxy)benzyl)benzonitrile,

[0129] 1-((8-Benzylchroman-2-yl)methyl)-4-methylpiperazine,

[0130] 1-(2-((2-benzyl-4-methylcyclohexyl)oxy)ethyl)-4-methylpiperazine,

[0131] 1-(2-((2-benzyl-4-methylcyclohexyl)oxy)ethyl)-4-methylpiperazine dihydrochloride,

[0132] 1-(2-(2-((5-chlorothien-2-yl)methyl)-4-methylphenoxy)ethyl)-4-methylpiperazine,

[0133] 1-(2-(2-(2-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine,

[0134] 1-(2-(2-(2-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine,

[0135] 1-(2-(2-(2-fluorobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine,

[0136] 1-(2-(2-(2-iodobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine,

[0137] 1-(2-(2-(3-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine,

[0138] 1-(2-(2-(3-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine,

[0139] 1-(2-(2-(4-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride,

[0140] 1-(2-(2-(Furan-2-ylmethyl)-4-methylphenoxy)ethyl)-4-methylpiperazine,

[0141] 1-(2-(2,4-dimethyl-6-(2-(trifluoromethyl)benzyl)phenoxy)ethyl)-4-methylpiperazine,

[0142] 1-(2-(2,4-dimethyl-6-(pyridin-2-ylmethyl)phenoxy)ethyl)-4-methylpiperazine,

[0143] 1-(2-(2,4-dimethyl-6-(pyridin-3-ylmethyl)phenoxy)ethyl)-4-methylpiperazine,

[0144] 1-(2-(2,4-dimethyl-6-(pyridin-4-ylmethyl)phenoxy)ethyl)-4-methylpiperazine,

[0145] 1-(2-(2-benzyl-3,6-dimethylphenoxy)ethyl)-4-methylpiperazine,

[0146] 1-(2-(2-benzyl-3-methoxyphenoxy)ethyl)-4-methylpiperazine,

[0147] 1-(2-(2-benzyl-3-methylphenoxy)ethyl)-4-methylpiperazine,

[0148] 1-(2-(2-benzyl-4-(tert-butyl)-6-methoxyphenoxy)ethyl)-4-methylpiperazine,

[0149] 1-(2-(2-benzyl-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine,

[0150] 1-(2-(2-benzyl-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine dihydrochloride,

[0151] 1-(2-(2-benzyl-4-chlorophenoxy)ethyl)-4-ethylpiperazine hydrochloride,

[0152] 1-(2-(2-benzyl-4-chlorophenoxy)ethyl)-4-methylpiperazine hydrochloride,

[0153] 1-(2-(2-benzyl-4-ethylphenoxy)ethyl)-4-methylpiperazine hydrochloride,

[0154] 1-(2-(2-benzyl-4-isopropylphenoxy)ethyl)-4-methylpiperazine,

[0155] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-ethylpiperazine hydrochloride,

[0156] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine,

[0157] 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine 2,3-dihydroxysuccinate,

[0158] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine 2-hydroxypropane-1,2,3-tricarboxylate,

[0159] 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2,2,2-trifluoroacetate),

[0160] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2-hydroxysuccinate),

[0161] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(phosphate),

[0162] 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimaleate,

[0163] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimethanesulfonate,

[0164] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride,

[0165] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine oxalate,

[0166] 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine sulfate,

[0167] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperazine,

[0168] 1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperidin-4-ol,

[0169] 1-(2-(2-benzyl-4-methylphenoxy)propyl)-4-methylpiperazine,

[0170] 1-(2-(2-benzyl-4-methylphenoxy)propyl)-4-methylpiperazine hydrochloride,

[0171] 1-(2-(2-benzyl-6-methylphenoxy)ethyl)-4-methylpiperazine,

[0172] 1-(2-(2-Benzylphenoxy)ethyl)-4-methylpiperazine hydrochloride,

[0173] 1-(2-(2-isobutyl-4-methylphenoxy)ethyl)-4-methylpiperazine,

[0174] 1-(2-(2-isobutyl-4-methylphenoxy)ethyl)-4-methylpiperazine dihydrochloride,

[0175] 1-(2-Benzyl-4-methylphenethyl)-4-methylpiperazine,

[0176] 1-(2-Benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-ol,

[0177] 1-(2-Benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-one,

[0178] 1-(3-(2-Benzyl-4-methylphenoxy)propyl)-4-methylpiperazine hydrochloride,

[0179] 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine,

[0180] 1-methyl-4-(2-(4-methyl-2-(1-phenylethyl)phenoxy)ethyl)piperazine,

[0181] 1-methyl-4-(2-(4-methyl-2-(1-phenylvinyl)phenoxy)ethyl)piperazine,

[0182] 1-methyl-4-(2-(4-methyl-2-(2-methylbenzyl)phenoxy)ethyl)piperazine,

[0183] 1-methyl-4-(2-(4-methyl-2-(3-methylbenzyl)phenoxy)ethyl)piperazine,

[0184] 1-Methyl-4-(2-(4-methyl-2-(thiophen-2-ylmethyl)phenoxy)ethyl)piperazine hydrochloride,

[0185] 2-(2-((1-hydroxyprop-2-yl)oxy)-3,5-dimethylbenzyl)benzonitrile,

[0186] 2-(2-(2-hydroxy-3-morpholinopropyl)-5-methylphenoxy)benzonitrile,

[0187] 2-(2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)phenyl)acetonitrile,

[0188] 2-(2,4-dimethyl-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile,

[0189] 2-(2,6-difluorobenzyl)-4-methyl-N-(2-morpholinoethyl)aniline,

[0190] 2-(2,6-difluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline,

[0191] 2-(2,6-difluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline,

[0192] 2-(2-Fluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline,

[0193] 2-(2-Fluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline,

[0194] 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile,

[0195] 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile hydrochloride,

[0196] 2-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile,

[0197] 2-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile hydrochloride,

[0198] 2-(3,5-dimethyl-2-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)benzyl)benzonitrile,

[0199] 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)-3-fluorobenzonitrile,

[0200] 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)aniline,

[0201] 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile,

[0202] 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile hydrochloride,

[0203] 2-(3,5-dimethyl-2-(3-morpholinopropoxy)benzyl)benzonitrile,

[0204] 2-(3,5-dimethyl-2-(3-morpholinopropyl)phenoxy)benzonitrile,

[0205] 2-(3,5-dimethyl-2-(methyl(2-morpholinoethyl)amino)benzyl)benzonitrile,

[0206] 2-(4-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile,

[0207] 2-(5-methyl-2-(2-(1-methylpiperidin-4-yl)ethoxy)benzyl)benzonitrile,

[0208] 2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile,

[0209] 2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile dihydrochloride,

[0210] 2-(5-methyl-2-(2-morpholinoethoxy)benzyl)cyclohexan-1-one,

[0211] 2-(5-methyl-2-(2-morpholinopropoxy)benzyl)benzonitrile,

[0212] 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile,

[0213] 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile hydrochloride,

[0214] 2-Benzyl-4-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline,

[0215] 2-Benzyl-4-methylphenyl 2-(4-methylpiperazin-1-yl)acetate,

[0216] 2-Benzyl-N,4-dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline,

[0217] 2-Benzyl-N,4-dimethyl-N-(2-morpholinoethyl)aniline,

[0218] 3-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile dihydrochloride,

[0219] 3-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)aniline,

[0220] 3-Bromo-2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile,

[0221] 3-Chloro-2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile,

[0222] 4-(1-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)prop-2-yl)morpholine,

[0223] 4-(2-(2-(1-(2-fluorophenyl)ethyl)-4,6-dimethylphenoxy)ethyl)morpholine,

[0224] 4-(2-(2-(1-(2-fluorophenyl)vinyl)-4,6-dimethylphenoxy)ethyl)morpholine,

[0225] 4-(2-(2-(2,4-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine,

[0226] 4-(2-(2-(2,5-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine,

[0227] 4-(2-(2-(2,6-dichlorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine,

[0228] 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine,

[0229] 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)propyl)morpholine,

[0230] 4-(2-(2-(2,6-difluorobenzyl)-4-methylphenoxy)ethyl)morpholine,

[0231] 4-(2-(2-(2-chlorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine,

[0232] 4-(2-(2-(2-fluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine,

[0233] 4-(2-(2-(3,5-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine,

[0234] 4-(2-(2,4-dimethyl-5-((perfluorophenyl)methyl)phenoxy)ethyl)morpholine,

[0235] 4-(2-(2,4-dimethyl-6-(2,4,5-trifluorobenzyl)phenoxy)ethyl)morpholine,

[0236] 4-(2-(2,4-dimethyl-6-(2-nitrobenzyl)phenoxy)ethyl)morpholine,

[0237] 4-(2-(2-benzyl-4-methylphenoxy)ethyl)-1,2,6-trimethylpiperazine,

[0238] 4-(2-(2-benzyl-4-methylphenoxy)ethyl)morpholine hydrochloride,

[0239] 4-(2-(2-benzyl-4-methylphenoxy)ethyl)thiomorpholine 1-oxide,

[0240] 4-(2-(2-ethyl-6-(2-fluorobenzyl)-4-methylphenoxy)ethyl)morpholine,

[0241] 4-(3-(2-(2-fluorophenoxy)-4,6-dimethylphenyl)propyl)morpholine,

[0242] 4-methyl-2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)phenol,

[0243] 4-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzoic acid ethyl ester dihydrochloride, and

[0244] Methyl 3-benzyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate.

[0245] Compounds defined by formula (I), which include compounds of formula (Ia) and (Ib), contain several chiral centers and may therefore exist as mixtures of stereoisomers, or they may be resolved into isomerically pure forms. Resolving stereoisomers increases the complexity of the manufacture and purification of these compounds, and it is only for economic reasons that these compounds are preferably used in the form of 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. Therefore, the chemical structures described herein include all possible stereoisomers and tautomeric forms of the compounds shown.

[0246] It should be noted that some compounds defined by formula (I) (including compounds of formula (Ia) and (IB)) are liquids and can therefore be used alone or in combination with other well-known solvents to dissolve other compounds, such as cooling compounds (some of which are described below, such as those cooling compounds described in the applicant's international patent applications PCT / EP2020 / 079009 and PCT / EP2020 / 083453, N-(4-(cyanomethyl)phenyl)-2- Isopropyl-5-methylcyclohexane-1-carboxamide, 2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexane-1-carboxamide, 3-(benzo[d][1,3]dioxol-5-yl)-N,N-diphenylacrylamide and N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide. This is particularly preferred because the handling of liquids (including solutions) facilitates metering and / or mixing of the compounds.

[0247] It should also be noted that the compounds defined by formula (I), which include compounds of formula (Ia) and (Ib), can exist in unsolvated forms as well as solvated forms (including hydrated forms), and as N-oxides. In general, the compounds can be hydrated, solvated or N-oxides. Certain compounds can exist in multiple 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.

[0248] "Solvate" refers to a compound formed by solvation (combination of solvent molecules with molecules or ions of a solute), or an aggregate consisting of solute ions or molecules, i.e., compounds defined by formula (I) (which include compounds of formula (Ia) and (Ib)) and one or more solvent molecules. When water is the solvent, the corresponding solvate is a "hydrate". Other suitable solvents may be, but are not limited to, acetone, acetonitrile, benzene, cyclohexane, dihydrolevoglucosenone, methyl-tetrahydrofuran, pentanediol, ethylene glycol, petroleum ether, ethyl lactate, methyl lactate, propyl lactate, butyl lactate, diethyl ether, tert-butyl methyl ether, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, ethanol, ethyl acetate, ethylene glycol, diethylene glycol, p-menthane (1-isopropyl-4-methylcyclohexane), propylene glycol, heptane, hexane, methanol, toluene and xylene.

[0249] "Salt" refers to a salt of a compound defined by formula (I) (which includes compounds of formula (Ia) and (Ib)) that has 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 acid proton with a metal ion, such as an alkali metal ion, an alkaline earth ion or an aluminum ion; or (2) when the acid 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 acid proton is coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.

[0250] In a second 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) and (Ib)) or a salt or solvate thereof.

[0251] 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) (which includes compounds of formula (Ia) and (Ib)) or a salt or solvate thereof.

[0252] The compound of formula (I) (including the compound of formula (Ia) and (Ib)) can be directly administered or administered as a solution or suspension, which contains an effective amount of the compound of formula (I). The effective amount depends, among other things, on the target TRPM8 area of ​​the human body and also on the cooling effect of the compound or compound mixture.

[0253] In a third aspect, there is provided a consumer product comprising a compound defined by formula (I), which includes compounds of formula (Ia) and (Ib), particularly a consumer product for contact with human skin and / or mucous membranes.

[0254] 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, sexual health and intimate care products.

[0255] In certain embodiments, the dental care product is an oral care product, a tooth care product, a denture cleanser, a denture adhesive, and the like.

[0256] 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.

[0257] In certain embodiments, the tobacco substitute product is a liquid or solid suitable for electronic consumption, such as a liquid for an electronic cigarette.

[0258] In certain embodiments, personal care products that contact mucous membranes are lip balms, nasal sprays, and eye drops.

[0259] Consumer products that come into contact with human skin include, but are not limited to, cosmetics. In certain embodiments, cosmetics are skin care products, especially bath products, skin washing and cleaning products, skin care products, eye makeup, nail care products, foot care products, etc. In certain embodiments, cosmetics are products with special effects, especially sunscreens, insect repellents, tanning products, pigment removal products, deodorants, antiperspirants, depilatories, and shaving products. In certain embodiments, cosmetics are hair care products, especially shampoos, hair care products, hair styling products, hair styling products, hair products, and hair dyeing products, as well as scalp care products, such as scalp cooling shampoos and lotions.

[0260] 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 a suitable consumer product depends largely on the specific role that this consumer product should meet, such as cleaning, softening, care, cooling, etc.

[0261] 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.

[0262] The use level of the compounds of the present invention (compounds defined by formula (I), including compounds of formula (Ia) and (Ib)) 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 may be about 0.00001% (0.01 ppm) to about 0.1% (1000 ppm) by weight of the composition; about 0.00005% (0.5 ppm) to about 0.1% (1000 ppm); about 0.0001% (1 ppm) to about 0.05% (500 ppm); or about 0.001% (10 ppm) to about 0.01% (100 ppm). When the compounds of the present invention are used in mouthwashes, use 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, such as 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.

[0263] The cooling effect (strength) of a compound is determined by its EC 50 Value definition. EC 50 (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. EC 50 It is a measure of concentration expressed in μM (μmolar) units, where 1 μM is equivalent to 1 μmol / L.

[0264] EC 50 Compounds at 10 μM or less are perceived by humans as cooling. 50 The lower the value, the higher the cooling effect. For example, EC 50 Compounds with values ​​of about 0.1 μM are considered to be strong cooling compounds.

[0265] However, the cooling properties of a compound depend not only on its intensity (potency; EC50), but also on 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.

[0266] The compounds of formula (I), which include compounds of formula (Ia) and (Ib), are very effective at relatively low concentrations. Therefore, it is preferred to prepare a stock solution which is further diluted before mixing with the consumer product. In addition to water, particularly suitable solvents are triacetin and propylene glycol. However, other solvent systems comprising surfactants may also be used.

[0267] In order to improve the cooling effect of the compounds as defined herein by formula (I), which includes compounds of formula (la) and (lb), 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.

[0268] 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 a change in the perceived cooling effect.

[0269] According to Kizilbash et al. (WO2019 / 121193A1), when combined with an agent having the property of enhancing the effect, both the cooling intensity and the flavor intensity can be enhanced. Therefore, the compound defined by formula (I) herein can be combined with an enhancer disclosed in WO2019 / 121193 in a specific embodiment, and WO2019 / 121193 is incorporated by reference, especially with regard to the content of synergists.

[0270] The compounds of formula (I), which include compounds of formula (Ia) and (Ib), may be used in combination with other cooling compounds known in the art.

[0271] Thus, in a fourth 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.

[0272] In a specific embodiment, the compounds of formula (I) (which includes compounds of formula (Ia) and (Ib)) can be combined with menthol (e.g., in the form of peppermint oil), menthone, p-menthane carboxamide, 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 Coolact 38D), isopulegol (known as Coolact P), monomenthyl succinate Menthyl glutarate, o-menthylglycerol, N,N-dimethyl succinamate menthyl, 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. Other cooling compounds that can be combined with the compounds of formula (I) are those described in the applicant's international patent applications PCT / EP2020 / 079009 and PCT / EP2020 / 083453.

[0273] 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.

[0274] In order to achieve more than just a cooling effect, the compounds of formula (I) (which includes compounds of formula (Ia) and (Ib)), their salts or solvates may be combined with other active substances, such as flavors, fragrances and sweeteners.

[0275] Examples of flavor ingredients include natural flavors, artificial flavors, spices, seasonings, etc. Exemplary flavor ingredients include synthetic flavor oils and flavoring aromatics and / or oils, oleoresins, essential oils and distillates and combinations comprising at least one of the foregoing.

[0276] 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, oil of bitter almonds, and cassia bark oil. 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.

[0277] 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, perilla flavor essence, such as juniper berry essence, ginger essence, star anise essence, horseradish essence, thyme essence, tarragon essence, dill essence, pepper essence, nutmeg essence, basil essence, parsley essence, marjoram essence, rosemary essence, bay leaf essence and wasabi (Japanese horseradish) essence; 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.

[0278] Generally any flavor or food additive (including food coloring) may be used, such as those described in "Essential guide to food additives" provided by Leatherhead Food International Ltd., third edition 2008, pages 101-321 (ISBN: 978-1-905224-50-0), which publication is incorporated herein by reference.

[0279] In a specific embodiment, the compound of formula (I) (including the compound of formula (Ia) and (Ib)) can be combined with anethole, levomenthol, levocarvone, ethyl maltol, vanillin, eucalyptol, eugenol, racemic menthol, cis-3-hexenol, linalool, peppermint oil (e.g., peppermint arvensis oil), peppermint piperita oil, oil), spearmint natural oil, spearmint Scotch oil), methyl cyclopentenolone (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, ethyl ionone, 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.

[0280] 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, hesperidin dihydrochalcone glycosides, naringin dihydrochalcone, mogroside V, monk fruit extract, sweet leaf 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 E Neoastilbin, 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 an amount below their sweetness detection threshold.

[0281] In certain embodiments, the compounds of Formula (I) may be combined with additional ingredients that together involve an orally acceptable carrier material.

[0282] In some aspects, the orally acceptable carrier may 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 may include 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 substantially 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, flavoring agents 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. Pat. Nos. 5,213,790; 5,145,666 and 5,281,410, all to Lukacovic et al., and U.S. Pat. Nos. 4,849,213 and 4,528,180 to Schaeffer. Mouthwash, rinse or mouth spray carrier materials typically include water, flavoring and sweeteners, etc., as disclosed, for example, in U.S. Pat. No. 3,988,433 to Benedict. Lozenge carrier materials typically include candy bases; chewing gum carrier materials include gum base, flavoring and sweeteners, as disclosed, for example, in U.S. Pat. No. 4,083,955 to Grabenstetter et al. Pouch carrier materials typically include a pouch, flavoring and sweeteners. For subgingival gels used to deliver active substances into or around periodontal pockets, a "subgingival gel carrier" is selected, as described, for example, in U.S. Pat. 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, among others.

[0283] Other suitable types of orally acceptable carrier materials or excipients are listed in WO 2010 / 059289, in particular pages 17-31, which are incorporated by reference.

[0284] Scientific literature indicates that activation of TRPM8 channels may help treat most TRPM8-mediated pathological symptoms (J. Med. Chem. 2016, 59 (22), 10006-10029). Therefore, it can be envisioned that compounds of formula (I) may also be suitable for treating prostate cancer, bladder weakness, inflammation or pain, including contacting patients with one or more compounds of formula (I) as defined herein. It can also be envisioned that compounds of formula (I) as defined herein are suitable for relieving symptoms of cough and cold, irritation, sore throat or hoarseness, and treating dysphagia in the throat (Int. J. Mol. Sci. 2018, 19, 4113).

[0285] Thus, in a fifth aspect there is provided a pharmaceutical composition comprising one or more compounds defined by formula (I) (which includes compounds of formula (Ia) and (Ib)) or a salt or solvate thereof.

[0286] 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 preparations.

[0287] In certain embodiments, the pharmaceutical composition is a nasal spray, a topical cream, a skin spray, a throat spray, or eye drops.

[0288] While some of the compounds falling within the definition of formula (I) above are known per se, other compounds are novel.

[0289] Therefore, in a sixth aspect of the present invention there is provided a compound of formula (I), a salt or a solvate thereof

[0290]

[0291] in

[0292] Ring A represents a phenyl ring, a cyclohexyl ring or a cyclohexenyl ring;

[0293] R 1 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl) and C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy, propoxy),

[0294] R 2 connected to the 3, 4 or 5 position of ring A and selected from C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl, isopropyl), C 1 -C 6Alkoxy (e.g. methoxy, ethoxy) and C(O)OC 1 -C 3 -alkyl (e.g. C(O)OCH 3 ),

[0295] R 3 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C 2 -C 6 alkenyl (eg, vinyl), OH and =O, and R 4 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C 2 -C 6 alkenyl (e.g. vinyl) and OH, provided that R 3 and R 4 At least one of is hydrogen, or

[0296] R 3 and R 1 Together with the carbon atoms to which they are attached, they form a six-membered ring system (i.e., R 3 and R 1 The divalent residue -CH 2 -CH 2 -), and R 4 For hydrogen,

[0297] R 5 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0298] R 6 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0299] m is 0,

[0300] p is 1,

[0301] W is selected from -CH 2 -, -O-, >C=O, -CH= and >NR 13 , where R 13 Selected from hydrogen and C 1 -C 3 Alkyl (e.g., methyl or isopropyl);

[0302] V is selected from >CH- and >N-,

[0303] Z is selected from -O-, >S=O, >CHR 12 、>NR12 , where R 12 For hydrogen, C 1 -C 3 Alkyl, OH or CH 2 OH,

[0304] Y is attached to position 2 or 3 of ring A and is selected from C 4 -C 6 Alkyl (e.g. isobutyl),

[0305]

[0306] in

[0307] Ring B represents a phenyl, thiophene, furan or pyridine ring,

[0308] R 11 Selected from CN, halogen, CH 2 CN、NO 2 NH 2 CF 3 、C(O)OC 2 H 5 , C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 2 -C 3 alkenyl and OH, and n is an integer from 0 to 5, provided that if n>1, then R 11 Can be the same or different,

[0309] X is selected from -CH 2 -、-O-、>CH-CH 3 、>CH=CH 2 , >C=O and >CHOH,

[0310] with the proviso that the compound of formula (I) is not 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine.

[0311] Furthermore, non-limiting examples are compounds of formula (I) wherein Y is attached to the 2 position and R 2 Connect to 4-bit.

[0312] Furthermore, non-limiting examples are compounds of formula (Ia), salts or solvates thereof,

[0313]

[0314] in

[0315] Ring A represents a phenyl ring, a cyclohexyl ring or a cyclohexenyl ring;

[0316] R1 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl) and C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy, propoxy),

[0317] R 2 Selected from C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl, isopropyl), C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy) and C(O)OC 1 -C 3 -alkyl (e.g. C(O)OCH 3 ),

[0318] R 3 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C 2 -C 6 alkenyl (eg, vinyl), OH and =O, and R 4 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl), C 2 -C 6 alkenyl (e.g. vinyl) and OH, provided that R 3 and R 4 At least one of is hydrogen, or

[0319] R 3 and R 1 Together with the carbon atoms to which they are attached, they form a six-membered ring system (i.e., R 3 and R 1 The divalent residue -CH 2 -CH 2 -), and R 4 For hydrogen,

[0320] R 5 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0321] R 6 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl, isobutyl),

[0322] m is 0,

[0323] p is 1,

[0324] W is selected from -CH 2 -, -O-, >C=O, -CH= and >NR 13 , where R 13 Selected from hydrogen and C 1 -C 3 Alkyl (e.g., methyl or isopropyl);

[0325] V is selected from >CH- and >N-,

[0326] Z is selected from -O-, >S=O, >CHR 12 、>NR 12 , where R 12 For hydrogen, C 1 -C 3 Alkyl, OH,

[0327] Ring B represents a phenyl, thiophene, furan or pyridine ring,

[0328] R 11 Selected from CN, halogen (such as F, Cl, Br, I), CH 2 CN、NO 2 NH 2 CF 3 、C(O)OC 2 H 5 , C 1 -C 3 Alkyl (such as methyl or ethyl), C 1 -C 3 Alkoxy (e.g. methoxy or ethoxy), C 2 -C 3 alkenyl (e.g., vinyl or allyl) and OH, and n is an integer from 0 to 5 (including 1, 2, and 3), provided that if n>1, then R 11 can be the same or different, and

[0329] X is attached to the 2 or 3 position of ring A and is selected from -CH 2 -、-O-、>CH-CH 3 、>CH=CH 2 , >C=O and >CHOH,

[0330] with the proviso that the compound of formula (I) is not 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine.

[0331] Furthermore, a non-limiting example is a compound of formula (Ia) wherein X is attached to the 2-position of ring A.

[0332] Furthermore, non-limiting examples are compounds of formula (Ib), salts or solvates thereof,

[0333]

[0334] in

[0335] R 1 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl) and C 1 -C 6 Alkoxy (e.g. methoxy),

[0336] R 2 Selected from C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl, isobutyl), C 1 -C 6 Alkoxy (e.g. methoxy, ethoxy) and C(O)OC 1 -C 3 -alkyl (e.g. C(O)OCH 3 ),

[0337] R 3 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl), C 2 -C 6 alkenyl (eg, vinyl), OH and =O, and R 4 Selected from hydrogen, C 1 -C 6 Alkyl (e.g. methyl, ethyl, isopropyl), C 2 -C 6 alkenyl (e.g. vinyl) and OH, provided that R 3 and R 4 At least one of is hydrogen, or

[0338] R 3 and R 1 Together with the carbon atoms to which they are attached, they form a six-membered ring system (i.e., R 3 and R 1 The divalent residue -CH 2 -CH 2 -), and R 4 For hydrogen,

[0339] R 5 Selected from hydrogen, F and C 1 -C 6 Alkyl (e.g. methyl, ethyl),

[0340] R 6 Selected from hydrogen, F and C 1 -C 6Alkyl (e.g. methyl, ethyl),

[0341] m is 0,

[0342] p is 1,

[0343] W is selected from -CH 2 -, -O-, >C=O, -CH= and >NR 13 , where R 13 Selected from hydrogen and C 1 -C 3 Alkyl (e.g., methyl or isopropyl);

[0344] V is selected from >CH- and >N-,

[0345] Z is selected from -O-, >S=O, >CHR 12 、>NR 12 , where R 12 For hydrogen, C 1 -C 3 Alkyl, OH or CH 2 OH,

[0346] R 11 Selected from CN, halogen (such as F, Cl, Br, I), CH 2 CN、NO 2 NH 2 CF 3 、C(O)OC 2 H 5 , C 1 -C 3 Alkyl (such as methyl or ethyl), C 1 -C 3 Alkoxy (e.g. methoxy or ethoxy), C 2 -C 3 alkenyl (e.g., vinyl or allyl) and OH, and n is an integer from 0 to 5 (including 1, 2, and 3), provided that if n>1, then R 11 can be the same or different, and

[0347] X is selected from -CH 2 -、-O-、>CH-CH 3 、>CH=CH 2 , >C=O and >CHOH,

[0348] with the proviso that the compound of formula (Ib) is not 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine.

[0349] The compounds of formula (I) are compounds known per se or can be prepared by a person skilled in the art using known synthesis methods.

[0350] Where W is NR 13 (R 13 C 1 -C 3 The compound of formula (I) wherein W is NH (alkyl) can be prepared by reacting the compound of formula (I) wherein W is NH with a suitable carbonyl compound such as formaldehyde (e.g. paraformaldehyde or formalin), acetone, acetaldehyde or propionaldehyde under the action of a reducing agent (e.g. sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride) in a suitable solvent (e.g. acetic acid, THF, ethanol) at a suitable temperature (25°C, 40°C).

[0351] Compounds of formula (I) can generally be prepared by reacting a suitable carbonyl compound 2 (e.g., an aldehyde, ketone, or carboxylic acid) with an amine 3 in the presence of a reducing agent (e.g., sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, formic acid, or hydrogen in the presence of a homogeneous or heterogeneous metal catalyst such as a palladium catalyst or a ruthenium catalyst). The reaction can be carried out in a single step or in two operations, wherein the amine 3 is first reacted with the carbonyl 2 and then subjected to the reducing agent. The reaction is carried out in a suitable solvent such as, but not limited to, tetrahydrofuran (THF), dichloromethane (DCM), acetic acid, toluene, water, ethanol, or in the absence of a solvent, and may benefit from the presence of a base such as an amine base (e.g., triethylamine, pyridine, or diisopropylethylamine (DIPEA)) or an inorganic base (e.g., sodium hydroxide or potassium carbonate). The reaction is carried out at a suitable temperature (e.g., 0°C, 25°C, 80°C, or 120°C), which may vary depending on the protocol used (i.e., if the reaction is carried out in a single operation or involves the isolation of an intermediate formed by the reaction between 2 and 3). In some cases, for example when R 4 When OH, it may be necessary to activate 2 by reacting 2 with an activating agent such as thionyl chloride or oxalyl chloride (optionally in the presence of catalytic N,N-dimethylformamide) in a suitable solvent such as dichloromethane or neat at a suitable temperature (e.g., 0° C., 24° C., or 70° C.). The resulting intermediate can then be reacted with amine 3 as described above.

[0352]

[0353] Compounds of formula (I) can also be prepared by reacting amine 3 with halide 4, optionally in the presence of a base such as an amine base (e.g., triethylamine, pyridine or diisopropylethylamine (DIPEA)) or an inorganic base (e.g., sodium hydride, sodium hydroxide, potassium carbonate or potassium phosphate). The reaction is carried out in a suitable solvent such as N,N-dimethylformamide (DMF), tetrahydrofuran (THF) or toluene at a suitable temperature (e.g., 0° C., 25° C. or 100° C.). In some cases, it may be advantageous to use a catalytic amount of an additive such as potassium iodide, sodium iodide or tetrabutylammonium iodide.

[0354]

[0355] Halides 4 can in turn be prepared from carbonyl compounds 3 by reducing 3 with a suitable reducing agent (e.g. sodium borohydride, sodium triacetoxyborohydride, lithium aluminum hydride or hydrogen in the presence of a homogeneous or heterogeneous metal catalyst such as a palladium catalyst or a ruthenium catalyst) in a suitable solvent such as tetrahydrofuran (THF), dichloromethane (DCM), toluene, water, ethanol or methanol at a suitable temperature (e.g. 0°C or 25°C). The alcohol resulting from this reduction can then be replaced with a halogen by reacting it with a suitable reagent such as, but not limited to, bromine, carbon tetrabromide, carbon tetrachloride, N-bromosuccinimide or N-chlorosuccinimide and in the presence of a phosphine such as triphenylphosphine or tributylphosphine. This is carried out in a suitable solvent such as dichloromethane, toluene, tetrahydrofuran or acetonitrile at a suitable temperature (e.g. 25°C, 40°C, 100°C).

[0356] Alternatively, compounds of formula (I) can be prepared by reacting intermediate 5 and halide 6, optionally in the presence of a base such as an amine base (e.g., triethylamine, pyridine or diisopropylethylamine (DIPEA)) or an inorganic base (e.g., sodium hydroxide, potassium hydroxide or potassium carbonate), in a suitable solvent (e.g., DMF, dimethyl sulfoxide (DMSO), acetonitrile, THF, toluene, isopropanol or ethanol), at a suitable temperature (e.g., 25° C., 80° C., 100° C., 150° C.). In some cases, it may be advantageous to use a catalytic amount of an additive such as potassium iodide, sodium iodide or tetrabutylammonium iodide.

[0357]

[0358] Compounds 2 in which W is O or NH can be prepared in a similar manner by reacting 5 with a halide 7. As described above, this is optionally carried out in the presence of a base such as an amine base (e.g., triethylamine, pyridine, or diisopropylethylamine (DIPEA)) or an inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodium hydride, or potassium carbonate), in a suitable solvent (e.g., DMF, dimethyl sulfoxide (DMSO), acetonitrile, THF, toluene, isopropanol, or ethanol), at a suitable temperature (e.g., 0° C., 25° C., 80° C., 100° C., 150° C.). In some cases, it may be advantageous to use a catalytic amount of an additive such as potassium iodide, sodium iodide, or tetrabutylammonium iodide.

[0359]

[0360] Where W is CH 2Compound 2 can be synthesized by reacting olefin 8 with hydrogen at a suitable pressure (e.g., 1 bar or 10 bar), in the presence of a metal catalyst such as a palladium catalyst (e.g., palladium carbon or palladium acetate) or a rhodium catalyst (e.g., rhodium on alumina), in a suitable solvent (e.g., THF, ethyl acetate, ethanol or methanol), at a suitable temperature (e.g., 25°C).

[0361]

[0362] Compound 8 can be prepared by reacting aldehyde 9 and compound 10 in the presence of an amine such as piperidine or pyrrolidine and a base such as pyridine or triethylamine at an appropriate temperature (eg, 100°C or 140°C).

[0363]

[0364] Where W is CH 2 Compound 2 can also be prepared by reacting triflate 11 with an allylation agent such as allyltributylstannane or allyl acetate in the presence of a metal catalyst such as a palladium catalyst (e.g. Pd(Ph 3 P) 4 , palladium acetate or tris(dibenzylideneacetone)dipalladium(0)), optionally in the presence of a salt such as lithium chloride. The reaction is carried out in a suitable solvent such as DMF or acetonitrile at a suitable temperature (e.g., 70°C or 90°C). The resulting intermediate can be functionalized, for example, by epoxidation, which is carried out by exposing it to an epoxidizing agent such as 3-chloroperbenzoic acid (mCPBA), peracetic acid, dimethyldioxirane (DMDO) or methyl(trifluoromethyl)dioxirane (TFDO) in a suitable solvent such as EtOH, THF, DMF or MeOH at a suitable temperature (e.g., 50°C or 70°C). The resulting epoxide can then be functionalized by reacting with an amine 3 in a suitable solvent such as EtOH, THF, DMF or MeOH at a suitable temperature (e.g., 50°C or 70°C).

[0365]

[0366] Triflate 11 can be prepared by reacting 5 wherein W is O with a sulfonating agent such as trifluoromethanesulfonic anhydride, optionally in the presence of a base such as an amine base (e.g., triethylamine, pyridine, or diisopropylethylamine (DIPEA)) or an inorganic base (e.g., potassium carbonate), in a suitable solvent such as dichloromethane, at a suitable temperature (e.g., 0°C, 25°C).

[0367] Triflate 11 can also be used to prepare 5 wherein W is NH by reacting 11 with an amine source such as benzylamine, optionally in the presence of a base such as an amine base (e.g., triethylamine, diisopropylethylamine (DIPEA)) or an inorganic base (e.g., potassium carbonate, cesium carbonate), in the presence of a metal catalyst such as a palladium catalyst (e.g., Pd(Ph 3 P) 4 , palladium acetate or tris(dibenzylideneacetone)dipalladium(0)), and optionally in the presence of a ligand such as triphenylphosphine or 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (which may be an enantiomerically pure R- or S-enantiomer or a racemate). The reaction is carried out in a suitable solvent such as toluene, DMF or in the absence of a solvent and at a suitable temperature (e.g. 70°C, 100°C or 120°C). The resulting benzyl protected aniline can then be deprotected by reacting it with hydrogen at a suitable pressure (e.g. 1 bar or 10 bar), in the presence of a metal catalyst such as a palladium catalyst (e.g. palladium carbon or palladium acetate), in a suitable solvent (e.g. THF, ethyl acetate, ethanol or methanol or in the absence of a solvent), at a suitable temperature (e.g. 25°C) to give 5 wherein W is NH.

[0368] Compounds 12 wherein X is >C=O can be prepared by reacting phenol 13 and acyl halide 14, optionally in the presence of a base such as an amine base (e.g., triethylamine, diisopropylethylamine (DIPEA)) or an inorganic base (e.g., potassium carbonate or sodium hydroxide), in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, water, dioxane, ethanol, xylene, chlorobenzene, or without solvent), at a suitable temperature (e.g., 0° C., 25° C.). The resulting intermediate can be rearranged by reaction with a Lewis acid such as aluminum trichloride in a suitable solvent (e.g., xylene, chlorobenzene, or without solvent), at a suitable temperature (e.g., 120° C. or 150° C.). In some cases, the above two operations can be combined into a single step, in which case the base can be suppressed.

[0369] The obtained compound 12 wherein X is >C=O can be further converted to 12 wherein X is >CHOH by reacting with a reducing agent (e.g., sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, or hydrogen in the presence of a homogeneous or heterogeneous metal catalyst such as a palladium catalyst (e.g., palladium carbon) or a ruthenium catalyst) in a suitable solvent such as tetrahydrofuran (THF), dichloromethane (DCM), acetic acid, toluene, water, or ethanol at a suitable temperature (e.g., 0° C., 25° C., 40° C.). The obtained compound 12 wherein X is >CHOH can be further converted to 12 wherein X is >CHOH by reacting with a hydride source such as triethylsilane, phenylsilane, or polymethylhydrosiloxane (PMHS) in the presence of an acid such as trifluoroacetic acid in a suitable solvent such as DCM at a suitable temperature (e.g., 0° C. or 25° C.).2 of compound 12.

[0370] Where X is >C=CH 2 Compound 12 can be directly obtained from compound 12 wherein X is >C=O by reacting with a Grignard reagent such as methylmagnesium chloride, methylmagnesium iodide or methylmagnesium bromide in a suitable solvent (such as ether, THF or hexane) at a suitable temperature (such as 0°C, 25°C, 40°C). The resulting carbinol is then eliminated by treating with an acid (such as acetic acid, trifluoroacetic acid or hydrochloric acid) in a suitable solvent (such as DCM) at a suitable temperature (such as 0°C, 25°C, 40°C). Then, compound 12 wherein X is >C=CH 2 Compound 12 can be converted to wherein X is >CH-CH by reacting with hydrogen at an appropriate pressure (e.g., 1 bar or 10 bar), in the presence of a metal catalyst such as a palladium catalyst (e.g., palladium carbon or palladium acetate), in an appropriate solvent (e.g., THF, ethyl acetate, ethanol or methanol or no solvent), at an appropriate temperature (e.g., 25° C.). 3 of compound 12.

[0371]

[0372] Compound 15 can be prepared by reacting phenol 13 with benzyl halide 16 in the presence of zinc (II) chloride, in a suitable solvent (e.g., chlorobenzene, toluene, or no solvent), at a suitable temperature (e.g., 120° C. or 140° C.). Alternatively, phenol 13 can be reacted with benzyl halide 16 in the presence of a base such as an amine base (e.g., triethylamine, pyridine, or diisopropylethylamine (DIPEA)) or an inorganic base (e.g., sodium hydroxide, potassium hydroxide, or potassium carbonate), in a suitable solvent (e.g., acetonitrile, acetone, THF, or DMF), at a suitable temperature (e.g., 25° C., 40° C., or 70° C.). The intermediate thus obtained can then be rearranged to 15 by reacting with titanium (IV) chloride in a suitable solvent (e.g., DCM), at a suitable temperature (e.g., −10° C., 0° C., or 25° C.).

[0373]

[0374] It must be mentioned that certain sensitive functional groups may be passed through the preparation sequence in a protected or masked form and revealed at a later point in the synthetic sequence by standard methods known to those skilled in the art. For example, aryl halide 17 can be reacted with a cyanide source such as copper(I) cyanide in a suitable solvent such as N-methyl-2-pyrrolidone (NMP) or DMF at a suitable temperature such as 140°C or 200°C to give cyanide 18.

[0375]

[0376] Bromide 19 can be reacted with an iodide source such as copper (I) iodide in the presence of sodium trifluoroacetate d in a suitable solvent such as DMF and toluene at a suitable temperature (120 °C or 150 °C) to give iodide 20.

[0377]

[0378] The nitro compound 21 can be reacted with hydrogen at a suitable pressure (e.g., 1 bar or 10 bar), in the presence of a metal catalyst such as a palladium catalyst (e.g., palladium carbon or palladium acetate), in a suitable solvent (e.g., THF, ethyl acetate, ethanol or methanol or no solvent), at a suitable temperature (e.g., 25° C.) to give aniline 22.

[0379]

[0380] The above examples are by no means limiting or exhaustive, and one skilled in the art will recognize the general applicability of functional group manipulations in preparing compounds of formula (I).

[0381] Compound 23 can be reacted with compound 24 with an oxidant (e.g., pyridinium chlorochromate, pyridinium dichromate, Dess-Martin oxidant (triacetic acid 3-oxo-1,3-dihydro-1λ 5 ,2-benzoiodooxolane-1,1,1-triyl ester) or DMSO in the presence of an activating agent such as oxalyl chloride) is optionally oxidized in the presence of a base such as triethylamine, pyridine or diisopropylethylamine (DIPEA) in a suitable solvent such as DCM, THF at a suitable temperature (which can vary from -78°C to 25°C and further up to 40°C depending on the selected oxidant). Compound 24 can be prepared by reacting compound 25 with a borane source such as borane dimethyl sulfide or 9-borabicyclo[3.3.1]nonane (9-BBN) in a suitable solvent such as THF at a suitable temperature (e.g. 0°C, 25°C), followed by treatment with an aqueous base such as NaOH and an oxidant such as hydrogen peroxide at a suitable temperature (e.g. 0°C, 25°C).

[0382]

[0383] Compound 25 can be directly converted to certain compounds of formula (I) by epoxidation by exposing it to an epoxidation reagent (e.g., 3-chloroperbenzoic acid (mCPBA), peracetic acid, dimethyldioxirane (DMDO), or methyl(trifluoromethyl)dioxirane (TFDO)) in a suitable solvent (e.g., dichloromethane or diethyl ether) at a suitable temperature (e.g., 0°C or 25°C), and then reacting the formed epoxide with amine 3 in a suitable solvent (e.g., EtOH, THF, DMF, or MeOH) at a suitable temperature (e.g., 50°C or 70°C).

[0384] Compound 26 can be prepared by reacting alcohol 27 with halide 28 in the presence of a base such as an inorganic base (e.g., potassium phosphate), a copper catalyst (e.g., copper (I) iodide) and picolinic acid, in an appropriate solvent (e.g., DMSO, DMF or N-methyl-2-pyrrolidone (NMP)), at an appropriate temperature (e.g., 90°C or 120°C).

[0385]

[0386] Similar reaction conditions and reagents can be used to prepare 29 from 30 and 28 by reaction in the presence of a base such as an inorganic base (e.g., potassium phosphate), a copper catalyst (e.g., copper(I) iodide), and picolinic acid at an appropriate temperature (e.g., 90° C. or 120° C.) in an appropriate solvent (e.g., DMSO, DMF, or N-methyl-2-pyrrolidone (NMP)).

[0387]

[0388] Compound 31 can be prepared by reducing 32 by reaction with a reducing agent (e.g., lithium aluminum hydride, diisobutylaluminum hydride or hydrogen in the presence of a homogeneous or heterogeneous metal catalyst such as a palladium catalyst (e.g., palladium on carbon) or a ruthenium catalyst) in an appropriate solvent such as tetrahydrofuran (THF), dichloromethane (DCM), toluene, water or ethanol at an appropriate temperature (e.g., 0°C, 25°C, 40°C).

[0389]

[0390] Compound 33 can be prepared by reacting alcohol 34 with allylic halide 35, optionally in the presence of a base such as an amine base (e.g., triethylamine, pyridine, or diisopropylethylamine (DIPEA)) or an inorganic base (e.g., sodium hydroxide, sodium hydride, potassium hydroxide, or potassium carbonate), in a suitable solvent (e.g., acetone, DMF, DMSO, acetonitrile, THF, toluene, isopropanol or ethanol, water, or without solvent), at a suitable temperature (e.g., 0° C., 25° C., or 60° C.). The resulting ether intermediate can then be further converted to 33 by heating to a suitable temperature (e.g., 150° C. or 200° C.) in a suitable solvent (e.g., DMF, DMSO, or without solvent).

[0391]

[0392] Compound 36 can be prepared by reducing compound 37 with hydrogen at an appropriate pressure (e.g., 1 bar, 5 bar, or 10 bar), in the presence of a metal catalyst such as a palladium catalyst (e.g., palladium carbon or palladium acetate) or a rhodium catalyst (e.g., rhodium on alumina), in an appropriate solvent (e.g., THF, ethyl acetate, ethanol, or methanol, or without solvent), at an appropriate temperature (e.g., 25° C. or 50° C.). Compound 37 can be prepared by reacting aldehyde 38 with cyclohexanone in the presence of a base such as an inorganic base (e.g., sodium hydroxide or potassium hydroxide), in an appropriate solvent (e.g., water alone or a mixture of water and other solvents such as THF or dioxane), at an appropriate temperature (e.g., 0° C., 25° C., or 40° C.).

[0393]

[0394] It must be noted that many of the above general methods involving amines as substrates can be carried out with salts of the corresponding amines, such as the hydrochlorides, hydrobromides, oxalates, phosphates, etc. In those cases, it may be necessary to use an additional base, such as an amine base (e.g., triethylamine, pyridine, or diisopropylethylamine (DIPEA)) or an inorganic base (e.g., sodium hydride, sodium hydroxide, potassium carbonate, or potassium phosphate) to allow the reaction to occur, a fact that will be recognized by those skilled in the art.

[0395] It must also be noted that a different order of steps from the order of steps described herein for preparing compounds of formula (I) is also possible and in some cases advantageous. As will be appreciated by those skilled in the art, this can eliminate the need to protect groups carrying sensitive functional groups throughout the synthesis.

[0396] 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 should be understood that variations and modifications may be made by those skilled in the art. Example

[0397] Example 1: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride

[0398] Example 1a: Ethyl 2-(2-benzyl-4-methylphenoxy)acetate

[0399] A solution of 2-benzyl-4-methylphenol (0.70 g, 3.53 mmol) in DMF (N,N-dimethylformamide) (5 mL) was treated with potassium carbonate (1.46 g, 10.6 mmol, 3.0 equiv.) and then ethyl 2-chloroacetate (0.45 mL, 4.24 mmol, 1.2 eq.). The resulting mixture was stirred at rt (room temperature, i.e., approximately 25° C.) overnight and then diluted with MTBE (methyl tert-butyl ether) (50 mL) and filtered, washing with additional MTBE (50 mL). The filtrate was washed with water (2×50 mL), brine (50 mL), and MgSO 4 Drying and concentration under reduced pressure gave ethyl 2-(2-benzyl-4-methylphenoxy)acetate (1.0 g, 3.51 mmol, quantitative yield) as a colorless liquid, which was used in the next step without purification. GC / MS (EI, 70 eV) m / z (%): 284 (70, [M] + ), 197(100), 196(22), 195(99), 181(31), 166(22), 165(71), 152(30), 91(96), 29(35).

[0400] Example 1b: 2-(2-Benzyl-4-methylphenoxy)acetic acid:

[0401] To a solution of ethyl 2-(2-benzyl-4-methylphenoxy)acetate (1.00 g, 3.53 mmol) in THF (tetrahydrofuran) (15 mL) was added 2 M aqueous NaOH (10 mL) and the mixture was heated to reflux for 2 h. The mixture was cooled, poured into ice-cold 1 M aqueous HCl (30 mL), extracted with MTBE (2×50 mL), washed with brine (50 mL), and washed with MgSO 4 Drying and concentration under reduced pressure gave 2-(2-benzyl-4-methylphenoxy)acetic acid (0.78 g, 3.04 mmol, 86% yield) as a white solid, which was used in the next step without further purification. GC / MS (EI, 70 eV) m / z (%): 256 (82, [M] + ), 197(44), 196(26), 195(100), 181(41), 166(23), 165(43), 91(68), 77(19), 31(30). 1 H NMR (400 MHz, CDCl3 ): δ=7.19-7.34 (m, 5H), 7.01 (s, 2H), 6.71 (d, J=8.1Hz, 1H), 4.61 (s, 2H), 4.04 (s, 2H), 2.29ppm (s, 3H). 13 C NMR (101 MHz, CDCl 3 ): δ=173.0, 153.1, 140.8, 131.8, 131.6, 129.9, 128.7, 128.4, 127.9, 126.0, 111.8, 65.4, 36.3, 20.6ppm.

[0402] Example 1c: 2-(2-Benzyl-4-methylphenoxy)acetyl chloride:

[0403] 2-(2-Benzyl-4-methylphenoxy)acetic acid (0.68 g, 2.65 mmol) was treated with thionyl chloride (1.36 mL, 18.6 mmol, 7 equiv.) and the mixture was heated to 70° C. for 1 hour. The mixture was evaporated under reduced pressure to give 2-(2-benzyl-4-methylphenoxy)acetyl chloride (0.73 g, 2.65 mmol, quantitative yield) as a white solid which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ): δ=7.10-7.33 (m, 5H), 6.96-7.03 (m, 2H), 6.66 (d, J=8.1Hz, 1H), 4.89 (s, 2H), 4.02 (s, 2H), 2.28ppm (s, 3H). 13 C NMR (101 MHz, CDCl 3 ): δ=170.3, 152.7, 140.7, 132.1, 131.9, 130.2, 128.9, 128.3, 127.8, 125.9, 111.9, 73.1, 35.9, 20.6ppm.

[0404] Example 1d: 2-(2-Benzyl-4-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone hydrochloride:

[0405] A solution of 2-(2-benzyl-4-methylphenoxy)acetyl chloride (0.36 g, 1.30 mmol) in DCM (dichloromethane) (7 mL) was cooled to 0°C and then treated with 1-methylpiperazine (0.143 g, 1.43 mmol, 1.1 equiv.) and stirred at room temperature for 40 hours. The resulting white solid was filtered and dried in vacuo to give 2-(2-benzyl-4-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone hydrochloride (0.43 g, 1.15 mmol, 88% yield) as a white solid which was used in the next step without further purification. LC-MS (ESI+): 339 ([M+H] + ). 13 C NMR (101 MHz, CDCl 3 ): δ=166.9, 153.5, 141.1, 132.5, 131.6, 128.6, 128.5, 128.4, 128.1, 126.2, 111.5, 68.6, 53.1, 52.8, 43.4, 42.1, 36.3, 20.5ppm.

[0406] Example 1e: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride:

[0407] LAH(LiAlH 4 A suspension of 2-(2-benzyl-4-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone hydrochloride (0.150 g, 0.400 mmol) in THF (tetrahydrofuran) (8 mL) was treated portionwise with solid 2-(2-benzyl-4-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone hydrochloride (0.150 g, 0.400 mmol). After the initial gas evolution subsided, the mixture was heated to 50° C. for 1 hour. After cooling to room temperature, the mixture was quenched by the addition of EtOAc (ethyl acetate) (1 mL) and then saturated aqueous potassium sodium tartrate (Rochelle salt solution) (10 mL), and the slurry was stirred overnight. The resulting mixture was diluted with water (20 mL) and saturated aqueous sodium bicarbonate (20 mL), extracted with EtOAc (2×50 mL), and washed with MgSO 4 The mixture was dried and concentrated under reduced pressure. The resulting pale yellow liquid was taken up in ether (10 mL) and treated with 2M HCl in ether (0.4 mL), resulting in the formation of a white precipitate. The precipitate was filtered and dried under reduced pressure to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride (0.129 g, 0.357 mmol, 89% yield) as a white solid. LC-MS (ESI+): 325 ([M+H] + ). 13C NMR (101 MHz, methanol-d4): δ = 153.5, 141.1, 131.7, 131.0, 128.5, 128.1, 128.1, 127.8, 125.6, 111.7, 63.0, 56.0, 49.7, 49.1, 41.9, 35.7, 19.2 ppm.

[0408] Example 2: 4-(2-(2-benzyl-4-methylphenoxy)ethyl)morpholine hydrochloride

[0409] Example 2a: 2-(2-Benzyl-4-methylphenoxy)-1-morpholinoethanone:

[0410] A solution of 2-(2-benzyl-4-methylphenoxy)acetyl chloride (0.36 g, 1.3 mmol) in DCM (10 mL) was treated with pyridine (0.12 mL, 1.4 mmol, 1.1 equiv.) and then morpholine (0.125 g, 1.4 mmol, 1.1 equiv.) at 0°C and the resulting mixture was stirred at room temperature for 40 hours. The resulting mixture was diluted with EtOAc (50 mL), washed with water (2×20 mL), brine (20 mL), and MgSO 4 The mixture was dried and concentrated under reduced pressure. The material was then purified by flash column chromatography on silica gel using a gradient of EtOAc in hexanes to afford 2-(2-benzyl-4-methylphenoxy)-1-morpholinoethanone (0.245 g, 0.75 mmol, 58% yield) as a colorless liquid. GC / MS (EI, 70 eV) m / z (%): 325 (9, [M] + ), 198(17), 197(100), 195(14), 193(11), 165(23), 152(11), 100(14), 91(35), 70(10), 56(14). 1 H NMR (400 MHz, CDCl 3 ): δ=7.25-7.31(m, 2H), 7.16-7.23(m, 3H), 6.97-7.05(m, 2H), 6.83(d, J=8.3Hz, 1H ), 4.65 (s, 2H), 3.98 (s, 2H), 3.54-3.68 (m, 4H), 3.27-3.41 (m, 4H), 2.29ppm (s, 3H). 13 C NMR (101 MHz, CDCl 3): δ=166.9, 153.6, 140.9, 131.9, 130.9, 129.0, 128.7, 128.3, 128.0, 125.9, 111.4, 68.4, 66.7, 66.6, 45.7, 42.4, 36.2, 20.5ppm.

[0411] Example 2b: 4-(2-(2-benzyl-4-methylphenoxy)ethyl)morpholine hydrochloride:

[0412] A suspension of LAH (13 mg, 0.34 mmol, 1.1 equiv.) in THF (3 mL) was treated dropwise with a solution of 2-(2-benzyl-4-methylphenoxy)-1-morpholinoethanone (0.100 g, 0.31 mmol) in THF (3 mL) at room temperature. After the initial gas evolution subsided, the mixture was heated to 50 °C for 1 hour. After cooling to room temperature, the mixture was quenched by the addition of EtOAc (ethyl acetate) (1 mL) followed by aqueous potassium sodium tartrate (Rochelle salt solution) (10 mL), and the slurry was stirred overnight. The resulting mixture was diluted with water (20 mL) and saturated aqueous sodium bicarbonate (20 mL), extracted with EtOAc (2×50 mL), and washed with MgSO 4 The mixture was dried and concentrated under reduced pressure. The resulting pale yellow liquid was taken up in ether (10 mL) and treated with 2M HCl in ether (0.4 mL), resulting in the formation of a white precipitate. The precipitate was filtered and dried under reduced pressure to give 4-(2-(2-benzyl-4-methylphenoxy)ethyl)morpholine hydrochloride (29 mg, 0.083 mmol, 27% yield) as a white solid. LC-MS (ESI+): 312 ([M+H] + ). 1 H NMR (400MHz, methanol-d4): δ=7.24-7.31 (m, 2H), 7.14-7.21 (m, 1H), 7.07-7.14 (m, 3H), 7.03 (d, J=2.0Hz, 1H), 6.93 (d, J=8.3Hz, 1H), 4.29-4.38(m, 2H), 4.02(s, 2H), 3.79-3.95(m, 2H), 3.58-3.74(m, 2H), 3.53(dd, J=5.3, 4.0Hz, 2H), 3.21-3.31(m, 2H), 3.08(br s, 2H), 2.29ppm (s, 3H). 13C NMR (101 MHz, methanol-d4): δ = 153.6, 141.2, 131.9, 131.0, 128.4, 128.0, 128.0, 127.9, 125.6, 111.5, 63.5, 62.7, 56.4, 52.5, 35.7, 19.2 ppm.

[0413] Example 3: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine

[0414] 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride (0.10 g, 0.28 mmol) was dissolved in 2M aqueous NaOH (10 mL) and extracted with MTBE (3×20 mL). The combined extracts were washed with brine (20 mL) and precipitated with MgSO 4 The mixture was dried and concentrated under reduced pressure. The resulting material was purified by flash chromatography on silica gel, eluting with a gradient mixture of triethylamine, ethanol and EtOAc (ratio 1:9:90) in hexane to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine (70 mg, 0.22 mmol, 77% yield) as a light yellow liquid. GC / MS (EI, 70 eV) m / z (%): 324 (1, [M] + ), 127(43), 126(7), 114(7), 113(100), 91(6), 70(31), 58(5), 56(11), 43(9), 42(11).

[0415] Example 4: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(phosphate)

[0416] A solution of phosphoric acid (85 wt%, 0.35 g, 3.1 mmol) in ethanol (15 mL) was reacted with a solution of 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine (1.00 g, 3.08 mmol) in ethanol (15 mL) at room temperature and the resulting suspension was stirred for 15 minutes. The formed solid was filtered and dried in a vacuum oven to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(phosphate) (0.80 g, 1.5 mmol, 50% yield) as a white solid. Analytical calculation (%), C 21 H 34 N 2 O 9 P 2(520.46 g / mol): C 48.46, H 6.58, N 5.38, O27.67, P 11.90, found: C 48.21, H 6.50, N 5.41.

[0417] Example 5: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2,2,2-trifluoroacetate)

[0418] A solution of TFA (2,2,2-trifluoroacetic acid) (0.35 g, 3.1 mmol, 2 equiv.) in ethanol (10 mL) was treated with a solution of 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine (0.50 g, 1.54 mmol) in ethanol (10 mL) at room temperature. The resulting mixture was evaporated to dryness and the resulting solid was suspended in diethyl ether and filtered, washed with cold diethyl ether and then with hexanes. The solid was dried in a vacuum oven to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2,2,2-trifluoroacetate) (0.715 g, 1.29 mmol, 84% yield) as a white solid. Analytical Calcd. (%), C 25 H 30 N 2 O 5 F 6 (552.51 g / mol): C 54.35, H 5.47, N 5.07, O 14.48, F 20.63, found: C 54.42, H 5.44, N 5.07.

[0419] Example 6: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2-hydroxysuccinate)

[0420] A solution of 2-hydroxysuccinic acid (0.33 g, 2.47 mmol) in ethanol (10 mL) was treated with a solution of 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine (0.80 g, 2.47 mmol) in ethanol (10 mL) at room temperature. The resulting solid was filtered and washed with ether and hexanes, then dried in a vacuum oven to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2-hydroxysuccinate) (0.715 g, 1.20 mmol, 48% yield) as a white solid. Analytical Calcd (%), C 29 H 40 N 2 O 11(592.64 g / mol): C 58.77, H 6.80, N 4.73, O 29.70, found: C 57.87, H 6.64, N 4.71.

[0421] Example 7: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine 2,3-dihydroxysuccinate

[0422] A solution of 2,3-dihydroxysuccinic acid (0.46 g, 3.1 mmol) in ethanol (10 mL) was treated with a solution of 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine (1.0 g, 3.1 mmol) in ethanol (10 mL) at room temperature. The resulting mixture was stirred for 30 minutes, then evaporated to dryness and the resulting solid was suspended in hexane and filtered, washed with cold hexane. The solid was dried in a vacuum oven to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine 2,3-dihydroxysuccinate (1.3 g, 2.74 mmol, 89% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ=7.37-8.54(m, 4H), 7.19-7.29(m, 4H), 7.12-7.18(m, 1H), 6.93-7.01(m, 2H), 6.85(d, J =9.0Hz, 1H), 4.13 (s, 2H), 4.02 (t, J = 5.5Hz, 2H), 3.86 (s, 2H), 2.53-2.92 (m, 10H), 2.45 (s, 3H), 2.19ppm (s, 3H). 13 C NMR (101MHz, DMSO-d6): δ=174.5, 154.4, 141.6, 131.4, 129.4, 128.8, 126.1, 112.2, 72.4, 66.4, 56.6, 53.8, 51.6, 44.2, 35.9, 20.6ppm.

[0423] Example 8: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimaleate

[0424] A solution of maleic acid (0.29 g, 2.47 mmol) in ethanol (10 mL) was treated with a solution of 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine (0.80 g, 2.47 mmol) in ethanol (10 mL) at room temperature. The resulting solid was filtered and washed with ether and hexane, then dried in a vacuum oven to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimaleate (0.65 g, 1.17 mmol, 47% yield) as a white solid. Analytical calculation (%), C 29 H 36 N 2 O 9 (556.61 g / mol): C 62.58, H 6.52, N 5.03, O 25.87, found: C 62.34, H 6.50, N 5.05.

[0425] Example 9: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimethanesulfonate

[0426] A solution of methanesulfonic acid (0.35 mL, 5.42 mmol) in ethanol (10 mL) was treated with a solution of 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine (0.88 g, 2.71 mmol) in ethanol (10 mL) at room temperature. The resulting mixture was stirred for 30 minutes and then evaporated to dryness, and the resulting solid was suspended in ether and filtered, washed with cold ether and then with hexanes. The solid was dried in a vacuum oven to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimethanesulfonate (1.22 g, 2.36 mmol, 87% yield) as a white solid. Analytical calculation value (%), C 23 H 36 N 2 O 7 S 2 (516.68 g / mol): C 53.47, H 7.02, N 5.42, O 21.68, S 12.41, found: C 52.72, H 6.95, N5.40.

[0427] Example 10: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine sulfate

[0428] A solution of sulfuric acid (0.16 mL, 3.1 mmol) in ethanol (10 mL) was treated with a solution of 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine (1.0 g, 3.1 mmol) in ethanol (10 mL) at room temperature. The resulting solid was filtered and washed with ether and hexanes, then dried in a vacuum oven to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine sulfate (1.21 g, 2.86 mmol, 93% yield) as a white solid. LC-MS (ESI-): 97 ([HSO 4 ] - ). LC-MS (ESI+): 324 ([M+H] + ).

[0429] Example 11: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine citrate

[0430] A solution of citric acid (0.59 g, 3.1 mmol) in ethanol (10 mL) was treated with a solution of 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine (1.0 g, 3.1 mmol) in ethanol (10 mL) at room temperature. The resulting mixture was stirred for 30 minutes and then evaporated to dryness, and the resulting solid was suspended in ether and filtered, washed with cold ether and then with hexanes. The solid was dried in a vacuum oven to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine citrate (1.22 g, 2.36 mmol, 77% yield) as a white solid. LC-MS (ESI+): 324 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6): δ=8.02-13.16(m, 4H), 7.23-7.29(m, 2H), 7.18-7.22(m, 2H), 7.13-7.18(m, 1H), 6.94-7.00(m, 2H), 6.86(d, J=8 .1Hz, 1H), 4.03 (t, J=5.5Hz, 2H), 3.86 (s, 2H), 2.81-3.02 (range, 4H), 2.76 (t, J=5.4Hz, 2H), 2.54-2.72 (m, 10H), 2.20ppm (s, 3H). 13C NMR (101MHz, DMSO-d6): δ=177.0, 171.8, 154.4, 141.5, 131.4, 129.5, 129.4, 129.0, 1 28.6, 128.2, 126.2, 112.2, 72.0, 66.4, 56.4, 53.6, 51.2, 44.5, 43.7, 35.9, 20.6ppm.

[0431] Example 12: 1-(2-(2-Benzyl-4-methylphenoxy)propyl)-4-methylpiperazine

[0432] Example 12a: Ethyl 2-(2-benzyl-4-methylphenoxy)propionate:

[0433] Prepared in analogy to Example 1a from 2-benzyl-4-methylphenol (5.0 g, 25.2 mmol) and ethyl 2-bromopropionate (5.48 g, 30.3 mmol, 1.2 equiv.) to afford ethyl 2-(2-benzyl-4-methylphenoxy)propionate (5.55 g, 18.6 mmol, 74% yield) as a colorless liquid after flash column chromatography on silica gel eluting with EtOAc / hexane. GC / MS (EI, 70 eV) m / z (%): 298 (39, [M] + ), 198(20), 197(100), 195(18), 166(17), 165(43), 121(46), 120(22), 105(40), 91(25). 1 H NMR (400 MHz, CDCl 3 ): δ=7.30-7.36(m, 4H), 7.20-7.28(m, 1H), 6.96-7.02(m, 2H), 6.67-6.72(m, 1H), 4.76(q, J=6.8Hz, 1H), 4.26( q, J=7.1Hz, 2H), 4.10-4.16 (m, 1H), 4.07 (s, 1H), 2.30 (s, 3H), 1.62 (d, J=6.8Hz, 3H), 1.30ppm (t, J=7.1Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ): δ=172.5, 153.4, 141.3, 131.5, 130.6, 130.2, 129.1, 128.2, 127.6, 125.7, 112.0, 73.0, 61.1, 36.1, 20.6, 18.6, 14.2ppm.

[0434] Example 12b: 1-(2-(2-Benzyl-4-methylphenoxy)propyl)-4-methylpiperazine

[0435] A solution of ethyl 2-(2-benzyl-4-methylphenoxy)propanoate (5.50 g, 18.4 mmol) in DCM (40 mL) was cooled to -78 °C and treated dropwise with DIBAL-H (diisobutylaluminum hydride) solution (1 M in toluene, 38.7 mL, 38.7 mmol, 2.1 equiv.). The resulting mixture was allowed to warm to room temperature over 1 h, then cooled to 5 °C and quenched with EtOAc (3 mL), treated with Rochelle salt solution (50 mL) and stirred at room temperature for 3 h. The mixture was extracted with DCM (3 x 100 mL), washed with water (100 mL), and precipitated with MgSO 4 Dry and concentrate under reduced pressure to obtain crude intermediate alcohol 2-(2-benzyl-4-methylphenoxy) propan-1-ol (4.4g, 15mmol), which is dissolved in DCM (30mL) and slowly added to a suspension of diatomaceous earth (3.9g) and PCC (pyridinium chlorochromate) (3.88g, 18.0mmol) in DCM (20mL) at room temperature. The resulting mixture is stirred at room temperature for 5 hours, then filtered and concentrated through a silica gel plug to obtain crude intermediate aldehyde 2-(2-benzyl-4-methylphenoxy) propanal (3.85g, 10.2mmol). It is dissolved in DCM (40mL) and treated with 1-methylpiperazine (1.12g, 11.2mmol), then sodium triacetoxyborohydride (2.38g, 11.2mmol) is added in batches. The resulting mixture is stirred at room temperature for 3 hours, then poured into ice-cold saturated NaHCO 3 The mixture was added to an aqueous solution (100 mL), extracted with DCM (3 × 50 mL), washed with water (100 mL), and precipitated with MgSO 4 The mixture was dried and concentrated under reduced pressure. The material was then purified by flash column chromatography on silica gel, eluting with a gradient mixture of triethylamine, ethanol and EtOAc (ratio 1:9:90) in hexane to give 1-(2-(2-benzyl-4-methylphenoxy)propyl)-4-methylpiperazine (1.55 g, 4.58 mmol, 25% yield) as a colorless liquid. GC / MS (EI, 70 eV) m / z (%): 338 (1, [M] + ), 141(13), 140(9), 114(7), 113(100), 100(6), 98(6), 70(29), 56(6), 43(6), 42(10). 1 H NMR (400 MHz, CDCl 3): δ=7.21-7.31 (m, 4H), 7.16-7.21 (m, 1H), 6.99 (dd, J=8.3, 2.0Hz, 1H), 6.94 (d, J=2.0Hz, 1H), 6.83 (d, J=8.3Hz, 1H), 4.50-4.59 (m, 1H), 3.9 6 (s, 2H), 2.67 (dd, J=13.1, 6.2Hz, 1H), 2.49 (dd, J=13.1, 4.8Hz, 1H), 2.33-2.71 (m, 8H), 2.29 (s, 3H), 2.27 (s, 3H), 1.23ppm (d, J=6.4Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ): δ=153.3, 141.5, 131.5, 130.4, 129.5, 129.0, 128.1, 127.6, 125.6, 112.9, 72.4, 63.7, 55.3, 53.8, 46.1, 36.2, 20.5, 18.6ppm.

[0436] Example 13: 1-(2-(2-benzyl-4-methylphenoxy)propyl)-4-methylpiperazine hydrochloride

[0437] A solution of 1-(2-(2-benzyl-4-methylphenoxy)propyl)-4-methylpiperazine (0.63 g, 1.86 mmol) in diethyl ether was treated with 2M HCl in diethyl ether (2.5 mL, 5 mmol) at room temperature and the resulting solid was filtered and washed with diethyl ether and then with hexanes and then dried in a vacuum oven to give 1-(2-(2-benzyl-4-methylphenoxy)propyl)-4-methylpiperazine hydrochloride (0.52 g, 1.39 mmol, 75% yield) as a white solid. LC-MS (ESI+): 339 ([M+H] + ). 13 CNMR (101MHz, DMSO-d6): δ=151.8, 141.6, 131.7, 131.1, 130.4, 129.3, 128.6, 128.2, 126.2, 114.5, 69.3, 49.4-50.1(br), 36.1, 20.7, 17.3ppm.

[0438] Example 14: 1-(2-(2-benzyl-4-ethylphenoxy)ethyl)-4-methylpiperazine hydrochloride

[0439] Prepared in a similar sequence to Example 12 from 2-benzyl-4-ethylphenol, ethyl 2-chloroacetate and 1-methylpiperazine to give 1-(2-(2-benzyl-4-ethylphenoxy)ethyl)-4-methylpiperazine, which was precipitated as the hydrochloride salt according to the method described in Example 13 to give 1-(2-(2-benzyl-4-ethylphenoxy)ethyl)-4-methylpiperazine hydrochloride as a white solid. LC-MS (ESI+): 339 ([M+H] + ). 1 H NMR (400MHz, DMSO-d6): δ=11.48-13.47(m, 1H), 7.26-7.34(m, 2H), 7.15-7.25( m, 3H), 7.06 (dd, J=8.3, 2.2Hz, 1H), 7.00 (s, 1H), 6.93 (d, J=8.3Hz, 1H), 4.40 (br s, 2H), 3.95 (s, 2H), 3.39-3.78 (m, 10H), 2.82 (br s, 3H), 2.46-2.57 (m, 3H), 1.13ppm (t, J=7.6Hz, 3H). 13 C NMR (101MHz, DMSO-d6): δ=153.9, 141.3, 136.8, 130.4, 129.4, 129.1, 128.8, 12 7.0, 126.3, 112.3, 63.3, 49.7-50.6(br), 48.9-49.6(br), 35.9, 27.8, 16.4ppm.

[0440] Example 15: 1-Methyl-4-(2-(4-methyl-2-(thien-2-ylmethyl)phenoxy)ethyl)piperazine hydrochloride

[0441] Example 15a: 4-methyl-2-(thiophen-2-ylmethyl)phenol

[0442] A mixture of p-cresol (20.8 g, 192 mmol, 5 equiv.) and trifluoromethanesulfonic acid (0.404 g, 2.69 mmol, 0.07 equiv.) was treated dropwise with methyl thiophene-2-methylacetate (6 g, 38.4 mmol) at room temperature over 5 minutes, and the resulting mixture was heated to 100 °C for 1 hour. The resulting mixture was cooled to room temperature and poured onto water (200 mL), extracted with EtOAc (3×100 mL), washed with water (100 mL), brine (100 mL), and MgSO 4The crude product was purified by flash column chromatography on silica gel with a gradient of EtOAc in hexanes to give 4-methyl-2-(thiophen-2-ylmethyl)phenol (1.3 g, 5.98 mmol, 16% yield) as a colorless liquid. LC-MS (ESI+): 331 ([M+H] + ).

[0443] Example 15b: 1-Methyl-4-(2-(4-methyl-2-(thiophen-2-ylmethyl)phenoxy)ethyl)piperazine hydrochloride

[0444] Prepared in a similar sequence to Example 12 from 4-methyl-2-(thiophen-2-ylmethyl)phenol, ethyl 2-chloroacetate and 1-methylpiperazine to give 1-methyl-4-(2-(4-methyl-2-(thiophen-2-ylmethyl)phenoxy)ethyl)piperazine, which was precipitated as the hydrochloride salt according to the method described in Example 13 to give 1-methyl-4-(2-(4-methyl-2-(thiophen-2-ylmethyl)phenoxy)ethyl)piperazine hydrochloride as a white solid. LC-MS (ESI+): 331 ([M+H] + ). 13 C NMR (101MHz, DMSO-d6): δ=153.5, 144.1, 131.1, 130.3, 129.0, 128.6, 127.3, 125.6, 124.5, 112.3, 63.3, 48.98-50.57(br), 30.2, 20.6ppm.

[0445] Example 16: 4-(2-(2-benzyl-4-methylphenoxy)ethyl)thiomorpholine 1-oxide

[0446] Example 16a: 4-(2-(2-benzyl-4-methylphenoxy)ethyl)thiomorpholine

[0447] In a similar order to Example 12, 4-(2-(2-benzyl-4-methylphenoxy)ethyl)thiomorpholine was prepared from 2-benzyl-4-methylphenol, ethyl 2-chloroacetate and thiomorpholine as a colorless liquid. GC / MS (EI, 70 eV) m / z (%): 327 (3, [M] + ), 165(4), 130(6), 118(5), 117(7), 116(100), 91(7), 88(8), 56(7), 55(3), 42(4). 1 H NMR (400 MHz, CDCl 3): δ=7.12-7.27 (m, 5H), 6.97 (dd, J=8.3, 1.8Hz, 1H), 6.91 (d, J=2.1Hz, 1H), 6.73 (d, J=8.2Hz, 1 H), 4.01 (t, J=5.6Hz, 2H), 3.93 (s, 2H), 2.73-2.80 (m, 6H), 2.59-2.64 (m, 4H), 2.24ppm (s, 3H). 13 C NMR (101 MHz, CDCl 3 ): δ=154.5, 141.3, 131.4, 129.9, 129.4, 128.8, 128.2, 127.7, 125.8, 111.4, 66.4, 58.2, 55.3, 36.2, 28.0, 20.5ppm.

[0448] Example 16b: 4-(2-(2-benzyl-4-methylphenoxy)ethyl)thiomorpholine 1-oxide

[0449] A solution of 4-(2-(2-benzyl-4-methylphenoxy)ethyl)thiomorpholine (0.66 g, 2.02 mmol) in ethanol (10 mL) was treated with NaIO at 5 °C. 4 (0.45 g, 2.1 mmol, 1.04 equiv.) and allowed to warm to room temperature. After 15 h, the mixture was filtered, diluted with EtOAc (50 mL), washed with water (50 mL), brine (50 mL), and washed with MgSO 4 The crude product was purified by flash column chromatography on silica gel with a gradient of EtOAc in hexane to give 4-(2-(2-benzyl-4-methylphenoxy)ethyl)thiomorpholine 1-oxide (0.36 g, 1.05 mmol, 52% yield) as a yellow liquid. GC / MS (EI, 70 eV) m / z (%): 343 (9, [M] + ), 326(16), 165(12), 132(16), 116(100), 91(18), 88(26), 77(11), 56(32), 55(10), 42(11). 1 H NMR (400 MHz, CDCl 3): δ=7.12-7.28 (m, 5H), 6.99 (dd, J=8.2, 1.7Hz, 1H), 6.93 (d, J=2.0Hz, 1H), 6.74 (d, J=8.2Hz, 1H), 4.03 (t , J=5.3Hz, 2H), 3.94 (s, 2H), 3.07-3.16 (m, 2H), 2.81 (t, J=5.3Hz, 2H), 2.66-2.78 (m, 6H), 2.25ppm (s, 3H). 13 CNMR (101MHz, CDCl 3 ): δ=154.4, 141.2, 131.6, 130.1, 129.1, 128.6, 128.2, 127.8, 125.8, 111.4, 66.7, 57.2, 46.8, 44.9, 36.2, 20.5ppm.

[0450] Example 17: 1-(2-(2-(4-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride

[0451] Prepared in a similar sequence to Example 12 from 2-(4-chlorobenzyl)-4-methylphenol, ethyl 2-chloroacetate and 1-methylpiperazine to give 1-(2-(2-(4-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine which was precipitated as the hydrochloride salt according to the method described in Example 13 to give 1-(2-(2-(4-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride as a white solid. LC-MS (ESI+): 359 ([M+H] + ). 13 C NMR (101 MHz, CDCl 3 ): δ=152.9, 139.8, 132.6, 131.6, 131.3, 129.8, 128.8, 128.7, 127.3, 111.4, 62.8, 56.4, 49.7, 49.0, 42.9, 36.0, 20.5ppm.

[0452] Example 18: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-ethylpiperazine hydrochloride

[0453] Prepared in a similar sequence to Example 12 from 2-benzyl-4-methylphenol, ethyl 2-chloroacetate and 1-ethylpiperazine to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-ethylpiperazine, which was precipitated as the hydrochloride salt according to the method described in Example 13 to give 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-ethylpiperazine hydrochloride as a white solid. LC-MS (ESI+): 339 ([M+H]+ ). 1 H NMR (400MHz, DMSO-d6): δ=11.82-12.38(m, 1H), 7.27-7.36(m, 2H), 7.15-7.26(m, 3H ), 7.03 (dd, J=8.2, 1.8Hz, 1H), 6.96 (d, J=1.7Hz, 1H), 6.91 (d, J=8.3Hz, 1H), 4.39 (br s, 2H), 3.95 (s, 2H), 3.34-3.80 (m, 10H), 3.17 (br s, 2H), 2.21 (s, 3H), 1.28ppm (t, J=7.2Hz, 3H).

[0454] Example 19: 4-(2-(2-ethyl-6-(2-fluorobenzyl)-4-methylphenoxy)ethyl)morpholine

[0455] Example 19a: 2-Ethyl-4-methylphenyl 2-fluorobenzoate

[0456] A solution of 2-ethyl-4-methylphenol (4.16 g, 30.5 mmol) in DCM (30 ml) was treated with 2-fluorobenzoyl chloride (4.01 ml, 33.6 mmol) at 0°C, followed by the dropwise addition of triethylamine (4.26 ml, 30.5 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then poured into ice-cold 1 M aqueous HCl (100 mL), extracted with MTBE (2×100 mL), washed with brine (50 mL), and precipitated with MgSO 4 Drying and concentration under reduced pressure gave 2-ethyl-4-methylphenyl 2-fluorobenzoate (7.9 g, 30.5 mmol, quantitative) as a pale yellow liquid, which was used in the next step without further purification. GC / MS (EI, 70 eV) m / z (%): 258 (6, [M] + ), 135(2), 124(8), 123(100), 115(2), 95(17), 91(6), 77(3), 75(6), 65(2). 1 HNMR (400 MHz, CDCl 3 ): δ=8.14 (td, J=7.5, 1.8Hz, 1H), 7.59-7.66 (m, 1H), 7.31 (td, J=7.6, 1.2Hz, 1H), 7.24 (ddd, J=10.8, 8.3, 1.0H z, 1H), 7.14 (d, J=1.2Hz, 1H), 7.07-7.09 (m, 2H), 2.62 (q, J=7.6Hz, 2H), 2.39 (s, 3H), 1.24ppm (t, J=7.6Hz, 3H).

[0457] Example 19b: (3-ethyl-2-hydroxy-5-methylphenyl)(2-fluorophenyl)methanone

[0458] A solution of 2-ethyl-4-methylphenyl 2-fluorobenzoate (1.00 g, 3.87 mmol) in chlorobenzene (1 ml) was treated with aluminum chloride (1.03 g, 7.7 mmol) in one portion and the mixture was heated to reflux (oil bath at 150 °C) for 1 hour. The resulting mixture was cooled to room temperature and poured into ice-cold 1 M aqueous HCl (20 mL), extracted with MTBE (3 × 20 mL), washed with brine (30 mL), and washed with MgSO 4 Drying and concentration under reduced pressure gave a material which was purified by flash column chromatography on silica gel eluting with a gradient of EtOAc in hexanes to give (3-ethyl-2-hydroxy-5-methylphenyl)(2-fluorophenyl)methanone (1.0 g, 3.87 mmol, quantitative) as a pale yellow liquid which was used in the next step without further purification. GC / MS (EI, 70 eV) m / z (%): 258 (82, [M] + ), 257(36), 163(37), 147(67), 135(29), 134(83), 123(100), 95(64), 91(45), 75(24).

[0459] Example 19c: 2-Ethyl-6-(2-fluorobenzyl)-4-methylphenol

[0460] A solution of (3-ethyl-2-hydroxy-5-methylphenyl)(2-fluorophenyl)methanone (1.00 g, 3.87 mmol) in ethanol (12 ml) was treated with sodium borohydride (0.146 g, 3.87 mmol) at 0°C and allowed to reach room temperature. After 30 minutes, the mixture was poured into saturated NH 4 The mixture was added to an aqueous solution of Cl (50 mL), extracted with MTBE (2 × 100 mL), washed with brine (50 mL), and precipitated with MgSO 4 The resulting material was dissolved in DCM (10 ml) and treated with triethylsilane (1.841 ml, 11.52 mmol) at 0°C, followed by TFA (0.888 ml, 11.52 mmol). The resulting yellow mixture was stirred at room temperature for 15 hours and then poured into ice-cold saturated NaHCO 3 The mixture was added to an aqueous solution (50 mL), extracted with MTBE (2 × 100 mL), washed with brine (50 mL), and precipitated with MgSO 4The crude product was purified by flash column chromatography on silica gel using a gradient of EtOAc in hexane to give 2-ethyl-6-(2-fluorobenzyl)-4-methylphenol (0.94 g, 3.84 mmol, quantitative) as a yellow liquid. GC / MS (EI, 70 eV) m / z (%): 244 (100, [M] + ), 215(25), 148(63), 135(41), 133(98), 109(61), 105(52), 96(48), 91(33), 77(24). 1 H NMR (400 MHz, CDCl 3 ): δ=7.03-7.28 (m, 4H), 6.88 (d, J=2.0Hz, 1H), 6.83 (s, 1H), 4.63 (d, J=2.2Hz, 1 H), 3.99 (s, 2H), 2.61 (q, J=7.6Hz, 2H), 2.26 (s, 3H), 1.25ppm (t, J=7.6Hz, 3H).

[0461] Example 19d: 4-(2-(2-ethyl-6-(2-fluorobenzyl)-4-methylphenoxy)ethyl)morpholine

[0462] A solution of 2-ethyl-6-(2-fluorobenzyl)-4-methylphenol (0.939 g, 3.84 mmol) in isopropanol (7 ml) was treated with 4-(2-chloroethyl)morpholine hydrochloride (1.073 g, 5.77 mmol) and then with KOH (0.647 g, 11.53 mmol) at room temperature. The resulting pale yellow mixture was heated at reflux for 15 hours, then cooled to room temperature and poured into dilute NH 4 Cl aqueous solution (100 mL), extracted with MTBE (2×100 mL), washed with water (50 mL), brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. The resulting material was subjected to silica gel flash column chromatography, eluting with a gradient of EtOAc in hexane to give 4-(2-(2-ethyl-6-(2-fluorobenzyl)-4-methylphenoxy)ethyl)morpholine (0.83 g, 2.33 mmol, 61% yield) as a colorless liquid. GC / MS (EI, 70 eV) m / z (%): 357 (1, [M] + ), 270(5), 114(21), 109(10), 101(6), 100(100), 70(3), 56(7), 55(4), 42(5), 28(4). 1 H NMR (400 MHz, CDCl 3): δ=7.16-7.24 (m, 1H), 7.02-7.15 (m, 3H), 6.93 (d, J=1.7Hz, 1H), 6.73 (d, J=2.0Hz, 1H), 4.06 (s, 2H), 3.88 (t, J=5.7Hz, 2H) , 3.71-3.78 (m, 4H), 2.77 (t, J=5.7Hz, 2H), 2.69 (q, J=7.6Hz, 2H), 2.50-2.60 (m, 4H), 2.26 (s, 3H), 1.26ppm (t, J=7.6Hz, 3H).

[0463] Example 20: 1-(2-(2-benzyl-4-chlorophenoxy)ethyl)-4-methylpiperazine hydrochloride

[0464] Prepared in a similar order to Example 12 from 2-benzyl-4-chlorophenol, ethyl 2-chloroacetate and 1-methylpiperazine to give 1-(2-(2-benzyl-4-chlorophenoxy)ethyl)-4-methylpiperazine which was precipitated as the hydrochloride salt according to the method described in Example 13 to give 1-(2-(2-benzyl-4-chlorophenoxy)ethyl)-4-methylpiperazine hydrochloride as a white solid.

[0465] Example 21: 1-(2-(2-benzyl-4-chlorophenoxy)ethyl)-4-ethylpiperazine hydrochloride

[0466] Prepared in a similar order to Example 12 from 2-benzyl-4-chlorophenol, ethyl 2-chloroacetate and 1-ethylpiperazine to give 1-(2-(2-benzyl-4-chlorophenoxy)ethyl)-4-ethylpiperazine which was precipitated as the hydrochloride salt according to the method described in Example 13 to give 1-(2-(2-benzyl-4-chlorophenoxy)ethyl)-4-ethylpiperazine hydrochloride as a white solid.

[0467] Example 22: 1-(2-(2-Benzylphenoxy)ethyl)-4-methylpiperazine hydrochloride

[0468] Prepared in a similar order to Example 12 from 2-benzylphenol, ethyl 2-chloroacetate and 1-methylpiperazine to give 1-(2-(2-benzylphenoxy)ethyl)-4-methylpiperazine which was precipitated as the hydrochloride salt according to the method described in Example 13 to give 1-(2-(2-benzylphenoxy)ethyl)-4-methylpiperazine hydrochloride as a white solid.

[0469] Example 23: 4-(2-(2-Benzyl-4-methylphenoxy)ethyl)-1,2,6-trimethylpiperazine

[0470] Example 23a: Ethyl 2-(2-benzyl-4-methylphenoxy)acetate

[0471] A solution of 2-benzyl-4-methylphenol (3.00 g, 15.0 mmol, 1.0 equiv.) in 35 ml of DMF (dimethylformamide) was treated with potassium carbonate (6.22 g, 45.0 mmol, 3.0 equiv.) and then 2.0 ml of ethyl 2-chloroacetate (2.206 g, 18.0 mmol, 1.2 equiv.) was added. The yellow suspension was heated to 60° C. for 3 h. The reaction mixture was then poured into ice water and extracted twice with MTBE. The organic layer was washed twice with water and MgSO 4 The volatiles were dried and removed under vacuum. The crude product was purified by flash column chromatography using a gradient of 0-40% EtOAc / hexanes to give ethyl 2-(2-benzyl-4-methylphenoxy)acetate (3.93 g, 88% yield). GC / MS (EI): m / z (%): (EI, 70 eV): 284 (62, [M]+·), 197 (100), 196 (23), 195 (91), 182 (16), 181 (27), 166 (18), 165 (56), 152 (24), 91 (79).

[0472] Example 23b: 2-(2-Benzyl-4-methylphenoxy)ethan-1-ol

[0473] Ethyl 2-(2-benzyl-4-methylphenoxy)acetate (3.9 g, 13.72 mmol, 1.0 eq.) and 32 ml of methanol were charged into a 250 ml 2-neck round bottom flask. The mixture was cooled to 5 °C and NaBH 4 (0.315 gm, 0.5 equiv., 8.32 mmol) and stirred at ambient temperature for 1 hour. The reaction was poured into 50 ml of saturated NaHCO 3 The aqueous layer was washed with H 2 O and extracted twice with MTBE. The combined organic layers were washed with MgSO 4 Dry, filter, evaporate the volatiles, and dry the product under high vacuum to give 3.59 g of 2-(2-benzyl-4-methylphenoxy)ethanol (89% yield). GC / MS (EI): m / z (%): (EI, 70 eV): 242 (24, [M]+·), 198 (24), 165 (31), 152 (18), 120 (74), 92 (46), 91 (100), 77 (26), 65 (24), 45 (41).

[0474] Example 23c: 2-Benzyl-1-(2-bromoethoxy)-4-methylbenzene

[0475] In a 250 mL 2-neck round bottom flask, CBr 4(5.75 g, 17.33 mmol, 1.2 equiv.) was added to 2-(2-benzyl-4-methylphenoxy)ethanol (3.5 g, 14.44 mmol, 1.0 equiv.) and PPh at 0-5 °C. 3 (4.55 g, 17.33 mmol, 1.2 equiv.) in 45 ml CH 3 The reaction was stirred at ambient temperature for 3 hours. The volatiles were then removed and the residue was dissolved in heptane and 4:1 MeOH / H 2 O mixture. The organic layer was washed with MeOH / H 2 The mixture was washed three times with 4:1 MgSO4 and the aqueous layer was re-extracted with heptane. The combined organic layers were washed with MgSO4:1 MgSO4. 4 Dry, filter and remove volatiles under reduced pressure. The product was then dried under high vacuum to give 4.88 g of 2-benzyl-1-(2-bromoethoxy)-4-methylbenzene (90% purity, 100% yield), which was used without further purification. GC / MS (EI): m / z (%): (EI, 70 eV): 306 (50), 304 (51, [M]+·), 197 (100), 165 (48), 154 (36), 153 (34), 152 (41), 120 (88), 117 (46), 91 (65).

[0476] Example 23d: 4-(2-(2-Benzyl-4-methylphenoxy)ethyl)-1,2,6-trimethylpiperazine

[0477] To a suspension of NaH (0.15 g, 3.28 mmol, 1.2 equiv.) in 3 ml of DMF was added 1,2,6-trimethylpiperazine (0.35 g, 2.72 mmol, 1.0 equiv.) in 1 ml of DMF at 3°C ​​and the solution was stirred at ambient temperature for 20 min. 2-Benzyl-1-(2-bromoethoxy)-4-methylbenzene (1.0 g, 3.28 mmol, 1.2 equiv.) in 2 ml of DMF was added at 3°C ​​and the reaction mixture was further stirred at ambient temperature for 5 hours. The mixture was then cooled to 3°C and treated with saturated NaHCO 3 Dilute and pour in 25ml H 2 O. The product was extracted twice with EtOAc and 2 O. The organic layer was washed with MgSO 4 The volatiles were dried and evaporated. A gradient of 10-100% EtOAc / EtOH / NH 4A mixture of OH (90:9:1) in hexanes was purified by flash column chromatography to give 4-(2-(2-benzyl-4-methylphenoxy)ethyl)-1,2,6-trimethylpiperazine (0.37 g, 32% yield) as a light yellow liquid. 1 H NMR (500 MHz, CDCl 3 )δ (ppm) = 7.32-7.22 (m, 4H), 7.21-7.15 (m, 1H), 7.02-6.96 (m, 1H), 6.93 (d, J = 2.1Hz, 1H), 6.77 (d, J = 8.2Hz, 1H), 4.07 (t, J = 5.8Hz, 2H), 3.96 ( s, 2H), 2.88-2.81 (m, 2H), 2.72 (t, J=5.8Hz, 2H), 2.31-2.24 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 2.05 (t, J=11.0Hz, 2H), 1.08 (d, J=6.4Hz, 6H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=154.5, 141.3, 131.2, 129.8, 129.6, 128.9, 128.2, 127.6, 125.7, 111.6, 66.5, 61.7, 57.9, 57.1, 37.9, 36.0, 20.5, 18.3. GC / MS (EI): m / z (%): (EI, 70eV): 352 (1, [M] + ·), 155 (66, [M] + ·), 142 (10), 141 (100), 126 (18), 98 (9), 91 (10), 84 (27), 57 (16), 56 (23), 42 (18).

[0478] Example 24: 2-Benzyl-4-methylphenyl trifluoromethanesulfonate

[0479] In a 250 ml 3-neck round bottom flask, 2-benzyl-4-methylphenol (3.20 g, 16.14 mmol, 1.0 equiv.) and a catalytic amount of DMAP (N,N-dimethyl-4-aminopyridine, 0.3 g, 2.421 mmol, 0.15 equiv.) were added in 54 ml CH 2 Cl 2 The solution in was cooled to 0°C. 3.4 ml (24.21 mmol, 1.5 equiv.) of Et 3N, and then 4.1 ml of trifluoromethanesulfonic anhydride (6.83 g, 24.21 mmol, 1.5 equiv.) was added dropwise via syringe to give a dark red solution. The ice bath was then removed and the reaction was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated and washed with CH 2 Cl 2 Dilution and volatiles were evaporated again (3 times in total). The crude material was then purified by column chromatography using a gradient of 0-15% EtOAc / cyclohexane to give 2-benzyl-4-methylphenyl trifluoromethanesulfonate (4.83, 95% purity, 86% yield). GC / MS (EI): m / z (%): (EI, 70 eV): 330 (53, [M]+·), 197 (100), 182 (24), 181 (29), 169 (56), 165 (31), 154 (47), 153 (32), 152 (33), 91 (38).

[0480] Example 25: N,2-Dibenzyl-4-methylaniline

[0481] Cs 2 CO 3 (1.97 g, 6.05 mmol, 2.0 equiv.), 0.29 g (S)-BINAP (0.29 g, 0.45 mmol, 0.15 equiv.) and Pd(OAc) 2 (70 mg, 0.303 mmol, 0.1 equiv.) was added to a solution of 2-benzyl-4-methylphenyl trifluoromethanesulfonate (1.00 g, 3.03 mmol, 1.0 equiv.), benzylamine (0.97 g, 9.08 mmol, 3.0 equiv.) in 15 ml of toluene. The resulting red suspension was then purged with nitrogen at ambient temperature and then heated to 100 ° C with vigorous stirring. After 3 hours, the reaction mixture was cooled to ambient temperature. The mixture was then diluted with EtOAc and poured into H 2 O, and 12 ml of 1M HCl, H 2 O and brine. The aqueous layer was re-extracted with EtOAc and the organic layer was washed with MgSO 4 Dry, filter and evaporate the volatiles. The crude material was then purified by column chromatography using a gradient of 0-100% EtOAc / heptane to afford 0.67 g (76% yield) of N,2-dibenzyl-4-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 288 (10), 287 (41, [M]+·), 197 (16), 196 (100), 194 (21), 181 (33), 180 (37), 165 (11), 91 (66), 65 (16).

[0482] Example 26: 2-Benzyl-4-methylaniline

[0483] In a 250 ml 3-neck round bottom flask, 150 mg of Pd / C was added to N,2-dibenzyl-4-methylaniline in 25 mL of THF (tetrahydrofuran). The resulting solution was purged with argon three times and then filled with H 2 The balloon was purged 3 more times. The reaction was then stirred at ambient temperature under a hydrogen atmosphere from a freshly filled balloon. The mixture was then filtered through diatomaceous earth and washed with hexane. The volatiles of the mother liquor were evaporated and the crude product was dried under high vacuum. Purification by column chromatography using a gradient of 0-20% EtOAc / heptane gave 2-benzyl-4-methylaniline (0.8 g, 78% yield). GC / MS (EI): m / z (%): (EI, 70 eV): 198 (15), 197 (100, [M] + ·), 196 (25), 182 (46), 181 (17), 180 (22), 165 (26), 120 (34), 106 (19), 91 (19).

[0484] Example 27: N-(2-Benzyl-4-methylphenyl)-2-bromoacetamide

[0485] At 5 °C, 3 mL of Et 2 2-Bromoacetyl bromide (0.20 g, 1.0 mmol, 1.0 equiv.) in 0.5% CO was added to 3 mL of Et 2 2-Benzyl-4-methylaniline (0.20 g, 1.0 mmol, 1.0 equiv.) in 0, whereupon a white solid precipitated. The reaction was stirred at ambient temperature for 2 h. The suspension was then dissolved in CH 2 Cl 2 The mixture was washed twice with hydrochloric acid (2M) and then with CH 2 Cl 2 The organic layer was extracted with MgSO 4 The crude product was suspended in hexane, the solvent was filtered off and the solid was further washed with hexane. The off-white solid was dried to give 0.25 g of N-(2-benzyl-4-methylphenyl)-2-bromoacetamide (77% yield). GC / MS (EI): m / z (%): (EI, 70 eV): 317 (38, [M] + ·), 224 (55), 196 (100), 194 (63), 181 (51), 180 (81), 160 (83), 146 (57), 142 (38), 91 (77).

[0486] Example 28: N-(2-Benzyl-4-methylphenyl)-2-morpholinoacetamide

[0487] In a 100 mL 3-neck round bottom flask, N-(2-benzyl-4-methylphenyl)-2-bromoacetamide (0.35 g, 1.163 mmol, 1.0 equiv.), morpholine (1.0 mL, 1.1013 g, 11.63 mmol, 10 equiv.) and K 2 CO 3 A mixture of (0.32 g, 2.325 mmol, 2.0 equiv.) in 20 mL of toluene was refluxed overnight. The reaction mixture was then cooled to ambient temperature, filtered and the volatiles removed under reduced pressure. The crude product was then purified by flash column chromatography using a gradient of 10-100% EtOAc / heptane to give N-(2-benzyl-4-methylphenyl)-2-morpholinoacetamide (0.35 g, 93% yield) as an off-white solid. GC / MS (EI): m / z (%): (EI, 70 eV): 324 (2, [M]+·), 194 (3), 180 (3), 101 (7), 100 (100), 91 (3), 86 (3), 70 (3), 56 (10), 42 (5).

[0488] Example 29: 2-Benzyl-4-methyl-N-(2-morpholinoethyl)aniline

[0489] LiAlH 4 (0.16 g, 4.32 mmol, 4.0 equiv.) and 4 mL of THF were charged into a 250 mL 3-neck round bottom flask and cooled to 3-8° C. N-(2-benzyl-4-methylphenyl)-2-morpholinoacetamide (0.35 g, 1.1 mmol, 1.0 equiv.) in 6 ml of THF was added dropwise and then heated to 60° C. for 3 hours. As the reaction was not complete, another 3 equivalents (120 mg) of LiAlH 4 The reaction was then heated to 60 °C overnight. The reaction was cooled to 3 °C and 0.3 mL of H 2 O, then add 0.3 mL of NaOH (NaOH), and then add 0.9 mL of H 2 O. The ice bath was then removed and the mixture was stirred at ambient temperature for 10 minutes before sufficient MgSO 4 and stirred for another 5 minutes. The mixture was filtered and the volatiles were evaporated. Purification by flash column chromatography using a gradient of 40-100% EtOAc / heptane gave 2-benzyl-4-methyl-N-(2-morpholinoethyl)aniline (0.28 g, 84% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl 3)δ (ppm) = 7.35-7.28 (m, 2H), 7.27-7.19 (m, 3H), 7.07-7.00 (m, 1H), 6.94 (d, J = 2.0Hz, 1H), 6.59 (d, J = 8.1Hz, 1H), 4.17 (br s, 1H), 3.92 (s, 2H), 3.55 (t, J=4.4Hz, 4H), 3.11 (t, J=5.6Hz, 2H), 2.57 (dd, J=5.3, 6.5Hz, 2H), 2.35 (t, J=4.4Hz, 4H), 2.29 (s, 3H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=144.2, 139.8, 131.6, 128.6, 128.4, 128.1, 126.3, 126.2, 124.8, 110.9, 66.9, 57.0, 53.2, 40.2, 38.0, 20.4. GC / MS (EI): m / z (%): (EI, 70eV): 310(6, [M]+·), 211(6), 210(33), 132(9), 117(7), 105(4), 101(18), 100(100), 91(8), 56(10).

[0490] Example 30: 2-Benzyl-N,4-dimethyl-N-(2-morpholinoethyl)aniline

[0491] Paraformaldehyde (0.275 g, 8.7 mmol, 10 equiv.) was added to 2-benzyl-4-methyl-N-(2-morpholinoethyl)aniline (0.27 g, 0.87 mmol, 1.0 equiv.) in 6 ml AcOH (acetic acid) at ambient temperature and the mixture was stirred for 1 hour at ambient temperature. Sodium cyanoborohydride (0.26 g, 4.17 mmol, 4.8 equiv.) was added portionwise and the reaction was stirred overnight. The reaction was poured into 40 ml ice-cold NaOH (2 M) and extracted twice with DCM, washed with 40 ml pH 7 phosphate buffer, and washed with MgSO 4 The volatiles were dried and evaporated. A gradient of 10-100% EtOAc / EtOH / NH 4 A mixture of OH (90:9:1) in hexanes was purified by flash column chromatography to give 2-benzyl-N,4-dimethyl-N-(2-morpholinoethyl)aniline (0.22 g, 78% yield) as a light yellow liquid. 1 H NMR (400 MHz, CDCl 3)δ (ppm) = 7.22-7.29 (m, 2H), 7.13-7.20 (m, 3H), 7.08 (d, J = 8.1Hz, 1H), 7.00 (dd, J = 8.2, 1.8Hz, 1H), 6.91 (d, J = 2.0Hz , 1H), 4.05(s, 2H), 3.64(m, 4H), 2.93-3.04(m, 2H), 2.61(s, 3H), 2.37-2.41(m, 2H), 2.33-2.36(m, 4H), 2.24(s, 3H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=149.6, 141.9, 136.8, 133.5, 131.6, 129.0, 128.2, 127.7, 125.6, 121.3, 66.9, 56.9, 54.4, 54.0, 43.8, 36.6, 20.9. GC / MS (EI): m / z (%): (EI, 70eV): 324 (2, [M] +·), 225 (18), 224 (100), 208 (6), 165 (8), 132 (12), 131 (4), 117 (4), 100 (24), 91 (29), 56 (7).

[0492] Example 31: 2-Benzyl-4-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline

[0493] Prepared according to Example 29: using N-methylpiperazine instead of morpholine. N-(2-benzyl-4-methylphenyl)-2-(4-methylpiperazin-1-yl)acetamide (0.88 g, 2.61 mmol, 1.0 equiv.) in 20 ml THF was added to LiAlH 4 (0.44 g, 11.47 mmol, 4.4 equiv.). The reaction mixture was stirred at ambient temperature for 2 hours and further stirred at 60°C for 7 hours. The reaction mixture was then cooled with an ice bath and 0.5 ml of H 2 O, then add 0.5 ml of 3M NaOH, and then add 1.5 ml of H 2 O. The mixture was stirred at ambient temperature for 10 min, then MgSO 4 The mixture was stirred for 5 minutes. After filtration, the volatiles were removed under reduced pressure. A gradient of 10-100% EtOAc / EtOH / NH 4A mixture of OH (90:9:1) in hexanes was purified by flash column chromatography to give 2-benzyl-4-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline (0.7 g, 87% purity, 72% yield). 1 HNMR (400 MHz, CDCl 3 )δ (ppm) = 7.32-7.27 (m, 2H), 7.24-7.18 (m, 3H), 7.01 (dd, J = 1.7, 8.1Hz, 1H), 6.90 (d, J = 2.0Hz, 1H), 6.61-6.54 (m, 1H), 4.20 (br s, 1H), 3.92-3.85 (m, 2H), 3.09 (t, J=5.9Hz, 2H), 2.56 (t, J=5.9Hz, 2H), 2.52-2.30 (m, 8H), 2.27 (s, 3H), 2.27 (s, 3H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=144.3, 139.8, 131.4, 128.6, 128.5, 128.1, 126.2, 126.0, 124.9, 110.9, 56.5, 55.0, 52.7, 46.0, 40.6, 38.0, 20.4. GC / MS (EI): m / z (%): (EI, 70eV): 323 (3, [M] +·), 223 (14), 210 (8), 132 (6), 117 (5), 114 (16), 113 (100), 91 (8), 70 (37), 43 (7), 42 (10).

[0494] Example 32: 2-Benzyl-N,4-dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline

[0495] Prepared according to Example 30, using N-methylpiperazine instead of morpholine. To a solution of 2-benzyl-4-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline (0.17 g, 0.53 mmol, 1.0 equiv.) in 4 mL of AcOH was added paraformaldehyde (0.17 g, 5.26 mmol, 10.0 equiv.) and the mixture was stirred at ambient temperature for 1 hour. NaBH was then added portionwise. 3 CN (0.16 g, 2.52 mmol, 4.8 equiv.) and the reaction was stirred at ambient temperature overnight. The reaction was then poured onto 40 mL of ice-cold 2M NaOH (pH 14) and stirred with CH 2 Cl 2 The organic layer was then washed with 30 mL of pH 7 phosphate buffer (K 2 HPO4 Buffer / KH 2 PO 4 Buffer 2:1) and washed with MgSO 4 Dry, filter and remove volatiles under reduced pressure. Use a gradient of 10-100% EtOAc / EtOH / NH 4 A mixture of OH (90:9:1) in heptane was purified by flash column chromatography to give 2-benzyl-N,4-dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline (0.14 g, 79% yield) as a yellow liquid. 1 H NMR (400 MHz, CDCl 3 )δ (ppm) = 7.24-7.31 (m, 2H), 7.16-7.23 (m, 3H), 7.10 (d, J = 8.1Hz, 1H), 7.02 (dd, J = 8.1, 2.0Hz, 1H), 6 .93(d, J=2.0Hz, 1H), 4.08(s, 2H), 2.97-3.04(m, 2H), 2.63(s, 3H), 2.40-2.45(m, 2H), 2.33-2.51(br m, 8H), 2.27-2.29 (m, 3H), 2.26-2.27 (m, 3H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=149.7, 141.9, 136.8, 133.4, 131.5, 129.0, 128.2, 127.6, 125.6, 121.3, 56.5, 55.1, 54.7, 53.4, 46.0, 43.8, 36.6, 20.9. GC / MS (EI): m / z (%): (EI, 70eV): 337 (1, [M] +·), 237 (23), 225 (17), 224 (92), 165 (10), 132 (14), 113 (100), 91 (30), 70 (45), 43 (11), 42 (15).

[0496] Example 33: N-(2,6-difluorobenzyl)-4-methylaniline

[0497] In a 100 mL 3-neck round-bottom flask, p-methylaniline (8.6 g, 80 mmol, 4.0 equiv.), NaHCO 3 (2.11 g, 25 mmol, 1.25 equiv.) and 2 mL H 2O was heated to 95°C. 2,6-Difluorobenzyl chloride (3.26 g, 20 mmol, 1.0 equiv.) was added portionwise at 95°C over 45 minutes. The brown mixture was then stirred at 95°C for 2 hours and then cooled to 50°C. The hot mixture was filtered and washed with EtOAc and brine. The organic layer was washed with MgSO 4 Dry, filter and evaporate the volatiles and further dry under high vacuum. Purify by flash column chromatography using a gradient of 0-10% EtOAc / heptane to give N-(2,6-difluorobenzyl)-4-methylaniline (4.32 g, 92% yield) as a yellow liquid. GC / MS (EI): m / z (%): (EI, 70 eV): 233 (48, [M]+·), 232 (21), 127 (100), 120 (17), 107 (9), 106 (31), 101 (10), 91 (10), 79 (13), 77 (24).

[0498] Example 34: 2-(2,6-difluorobenzyl)-4-methylaniline

[0499] In a 15 mL Ace pressure tube, place N-(2,6-difluorobenzyl)-4-methylaniline (1.0 g, 4.29 mmol, 1.0 equiv.) and 1.2 mL of p-methylaniline. Heat the mixture to 190 °C, then add AlCl 3 (0.17 g, 1.29 mmol, 0.3 eq) at which point the solution turned green-black. The reaction was heated to 200 °C overnight and the resulting dark blue mixture was cooled to ambient temperature. The mixture was poured into excess NaOH (2 M) and extracted twice with EtOAc, then washed with brine. The combined organic layers were washed with MgSO 4 Dry, filter and evaporate the volatiles. Purify by flash column chromatography using a gradient of 0-10% EtOAc / heptane to give 2-(2,6-difluorobenzyl)-4-methylaniline (0.31 g, 20% yield) as a red solid. GC / MS (EI): m / z (%): (EI, 70 eV): 234 (15), 233 (100, [M]+·), 232 (15), 218 (12), 212 (39), 198 (31), 127 (27), 120 (25), 106 (47), 77 (18).

[0500] Example 35: 2-Bromo-N-(2-(2,6-difluorobenzyl)-4-methylphenyl)acetamide

[0501] Prepared according to Example 27, using 2-(2,6-difluorobenzyl)-4-methylaniline instead of 2-benzyl-4-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 355 (33), 353 (30, [M]+·), 274 (24), 260 (50), 212 (100), 211 (25), 146 (46), 127 (55), 93 (21), 42 (30).

[0502] Example 36: N-(2-(2,6-difluorobenzyl)-4-methylphenyl)-2-morpholinoacetamide

[0503] Prepared according to Example 28, using 2-bromo-N-(2-(2,6-difluorobenzyl)-4-methylphenyl)acetamide instead of N-(2-benzyl-4-methylphenyl)-2-bromoacetamide. GC / MS (EI): m / z (%): (EI, 70 eV): 360 (2, [M] +·), 212 (4), 127 (4), 101 (6), 100 (100), 86 (3), 70 (3), 56 (6), 43 (2), 42 (6), 28 (3).

[0504] Example 37: 2-(2,6-difluorobenzyl)-4-methyl-N-(2-morpholinoethyl)aniline

[0505] Prepared according to Example 29, substituting N-(2-(2,6-difluorobenzyl)-4-methylphenyl)-2-morpholinoacetamide (0.72 g, 2.0 mmol, 1.0 equiv.) for N-(2-benzyl-4-methylphenyl)-2-morpholinoacetamide, to afford 0.22 g (32% yield) of 2-(2,6-difluorobenzyl)-4-methyl-N-(2-morpholinoethyl)aniline. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 7.21 (tt, J = 6.4, 8.4Hz, 1H), 6.96 (dd, J = 1.5, 8.5Hz, 1H), 6.90 (t, J = 7.9Hz, 2H), 6.80 (s, 1H), 6.57 (d, J = 8.3Hz, 1H), 4.53 (br s, 1H), 3.85 (s, 2H), 3.77-3.71 (m, 4H), 3.19 (t, J=5.9Hz, 2H), 2.74-2.66 (m, 2H), 2.56-2.46 (m, 4H), 2.21 (s, 3H). 13 C NMR (101 MHz, CDCl 3)δ(ppm)=161.7, 143.8, 141.1, 130.0, 128.0, 126.2, 122.9, 115.4, 111.3, 110.9, 67.1, 57.1, 53.4, 40.6, 23.8, 20.5. GC / MS (EI): m / z (%): (EI, 70eV): 346 (5, [M] +·), 247 (5), 246 (30), 245 (4), 132 (6), 127 (9), 117 (6), 101 (19), 100 (100), 56 (5).

[0506] Example 38: 2-(2,6-difluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline

[0507] Prepared according to Example 30, substituting 2-(2,6-difluorobenzyl)-4-methyl-N-(2-morpholinoethyl)aniline (0.21 g, 0.61 mmol, 1.0 equiv.) for benzyl-4-methyl-N-(2-morpholinoethyl)aniline, to afford 0.184 g (84% yield) of 2-(2,6-difluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline. 1 H NMR (400 MHz, CDCl 3 )δ (ppm) = 7.24-7.15 (m, 1H), 7.09 (d, J = 8.1Hz, 1H), 7.00 (dd, J = 1.7, 8.1Hz, 1H), 6.94-6.84 (m, 2H), 6. 71 (s, 1H), 4.12 (s, 2H), 3.76-3.66 (m, 4H), 3.14-3.04 (m, 2H), 2.67 (s, 3H), 2.44 (s, 6H), 2.21 (s, 3H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=161.9, 149.1, 135.2, 133.7, 129.5, 127.7, 127.6, 121.3, 117.0, 111.1, 66.9, 56.9, 54.0, 44.2, 23.2, 21.0. GC / MS (EI): m / z (%): (EI, 70eV): 360 (1, [M] +·), 261 (18), 260 (100), 244 (4), 201 (4), 133 (4), 132 (18), 128 (3), 127 (43), 117 (4), 100 (19).

[0508] Example 39: N-(2,6-difluorobenzyl)-2,4-dimethylaniline

[0509] Prepared according to Example 33, using 2,4-dimethylaniline instead of p-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): MS (EI, 70 eV): 248 (6), 247 (35, [M] +·), 246 (7), 134 (7), 127 (35), 121 (9), 120 (100), 118 (5), 91 (12), 77 (14).

[0510] Example 40: 2-(2,6-difluorobenzyl)-4,6-dimethylaniline

[0511] Prepared according to Example 34, using N-(2,6-difluorobenzyl)-2,4-dimethylaniline instead of N-(2,6-difluorobenzyl)-4-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 248 (16), 247 (100, [M]+·), 246 (13), 232 (20), 226 (29), 212 (33), 134 (20), 127 (15), 120 (63), 91 (14).

[0512] Example 41: 2-Bromo-N-(2-(2,6-difluorobenzyl)-4,6-dimethylphenyl)acetamide

[0513] Prepared according to Example 27, substituting 2-(2,6-difluorobenzyl)-4,6-dimethylaniline for 2-benzyl-4-methylaniline. 1 H NMR (400 MHz, CDCl 3 )δ (ppm) = 7.88-7.76 (m, 1H), 7.19 (tt, J = 6.6, 8.3Hz, 1H), 0.00 (d, J = 12.7Hz, 2H), 0.0 0 (t, J=7.8Hz, 2H), 4.11 (s, 2H), 3.93 (s, 2H), 3.87 (s, 1H), 2.26 (s, 3H), 2.21 (s, 3H).

[0514] Example 42: N-(2-(2,6-difluorobenzyl)-4,6-dimethylphenyl)-2-morpholinoacetamide Prepared according to Example 28, substituting 2-bromo-N-(2-(2,6-difluorobenzyl)-4,6-dimethylphenyl)acetamide for N-(2-benzyl-4-methylphenyl)-2-bromoacetamide. 1 H NMR (400 MHz, CDCl 3)δ (ppm) = 8.70 (s, 1H), 7.18 (tt, J = 8.3, 6.6Hz, 1H), 6.93 (s, 1H), 6.84-6.91 (m, 3H), 3.91 ( s, 2H), 3.74-3.79 (m, 4H), 3.20-3.27 (m, 2H), 2.68-2.74 (m, 4H), 2.23 (s, 3H), 2.18 (s, 3H) 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=168.9, 161.4(2), 137.3, 135.7, 135.3, 130.4, 130.0, 128.3, 128.0(2), 111.3(2), 67.1(2), 62.1, 54.2(2), 24.5, 21.0, 18.8.

[0515] Example 43: 2-(2,6-difluorobenzyl)-4,6-dimethyl-N-(2-morpholinoethyl)aniline

[0516] Prepared according to Example 29, using N-(2-(2,6-difluorobenzyl)-4,6-dimethylphenyl)-2-morpholinoacetamide (0.34 g, 0.91 mmol, 1.0 equiv.) instead of benzyl-4-methyl-N-(2-morpholinoethyl)aniline, 0.143 g (43% yield) of 2-(2,6-difluorobenzyl)-4,6-dimethyl-N-(2-morpholinoethyl)aniline was obtained. GC / MS (EI): m / z (%): (EI, 70 eV): 360 (6, [M]+·), 261 (9), 260 (44), 259 (16), 131 (6), 127 (11), 101 (14), 100 (100), 56 (8), 42 (7).

[0517] Example 44: 2-(2,6-difluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline

[0518] Prepared according to Example 30, substituting 2-(2,6-difluorobenzyl)-4,6-dimethylaniline (0.14 g, 0.39 mmol, 1.0 equiv.) for 2-benzyl-4-methylaniline, to afford 0.104 g (70% yield) of 2-(2,6-difluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline. 1 H NMR (400 MHz, CDCl 3)δ (ppm) = 7.13-7.26 (m, 1H), 6.91 (t, J = 7.8Hz, 2H), 6.83 (d, J = 1.0Hz, 1H), 6.53 (s, 1H ), 4.04-4.18(m, 2H), 3.73(t, J=4.7Hz, 4H), 2.81(s, 3H), 2.37-2.61(m, 8H), 2.30(s, 3 H), 2.18 (s, 3 H). 13 C NMR (101 MHz, CDCl 3 ) δ (ppm)=161.7 (2), 146.1, 137.1, 134.9, 134.8, 130.5, 127.6, 127.0, 117.3, 111.1(2), 66.8(2), 58.0, 53.9(2), 53.0, 40.8, 24.3, 20.9, 19.2.

[0519] GC / MS (EI): m / z (%): (EI, 70eV): 374 (1, [M] +·), 275 (20), 274 (100), 201 (4), 146 (14), 131 (5), 127 (14), 100 (35), 56 (7), 42 (7), 28 (5).

[0520] Example 45: N-(2-fluorobenzyl)-4-methylaniline

[0521] Prepared according to Example 33, substituting 2-fluorobenzyl chloride for 2,6-difluorobenzyl chloride. GC / MS (EI): m / z (%): (EI, 70 eV): 215 (44, [M]+·), 214 (19), 120 (19), 110 (8), 109 (100), 106 (16), 91 (11), 83 (14), 79 (8), 77 (16).

[0522] Example 46: 2-(2-Fluorobenzyl)-4-methylaniline

[0523] Prepared according to Example 34, using N-(2-fluorobenzyl)-4-methylaniline instead of N-(2,6-difluorobenzyl)-4-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 216 (15), 215 (100, [M]+·), 200 (17), 194 (52), 183 (16), 180 (29), 120 (30), 109 (18), 106 (30), 77 (16).

[0524] Example 47: 2-Bromo-N-(2-(2-fluorobenzyl)-4-methylphenyl)acetamide

[0525] Prepared according to Example 27, using 2-(2-fluorobenzyl)-4-methylaniline instead of 2-benzyl-4-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 337 (28), 335 (28, [M]+·), 242 (50), 198 (29), 194 (100), 146 (43), 123 (29), 121 (32), 109 (52), 42 (27).

[0526] Example 48: N-(2-(2-fluorobenzyl)-4-methylphenyl)-2-morpholinoacetamide

[0527] Prepared according to Example 28, using 2-bromo-N-(2-(2-fluorobenzyl)-4-methylphenyl)acetamide instead of N-(2-benzyl-4-methylphenyl)-2-bromoacetamide. GC / MS (EI): m / z (%): (EI, 70 eV): 342 (3, [M] +·), 194 (4), 146 (3), 109 (3), 101 (6), 100 (100), 70 (2), 56 (6), 42 (5), 28 (3).

[0528] Example 49: 2-(2-Fluorobenzyl)-4-methyl-N-(2-morpholinoethyl)aniline

[0529] Prepared according to Example 29, using N-(2-(2-fluorobenzyl)-4-methylphenyl)-2-morpholinoacetamide (0.38 g, 1.11 mmol, 0.1 equiv.) instead of benzyl-4-methyl-N-(2-morpholinoethyl)aniline, 0.092 g (25% yield) of 2-(2-fluorobenzyl)-4-methyl-N-(2-morpholinoethyl)aniline was obtained. GC / MS (EI): m / z (%): (EI, 70 eV): 328 (5, [M]+·), 229 (5), 228 (28), 132 (6), 117 (6), 109 (8), 105 (4), 101 (18), 100 (100), 56 (7).

[0530] Example 50: 2-(2-Fluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline

[0531] Prepared according to Example 30, substituting 2-(2-fluorobenzyl)-4-methyl-N-(2-morpholinoethyl)aniline (0.37 g, 0.013 mmol, 1.0 equiv.) for benzyl-4-methyl-N-(2-morpholinoethyl)aniline, to afford 0.38 g (98% yield) of 2-(2-fluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline. 1 H NMR (400 MHz, CDCl 3)δ (ppm) = 7.22-7.14 (m, 1H), 7.12-7.09 (m, 1H), 7.08-7.00 (m, 4H), 6.92-6.87 (m, 1H), 4.09 (s, 2H), 3.70-3.64 (m, 4H), 3.04-2.98 (m, 2H), 2.63 (s, 3H), 2.44-2.35 (m, 6H), 2.26 (s, 3H) 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=161.2, 149.6, 135.7, 133.6, 131.2, 131.1, 128.7, 127.9, 127.4, 123.8, 121.4, 115.1, 66.9, 56.9, 54.4, 54.0, 43.8, 29.5, 20.9

[0532] GC / MS (EI): m / z (%): (EI, 70eV): 342(2, [M]+·), 243(19), 242(100), 226(5), 183(8), 132(16), 131(4), 117(4), 109(34), 100(25), 56(4).

[0533] Example 51: N-(2-fluorobenzyl)-2,4-dimethylaniline

[0534] Prepared according to Example 33, substituting 2-fluorobenzyl chloride for 2,6-difluorobenzyl chloride and 2,4-dimethylaniline for p-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 229 (54, [M] +·), 228 (12), 134 (14), 121 (10), 120 (100), 118 (10), 109 (96), 91 (19), 83 (17), 77 (20).

[0535] Example 52: 2-(2-Fluorobenzyl)-4,6-dimethylaniline

[0536] Prepared according to Example 34, substituting N-(2-fluorobenzyl)-2,4-dimethylaniline for N-(2,6-difluorobenzyl)-4-methylaniline and 2,4-dimethylaniline for p-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 230 (16), 229 (100, [M]+·), 214 (18), 208 (32), 194 (32), 134 (24), 120 (34), 109 (24), 91 (17), 77 (11).

[0537] Example 53: 2-Bromo-N-(2-(2-fluorobenzyl)-4,6-dimethylphenyl)acetamide

[0538] Prepared according to Example 27, using 2-(2-fluorobenzyl)-4,6-dimethylaniline instead of 2-benzyl-4-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 351 (38), 349 (36, [M]+·), 256 (86), 212 (31), 208 (100), 160 (77), 123 (38), 121 (39), 109 (63), 42 (32).

[0539] Example 54: N-(2-(2-fluorobenzyl)-4,6-dimethylphenyl)-2-morpholinoacetamide

[0540] Prepared according to Example 28, using 2-bromo-N-(2-(2-fluorobenzyl)-4,6-dimethylphenyl)acetamide instead of N-(2-benzyl-4-methylphenyl)-2-bromoacetamide. GC / MS (EI): m / z (%): (EI, 70 eV): 356 (3, [M] +·), 208 (3), 109 (3), 101 (6), 100 (100), 86 (2), 70 (3), 56 (6), 42 (4), 28 (2).

[0541] Example 55: 2-(2-Fluorobenzyl)-4,6-dimethyl-N-(2-morpholinoethyl)aniline

[0542] Prepared according to Example 29, using N-(2-(2-fluorobenzyl)-4,6-dimethylphenyl)-2-morpholinoacetamide (1.0 g, 2.8 mmol, 1.0 equiv.) instead of benzyl-4-methyl-N-(2-morpholinoethyl)aniline, 0.47 g (47% yield) of 2-(2-fluorobenzyl)-4,6-dimethyl-N-(2-morpholinoethyl)aniline was obtained. GC / MS (EI): m / z (%): (EI, 70 eV): 342 (6, [M]+·), 243 (10), 242 (58), 241 (21), 183 (6), 146 (7), 131 (11), 109 (16), 101 (14), 100 (100), 56 (8).

[0543] Example 56: 2-(2-Fluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline

[0544] Prepared according to Example 30, substituting 2-(2-fluorobenzyl)-4,6-dimethyl-N-(2-morpholinoethyl)aniline (0.46 g, 1.34 mmol, 1.0 equiv.) for benzyl-4-methyl-N-(2-morpholinoethyl)aniline, to afford 0.38 g (79% yield) of 2-(2-fluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline. 1 H NMR (400 MHz, CDCl 3 )δ (ppm) = 7.21-7.14 (m, 1H), 7.04 (d, J = 9.0Hz, 1H), 7.03-6.99 (m, 2H), 6.87 (d, J = 2.0Hz, 1H), 6.74 (d, J = 1.5Hz, 1H), 4.07 (s, 2H), 3.68(t, J=4.6Hz, 4H), 3.22-3.02(m, 2H), 2.69(s, 3H), 2.50-2.40(m, 2H), 2.41-2.34(m, 4H), 2.29(s, 4H), 2.23(s, 3H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=161.1, 146.9, 138.9, 137.4, 134.9, 130.9, 130.7, 129.1, 128. 9, 127.3, 123.8, 115.0, 67.0, 58.0, 54.0, 53.3, 40.9, 30.7, 20.8, 19.2. GC / MS (EI): m / z (%): (EI, 70eV): 356 (1, [M] +·), 257 (19), 256 (100), 240 (4), 183 (8), 146 (14), 131 (5), 109 (15), 100 (32), 56 (6), 42 (4).

[0545] Example 57: N-(2-bromobenzyl)-2,4-dimethylaniline

[0546] Prepared according to Example 33, substituting 2-bromobenzyl chloride for 2,6-difluorobenzyl chloride and 2,4-dimethylaniline for p-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 291 (28), 289 (28, [M]+·), 171 (36), 169 (38), 134 (26), 120 (100), 91 (27), 90 (22), 89 (19), 77 (23).

[0547] Example 58: 2-(2-Bromobenzyl)-4,6-dimethylaniline

[0548] Prepared according to Example 34, substituting N-(2-bromobenzyl)-2,4-dimethylaniline for N-(2,6-difluorobenzyl)-4-methylaniline and 2,4-dimethylaniline for p-methylaniline. GC / MS (EI): m / z (%): (EI, 70 eV): 291 (39), 289 (38, [M]+·), 210 (91), 208 (75), 195 (47), 194 (100), 180 (32), 97 (21), 96 (34), 91 (21).

[0549] Example 59: 2-(2-bromobenzyl)-4,6-dimethyl-N-(2-morpholinoethyl)aniline

[0550] 2-(2-Bromobenzyl)-4,6-dimethylaniline (2.2 g, 7.58 mmol, 1.0 equiv.), 4-(2-bromoethyl)morpholine (1.471, 7.58 mmol, 1.0 equiv.) and tetrabutylammonium iodide (0.56 g, 1.516 mmol, 0.2 equiv.) were combined in 40 mL of DMF (dimethylformamide). 3.2 mL of N-ethyldiisopropylamine (2.45 g, 18.95 mmol, 2.5 equiv.) was added and the reaction was heated overnight. The reaction mixture was then cooled to ambient temperature and poured into saturated NaHCO 3 The product was extracted twice with EtOAc. The combined organic layers were washed three times with water and washed with MgSO 4 Dry, filter and evaporate the volatiles. Purify by flash column chromatography using a gradient of 0-10% EtOAc to give 0.55 g (17% yield) of 2-(2-bromobenzyl)-4,6-dimethyl-N-(2-morpholinoethyl)aniline. GC / MS (EI): m / z (%): (EI, 70 eV): 402 (4, [M]+·), 302 (15), 222 (17), 100 (100).

[0551] Example 60: 2-(2-bromobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline

[0552] Prepared according to Example 30, using 2-(2-bromobenzyl)-4,6-dimethyl-N-(2-morpholinoethyl)aniline (0.54 g, 1.34 mmol, 1.0 equiv.) instead of benzyl-4-methyl-N-(2-morpholinoethyl)aniline, 0.42 g (69% yield) of 2-(2-bromobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline was obtained. GC / MS (EI): m / z (%): (EI, 70 eV): 416 (1, [M]+·), 319 (17), 318 (94), 317 (19), 316 (100), 207 (14), 179 (18), 178 (17), 146 (20), 100 (93), 56 (15).

[0553] Example 61: 2-(3,5-dimethyl-2-(methyl(2-morpholinoethyl)amino)benzyl)benzonitrile

[0554] In a 25 mL 3-neck round bottom flask, 2-(2-bromobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline (50 mg, 0.12 mmol, 1.0 equiv.) and copper (I) cyanide (13 mg, 0.14 mmol, 1.2 equiv.) were suspended in 4 mL DMF (dimethylformamide), and the suspension was heated to reflux overnight. After cooling to room temperature, the mixture was washed with saturated NH 4 The organic layer was quenched with aqueous Cl solution and extracted twice with EtOAc. 4 Dry, filter and remove volatiles under reduced pressure. Use a gradient of 0-10% EtOAc / EtOH / NH 4 A mixture of 1H-(4-(4-(2-((4-(2-morpholinoethyl)amino)benzyl)benzonitrile and 1H-(4-(2-((4-(2-morpholinoethyl)amino)benzyl)benzonitrile)) was purified by flash column chromatography to afford 16 mg (37% yield) of 2-(3,5-dimethyl-2-(methyl(2-morpholinoethyl)amino)benzyl)benzonitrile as an orange viscous liquid. 1 HNMR (400 MHz, CDCl 3 )δ (ppm) = 7.65 (dd, J = 1.1, 7.7Hz, 1H), 7.43 (dt, J = 1.5, 7.7Hz, 1H), 7.27 (dt, J = 1.0, 7.6Hz, 1H), 7.08 (d, J = 7.8Hz, 1H), 6.89 (d, J=1.7Hz, 1H), 6.74 (d, J=1.5Hz, 1H), 4.26 (d, J=7.6Hz, 2H), 3.73-3.58 (m, 4H), 3.21-2.92 (m, 2H), 2.63 (s, 3H), 2.33 (br s, 4H), 2.28 (s, 3H), 2.25 (s, 3H), 2.19-2.03 (m, 2H). 13C NMR (101 MHz, CDCl 3 )δ(ppm)=146.8, 146.5, 138.3, 137.6, 135.1, 132.6, 132.5, 131.4, 129.7, 1 29.2, 126.2, 118.4, 112.7, 66.9, 57.9, 54.0, 53.1, 41.0, 36.7, 20.8, 19.3. GC / MS (EI): m / z (%): (EI, 70eV): 363 (0, [M] +·), 264 (20), 263 (100), 247 (4), 190 (5), 146 (12), 131 (5), 116 (4), 100 (38), 56 (6), 42 (6).

[0555] Example 62: 1-allyl-2-benzyl-4-methylbenzene

[0556] Pd(PPh 3 ) 4 (0.5 g, 0.30 mmol, 0.1 equiv.), LiCl (0.22 g, 1.50 mmol, 1.5 equiv.) and 1.2 mL of allyltributylstannane (12 g, 3.60 mmol, 1.2 equiv.) were added to 2-benzyl-4-methylphenyl trifluoromethanesulfonate in 30 mL of DMF, and the resulting yellow suspension was purged with nitrogen at ambient temperature. The reaction mixture was then heated to 90 ° C overnight. The mixture was washed with H 2 O and EtOAc and filtered through celite and further washed with heptane. The organic layer was separated and washed with H 2 O, and the aqueous layer was re-extracted with heptane. The organic layer was washed with MgSO 4 Dry, filter and remove volatiles under reduced pressure. Purify by flash column chromatography using a gradient of 0-10% EtOAc / heptane to give 1-allyl-2-benzyl-4-methylbenzene in quantitative yield as a light yellow liquid. GC / MS (EI): m / z (%): (EI, 70 eV): 222 (57, [M]+·), 193 (72), 179 (44), 178 (77), 165 (47), 131 (55), 129 (100), 128 (47), 115 (47), 91 (59).

[0557] Example 63: 2-(2-Benzyl-4-methylbenzyl)oxirane

[0558] 3-Chloroperbenzoic acid (1.21 g, 5.4 mmol, 1.2 equiv.) was added to 22 mL of CH 2 Cl 2The reaction was then stirred at ambient temperature for 2.5 h, and the mixture was then treated with H 2 O and diluted with EtOAc and filtered through Celite, then washed with heptane. The organic layer was separated and the aqueous layer was re-extracted with heptane. The organic layer was washed with MgSO 4 Dry, filter and remove volatiles under reduced pressure. Purify by flash column chromatography using a gradient of 0-10% EtOAc / heptane to give 2-(2-benzyl-4-methylbenzyl)oxirane as a light yellow liquid in quantitative yield. GC / MS (EI): m / z (%): (EI, 70 eV): 238 (1, [M] +·), 220 (76, [M] +·), 205 (75), 193 (55), 192 (38), 179 (91), 178 (100), 165 (77), 129 (54), 115 (70), 91 (71).

[0559] Example 64: 1-(2-Benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-ol

[0560] 2-(2-Benzyl-4-methylbenzyl)oxirane (0.46 g, 1.93 mmol, 1.0 equiv.) was dissolved in 10 mL EtOH and 1-methylpiperazine (0.21 g, 2.085 mmol, 1.1 equiv.) was added. The solution was stirred at 70 °C (oil bath) for 20 h. The reaction was then cooled to ambient temperature and the volatiles were removed. A gradient of 10-100% EtOAc / EtOH / NH 4 A mixture of OH (90:9:1) in heptane was purified by flash column chromatography to give 1-(2-benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-ol (0.45 g, 69% yield) as a yellow liquid. 1 H NMR (400 MHz, CDCl 3)δ (ppm) = 7.12-7.18 (m, 2H), 7.03-7.09 (m, 2H), 6.98-7.03 (m, 2H), 6.91 (dd, J = 7.7, 1.3 Hz, 1H), 6.85-6.88 (m, 1H), 3.95 (d, J = 26.7Hz, 1H), 3.88 (d, J = 26.4Hz, 1H), 3.54-3.65 (m , 1H), 2.66 (dd, J=14.2, 7.3Hz, 1H), 2.51 (dd, J=14.2, 5.4Hz, 1H), 2.39-2.47 (m, 2H), 2. 21-2.38 (m, 5H), 2.20 (s, 3H), 2.15 (s, 3H), 2.12 (d, J=6.1Hz, 1H), 2.10 (d, J=1.2Hz, 1H). 13 CNMR (100MHz, CDCl 3 )δ(ppm)=141.1, 138.6, 136.0, 133.8, 131.6, 130.6, 128.7, 128.4, 127.3, 125.9, 66.8, 63.5, 55.2, 46.0, 39.1, 37.7, 21.0. GC / MS (EI): m / z (%): (EI, 70eV): 338 (0, [M] +·), 178 (5), 165 (6), 115 (5), 114 (48), 113 (100), 91 (8), 70 (30), 56 (5), 43 (7), 42 (8).

[0561] Example 65: 1-(2-Benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-one

[0562] In a 25 mL 3-neck round bottom flask, 3 mL of CH 2 Cl 2 1-(2-benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-ol (0.15 g, 044 mmol, 1.0 equiv.), 4-methylmorpholine N-oxide (80 mg, 0.665 mmol, 1.5 equiv.) and 0.28 g of Molecular sieves. Tetrapropylammonium perruthenate (8 mg, 0.022 mmol, 0.05 equiv) was added to the solution. The resulting brown solution was stirred at ambient temperature for 40 minutes. The reaction mixture was then filtered using a short silica gel pad and eluted with EtOAc / EtOH / NH 4 The filtrate was concentrated under reduced pressure and dried under high vacuum. A gradient of 10-100% EtOAc / EtOH / NH 4A mixture of 1-(2-benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-ol and the starting material was purified by flash column chromatography to give 61 mg of a mixture containing a 1:1 mixture of 1-(2-benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-ol and the starting material as a yellow liquid. 3 mg of the title compound was isolated using preparative RP-HPLC (reverse phase high pressure liquid chromatography) on a Kinete×C18 column (5 μm particle size, 4.6×150 mm, equipped with a precolumn) with an elution system consisting of A(CH 3 CN:H 2 O, 5:95 + 0.1% trifluoroacetic acid) and B (ACN:H 2 O, 95:5 + 0.085% trifluoroacetic acid) using a gradient from 10% to 100% B, 10% B / min. 1 H NMR (500MHz, DMSO-d6) δ (ppm) = 7.27 (t, J = 7.2Hz, 2H), 7.19 (t, J = 7.6Hz, 1H), 7.10 (d, J = 7.3Hz, 2H), 7.04 (d, J = 7.9Hz, 1H), 7.01 (d, J = 7.6Hz, 1H) , 6.96(s, 1H), 3.86(s, 2H), 3.73(s, 2H), 3.30-3.41(m, 4H), 2.96-3.07( m, 2H), 2.82-2.91 (m, 2H), 2.77 (s, 3H), 2.39-2.48 (m, 2H), 2.25 (s, 3H).

[0563] 13 C NMR (151MHz, DMSO-d6) δppm=205.8, 140.8, 139.6, 136.3, 131.6, 131.3, 130.5, 129.1(2), 128.9(2), 127.5, 126.4, 65.1, 53.0(2), 49.6(2), 44.3 42.6, 38.7, 21.1. GC / MS (EI): m / z (%): MS (EI, 70 eV): 336 (2, [M] +·), 179 (3), 178 (4), 165 (4), 114 (7), 113 (100), 98 (4), 70 (27), 56 (3), 43 (2), 42 (5).

[0564] Example 66: (E)-3-(2-Benzyl-4-methylphenyl)acrylic acid

[0565] 2-Benzyl-4-methylbenzaldehyde (1.0 g, 3.8 mmol, 1.0 equiv.), malonic acid (1.0 g, 9.5 mmol, 2.5 equiv.) and 80 mL of piperidine in 4 mL of pyridine were heated to 105 °C until no more CO was observed. 2 Formation (4 hours). The reactants were then poured into 40 ml of ice-cold 2M aqueous HCl solution under continuous stirring. The resulting suspension was filtered (pH 1) and the solid (E)-3-(2-benzyl-4-methylphenyl)acrylic acid was washed with 25 ml of HCl (2M). The solid was then transferred to a round-bottom flask and dried overnight at ambient temperature and 0.10 mbar. The product (1.2 g, 62% purity, 78% yield) was used in the next step without further purification. GC / MS (EI): m / z (%): (EI, 70 eV): 252 (9, [M]+·), 206 (29), 193 (24), 192 (100), 191 (37), 178 (32), 161 (54), 129 (22), 128 (21), 115 (34), 91 (22).

[0566] Example 67: (E)-3-(2-Benzyl-4-methylphenyl)-1-(piperidin-1-yl)prop-2-en-1-one

[0567] (E)-3-(2-Benzyl-4-methylphenyl)acrylic acid (0.38 g, 1.5 mmol, 1.2 equiv.) was dissolved in 0.35 mL SOCl 2 (0.59 g, 5.0 mmol, 4.0 equiv.) and stirred at room temperature under an inert atmosphere for 1 hour. The reaction mixture was concentrated in vacuo and the residue was washed with 5 mL of CH 2 Cl 2 Dilute and add 10 mL of CH 2 Cl 2 1-Methylpiperazine (0.13 g, 1.25 mmol, 1.0 equiv.) and 0.4 mL Et 3 N (2.5 mmol, 2.0 equiv.). The reaction was stirred at ambient temperature for 5 minutes, and then the brown solution was heated to reflux for 2 hours. After cooling to ambient temperature, the reaction was poured into saturated NaHCO 3 In aqueous solution, CH 2 Cl 2 The combined organic layers were washed with MgSO 4 Dry, filter and remove volatiles under reduced pressure. Use a gradient of 10-100% EtOAc / EtOH / NH 4A mixture of OH (90:9:1) in heptane was purified by flash column chromatography to give (E)-3-(2-benzyl-4-methylphenyl)-1-(4-methylpiperazin-1-yl)prop-2-en-1-one (0.32 g, 38% yield) as a viscous yellow liquid.

[0568] LC / MS(ESI): 335(M+H)+, 357(M+Na)+, 669(2M+H)+.

[0569] Example 68: (E)-1-(3-(2-benzyl-4-methylphenyl)allyl)-4-methylpiperazine and 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine

[0570] (E)-3-(2-Benzyl-4-methylphenyl)-1-(4-methylpiperazin-1-yl)prop-2-en-1-one (0.3 g, 0.9 mmol, 1.0 equiv.) in 3 mL THF was slowly added to LiAlH 4 (37 mg, 1.0 mmol, 1.1 equiv.) in 5 mL THF. The reaction was stirred at ambient temperature for 45 minutes. Thereafter, the reaction mixture was cooled to 3 °C and 0.1 mL H 2 O, then 0.1 mL NaOH (3 M) was added, and then 0.3 mL H 2 O. The white suspension was stirred at ambient temperature for 20 min, then MgSO 4 The mixture was then filtered and the volatiles were evaporated. A gradient of 20-100% EtOAc / EtOH / NH 4 A mixture of (E)-1-(3-(2-benzyl-4-methylphenyl)allyl)-4-methylpiperazine and 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine was purified by flash column chromatography to give 96 mg of a 4:1 mixture of (E)-1-(3-(2-benzyl-4-methylphenyl)allyl)-4-methylpiperazine and 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine. Major: GC / MS (EI): m / z (%): (EI, 70 eV): 320 (64, [M] +·), 179 (25), 158 (29), 128 (28), 99 (46), 91 (100), 70 (27), 56 (34), 43 (23), 42 (25) Minor: GC / MS (EI): m / z (%): (EI, 70 eV): 322 (17, [M] +·), 178 (10), 165 (10), 127 (10), 113 (100), 100 (13), 91 (12), 70 (25), 43 (19), 42 (13).

[0571] Example 69: 1-(3-(2-Benzyl-4-methylphenyl)propyl)-4-methylpiperazine

[0572] The above mixture was separated by preparative HPLC to give a pure sample of 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine. 1 H NMR (400MHz, chloroform-d) δppm7.38 (d, J=7.8Hz, 1H), 7.24 (t, J=7.6Hz, 2H), 7.06-7.19 (m, 3H), 6.99-7.05 (m, 1H), 6.95 (s, 1H), 6.67 (d, J =15.6Hz, 1H), 6.04 (dt, J = 15.6, 6.8Hz, 1H), 4.02 (s, 2H), 3.06 (dd, J = 6.8, 1.2Hz, 2H), 2.52-2.57 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H). 13 C NMR (101 MHz, chloroform-d) δ ppm 140.8, 137.4, 137.3, 133.5, 131.3, 130.8, 128.6 (2), 128.37 (2), 127.4, 125.8, 61.3, 55.2 (2), 53.1 (2), 46.1, 39.2, 21.2.

[0573] Example 70: 1-(3-(2-Benzyl-4-methylphenyl)propyl)-4-methylpiperazine

[0574] A 4:1 mixture of 76 mg of (E)-1-(3-(2-benzyl-4-methylphenyl)allyl)-4-methylpiperazine and 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine in 10 ml of EtOH was hydrogenated with 40 mg of Pd / C for 6 h at ambient temperature. The mixture was then filtered through celite and the celite pad was washed thoroughly with ethanol. The filtrate was evaporated at 50° C. / 20 mbar. A gradient of 10-100% EtOAc / EtOH / NH 4 A mixture of OH (90:9:1) in heptane was purified by flash column chromatography to give 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine (36 mg, 43% yield) as a colorless liquid. 1 H NMR (400 MHz, CDCl 3) δ (ppm) = 7.25 (t, J = 7.3Hz, 2H), 7.16 (t, J = 7.3Hz, 1H), 7.11 (d, J = 7.8Hz, 2H), 7.06 (d, J = 7.8Hz, 1H), 6.99 (d, J = 7. 9Hz, 1H), 6.92 (s, 1H), 3.99 (s, 2H), 2.54 (t, J=8.0Hz, 2H), 2.18-2.52 (m, 10H), 2.28 (s, 3H), 2.27 (s, 3H), 1.65 (br quin, J=7.6Hz, 2H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=141.12, 138.09, 137.54, 135.42, 131.28, 129.31, 128.67(2), 128.37(2) , 127.30, 125.88, 58.23, 55.21(2), 53.20(2), 46.11, 38.87, 30.22, 28.27, 21.01. GC / MS (EI): m / z (%): MS (EI, 70 eV): 322 (18, [M] +·), 178 (10), 127 (11), 113 (100), 100 (13), 91 (12), 70 (28), 58 (10), 43 (20), 42 (14).

[0575] Example 71: (E)-2-Benzyl-1-(2-methoxyvinyl)-4-methylbenzene

[0576] 5.7 mL (5.7 mmol, 1.2 equiv.) of potassium tert-butoxide (1 M in THF) was added to methoxymethyltriphenylphosphonium chloride (1.96 g, 5.71 mmol, 1.2 equiv.) in 15 mL THF at 5-15°C. The resulting bright red mixture was stirred at ambient temperature for 15 minutes. 2-Benzyl-4-methylbenzaldehyde (1.0 g, 4.76 mmol, 1.0 equiv.) in 10 mL THF was then added and the reaction was stirred at ambient temperature for 45 minutes. The reaction mixture was then diluted with heptane and washed with 4:1 MeOH / H 2O mixture was washed three times. The aqueous layer was re-extracted with heptane. The combined organic layers were dried over magnesium sulfate, filtered and the volatiles were evaporated to give 1.0 g of (E)-2-benzyl-1-(2-methoxyvinyl)-4-methylbenzene (71% yield, 80% purity) as a red liquid, which was used in the next step without further purification. GC / MS (EI): m / z (%): MS (EI, 70 eV): 238 (79, [M] + ·), 206 (100), 205 (38), 193 (44), 191 (63), 179 (35), 178 (93), 165 (50), 115 (39), 91 (44).

[0577] Example 72: 2-(2-Benzyl-4-methylphenyl)acetaldehyde

[0578] Perchloric acid (0.3 mL, 3.3 mmol, 1.0 equiv.) was added to 15 mL of Et 2 (E)-2-benzyl-1-(2-methoxyvinyl)-4-methylbenzene (0.79 g, 3.3 mmol, 1.0 equiv.) in 1% ethyl acetate (E) was added to 1% ethyl acetate (E) in 0.1% ethanol. The reaction was stirred at 5°C for 5 minutes. After that, the mixture was diluted with MTBE (methyl tert-butyl ether), poured onto 2M NaOH and washed with brine. The aqueous layer was re-extracted with MTBE. The combined organic layers were washed with MgSO 4 Dry, filter and remove volatiles under reduced pressure. Purify by flash column chromatography using a gradient of 0-10% EtOAc / heptane to give 2-(2-benzyl-4-methylphenyl)acetaldehyde (0.57 g, 67% purity, 51% yield) as a yellow liquid. GC / MS (EI): m / z (%): MS (EI, 70 eV): 224 (43, [M]+·), 206 (38), 195 (73), 181 (40), 180 (46), 179 (41), 178 (60), 166 (35), 165 (100), 91 (34).

[0579] Example 73: 1-(2-Benzyl-4-methylphenethyl)-4-methylpiperazine

[0580] In 20 mL CH 2 Cl 22-(2-Benzyl-4-methylphenyl)acetaldehyde (0.57 g, 2.54 mmol, 1.0 equiv.), 1-methylpiperazine (0.28 g, 2.80 mmol, 1.1 equiv.) in a 100 mL 3-neck round bottom flask were charged. Sodium triacetoxyborohydride (0.60 g, 2.8 mmol, 1.1 equiv.) was added portionwise to keep the internal temperature below 30°C. The pale yellow mixture was stirred at ambient temperature overnight. The reaction mixture was then cooled to 5°C and 20 mL of saturated NaHCO was added dropwise. 3 The mixture was extracted with DCM, and the organic layer was washed with water and MgSO 4 The mixture was dried and concentrated using a gradient of 10-100% EtOAc / EtOH / NH 4 A mixture of OH (90:9:1) in heptane was purified by flash column chromatography to give 1-(2-benzyl-4-methylphenethyl)-4-methylpiperazine (0.29 mg, 29% yield) as a colorless liquid. 1 H NMR (400 MHz, CDCl 3 )δ(ppm)=7.25(br t, J=7.8Hz, 2H), 7.17(br t, J=7.3Hz, 1H), 7.08-7.12 (m, 3H), 7.00 (dd, J=7.8, 1.3Hz, 1H), 6.94 (s, 1H), 3.99 (s, 2H), 2.71-2.76 (m, 2H), 2.30-2.54 (m, 10H), 2.28 (s, 6H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=140.98, 138.35, 135.80, 129.83, 128.67(2), 128.40(2), 127.41, 128.68, 59.85, 55.12(2), 53.06(2), 46.07, 38.95, 29.87, 21.00. GC / MS (EI): m / z (%): MS (EI, 70 eV): 308 (1, [M] +·), 179 (4), 178 (4), 165 (5), 114 (8), 113 (100), 91 (5), 70 (29), 56 (4), 43 (4), 42 (8).

[0581] Example 74: 2-Benzyl-4-methylphenyl 2-chloroacetate

[0582] 2-Benzyl-4-methylphenol (2.0 g, 10.1 mmol, 1.0 equiv.) and a catalytic amount of DMAP (0.06 g, 0.5 mmol, 0.05 equiv.) were dissolved in 7.0 mL of Et 3The solution in N (50.4 mmol, 5 equiv.) was cooled to 0°C. 2-Chloroacetyl chloride (1.0 mL, 1.37 g, 21.1 mmol, 1.2 equiv.) was added dropwise, at which point the color turned dark brown. The ice bath was removed and the reaction was stirred at ambient temperature overnight. The reaction mixture was then diluted with MTBE and poured into H 2 O and extracted twice with MTBE. The combined organic layers were washed with brine and washed with MgSO 4 Dry, filter and evaporate the volatiles. Purify by flash column chromatography using a gradient of 0-20% EtOAc / heptane to give 2-benzyl-4-methylphenyl 2-chloroacetate (0.75 g, 88% purity, 34% yield) as a yellow liquid. GC / MS (EI): m / z (%): MS (EI, 70 eV): 274 (22, [M]+·), 198 (93), 197 (95), 183 (28), 181 (23), 165 (41), 153 (24), 152 (29), 120 (100), 91 (43), 77 (33).

[0583] Example 75: 2-Benzyl-4-methylphenyl 2-(4-methylpiperazin-1-yl)acetate

[0584] In 5mL CH 3 2-Benzyl-4-methylphenyl 2-chloroacetate (0.75 g, 2.73 mmol, 1.0 equiv.) in CN was added dropwise to 1-methylpiperazine (0.55 g, 5.46 mmol, 2.0 equiv.), KI (0.91 g, 5.46 mmol, 2.0 equiv.), potassium carbonate (0.76 g, 5.46 mmol, 2.0 equiv.) and sodium bicarbonate (0.46 g, 5.46 mmol, 2.0 equiv.) in 10 mL CH 3 CN. The pale yellow suspension was stirred at ambient temperature overnight. The reaction was then diluted with EtOAc, filtered and the volatiles evaporated. A gradient of 10-100% EtOAc / EtOH / NH 4 A mixture of OH (90:9:1) in heptane was purified by flash column chromatography to give 2-benzyl-4-methylphenyl 2-(4-methylpiperazin-1-yl)acetate (0.55 g, 60% yield) as a viscous yellow liquid. 1 H NMR (400 MHz, CDCl 3)δ (ppm) = 7.29-7.25 (m, 2H), 7.20 (s, 1H), 7.18-7.12 (m, 2H), 7.10-7.04 (m, 1H), 7.00 (d, J = 1.7Hz, 1 H), 6.99-6.95 (m, 1H), 3.88 (s, 2H), 3.34 (s, 2H), 2.72-2.56 (m, 4H), 2.56-2.44 (m, 4H), 2.31 (s, 6H). 13 C NMR (101 MHz, CDCl 3 )δ(ppm)=168.7, 146.5, 139.9, 135.8, 132.2, 131.7, 128.7, 128.5, 128.1, 126.2, 122.2, 59.0, 54.8, 52.9, 46.0, 36.4, 20.9. GC / MS (EI): m / z (%): MS (EI, 70 eV): 338 (4, [M] +·), 165 (4), 114 (9), 113 (100), 98 (5), 91 (4), 71 (4), 70 (31), 56 (5), 43 (5), 42 (12).

[0585] Example 76: 4-Methylbenzenesulfonic acid (8-benzylchroman-2-yl)methyl ester

[0586] In a 250 ml 3-neck round bottom flask, 2.20 g (6.58 mmol, 1.0 equiv.) of 4-methylbenzenesulfonic acid (8-hydroxychroman-2-yl)methyl ester and 1.6 mL (19.74 mmol, 3.0 equiv.) of pyridine were dissolved in 45 mL of CH 2 Cl 2 The solution in was treated with trifluoromethanesulfonic anhydride (2.2 mL, 3.71 g, 13.16 mmol, 2.0 equiv). The ice bath was removed and the reaction was stirred at ambient temperature for 2 h. The reaction was then poured into 50 mL of 0.5 M HCl and washed with CH 2 Cl 2 The combined organic layers were washed with brine and MgSO 4Dry, filter and evaporate the volatiles. Dry the crude product under high vacuum to give crude (8-(((trifluoromethyl)sulfonyl)oxy)chroman-2-yl)methyl 4-methylbenzenesulfonate (2.55 g, 83% yield), which was used in the next step without further purification. GC / MS (EI): m / z (%): MS (EI, 70 eV): 466 (0, [M]+·), 161 (17), 155 (18), 133 (12), 105 (13), 92 (15), 91 (100), 77 (13), 69 (20), 65 (41), 39 (13).

[0587] Example 77: (8-(((trifluoromethyl)sulfonyl)oxy)chroman-2-yl)methyl 4-methylbenzenesulfonate

[0588] Benzylboronic acid pinacol ester (0.45 g, 2.1 mmol, 3.0 equiv.), 4-methylbenzenesulfonic acid (8-(((trifluoromethyl)sulfonyl)oxy)chroman-2-yl)methyl ester (0.32 g, 0.67 mmol, 1.0 equiv.), K 3 PO 4 (0.29 g, 1.37 mmol, 2.0 equiv.), SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 62 mg, 0.15 mmol, 0.22 equiv.) and Pd(OAc) 2 (23 mg, 0.1 mmol, 0.15 equiv.) in 5.5 mL toluene / H 2 The mixture in a ratio of 1:1 was purged with nitrogen for 10 minutes. The reaction was then heated to 110 °C for 2 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (20 mL) and brine. The aqueous layer was re-extracted with EtOAc and the organic layer was washed with MgSO 4 Dry, filter and evaporate the volatiles. Purify by flash column chromatography using a gradient of 10-100% EtOAc / heptane to give 4-methylbenzenesulfonic acid (8-benzylchroman-2-yl)methyl ester acetate (0.25 g, 86% yield) as a viscous yellow liquid. GC / MS (EI): m / z (%): MS (EI, 70 eV): 408 (5, [M]+·), 236 (20), 235 (13), 223 (13), 195 (19), 194 (12), 178 (24), 165 (19), 145 (55), 91 (100), 65 (17).

[0589] Example 78: 1-((8-Benzylchroman-2-yl)methyl)-4-methylpiperazine

[0590] 1-Methylpiperazine (0.18 g, 1.76 mmol, 3.0 equiv.) in 1.5 mL of THF was added to 4-methylbenzenesulfonic acid (8-benzylchroman-2-yl)methyl ester (0.24 g, 0.59 mmol, 1.0 equiv.) in 3.5 mL of DMSO (dimethyl sulfoxide) at ambient temperature. The resulting mixture was stirred at 65° C. overnight. The reaction mixture was then cooled to ambient temperature and partitioned between EtOAc (20 mL) and water (3×20 mL). The aqueous layer was re-extracted with EtOAc and the organic layer was washed with MgSO 4 Dry, filter and evaporate the volatiles. Use a gradient of 10-100% EtOAc / EtOH / NH 4 A mixture of OH (90:9:1) in heptane was purified by flash column chromatography to give (8-benzylchroman-2-yl)methyl 4-methylbenzenesulfonate (125 mg, 95% purity, 60% yield) as a viscous yellow liquid. 1 H NMR (400 MHz, CDCl 3 )δ(ppm)=7.19-7.27(m, 4H), 7.15(br t, J=6.8Hz, 1H), 6.86-6.93 (m, 2H), 6.74 (t, J=7.5Hz, 1H), 4.12-4.22 (m, 1H), 3.92 (d, J=15.6Hz, 1H), 3.91 ( d, J=15.6Hz, 1H), 2.81-2.92 (m, 1H), 2.33-2.78 (m, 12H), 2.27 (s, 3H), 1.96-2.05 (m, 1H), 1.70-1.82 (m, 1H).

[0591] 13 C NMR (101 MHz, CDCl 3 ) δ (ppm) = 152.5, 141.2, 128.9 (3), 128.8, 128.2 (2), 127.7, 125.7, 121.7, 119.7, 74.7, 62.9, 55.2, 53.9, 46.1, 35.9, 26.3, 24.8. GC / MS (EI): m / z (%): MS (EI, 70eV): 336 (2, [M] + ·), 165 (4, [M] + ·), 139 (20), 114 (8), 113 (100), 98 (4), 91 (11), 70 (28), 56 (5), 43 (7), 42 (9).

[0592] Example 79: 2-(2,6-difluorobenzyl)-4,6-dimethylphenol

[0593] Zinc (II) chloride (0.5 g, 3.7 mmol) was added to a mixture of 2-(chloromethyl)-1,3-difluorobenzene 1 (3.0 g, 18.5 mmol) and 2,4-dimethylphenol (6.8 g, 55.4 mmol) under Ar and the resulting mixture was heated to 140 °C for 5 hours. After the reaction mixture was cooled to room temperature, water (100 mL) was added to quench the solution and the solution was extracted with MTBE (100 mL × 3). The combined organic phase was washed with water (100 mL) and MgSO 4 Dry and concentrate by rotary evaporation. The resulting liquid is further concentrated by kugelrohr distillation (0.2 mbar, 120°C) to remove unconsumed starting material 2,4-dimethylphenol, and the residue is purified by silica gel column chromatography (PE:MTBE=92:8) to obtain the title product (1.6 g, 32% yield) as a viscous liquid. GC / MS (EI): m / z (%): 248 (11) [M + ],233(25),215(10),201(4),183(11),134(50),121(20),106(18),91(20),77(10).

[0594] Example 80: 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine

[0595] A solution of 2-(2,6-difluorobenzyl)-4,6-dimethylphenol (0.37 g, 1.5 mmol), 4-(2-chloroethyl)morpholine hydrochloride (0.56 g, 3.0 mmol), potassium iodide (0.025 g, 0.15 mmol) and potassium carbonate (2.10 g, 14.9 mmol) in DMF (20 mL) was heated to reflux for 3 hours. After the mixture was cooled to room temperature, water (80 mL) was added, and the solution was extracted with dichloromethane (50 mL×3). The combined organic phases were washed with water (50 mL) and MgSO 4 After removing the solvent, the residue was purified by silica gel column chromatography (PE:MTBE=3:2) to obtain the title product (0.40 g, yield 73%) as a viscous liquid. GC / MS (EI): m / z (%): 361 (11) [M + ], 274(20), 227(7), 201(4), 183(4), 127(7), 114(28), 100(100), 85(1), 70(4). 1 H NMR (300 MHz, CDCl 3)δ7.26-7.14(m, 1H), 6.95-6.82(m, 3H), 6.54(s, 1H), 4.07(s, 2H), 3.97(t, J=5.8Hz, 2H) , 3.83-3.69 (m, 4H), 2.84 (t, J=5.8Hz, 2H), 2.69-2.53 (m, 4H), 2.29 (s, 3H), 2.17 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ163.6(q), 163.5(q), 160.3(q), 160.2(q), 153.3(q), 133.4(q), 131.5(q ), 130.5(q), 130.3(t), 128.2(t), 128.0(t), 127.9(t), 127.4(t), 116.6(q) ,116.4(q),116.1(q),111.5(t),111.4(t),111.2(t),111.1(t),69.9(d), 67.1(d), 58.8(d), 54.4(d), 22.4(d), 22.3(d), 22.3(d), 20.9(s), 16.4(s).

[0596] Example 81: 4-(2-(2-(2,6-difluorobenzyl)-4-methylphenoxy)ethyl)morpholine

[0597] According to the general method of Example 80: a mixture of 2-(2,6-difluorobenzyl)-4-methylphenol (0.25 g, 1.1 mmol), 4-(2-chloroethyl)morpholine hydrochloride (0.40 g, 2.1 mmol), potassium carbonate (1.50 g, 10.7 mmol) and potassium iodide (0.035 g, 0.20 mmol) in DMF (13 mL) was reacted to give the title product (0.30 g, yield 65%) as a viscous liquid. GC / MS (EI): m / z (%): 347 (8) [M + ], 260(4), 213(4), 201(4), 165(2), 127(7), 114(8), 100(100), 85(1), 70(4). 1 H NMR (300 MHz, CDCl 3 )δ7.23-7.11(m, 1H), 6.96-6.82(m, 3H), 6.80-6.71(m, 2H), 4.11(t, J=5.8Hz, 2H), 3.99( s, 2H), 3.73 (t, J=5.8Hz, 4H), 2.82 (t, J=5.8Hz, 2H), 2.59 (t, J=5.8Hz, 4H), 2.21 (s, 3H).13 C NMR (75 MHz, CDCl 3 )δ163.6(q), 163.5(q), 160.4(q), 160.2(q), 154.4(q), 130.2(t), 129.9(q), 127.9(t), 127.9(t), 127.8(t), 127.7(t), 127.3(q), 116.4(q), 111.4(t), 111.3(t), 111.2(t), 111.0(t), 67.2(d), 66.6(d), 57.8(d), 54.3(d), 22.6(d), 20.7(s).

[0598] Example 82: 4-(2-(2-(2-fluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine

[0599] Following the general procedure of Example 80: a mixture of 2-(2-fluorobenzyl)-4,6-dimethylphenol (0.40 g, 1.7 mmol) (prepared in a manner similar to Example 79), 4-(2-chloroethyl)morpholine hydrochloride (0.60 g, 3.5 mmol), potassium carbonate (2.40 g, 17.4 mmol) and potassium iodide (0.060 g, 0.30 mmol) in DMF (15 mL) was reacted to give the title product (0.40 g, 64% yield) as a viscous liquid. GC / MS (EI): m / z (%): 343 (10) [M + ],256(26),227(7),183(5),165(3),133(1),114(22),100(100),87(1),70(3). 1 H NMR (300 MHz, CDCl 3 )δ7.21-7.10(m, 1H), 7.10-6.97(m, 3H), 6.86(s, 1H), 6.71(s, 1H), 4.02(s, 2H), 3.85(t, J=5.7 Hz, 2H), 3.76-3.67 (m, 4H), 2.73 (t, J=5.7Hz, 2H), 2.57-2.46 (m, 4H), 2.27 (s, 3H), 2.20 (s, 3H). 13 C NMR (75 MHz, CDCl 3)δ162.7(q), 159.4(q), 153.6(q), 133.4(q), 132.1(q), 131.1(t), 131.0(t), 130.7(q), 130.4(t), 129.0(t), 128.2(q), 128.0(q), 127. 7(t), 127.7(t), 124.1(t), 124.1(t), 115.3(t), 115.0(t), 70.0(d), 67.0(d), 58.8(d), 54.3(d), 28.6(d), 28.6(d), 20.9(s), 16.5(s).

[0600] Example 83: 4-(1-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)prop-2-yl)morpholine and 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)propyl)morpholine

[0601] According to the general method of Example 80: 2-(2,6-difluorobenzyl)-4,6-dimethylphenol (0.4 g, 1.6 mmol), 4-(2-chloropropyl)morpholine hydrochloride (0.6 g, 3.2 mmol), potassium carbonate (2.3 g, 16.1 mmol) and potassium iodide (0.05 g, 0.3 mmol) in DMF (20 mL) were reacted to give 4-(1-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)prop-2-yl)morpholine (0.20 g, 0.50 mmol, yield 31%) (as a viscous liquid) and 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)propyl)morpholine (0.12 g, 0.32 mmol, yield 19%) (as a viscous liquid).

[0602] 4-(1-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)propan-2-yl)morpholine: GC / MS (EI): m / z (%): 375 (1) [M + ], 245(1), 227(2), 201(2), 183(2), 128(7), 114(100), 98(1), 84(1), 70(3). 1 H NMR (300 MHz, CDCl 3)δ7.25-7.15(m, 1H), 6.94-6.88(m, 2H), 6.84(s, 1H), 6.51(s, 1H), 4.07(s, 2H), 3.96-3.91(m, 1H), 3.8 2-3.66 (m, 5H), 3.12-2.96 (m, 1H), 2.76-2.61 (m, 4H), 2.29 (s, 3H), 2.16 (s, 3H), 1.25 (d, J=6.7Hz, 3H). 13 C NMR (75 MHz, CDCl 3 )δ163.6(q), 163.5(q), 160.3(q), 160.2(q), 153.2(q), 133.4(q), 131.4 (q), 130.6(q), 130.3(t), 128.2(t), 128.1(t), 127.9(t), 127.3(t), 116. 6(q), 116.3(q), 116.7(q), 111.5(t), 111.4(t), 111.3(t), 111.2(t), 74 .2(d), 67.5(d), 59.8(t), 50.0(d), 22.2(d), 20.9(s), 16.6(s), 12.8(s).

[0603] 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)propyl)morpholine: GC / MS (EI): m / z (%): 375 (1) [M + ], 341(1), 288(15), 227(5), 201(5), 128(30), 100(100), 91(1), 77(1), 56(7). 1 HNMR (300 MHz, CDCl 3 )δ7.25-7.13(m, 1H), 6.94-6.85(m, 2H), 6.82(s, 1H), 6.49(s, 1H), 4.40-4.24(m, 1H), 4.07(s, 2H), 3.7 6-3.61 (m, 4H), 2.87-2.72 (m, 1H), 2.64-2.45 (m, 5H), 2.27 (s, 3H), 2.15 (s, 3H), 1.27 (d, J=6.2Hz, 3H). 13 C NMR (75 MHz, CDCl 3)δ163.61(q), 163.49(q), 160.33(q), 160.21(q), 151.82(q), 132.62(q), 131.97 (q), 130.52(q), 130.36(t), 128.07(t), 127.93(t), 127.79(t), 127.12(t), 116.7 9(q), 116.53(q), 116.26(q), 111.43(t), 111.32(t), 111.20(t), 111.09(t), 75. 77(t), 67.17(d), 64.95(d), 54.77(d), 23.06(d), 20.88(s), 18.84(s), 17.40(s).

[0604] Example 84: 4-(2-(2-(2-chlorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine

[0605] According to the general method of Example 80: a mixture of 2-(2-chlorobenzyl)-4,6-dimethylphenol (0.38 g, 1.5 mmol) (prepared in a similar manner to Example 79), 4-(2-chloroethyl)morpholine hydrochloride (0.57 g, 3.1 mmol), potassium carbonate (2.13 g, 15.4 mmol) and potassium iodide (0.050 g, 0.31 mmol) in DMF (15 mL) was reacted to give the title product (0.20 g, yield 35%) as a viscous liquid. GC / MS (EI): m / z (%): 359 (1) [M + ],272(20),209(1),141(30),100(100),87(1),56(5). 1 H NMR (300 MHz, CDCl 3 )δ7.44-7.34(m, 1H), 7.20-7.10(m, 2H), 7.08-6.98(m, 1H), 6.89(s, 1H), 6.65(s, 1H), 4.11(s, 2H), 3.84 (t, J=5.7Hz, 2H), 3.72-3.69 (m, 4H), 2.71 (t, J=5.7Hz, 2H), 2.55-2.43 (m, 4H), 2.27 (s, 3H), 2.22 (s, 3H). 13 CNMR (75MHz, CDCl 3)δ153.8(q), 138.8(q), 134.2(q), 133.5(q0, 131.9(q), 130.8(q), 130.8(t), 130.5(t), 129.4(t), 129.1(t), 127.5(t), 126.9(t), 69.9(d), 67.0(d), 58.7(d), 54.2(d), 33.4(d), 20.9(s), 16.5(s).

[0606] Example 85: 4-(2-(2-(2,5-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine

[0607] According to the general method of Example 80: a mixture of 2-(2,5-difluorobenzyl)-4,6-dimethylphenol (0.30 g, 1.2 mmol) (prepared in a similar manner to Example 79), 4-(2-chloroethyl)morpholine hydrochloride (0.45 g, 2.4 mmol), potassium carbonate (1.67 g, 12.1 mmol) and potassium iodide (0.040 g, 0.24 mmol) in DMF (13 mL) was reacted to give the title product (0.36 g, yield 80%) as a viscous liquid. GC / MS (EI): m / z (%): 361 (1) [M + ], 346(1), 274(20), 227(5), 201(5), 127(7), 100(100), 87(2), 70(5), 56(10). 1 H NMR (300 MHz, CDCl 3 )δ7.02-6.92(m, 1H), 6.88(s, 1H), 6.87-6.78(m, 2H), 6.75(s, 1H), 3.99(s, 2H), 3.85(t, J=5.7 Hz, 2H), 3.77-3.69 (m, 4H), 2.73 (t, J=5.7Hz, 2H), 2.60-2.47 (m, 4H), 2.28 (s, 3H), 2.23 (s, 3H); 13 C NMR (75 MHz, CDCl 3)δ160.4(q), 160.4(q), 158.6(q), 158.5(q), 157.2(q), 157.2(q), 155.4(q), 155.3(q), 153.7(q) , 133.6(q), 131.4(q), 131.0(q), 130.9(t), 130.3(q), 130.2(q), 130.1(q), 130.0(q), 129.1(t), 117.6(t), 117.5(t), 117.3(t), 117.2(t), 116.2(t), 116.1(s), 115.9(t), 115.8(t), 114.2(t), 1 14.1(t), 113.9(t), 113.7(t), 70.1(d), 67.0(d), 58.8(d), 54.3(d), 28.8(d), 20.9(s), 16.5(s).

[0608] Example 86: 1-(2-(2-(2-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine

[0609] According to the general method of Example 80: a mixture of 2-(2-chlorobenzyl)-4-methylphenol (0.50 g, 2.2 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.01 g, 4.3 mmol), potassium carbonate (2.97 g, 21.5 mmol) and potassium iodide (0.070 g, 0.43 mmol) in DMF (volume: 15 mL) was reacted to give the title product (0.63 g, yield 78%) as a viscous liquid. GC / MS (EI): m / z (%): 358 (2) [M + ], 281(2), 253(2), 207(2), 183(10), 195(8), 165(7), 127(40), 113(100), 70(40). 1 H NMR (300 MHz, CDCl 3 )δ7.41-7.31(m, 1H), 7.16-7.07(m, 2H), 7.07-6.96(m, 2H), 6.86(s, 1H), 6.76(d, J=8.2Hz, 1H) , 4.12-4.00 (m, 4H), 2.73 (t, J=5.6Hz, 2H), 2.53 (s, 4H), 2.40 (s, 4H), 2.27 (s, 3H), 2.23 (s, 3H). 13 C NMR (75 MHz, CDCl 3)δ154.7(q), 138.8(q), 134.3(q), 131.4(t), 130.6(t), 129.9(q), 129.3(t), 128.0(t), 127.8(q), 127.2(t), 126.6(t), 111.4(t), 66.8(d), 57.3(d), 55.2(d), 53.6(d), 46.1(s), 33.5(d), 20.6(s).

[0610] Example 87: 4-(2-(2-(2,4-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine

[0611] According to the general method of Example 80: a mixture of 2-(2,4-difluorobenzyl)-4,6-dimethylphenol (0.28 g, 1.1 mmol) (prepared in a similar manner to Example 79), 4-(2-chloroethyl)morpholine hydrochloride (0.41 g, 2.2 mmol), potassium carbonate (1.53 g, 11.1 mmol) and potassium iodide (0.040 g, 0.22 mmol) in DMF (13 mL) was reacted to give the title product (0.30 g, yield 73%) as a viscous liquid. GC / MS (EI): m / z (%): 361 (1) [M + ], 341(1), 274(10), 227(5), 183(2), 127(7), 114(20), 100(100), 87(1), 70(3). 1 H NMR (300 MHz, CDCl 3 )δ7.11-7.04(m, 1H), 6.88(s, 1H), 6.84-6.72(m, 2H), 6.70(s, 1H), 3.97(s, 2H), 3.86(t, J=5.7 Hz, 2H), 3.74-3.71 (m, 4H), 2.75 (t, J=5.7Hz, 2H), 2.60-2.48 (m, 4H), 2.28 (s, 3H), 2.22 (s, 3H). 13 C NMR (75 MHz, CDCl 3)δ163.2(q), 163.1(q), 162.5(q), 162.4(q), 160.0(q), 159.8(q), 159.2(q), 159.1(q), 153.6(q) ), 133.6(q), 131.9(q), 131.7(t), 131.7(t), 131.6(t), 131.5(t), 130.9(q), 130.6(t), 128.9(t) , 124.1(q), 124.1(q), 123.9(q), 123.9(q), 111.3(t), 111.2(t), 111.0(t), 110.9(t), 103.9(t), 103.6(t), 103.2(t), 70.0(d), 67.0(d), 58.8(d), 54.3(d), 28.1(d), 28.1(d), 20.9(s), 16.5(s).

[0612] Example 88: 4-(2-(2-(2,6-dichlorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine

[0613] According to the general method of Example 80: a mixture of 2-(2,6-dichlorobenzyl)-4,6-dimethylphenol (0.50 g, 0.89 mmol) (prepared in a similar manner to Example 79), 4-(2-chloroethyl)morpholine hydrochloride (0.33 g, 1.9 mmol), potassium carbonate (1.23 g, 8.9 mmol) and potassium iodide (0.030 g, 0.18 mmol) in DMF (15 mL) was reacted to give the title product (0.21 g, 57% yield) as a viscous liquid. GC / MS (EI): m / z (%): 393 (1) [M + ], 241(1), 306(6), 243(5), 193(5), 165(5), 114(400), 100(100), 84(1), 70(3). 1 H NMR (300 MHz, CDCl 3 )δ7.36 (d, J=8.0Hz, 2H), 7.23-7.12 (m, 1H), 6.85 (s, 1H), 6.17 (d, J=7.5Hz, 1H), 4.35 (s, 2H), 4.02 (t, J=5.8Hz, 2H), 3.83-3.71 (m, 4H), 2.86 (t, J=5.8Hz, 2H), 2.72-2.55 (m, 4H), 2.30 (s, 3H), 2.12 (s, 3H). 13 C NMR (75 MHz, CDCl 3)δ153.4(q), 136.6(q), 136.4(q), 133.3(q), 130.5(q), 130.4(q), 130.2(t), 128.4(t), 128.3(t), 125.9(t), 69.7(d), 67.1(d), 58.9(d), 54.4(d), 31.3(d), 21.0(s), 16.4(s).

[0614] Example 89: 4-(2-(2-(3,5-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine

[0615] According to the general method of Example 80: a mixture of 2-(3,5-difluorobenzyl)-4,6-dimethylphenol (0.27 g, 1.1 mmol) (prepared in a similar manner to Example 79), 4-(2-chloroethyl)morpholine hydrochloride (0.41 g, 2.2 mmol), potassium carbonate (1.50 g, 10.9 mmol) and potassium iodide (0.040 g, 0.22 mmol) in DMF (15 mL) was reacted to give the title product (0.33 g, yield 81%) as a viscous liquid. GC / MS (EI): m / z (%): 361 (1) [M + ], 346(1), 274(10), 201(5), 183(2), 127(7), 114(15), 100(100), 87(1), 70(3). 1 H NMR (300 MHz, CDCl 3 )δ6.90 (s, 1H), 6.79-6.69 (m, 3H), 6.67-6.55 (m, 1H), 3.96 (s, 2H), 3.80 (t, J=5.7Hz, 2H ), 3.76-3.69 (m, 4H), 2.72 (t, J = 5.7Hz, 2H), 2.58-2.47 (m, 4H), 2.26 (d, J = 10.2Hz, 6H). 13 CNMR (75MHz, CDCl 3 )δ164.8(q), 164.6(q), 161.5(q), 161.4(q), 153.6(q), 145.7(q), 145 .6(q), 145.5(q), 133.7(q), 132.0(q), 131.1(q), 130.9(t), 129.2(t), 111.8(t), 111.7(t), 111.6(t), 111.5(t), 101.8(t), 101.5(t), 101.2 (t), 70.2(d), 67.0(d), 58.8(d), 54.3(d), 35.9(d), 20.8(s), 16.5(s).

[0616] Example 90: 4-(2-(2,4-dimethyl-6-(2,4,5-trifluorobenzyl)phenoxy)ethyl)morpholine

[0617] According to the general method of Example 80: a mixture of 2,4-dimethyl-6-(2,4,5-trifluorobenzyl)phenol (0.30 g, 1.1 mmol) (prepared in a similar manner to Example 79), 4-(2-chloroethyl)morpholine hydrochloride (0.42 g, 2.2 mmol), potassium carbonate (1.56 g, 11.3 mmol) and potassium iodide (0.040 g, 0.23 mmol) in DMF (15 mL) was reacted to give the title product (0.36 g, yield 80%) as a viscous liquid. GC / MS (EI): m / z (%): 379 (20) [M + ],292(17),245(8),219(6),201(5),145(7),114(14),100(100),85(1),70(3). 1 H NMR (300 MHz, CDCl 3 )δ7.04-6.83(m, 3H), 6.73(s, 1H), 3.94(s, 2H), 3.85(t, J=5.6Hz, 2H), 3.78-3.67(m , 4H), 2.74 (t, J=5.6Hz, 2H), 2.60-2.49 (m, 4H), 2.26 (d, J=7.1Hz, 3H), 2.23 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.6(q), 133.7(q), 131.3(q), 131.1(q), 131.0(t), 129.0(t), 124 .9(q), 124.9(q), 124.8(q), 124.7(q), 124.6(q), 124.6(q), 118.8(t), 118.7(t), 118.6(t), 118.5(t), 105.4(t), 105.2(t), 105.1(t), 104.8( t), 70.1(d), 67.0(d), 58.79(d), 54.3(d), 28.3(d), 20.8(s), 16.5(s).

[0618] Example 91: 1-(2-(2-(2-fluorobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine

[0619] According to the general method of Example 80: a mixture of 2-(2-fluorobenzyl)-4,6-dimethylphenol (0.25 g, 1.0 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine hydrochloride (0.41 g, 2.1 mmol), potassium carbonate (1.43 g, 10.3 mmol) and potassium iodide (0.030 g, 0.21 mmol) in DMF (10 mL) was reacted to give the title product (0.10 g, yield 26%) as a viscous liquid. GC / MS (EI): m / z (%): 356 (2) [M + ], 227(2), 209(2), 183(5), 165(3), 127(57), 113(100), 100(17), 84(7), 70(38). 1 H NMR (300 MHz, CDCl 3 )δ7.21-6.98(m, 4H), 6.86(s, 1H), 6.71(s, 1H), 4.00(s, 2H), 3.83(t, J=5.8Hz, 2H), 2.76 (t, J=5.8Hz, 2H), 2.54 (s, 8H), 2.36 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ162.7(q), 159.4(q), 153.6(q), 133.5(q), 132.1(t), 131.1(t), 131 .1(q), 130.8(q), 130.5(t), 129.1(t), 128.2(q), 128.0(q), 127.8(t) , 127.7(t), 124.1(t), 124.1(t), 115.3(t), 115.0(t), 70.2(d), 58.1( d), 54.9(d), 53.2(d), 45.7(s), 28.6(d), 28.5(d), 20.9(s), 16.5(s).

[0620] Example 92: 1-(2-(2-(2-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine

[0621] According to the general method of Example 80: a mixture of 2-(2-bromobenzyl)-4,6-dimethylphenol (0.15 g, 0.52 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.18 g, 0.77 mmol), potassium carbonate (0.57 g, 4.1 mmol) and potassium iodide (0.020 g, 0.10 mmol) in DMF (10 mL) was reacted to give the title product (0.050 g, yield 23%) as a viscous liquid. GC / MS (EI): m / z (%): 416 (2) [M + ], 360(1), 209(10), 195(8), 179(9), 165(7), 127(75), 113(100), 100(20), 70(40). CDCl 3 )δ7.56-7.51(m, 1H), 7.23-6.82(m, 4H), 6.63(s, 1H), 4.09(s, 2H), 3.82(s, 2H), 3.73(s, 2H), 2.92-2.46(m, 8H), 2.27(s, 3H), 2.22(s, 3H), 2.20(s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.8(q), 140.6(q), 133.5(q), 132.7(t), 131.9(q), 130.8(t), 130.6(t), 129.1(t), 127.8(t) , 127.5(t), 124.9(q), 70.2(d), 58.1(d), 54.9(d), 53.1(d), 45.7(s), 36.2(d), 20.9(s), 16.5(s).

[0622] Example 93: 1-(2-(2,4-dimethyl-6-(2-(trifluoromethyl)benzyl)phenoxy)ethyl)-4-methylpiperazine

[0623] Following the general procedure of Example 80: a mixture of 2,4-dimethyl-6-(2-(trifluoromethyl)benzyl)phenol (85 mg, 0.24 mmol, 80% purity) (prepared in a manner similar to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (114 mg, 0.49 mmol), potassium carbonate (335 mg, 2.43 mmol) and potassium iodide (8 mg, 0.05 mmol) in DMF (10 mL) was reacted to give the title product (14 mg, 0.03 mmol, 14% yield) as a viscous liquid. GC / MS (EI): m / z (%): 406 (1) [M +], 343(4), 256(18), 227(5), 183(4), 114(25), 100(100), 91(1), 84(1), 70(3). 1 H NMR (300 MHz, CDCl 3 )δ7.65 (d, J=7.7Hz, 1H), 7.38 (t, J=7.4Hz, 1H), 7.32-7.24 (m, 1H), 7.06 (d, J=7.7Hz, 1H), 6.89 (s, 1H), 6.60 (s, 1H), 4.19 (s, 2H), 3.81 (t, J=5.9Hz, 2H), 2.69 (t, J=5.9Hz, 2H), 2.75-2.37 (m, 8H), 2.31 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.8(q), 140.0(q), 133.6(q), 132.2(q), 131.9(t), 131.2(t), 130.9(q), 130.7(t), 129.5(t), 126. 1(t), 125.9(t), 125.8(t), 70.3(d), 58.0(d), 54.9(d), 53.3(d), 45.8(s), 31.9(d), 20.9(s), 16.6(s).

[0624] Example 94: 1-Methyl-4-(2-(4-methyl-2-(2-methylbenzyl)phenoxy)ethyl)piperazine

[0625] To sodium hydride (1.27 g, 29.7 mmol) in DMF (20 mL) was added 4-methyl-2-(2-methylbenzyl)phenol (1.00 g, 4.2 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.49 g, 6.4 mmol) and potassium iodide (0.14 g, 0.85 mmol). The resulting mixture was stirred at 60° C. overnight. Water was added to quench the reaction, the solution was extracted with EA (ethyl acetate), the solvent was removed and the residue was purified very carefully by silica gel column chromatography (PE:MTBE=1:1 to MTBE to DCM:methanol=10:1) to give the title product (0.30 mg, yield 20%) as a viscous liquid. GC / MS (EI): m / z(%): 338(5) [M + ],195(4),165(5),127(55),113(100),98(7),70(55). 1 H NMR (300 MHz, CDCl 3)δ7.20-7.05(m, 3H), 6.97-6.94(m, 2H), 6.80-6.69(m, 2H), 4.08(t, J=5.6Hz, 2H), 3.90( s, 2H), 2.77 (t, J=5.6Hz, 2H), 2.59-2.47 (m, 8H), 2.32 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ154.5(q), 139.1(q), 136.6(q), 130.9(t), 130.0(t), 129.9(t), 129.4(q), 128.7(t), 127.6(t), 126. 0(t), 125.9(t), 111.3(t), 66.7(d), 57.2(d), 54.9(d), 53.2(d), 45.8(s), 33.3(d), 20.6(s), 19.7(s).

[0626] Example 95: 1-(2-(2-(Furan-2-ylmethyl)-4-methylphenoxy)ethyl)-4-methylpiperazine

[0627] According to the general method of Example 80: a mixture of 2-(furan-2-ylmethyl)-4-methylphenol (0.83 g, 4.2 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.18 g, 5.0 mmol), potassium carbonate (2.89 g, 20.9 mmol) and potassium iodide (0.14 g, 0.84 mmol) in DMF (20 mL) was heated to 100° C. for 5 hours. Water was added to quench the reaction, the solution was extracted 3 times with EA, the solvent was removed, and the residue was purified by silica gel column chromatography (MTBE to DCM: methanol = 10: 1) to give the title product (0.47 g, yield 34%) as a viscous liquid. GC / MS (EI): m / z (%): 314 (30) [M + ],185(2),127(35),113(100),98(7),84(5),70(50). 1 HNMR (300 MHz, CDCl 3)δ7.30 (s, 1H), 6.98 (d, J = 8.2Hz, 1H), 6.93 (d, J = 8.2Hz, 1H), 6.74 (d, J = 8.2Hz, 1H), 6.26 (d, J = 2.8Hz, 1H), 5.95 (d, J = 2.8Hz, 1 H), 4.07 (t, J=5.6Hz, 2H), 3.92 (s, 2H), 2.80 (t, J=5.6Hz, 2H), 2.68-2.60 (m, 4H), 2.56-2.48 (m, 4H), 2.33 (s, 3H), 2.24 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ154.7(q), 154.4(q), 141.1(t), 131.1(t), 130.1(q), 128.2(t), 126.7(q), 111.7(t), 110.3(t), 106.0(t), 66.9(d), 57.3(d), 55.1(d), 53.3(d), 45.9(s), 28.7(d), 20.6(s).

[0628] Example 96: 1-(2-(2-benzyl-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine dihydrochloride

[0629] 1-(2-(2-benzyl-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine (160 mg, 0.47 mmol) was dissolved in 5 mL THF and 5 mL 3M aqueous HCl solution was added. The resulting mixture was stirred at rt (rt = room temperature) for half an hour, and then the mixture was concentrated to give the title product (170 mg, 21%) as a white solid. GC / MS (EI): m / z (%): 338 (5) [M + ],209(3),178(2),165(5),127(50),113(100),100(20),84(5),70(40).

[0630] Example 97: 4-(2-(2,4-dimethyl-6-(2-nitrobenzyl)phenoxy)ethyl)morpholine

[0631] According to the general method of Example 80: 4-(2-chloroethyl)morpholine hydrochloride (0.21 g, 1.1 mmol), 2,4-dimethyl-6-(2-nitrobenzyl)phenol (0.15 g, 0.6 mmol) (prepared in a similar manner to Example 79), potassium carbonate (0.77 g, 5.5 mmol) and potassium iodide (0.018 g, 0.11 mmol) were reacted in DMF (10 mL) to give the title product (70 mg, yield 41%) as a viscous liquid. GC / MS (EI): m / z (%): 370 (1) [M + ],238(2),224(5),111(15),100(100),93(2),84(1),70(3). 1 H NMR (300 MHz, CDCl 3 )δ7.80 (d, J=8.9Hz, 1H), 7.58 (d, J=9.1Hz, 1H), 7.39 (s, 1H), 7.35-7.27 (m, 1H), 7.16 (s, 1H), 7.03-6.94 (m, 1 H), 3.72-3.64 (m, 3H), 3.63-3.55 (m, 4H), 2.48 (t, J=5.6Hz, 3H), 2.36 (s, 3H), 2.33 (s, 3H), 2.34-2.28 (m, 4H). 13 C NMR (75 MHz, CDCl 3 )δ164.1(q), 157.7(q), 153.1(q), 134.5(t), 134.1(t), 132.3(t), 130.9(q), 128.7(q), 123.6(t), 122.5(t), 121.7(q), 115.8(q), 115.1(t), 70.8(d), 66.9(d), 58.3(d), 53.9(d), 20.8(s), 16.5(s).

[0632] Example 98: 1-(2-(2-benzyl-3-methoxyphenoxy)ethyl)-4-methylpiperazine

[0633] According to the general method of Example 80: a mixture of 2-benzyl-3-methoxyphenol (0.15 g, 0.70 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.33 g, 1.4 mmol), potassium carbonate (0.97 g, 7.00 mmol) and potassium iodide (0.020 g, 0.14 mmol) in DMF (10 mL) was reacted to give the title product (0.090 g, 37% yield) as a viscous liquid. GC / MS (EI): m / z (%): 340 (3) [M+ ], 249(1), 197(3), 165(5), 152(5), 127(50), 113(100), 100(10), 91(15), 70(45). 1 H NMR (300 MHz, CDCl 3 )δ7.25-7.05(m, 6H), 6.58-6.51(m, 2H), 4.07(t, J=5.6Hz, 2H), 4.01(s, 2H), 3.80 (s, 3H), 2.78 (t, J=5.6Hz, 2H), 2.70-2.35 (m, 8H), 2.32 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ158.4(q), 157.4(q), 141.8(q), 128.6(t), 127.9(t), 127.4(t), 125.3(t), 117.7(q), 104.6(t), 103.9(t), 66.7(d), 57.2(d), 55.8(s), 54.9(d), 53.2(d), 45.8(s), 28.8(d).

[0634] Example 99: 1-(2-(2-((5-chlorothien-2-yl)methyl)-4-methylphenoxy)ethyl)-4-methylpiperazine

[0635] According to the general method of Example 80: a mixture of 2-((5-chlorothiophen-2-yl)methyl)-4-methylphenol (1.00 g, 4.2 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.28 g, 5.4 mmol), potassium carbonate (4.63 g, 33.5 mmol) and potassium iodide (0.14 g, 0.84 mmol) in DMF (20 mL) was reacted to give the title product (0.62 g, 40% yield) as a viscous liquid. GC / MS (EI): m / z (%): 364 (8) [M + ], 331(4), 281(10), 253(8), 207(80), 127(40), 113(100), 96(5), 84(3), 70(40). 1 H NMR (300 MHz, CDCl 3)δ7.06-6.93 (m, 2H), 6.75 (d, J = 8.7Hz, 1H), 6.66 (d, J = 3.5Hz, 1H), 6.54 (d, J = 3.5Hz, 1H), 4.07 (t, J=11.0, 5.4Hz, 2H), 4.01 (s, 2H), 2.85-2.75 (m, 2H), 2.62-2.51 (m, 8H), 2.33 (s, 3H), 2.24 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ154.2(q), 143.4(q), 130.9(t), 130.1(q), 128.5(t), 128.1(q), 125.6(t), 124. 0(t), 111.6(t), 66.6(d), 57.3(d), 55.1(d), 53.3(d), 45.9(s), 31.1(d), 20.6(s).

[0636] Example 100: 1-(2-(2-Benzyl-6-methylphenoxy)ethyl)-4-methylpiperazine

[0637] According to the general method of Example 80: a mixture of 2-benzyl-6-methylphenol (0.20 g, 1.0 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.48 g, 2.0 mmol), potassium carbonate (1.39 g, 10.1 mmol) and potassium iodide (0.030 g, 0.20 mmol) in DMF (10 mL) was reacted to give the title product (0.040 g, yield 11%) as a viscous liquid. GC / MS (EI): m / z (%): 324 (5) [M + ], 268(1), 195(5), 165(15), 127(2), 128(55), 113(100), 100(20), 84(5), 70(40). 1 H NMR (300 MHz, CDCl 3 )δ7.26-6.85(m, 8H), 4.10-4.00(m, 2H), 3.90-3.75(m, 2H), 2.70-2.55(m, 10H), 2.44-2.24(m, 6H). 13 C NMR (75 MHz, CDCl 3)δ155.8(q), 141.2(q), 133.8(q), 131.1(q), 129.7(t), 128.9(t), 128.5(t), 126. 1(t), 124.2(t), 70.1(d), 57.9(d), 54.7(d), 52.8(d), 45.5(s), 35.9(d), 16.6(s).

[0638] Example 101: 1-(2-(2-benzyl-4-(tert-butyl)-6-methoxyphenoxy)ethyl)-4-methylpiperazine

[0639] A mixture of 2-benzyl-4-(tert-butyl)-6-methoxyphenol (0.25 g, 0.93 mmol) (prepared in a manner similar to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.44 g, 1.8 mmol), potassium carbonate (1.28 g, 9.2 mmol) and potassium iodide (0.030 g, 0.19 mmol) in DMF (10 mL) was heated to reflux overnight. Water was added, the solution was extracted 3 times with DCM, the solvent was removed and the residue was purified by silica gel column chromatography (MTBE, then DCM: methanol = 10: 1) to give the title product (0.28 g, yield 74%) as a viscous liquid. GC / MS (EI): m / z (%): 396 (5) [M + ],281(2),255(3),181(2),165(3),127(100),113(92),91(12),84(9),70(37). 1 H NMR (300 MHz, CDCl 3 )δ7.25-7.10 (m, 5H), 6.79 (d, J=2.1Hz, 1H), 6.75 (d, J=2.0Hz, 1H), 4.00 (s, 2H), 3.91 (t, J=5 .9Hz, 2H), 3.83 (s, 3H), 2.66 (t, J=5.9Hz, 2H), 2.55-2.38 (m, 8H), 2.30 (s, 3H), 1.27 (s, 9H). 13 C NMR (75 MHz, CDCl 3 )δ152.1(q), 146.8(q), 144.1(q), 141.6(q), 133.7(q), 128.8(t), 128.3(t), 125.8(t), 119.7(t) , 108.3(t), 70.0(d), 58.1(d), 55.8(s), 55.0(d), 53.2(d), 45.9(s), 36.5(d), 34.7(q), 31.6(s).

[0640] Example 102: 1-(2-(2-(3-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine

[0641] Following the general procedure of Example 80: a mixture of 2-(3-chlorobenzyl)-4-methylphenol (0.80 g, 3.4 mmol) (prepared in a manner similar to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.62 g, 6.9 mmol), potassium carbonate (4.75 g, 34.4 mmol) and potassium iodide (0.11 g, 0.69 mmol) in DMF (15 mL) was reacted to give the title product (0.67 g, 52% yield) as a viscous liquid. GC / MS (EI): m / z (%): 358 (3) [M + ], 253(1), 229(1), 195(4), 165(7), 127(52), 113(100), 70(33). 1 H NMR (300 MHz, CDCl 3 )δ7.23-7.05 (m, 4H), 6.98 (d, J=8.2Hz, 1H), 6.92 (s, 1H), 6.73 (d, J=8.2Hz, 1H), 4.04 (t, J=5.7Hz, 2H ), 3.89 (s, 2H), 2.75 (t, J=5.7Hz, 2H), 2.6-2.54 (m, 4H), 2.52-2.40 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ154.5(q), 143.5(q), 133.9(q), 131.4(t), 129.9(q), 129.5(t), 128.9(t), 128.6(q), 128.1(t), 127.1(t), 125.9(t), 111.6(t), 66.5(d), 57.3(d), 55.1(d), 53.5(d), 45.9(s), 36.1(d), 20.6(s).

[0642] Example 103: Methyl 3-benzyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate

[0643] A mixture of methyl 3-benzyl-4-hydroxybenzoate (0.15 g, 0.62 mmol) (prepared in a manner similar to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.29 g, 1.2 mmol), potassium carbonate (0.86 g, 6.2 mmol) and potassium iodide (0.021 g, 0.12 mmol) in DMF (10 mL) was heated to reflux for 4 hours. Water was added, the solution was extracted 3 times with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (MTBE to DCM: methanol = 10: 1) to give the title product (0.090 g, yield 40%) as a viscous liquid. GC / MS (EI): m / z (%): 368 (1) [M + ], 239(2), 207(5), 181(5), 165(10), 127(55), 113(100), 91(53), 70(40). 1 H NMR (300 MHz, CDCl 3 )δ7.90 (d, J=8.6Hz, 1H), 7.84 (s, 1H), 7.25-7.20 (m, 2H), 7.19-7.11 (m, 3H), 6.83 (d, J=8.6Hz, 1H), 4.11 (t, J=5 .6Hz, 2H), 3.96 (s, 2H), 3.85 (s, 3H), 2.78 (t, J=5.6Hz, 2H), 2.70-2.54 (m, 4H), 2.52-2. 40 (m, 4H), 2.32 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ167.1(q), 160.5(q), 140.5(q), 132.3(t), 130.1(t), 129.6(q), 128.8(t), 128.4(t), 126. 1(t), 122.5(q), 110.7(t), 66.8(d), 56.9(d), 55.0(d), 53.2(d), 52.0(s), 45.8(s), 36.4(d).

[0644] Example 104: 1-(2-(2,4-dimethyl-6-(pyridin-2-ylmethyl)phenoxy)ethyl)-4-methylpiperazine

[0645] A mixture of 2,4-dimethyl-6-(pyridin-2-ylmethyl)phenol hydrochloride (0.35 g, 0.98 mmol) (prepared in a manner similar to Example 79 and isolated as the hydrochloride salt in a manner similar to Example 96), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.46 g, 2.0 mmol), potassium carbonate (2.03 g, 14.7 mmol) and potassium iodide (16 mg, 0.098 mmol) in DMF (30 mL) was heated to reflux for 3 hours. Water was added, the solution was extracted 3 times with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (DCM: methanol = 10: 1) to give the title product (0.58 g, yield 66%) as a viscous liquid. GC / MS (EI): m / z (%): 339 (1) [M + ],268(4),221(10),181(2),165(5),127(60),113(100),98(10),70(85). 1 H NMR (300 MHz, CDCl 3 )δ8.50(d, J=4.7Hz, 1H), 7.55-7.50(m, 1H), 7.15-7.00(m, 2H), 6.85(s, 1H), 6.80(s, 1H), 4.16(s, 2H), 3.83 (t, J=5.7Hz, 2H), 2.72 (t, J=5.7Hz, 2H), 2.67-2.38 (m, 8H), 2.32 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ161.4(q), 153.6(q), 149.2(t), 136.5(t), 133.5(q), 131.9(q), 130.8(q), 130.6(t), 129.4(t) , 123.1(t), 121.1(t), 70.3(d), 58.1(d), 54.9(d), 53.2(d), 45.8(s), 38.8(d), 20.8(s), 16.5(s).

[0646] Example 105: 4-(2-(2,4-dimethyl-5-((perfluorophenyl)methyl)phenoxy)ethyl)morpholine

[0647] A mixture of 2,4-dimethyl-6-((perfluorophenyl)methyl)phenol (1.00 g, 3.3 mmol) (isolated as an isomeric by-product when 2,4-dimethyl-6-((perfluorophenyl)methyl)phenol was prepared by a method similar to Example 79), 4-(2-chloroethyl)morpholine hydrochloride (1.23 g, 6.6 mmol), potassium carbonate (4.57 g, 33.1 mmol) and potassium iodide (0.11 g, 0.66 mmol) in DMF (13 mL) was heated to reflux for 3 hours. The color of the reaction solution turned into a very dark color. Water was added, the solution was extracted 3 times with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (PE:MTBE=1:1) to give the title product (0.15 g, yield 10%). GC / MS (EI): m / z (%): 415 (1) [M + ], 237(2), 219(2), 181(5), 114(5), 100(100), 91(3), 70(4). 1 H NMR (300 MHz, CDCl 3 )δ6.95 (s, 1H), 6.55-6.44 (m, 1H), 4.07-3.89 (m, 4H), 3.80-3.65 (m, 4H), 2.87-2.69 (m, 2H), 2.66-2.50 (m, 4H), 2.28 (s, 3H), 2.15 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ155.3(q), 133.7(q), 133.4(q), 133.0(q), 132.9(t), 127.9(q), 125.7(q), 112. 0(t), 67.1(d), 66.7(d), 57.8(d), 54.3(d), 25.8(d), 25.8(d), 18.6(s), 15.8(s).

[0648] Example 106: 1-(2-(2-(3-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine

[0649] A mixture of 2-(3-bromobenzyl)-4,6-dimethylphenol (0.40 g, 1.4 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.49 g, 2.1 mmol), potassium carbonate (1.52 g, 11.0 mmol) and potassium iodide (0.050 g, 0.28 mmol) in DMF (10 mL) was heated to 100° C. overnight. Water was added, the solution was extracted 3 times with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (MTBE to DCM: methanol = 10: 1) to give the title product (0.25 g, yield 42%) as a viscous liquid. GC / MS (EI): m / z (%): 416 (2) [M + ], 209(5), 195(4), 179(4), 165(4), 127(65), 113(100), 100(15), 84(5), 70(40). 1 H NMR (300 MHz, CDCl 3 )δ7.35(s, 1H), 7.34-7.26(m, 1H), 7.20-7.07(m, 2H), 6.87(s, 1H), 6.73(s, 1H), 3.95(s, 2H), 3 .87-3.72(m, 2H), 2.81-2.70(m, 2H), 2.70-2.52(m, 8H), 2.26(s, 3H), 2.23(s, 3H), 2.22(s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.6(q), 143.9(q), 133.5(q), 132.6(q), 131.9(t), 130.9(q), 130.6(t), 129.9(t), 129.2(t), 129. 1(t), 127.6(t), 122.5(q), 70.3(d), 58.2(d), 55.0(d), 53.5(d), 45.9(s), 35.7(d), 20.9(s), 16.5(s).

[0650] Example 107: 1-(2-(2-benzyl-3,6-dimethylphenoxy)ethyl)-4-methylpiperazine

[0651] A mixture of 2-benzyl-3,6-dimethylphenol (0.22 g, 1.0 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.49 g, 2.1 mmol), potassium carbonate (1.43 g, 10.4 mmol) and potassium iodide (0.030 g, 0.21 mmol) in DMF (10 mL) was heated to 100° C. for 3 hours. Water was added, the solution was extracted 3 times with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (MTBE to DCM: methanol = 10: 1) to give the title product (0.15 g, yield 42%) as a viscous liquid. GC / MS (EI): m / z (%): 338 (3) [M + ], 209(5), 195(4), 178(45), 165(10), 127(45), 113(100), 100(35), 84(10), 70(40). 1 H NMR (300 MHz, CDCl 3 )δ7.25-7.18 (m, 2H), 7.16-7.04 (m, 3H), 7.00 (d, J=7.6Hz, 1H), 6.87 (d, J=7.7Hz, 1H), 4.10 (s, 2H), 3. 75 (t, J=5.9Hz, 2H), 2.67 (t, J=5.9Hz, 2H), 2.62-2.40 (m, 8H), 2.31 (s, 3H), 2.29 (s, 3H), 2.14 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ156.3(q), 140.9(q), 136.6(q), 131.7(q), 129.3(t), 128.4(t), 128.4(t), 128.2(t), 126. 0(t), 125.7(t), 70.4(d), 58.1(d), 55.0(d), 53.4(d), 45.9(s), 32.5(d), 19.8(s), 16.6(s).

[0652] Example 108: 1-(2-(2-benzyl-4-isopropylphenoxy)ethyl)-4-methylpiperazine

[0653] A mixture of 2-benzyl-4-isopropylphenol (0.25 g, 1.1 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.52 g, 2.2 mmol), potassium carbonate (1.53 g, 11.1 mmol) and potassium iodide (0.040 g, 0.22 mmol) in DMF (10 mL) was heated to reflux for 4 hours. Water was added, the solution was extracted 3 times with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (MTBE to DCM: methanol = 10: 1) to give the title product (0.16 g, yield 41%) as a viscous liquid. GC / MS (EI): m / z (%): 352 (2) [M + ], 207(4), 195(1), 178(2), 165(4), 127(45), 113(100), 100(5), 91(10), 70(45). 1 H NMR (300 MHz, CDCl 3 )δ7.29-7.11(m, 5H), 7.10-6.94(m, 2H), 6.84-6.71(m, 1H), 4.07(s, 2H), 3.96( s, 2H), 2.90-2.71 (m, 3H), 2.70-2.36 (m, 8H), 2.33 (s, 3H), 1.21 (d, J=3.7, 6H). 13 C NMR (75 MHz, CDCl 3 )δ154.7(q), 141.3(q), 141.1(q), 129.2(q), 129.1(t), 128.8(t), 128.2(t), 125.7(t), 124. 9(t), 111.3(t), 66.6(d), 57.3(d), 54.9(d), 53.3(d), 45.8(s), 36.5(d), 33.3(t), 24.3(s).

[0654] Example 109: 1-(2-((6-benzylbenzo[d][1,3]dioxol-5-yl)oxy)ethyl)-4-methylpiperazine

[0655] A mixture of 6-benzylbenzo[d][1,3]dioxol-5-ol (0.10 g, 0.44 mmol) (prepared in a manner similar to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.21 g, 0.88 mmol), potassium carbonate (0.61 g, 4.4 mmol) and potassium iodide (0.020 g, 0.090 mmol) in DMF (10 mL) was heated to reflux for 4 hours. Water was added, the solution was extracted 3 times with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (MTBE to DCM: methanol = 10: 1) to give the title product (0.09 g, 0.24 mmol, yield 54.3%) as a viscous liquid. GC / MS (EI): m / z (%): 354 (15) [M + ], 254(5), 225(5), 169(4), 152(5), 127(100), 113(85), 98(10), 84(12), 70(45). 1 H NMR (300 MHz, CDCl 3 )δ7.26-7.20(m, 2H), 7.18-7.11(m, 3H), 6.58(s, 1H), 6.50(s, 1H), 5.86(s, 2H), 3.98 (t, J=5.6Hz, 2H), 3.86 (s, 2H), 2.72 (t, J=5.6Hz, 2H), 2.70-3.38 (m, 8H), 2.32 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ151.4(q), 146.5(q), 141.4(q), 128.8(t), 128.4(t), 125.9(t), 122.2(q), 110. 4(t), 101.1(d), 96.1(t), 67.8(d), 57.3(d), 54.9(d), 53.3(d), 45.8(s), 35.9(d).

[0656] Example 110: 1-(2-((6-benzyl-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)-4-methylpiperazine

[0657] A mixture of 6-benzyl-2,3-dihydro-1H-inden-5-ol (0.22 g, 0.98 mmol) (prepared in a similar manner to Example 79), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.46 g, 2.0 mmol), potassium carbonate (1.36 g, 9.8 mmol) and potassium iodide (0.030 g, 0.20 mmol) in DMF (10 mL) was heated to 100° C. (heated at 150° C.) overnight. Water was added, the solution was extracted 3 times with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (MTBE to DCM: methanol = 10: 1) to give the title product (0.11 g, yield 30%) as a viscous liquid. GC / MS (EI): m / z (%): 350 (10) [M + ], 221(4), 207(4), 178(5), 165(4), 127(55), 113(100), 100(5), 91(10), 70(435). 1 H NMR (300 MHz, CDCl 3 )δ7.35-7.14(m, 5H), 6.95(s, 1H), 6.75(s, 1H), 4.18-3.87(m, 4H), 2.92-2.75(m, 6H), 2.66-2.42(m, 8H), 2.39-2.28(m, 3H), 2.05(m, 2H). 13 C NMR (75 MHz, CDCl 3 )δ155.4(q), 143.4(q), 141.7(q), 136.0(q), 128.9(t), 128.3(t), 127.5(q), 126.3(t), 125.7(t) , 108.0(t), 66.7(d), 57.3(d), 54.9(d), 53.3(d), 45.8(s), 36.3(d), 33.3(d), 32.2(d), 25.8(d).

[0658] Example 111: 1-(2-(2,4-dimethyl-6-(pyridin-3-ylmethyl)phenoxy)ethyl)-4-methylpiperazine

[0659] A mixture of 2,4-dimethyl-6-(pyridin-3-ylmethyl)phenol hydrochloride (0.35 g, 1.1 mmol) (prepared in a manner similar to Example 79 and isolated as a hydrochloride in a manner similar to Example 96), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.53 g, 2.2 mmol), potassium carbonate (2.32 g, 16.8 mmol) and potassium iodide (0.020 g, 0.11 mmol) in DMF (30 mL) was heated to reflux for 5 hours. Water was added, the solution was extracted 3 times with DCM, the solvent was removed and the residue was purified by silica gel column chromatography (DCM: methanol: TEA = 10: 1) to give the title product (0.22 g, yield 56%) as a viscous liquid. GC / MS (EI): m / z (%): 339 (30) [M + ], 324(5), 296(15), 283(20), 269(85), 127(60), 113(100), 98(15), 84(20), 70(90). 1 H NMR (300 MHz, CDCl 3 )δ8.49 (s, 1H), 8.41 (d, J = 4.7, 1H), 7.46 (d, J = 7.8Hz, 1H), 7.16 (dd, J = 7.8, 4.7Hz, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 3 .96 (s, 2H), 3.81 (t, J=5.7Hz, 2H), 2.74 (t, J=5.7Hz, 2H), 2.70-2.44 (m, 8H), 2.35 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.5(q), 150.3(t), 147.5(t), 136.8(q), 136.3(t), 133.6(q), 132.3(q), 130.9(q), 130.7(t) , 129.0(t), 123.4(t), 70.4(d), 58.1(d), 54.9(d), 53.1(d), 45.6(s), 33.3(d), 20.8(s), 16.5(s).

[0660] Example 112: 1-(2-(2-benzyl-3-methylphenoxy)ethyl)-4-methylpiperazine

[0661] A mixture of 2-benzyl-3-methylphenol (0.15 g, 0.76 mmol) (prepared in a similar manner to Example 79 and carefully separated from other regioisomers by chromatography), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.36 g, 1.5 mmol), potassium carbonate (1.05 g, 7.6 mmol) and potassium iodide (0.030 g, 0.15 mmol) in DMF (10 mL) was heated to reflux for 4 hours. Water was added, the solution was extracted 3 times with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (MTBE to DCM: methanol = 10: 1) to give the title product (0.10 g, yield 40%) as a viscous liquid. GC / MS (EI): m / z (%): 324 (5) [M + ], 209(4), 195(4), 178(4), 165(10), 127(75), 113(100), 100(15), 91(13), 70(80). 1 H NMR (300 MHz, CDCl 3 )δ7.25-7.17(m, 2H), 7.16-7.05(m, 4H), 6.85-6.71(m, 2H), 4.12-4.01(m , 4H), 2.75 (t, J=5.5Hz, 2H), 2.70-2.33 (m, 8H), 2.29 (s, 3H), 2.25 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ156.9(q), 140.9(q), 138.6(q), 128.2(t), 127.6(q), 127.1(t), 125.6(t), 122. 9(t), 109.2(t), 66.8(d), 57.2(d), 54.9(d), 53.3(d), 45.8(s), 31.9(d), 19.9(s).

[0662] Example 113: 4-methyl-2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)phenol

[0663] To a suspension of sodium hydride (56wt%, 0.95g, 22.2mmol) in DMF (10mL) was added 2,2'-methylenebis(4-methylphenol) (1.27g, 5.6mmol), and then 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.7g, 7.2mmol), and the resulting mixture was stirred at room temperature for 2 days. Water was added, the solution was extracted with EA, the solvent was removed, and the residue was purified by column chromatography (DCM: containing EA = 10: 1) to give 150mg of a brown solid. The obtained material was mixed with dilute hydrochloric acid, and the entire mixture was then concentrated to remove water to give the title product (0.11g, yield 6%) as a white solid. GC / MS (EI): m / z (%): 354 (26) [M + ], 339(3), 209(4), 165(4), 127(30), 113(100), 98(5), 84(3), 70(25).

[0664] Example 114: 1-(2-(2,4-dimethyl-6-(pyridin-4-ylmethyl)phenoxy)ethyl)-4-methylpiperazine

[0665] A mixture of 2,4-dimethyl-6-(pyridin-4-ylmethyl)phenol hydrochloride (0.19 g, 0.46 mmol) (prepared in a manner similar to Example 79 and isolated as a hydrochloride in a manner similar to Example 96), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.22 g, 0.91 mmol), potassium carbonate (0.95 g, 6.8 mmol) and potassium iodide (7.6 mg, 0.050 mmol) in DMF (volume: 30 mL) was heated to reflux overnight. Water was added, the solution was extracted 3 times with DCM, the solvent was removed and the residue was purified by silica gel column chromatography (DCM: methanol: TEA = 10: 1) to give the title product (0.060 g, yield 38%) as a viscous liquid. GC / MS (EI): m / z (%): 339 (10) [M + ], 324(53), 283(5), 260(8), 240(4), 213(75), 127(40), 113(100), 98(8), 84(8), 70(50). 1 H NMR (300 MHz, CDCl 3)δ8.43 (d, J=5.7Hz, 2H), 7.08 (d, J=5.7Hz, 2H), 6.82 (s, 1H), 6.69 (s, 1H), 3.93 (s, 2H), 3.76 (t, J=5.5Hz, 2H), 3.07(q, J=7.3Hz, 1H), 2.86-2.68(m, 9H), 2.52(s, 3H), 2.22(s, 3H), 2.18(s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.4(q), 150.5(q), 149.7(t), 133.8(q), 131.2(q), 130.9(t), 130.9(q), 129.3(t), 124 .1(t), 70.2(d), 57.6(d), 54.3(d), 51.8(d), 44.7(s), 35.5(d), 20.7(s), 16.5(s), 8.7(s).

[0666] Example 115: 1-((2-bromobenzyl)oxy)-2,4-dimethylbenzene

[0667] A suspension of potassium carbonate (42.4 g, 307 mmol), 1-bromo-2-(bromomethyl)benzene (48.6 g, 194 mmol) and 2,4-dimethylphenol (25.0 g, 205 mmol) in acetone (300 mL) was heated under reflux for 14 hours. The solvent was then removed by rotary evaporation, water (200 mL) was added, the solution was extracted with MTBE (100 mL×3), and the organic phase was washed with Na 2 SO 4 Drying and removal of the solvent afforded the title product (56.0 g, yield 89%) as a white solid, which was used directly in the next step. GC / MS (EI): m / z (%): 292 (98) [M + ],290(100)[M + ],211(5),171(24),121(5),90(45),77(25).

[0668] Example 116: 2-(2-bromobenzyl)-4,6-dimethylphenol

[0669] Titanium (IV) chloride (39.1 g, 206 mmol) was added dropwise to a solution of 1-((2-bromobenzyl)oxy)-2,4-dimethylbenzene in dichloromethane (200 mL) at 0°C, and the mixture was stirred at 0°C for 10 minutes. Water (150 mL) was added to quench the reaction, and the solution was extracted with dichloromethane (100 mL×3). The organic phase was precipitated with MgSO 4The residue was dried and the solvent was removed. The residual liquid was purified by silica gel column chromatography (PE:MTBE=95:5) to obtain the title product (11.5 g, yield 17%) as a colorless liquid. GC / MS (EI): m / z (%): 292 (95) [M + ],290(98)[M + ],211(90),196(80),181(40),165(50),134(100),91(40).

[0670] Example 117: 2-(2-Hydroxy-3,5-dimethylbenzyl)benzonitrile

[0671] A mixture of 2-(2-bromobenzyl)-4,6-dimethylphenol (1.0 g, 3.4 mmol) and copper (I) cyanide (0.33 g, 3.7 mmol) in N-methyl-2-pyrrolidone (10 mL) was heated to reflux for 1 hour. The cooled reaction mixture was diluted with water (20 mL), extracted with MTBE (50 mL×3), and washed with Na 2 SO 4 The residue was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:MTBE=85:15) to obtain the title product (0.46 g, yield 56%) as a light red solid. GC / MS (EI): m / z (%): 237 (100) [M + ],222(158),208(55),194(50),182(35),165(15),121(40),91(20),77(15).

[0672] Example 118: 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile

[0673] According to the general method of Example 80: a mixture of 2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile (0.65 g, 2.74 mmol), 4-(2-chloroethyl)morpholine (0.82 g, 5.48 mmol), potassium carbonate (3.79 g, 27.4 mmol) and potassium iodide (0.09 g, 0.55 mmol) in DMF (15 mL) was reacted to give the title product (0.83 g, yield 84%) as a viscous liquid. GC / MS (EI): m / z (%): 350 (7) [M + ],263(23),234(5),208(3),190(4),165(3),140(1),100(100),56(14). 1 H NMR (300 MHz, CDCl 3)δ7.64 (d, J=7.7Hz, 1H), 7.45 (t, J=7.3Hz, 1H), 7.32-7.19 (m, 2H), 6.90 (s, 1H), 6.71 (s, 1H), 4.23 (s, 2H), 3. 88 (t, J=5.7Hz, 2H), 3.77-3.63 (m, 4H), 2.74 (t, J=5.7Hz, 2H), 2.62-2.46 (m, 4H), 2.28 (s, 3H),), 2.22 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.7(q), 145.3(q), 133.7(q), 132.9(t), 132.8(t), 131.5(q), 131.1(t), 131.0(q), 130.1(t), 129. 2(t), 126.7(t), 118.5(q), 112.6(q), 70.2(d), 67.1(d), 58.8(d), 54.3(d), 34.4(d), 20.9(s), 16.5(s).

[0674] Example 119: 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile hydrochloride

[0675] To a solution of 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile (40 mg, 0.11 mmol) in methanol (15 mL) was added hydrogen chloride (224 mg, 1.1 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed and the residue was dried under reduced pressure at 90°C to give the title product (40 mg, yield 89%) as a viscous liquid. GC / MS (EI): m / z (%): 350 (3) [M + ], 263(14), 234(4), 190(3), 165(2), 140(1), 114(15), 100(100), 87(1), 70(3).

[0676] Example 120: 2-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile

[0677] According to the general method of Example 80: a mixture of 2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile (0.2 g, 0.843 mmol), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.298 g, 1.264 mmol), potassium carbonate (0.93 g, 6.7 mmol) and potassium iodide (0.028 g, 0.17 mmol) in DMF (10 mL) was reacted to give the title product (0.10 g, yield 31%) as a viscous liquid. GC / MS (EI): m / z (%): 363 (1) [M + ], 234(1), 208(4), 190(4), 165(3), 127(69), 113(100), 100(9), 84(6), 70(37). 1 H NMR (300 MHz, CDCl 3 )δ7.63 (d, J=7.7, 1H), 7.49-7.38 (m, 1H), 7.32-7.17 (m, 2H), 6.88 (s, 1H), 6.71 (s, 1H), 4.22 (s, 2H), 3 .86 (t, J=5.8Hz, 2H), 2.74 (t, J=5.8Hz, 2H), 2.70-2.34 (m, 8H), 2.28 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.7(q), 145.4(q), 133.6(q), 132.9(t), 132.7(t), 131.5(q), 131.0(t), 130.1(t), 129.1(t), 126. 6(t), 118.5(q), 112.5(q), 70.4(d), 58.2(d), 55.1(d), 53.7(d), 46.1(s), 34.3(d), 20.9(s), 16.5(s).

[0678] Example 121: 2-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile hydrochloride

[0679] To 2-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile (0.60 g, 1.6 mmol) in methanol (10 mL) was added hydrogen chloride (0.50 g, 4.8 mmol) and the resulting mixture was allowed to stand for half an hour. The solvent was then removed by rotary evaporation and the residue was dried on a Kugelrohr distiller (90° C., 0.1 mbar) to give the title product (0.65 g, yield 96%) as a light brown solid. GC / MS (EI): m / z (%): 363 (1) [M + ], 248(1), 208(4), 190(4), 165(3), 127(69), 113(100), 100(9), 84(6), 70(37).

[0680] Example 122: 2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile

[0681] According to the general method of Example 80: a mixture of 2-(2-hydroxy-5-methylbenzyl)benzonitrile (0.50 g, 2.2 mmol) (prepared in a similar sequence as described in Examples 115, 116 and 117), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.06 g, 4.5 mmol), potassium carbonate (3.10 g, 22.4 mmol) and potassium iodide (0.070 g, 0.45 mmol) in DMF (15 mL) was reacted to give the title product (0.48 g, 58% yield) as a brown viscous liquid. GC / MS (EI): m / z (%): 349 (1) [M + ], 248(1), 220(2), 190(6), 165(3), 127(58), 113(100), 98(5), 84(4), 70(34). 1 H NMR (300 MHz, CDCl 3 )δ7.62 (d, J=7.6Hz, 1H), 7.44 (t, J=7.6Hz, 1H), 7.30-7.20 (m, 2H), 7.02 (d, J=8.2Hz, 1H), 6.99 (s, 1H), 6.76 (d, J=8 .2Hz, 1H), 4.17 (s, 2H), 4.06 (t, J=5.7Hz, 2H), 2.75 (t, J=5.7Hz, 2H), 2.66-2.42 (m, 8H), 2.32 (s, 3H), 2.27 (s, 3H). 13 CNMR (75MHz, CDCl 3)δ154.5(q), 145.3(q), 132.7(t), 131.7(t), 130.1(q), 129.8(t), 128.6(t), 127.2(q), 126.4(t), 118.5(q), 112.6(q), 111.6(t), 66.4(d), 57.2(d), 55.0(d), 53.3(d), 45.9(s), 34.7(d), 20.6(s).

[0682] Example 123: 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)-3-fluorobenzonitrile

[0683] According to the general method of Example 80: 3-fluoro-2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile (0.15 g, 0.59 mmol) (prepared in a similar sequence as described in Examples 115, 116 and 117), 4-(2-chloroethyl)morpholine hydrochloride (0.22 g, 1.2 mmol), potassium carbonate (0.81 g, 5.9 mmol) and potassium iodide (0.020 g, 0.12 mmol) in DMF (15 mL) were reacted to give the title product (0.060 g, yield 26%) as a brown viscous liquid. GC / MS (EI): m / z (%): 368 (2) [M + ], 281(11), 208(2), 183(2), 158(1), 134(3), 114(19), 100(100), 85(1), 70(4). 1 H NMR (300 MHz, CDCl 3 )δ7.50 (d, J=7.2Hz, 1H), 7.41-7.27 (m, 2H), 6.86 (s, 1H), 6.37 (s, 1H), 4.27 (s, 2H), 3.99 (t, J=5. 8Hz, 2H), 3.82-3.67 (m, 4H), 2.83 (t, J=5.8Hz, 2H), 2.68-2.53 (m, 4H), 2.28 (s, 3H), 2.15 (s, 3H). 13 C NMR (75 MHz, CDCl 3)δ153.4(q), 133.4(q), 132.1(q), 131.8(q), 130.8(t), 130.7(q), 130.4(q), 129.1(t), 129.0(t), 128.9(t), 128.9(t), 127.1(t), 120.7(t), 120.4(t), 115.6(q), 115.5(q), 70.0(d), 67.1(d), 58.8(d), 54.4(d), 28.1(d), 20.9(s), 16.5(s).

[0684] Example 124: 2-(3,5-dimethyl-2-(2-morpholinopropoxy)benzyl)benzonitrile and 2-(3,5-dimethyl-2-((1-morpholinoprop-2-yl)oxy)benzyl)benzonitrile

[0685] According to the general method of Example 80: 4-(2-chloropropyl)morpholine hydrochloride (0.40 g, 2.0 mmol), 2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile (0.240 g, 0.99 mmol), potassium carbonate (1.37 g, 9.9 mmol) and potassium iodide (0.033 g, 0.20 mmol) were reacted in DMF (10 mL) to give 2-(3,5-dimethyl-2-(2-morpholinopropoxy)benzyl)benzonitrile (0.080 g, yield 22%) (as a brown viscous liquid) and 2-(3,5-dimethyl-2-((1-morpholinoprop-2-yl)oxy)benzyl)benzonitrile (0.040 g, yield 11%) (as a brown viscous liquid).

[0686] 2-(3,5-dimethyl-2-(2-morpholinopropoxy)benzyl)benzonitrile: GC / MS (EI): m / z (%): 364 (1) [M + ], 277(1), 234(2), 190(2), 165(1), 128(5), 114(100), 98(1), 84(1), 70(3). 1 H NMR (300 MHz, CDCl 3 )δ7.64 (d, J=7.7Hz, 1H), 7.46 (t, J=7.2Hz, 1H), 7.32-7.24 (m, 1H), 7.20 (d, J=7.9Hz, 1H), 6.90 (s, 1H), 6.70 (s, 1H), 4.23 (s, 2H ), 3.88-3.78(m, 1H), 3.73-3.58(m, 5H), 3.01-2.88(m, 1H), 2.66-2.52(m, 4H), 2.28(s, 3H), 2.22(s, 3H), 1.13(d, J=6.7Hz, 3H). 13C NMR (75 MHz, CDCl 3 )δ153.6(q), 145.3(q), 133.7(q), 132.9(t), 132.7(t), 131.3(q), 131.1(t), 131.0(q), 130.0(t), 129.2(t) , 126.6(t), 118.4(q), 112.6(q), 74.5(d), 67.4(d), 59.6(t), 49.8(d), 34.4(d), 20.9(s), 16.6(s), 12.5(s).

[0687] 2-(3,5-dimethyl-2-((1-morpholinopropan-2-yl)oxy)benzyl)benzonitrile: GC / MS (EI): m / z (%): 364 (1) [M + ], 349(2), 277(3), 234(10), 190(10), 165(1), 128(5), 114(100), 98(1), 84(1), 70(5).

[0688] Example 125: 2-(3,5-dimethyl-2-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)benzyl)benzonitrile

[0689] According to the general method of Example 80: a mixture of 2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile (0.15 g, 0.63 mmol), 4-(2-bromoethyl)tetrahydro-2H-pyran (0.24 g, 1.3 mmol), potassium carbonate (0.87 g, 6.3 mmol) and potassium iodide (0.020 g, 0.13 mmol) in DMF (15 mL) was reacted to give the title product (0.18 g, yield 79%) as a viscous liquid. GC / MS (EI): m / z (%): 349 (1) [M + ], 236(18), 222(5), 208(18), 182(13), 165(4), 130(2), 118(100), 83(7), 69(7). 1 H NMR (300 MHz, 1 H NMR (300 MHz, CDCl 3)δ7.64 (d, J=7.7, 1H), 7.48-7.44 (m, 1H), 7.36-7.23 (m, 1H), 7.16 (d, J=7.8Hz, 1H), 6.91 (s, 1H), 6.72 (s, 1H), 4.19 (s, 2H), 3.98-3.92 ( m, 2H), 3.77 (t, J=6.4Hz, 2H), 3.40-3.30 (m, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 1.72 (t, J=5.4Hz, 3H), 1.67-1.50 (m, 2H), 1.47-1.10 (m, 2H). 13 C NMR (75 MHz, CDCl 3 )δ153.7(s), 145.2(s), 133.5(s), 132.9(d), 132.6(d), 131.2(s), 131.0(d), 129.8(d), 129.1(d), 126. 5(d), 118.3(s), 112.5(s), 70.4(t), 68.0(t), 37.3(t), 34.3(t), 33.2(t), 31.9(d), 20.8(q), 16.4(q).

[0690] Example 126: 2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile dihydrochloride

[0691] To a solution of 2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile (0.62 g, 1.7 mmol) in methanol (10 mL) was added dropwise hydrogen chloride (0.52 g, 5.2 mmol) and the resulting mixture was allowed to stand at room temperature for 1 hour. The solvent was then removed by rotary evaporation under reduced pressure and the resulting solid was dried under vacuum at 80° C. for 1 hour in a Kugelrohr distiller. The desired product (0.67 g, yield 89%) was obtained as a light brown solid. GC / MS (EI): m / z (%): 349 (4) [M + ], 279(1), 220(2), 190(5), 165(3), 127(55), 113(100), 98(5), 84(4), 70(35).

[0692] Example 127: 2-(2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)phenyl)acetonitrile According to the general method of Example 80: a mixture of 2-(2-(2-hydroxy-3,5-dimethylbenzyl)phenyl)acetonitrile (0.18 g, 0.72 mmol) (prepared in a similar manner to Example 79), 4-(2-chloroethyl)morpholine hydrochloride (0.27 g, 1.4 mmol), potassium carbonate (0.99 g, 7.2 mmol) and potassium iodide (0.020 g, 0.14 mmol) in DMF (15 mL) was reacted to give the title product (0.050 g, yield 11%) as a viscous liquid. GC / MS (EI): m / z (%): 364 (2) [M + ], 277(15), 234(8), 209(5), 191(1), 165(3), 130(2), 100(100), 77(1), 56(6).

[0693] Example 128: 3-Bromo-2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile

[0694] According to the general method of Example 80: a mixture of 3-bromo-2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile (0.25 g, 0.79 mmol) (prepared in a similar sequence as described in Examples 115, 116 and 117, starting from 1,3-dibromo-2-(bromomethyl)benzene, replacing 1-bromo-2-(bromomethyl)benzene), 4-(2-chloroethyl)morpholine hydrochloride (0.29 g, 1.58 mmol), potassium carbonate (1.09 g, 7.91 mmol) and potassium iodide (0.03 g, 0.16 mmol) in DMF (15 mL) was heated to reflux for 3 hours. Water was added, the solution was extracted 3 times with DCM, the solvent was removed and the residue was purified by silica gel column chromatography (PE (petroleum ether): MTBE = 1: 1) to give the title product (0.22 g, 0.48 mmol, yield 60%) as a viscous liquid. GC / MS(EI): m / z(%): 430(2)[M + ],428(2)[M + ], 345(10), 343(10), 234(8), 204(8), 234(8), 114(25), 100(100), 88(3), 79(2), 70(10), 56(15).

[0695] Example 129: 2-(5-methyl-2-(2-morpholinopropoxy)benzyl)benzonitrile

[0696] According to the general method of Example 80: 2-(2-hydroxy-5-methylbenzyl)benzonitrile (0.30 g, 1.3 mmol), 4-(2-chloropropyl)morpholine hydrochloride (0.52 g, 2.6 mmol), potassium carbonate (1.8 g, 13 mmol) and potassium iodide (0.043 g, 0.26 mmol) were reacted in DMF (13 mL) to give the title product (0.010 g, yield 2%) as a viscous liquid. GC / MS (EI): m / z (%): 350 (2) [M + ], 263(52), 220(4), 204(2), 190(10), 178(5), 128(10), 1146(5), 100(100), 91(3), 77(2), 70(5), 56(10). 1 H NMR (300 MHz, CDCl 3 )δ7.63 (d, J=7.6Hz, 1H), 7.42 (t, J=7.2Hz, 1H), 7.29-7.22 (m, 2H), 7.17 (d, J =7.8Hz, 1H), 7.03 (d, J = 8.2Hz, 1H), 6.97 (s, 1H), 6.76 (d, J = 8.3Hz, 1H), 4.18 (s, 2H), 4.05-3.94 (m, 1H), 3.88-3.78 (m, 1H), 3.70-3.60 (m, 4H), 2.97-2.80 (m, 1H), 2.60-2.46 (m, 4H), 2.27 (s, 3H), 1.67 (s, 1H), 1.05 (d, J=6.7Hz, 3H). 13 C NMR (75 MHz, CDCl 3 )δ154.6(q), 145.4(q), 132.7(t), 131.8(t), 130.1(q), 129.7(t), 128.6(t), 127.0(q), 126.5(t), 118.4(q), 112.6(q), 111.4(t), 70.2(d), 67.5(d), 58.8(t), 49.9(d), 34.8(d), 20.6(s), 13.1(s).

[0697] Example 130: 3-Chloro-2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile

[0698] According to the general method of Example 80: a mixture of 3-chloro-2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile (0.080 g, 0.28 mmol) (prepared in a similar sequence as described in Examples 115, 116 and 117), 4-(2-chloroethyl)morpholine hydrochloride (0.10 g, 0.55 mmol), potassium carbonate (0.38 g, 2.8 mmol) and potassium iodide (9.2 mg, 0.06 mmol) in DMF (10 mL) was reacted to give the title product (0.070 g, 64% yield) as a viscous liquid. GC / MS (EI): m / z (%): 384 (1) [M + ], 297(10), 234(5), 204(2), 190(2), 128(7), 114(20), 100(100), 88(1), 70(3). 1 H NMR (300 MHz, CDCl 3 )δ7.64 (d, J=7.9Hz, 2H), 7.35 (t, J=7.9Hz, 1H), 6.85 (s, 1H), 6.10 (s, 1H), 4.41 (s, 2H), 4.01 (t, J= 5.7Hz, 2H), 3.82-3.69 (m, 4H), 2.85 (t, J=5.7Hz, 2H), 2.69-2.55 (m, 4H), 2.30 (s, 3H), 2.12 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.4(q), 142.1(q), 136.6(q), 134.4(t), 133.4(q), 131.7(t), 130.6(t), 129.9(q), 128.4(t), 126.2(t), 117.5(q), 116.0(q), 70.0(d), 67.1(d), 58.9(d), 54.4(d), 32.5(d), 21.0(s), 16.4(s).

[0699] Example 131: 2-(3,5-dimethyl-2-(3-morpholinopropoxy)benzyl)benzonitrile

[0700] According to the general method of Example 80: A mixture of 2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile (0.13 g, 0.55 mmol), 4-(3-chloropropyl)morpholine (0.13 g, 0.82 mmol), potassium carbonate (0.76 g, 5.5 mmol) and potassium iodide (0.020 g, 0.11 mmol) in DMF (10 mL) was heated to reflux for 3 hours. Water (50 mL) was added, the solution was extracted 3 times with DCM (3×30 mL), the solvent was removed, and the residue was purified by silica gel column chromatography (PE:MTBE=1:1) to give the title product (0.15 g, yield 71%) as a colorless liquid. GC / MS (EI): m / z (%): 364 (1) [M + ], 349(1), 234(2), 208(5), 128(25), 116(5), 100(100), 86(3), 70(10). 1 H NMR (300 MHz, CDCl 3 )δ7.63(s, 1H), 7.43(s, 1H), 7.26(s, 1H), 7.18(s, 1H), 6.89(s, 1H), 6.70(s, 1H), 4.19(s, 2H), 3.78 (d, J=3.7Hz, 2H), 3.68 (s, 4H), 2.59-2.35 (m, 6H), 2.26 (s, 2H), 2.21 (s, 2H), 1.95 (s, 2H). 13 CNMR (75MHz, CDCl 3 )δ153.6(q), 145.4(q), 133.6(q), 132.9(t), 132.7(t), 131.5(q), 131.2(q), 131.0(t), 130.0(t), 129.1(t) , 126.6(t), 118.4(q), 112.5(q), 70.9(d), 67.1(d), 55.4(d), 53.8(d), 34.4(d), 27.4(d), 20.9(s), 16.4(s).

[0701] Example 132: Ethyl 4-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzoate dihydrochloride

[0702] A solution of 1-(2-(2-(4-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine (0.30 g, 0.72 mmol) (prepared in a similar sequence of steps as described in Examples 79 and 80) in anhydrous THF (20 mL) was cooled to -78°C and n-butyllithium (0.5 ml, 1.6 N in hexane, 0.79 mmol) was added dropwise under argon and the solution was stirred at the same temperature for 1 hour before the addition of ethyl chloroformate (0.31 g, 2.9 mmol). After another 4 hours, saturated NH 4 Cl aqueous solution and the mixture was warmed to room temperature. THF was evaporated on a rotary evaporator. The residue was washed with CH 2 Cl 2 (20 mL × 3) extraction, the combined organic layer was washed with Na 2 SO 4 Dry, filter and concentrate in vacuo to obtain a crude liquid. The crude product was added to Biotage to obtain the title product (0.15 g, yield 50%) as a white solid. GC / MS (EI): m / z (%): 410 (4) [M + ], 365(5), 209(5), 195(3), 127(55), 113(100), 100(15), 84(5), 70(25).

[0703] Example 133: 3-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile dihydrochloride

[0704] To 3-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile (55 mg, 0.15 mmol) (prepared in a sequence similar to that described in Example 115, Example 116 and Example 117, then Example 80) in methanol (10 mL) was added hydrogen chloride (153 mg, 1.47 mmol) and the resulting mixture was allowed to stand for half an hour. The solvent was then removed by rotary evaporation to give the title product (55 mg, 0.14 mmol, yield 91%) as a light brown solid. GC / MS (EI): m / z (%): 363 (1) [M + ], 248(1), 204(3), 190(5), 165(2), 127(65), 113(100), 100(7), 84(6), 70(34).

[0705] Example 134: 2-(2,4-dimethyl-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile

[0706] Following the general procedure of Example 80: a mixture of 2-(5-hydroxy-2,4-dimethylbenzyl)benzonitrile (0.16 g, 0.66 mmol) (isolated as an isomeric byproduct in the preparation of 2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile according to the sequence described in Example 115, Example 116 and Example 117), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.31, 1.3 mmol), potassium carbonate (0.91 g, 6.6 mmol) and potassium iodide (0.022 g, 0.13 mmol) in DMF (10 mL) was reacted to give the title product (0.13 g, 52% yield) as a viscous liquid. GC / MS (EI): m / z (%): 361 (1) [M + ], 294(1), 204(2), 190(2), 165(2), 127(40), 113(100), 98(5), 84(3), 70(32). 1 H NMR (300 MHz, CDCl 3 )δ7.65 (d, J=7.0Hz, 1H), 7.44 (t, J=7.7Hz, 1H), 7.29 (d, J=7.5Hz, 1H), 7.01 (d, J=7.8Hz, 1H), 6.95 (s, 1H), 6.55 (s, 1H), 4.14 (s, 2H), 4.02 (t, J=5.6Hz, 2H), 2.82 (t, J=5.7Hz, 2H), 2.78-2.64 (m, 4H), 2.63-2.46 (m, 4H), 2.35 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ155.3(q), 144.7(q), 134.7(q), 133.1(t), 133.0(t), 132.9(t), 129.4(t), 128.5(q), 126.7(t), 125.5(q) , 118. 2(q), 113.5(t), 112.7(q), 66.8(d), 57.3(d), 55.1(d), 53.3(d), 45.8(s), 37.8(d), 18.7(s), 15.9(s).

[0707] Example 135: 2-(5-methyl-2-(2-(1-methylpiperidin-4-yl)ethoxy)benzyl)benzonitrile

[0708] Thionyl chloride (2.99 g, 25 mmol) was added to 3(10mL) in 2- (1-methylpiperidin-4-yl) ethane-1-ol (0.20g, 1.3mmol), and the resulting mixture was heated to reflux for 5 hours. The solvent was removed by rotary evaporation to obtain a crude chloride. The intermediate was mixed with 2- (2-hydroxy-5-methylbenzyl) benzonitrile (0.15g, 0.63mmol), potassium carbonate (1.74g, 12mmol) and potassium iodide (0.020g, 0.13mmol) in DMF (10mL), and then heated to reflux for 2 hours. After cooling to room temperature, water was added to dilute the solution, the solution was extracted with DCM, the solvent including DMF was removed, and the residue was purified by silica gel column chromatography (DCM: methanol = 10: 1) to obtain the title product (0.050g, yield 22%), which is a dark liquid. GC / MS (EI): m / z (%): 348 (60) [M + ],333(5),222(5),190(10),142(10),126(100),112(20),96(20),70(15). 1 H NMR (300 MHz, CDCl 3 )δ7.57 (d, J=7.6Hz, 1H), 7.40 (t, J=7.3Hz, 1H), 7.25-7.17 (m, 1H), 7.10 (d, J=7.8Hz, 1H), 6.98 (d, J=8.2Hz, 1H), 6.91 (s, 1H), 6.68 (d, J= 8.3Hz, 1H), 4.07 (s, 2H), 3.86 (t, J=5.5Hz, 2H), 3.26 (d, J=11.4Hz, 2H), 2.60 (s, 3H), 2.55-2.49 (m, 1H), 2.22 (s, 3H), 1.88-1.45 (m, 8H). 13 C NMR (75 MHz, CDCl 3 )δ154.4(q), 145.3(q), 132.9(t), 132.6(t), 131.7(q), 129.9(t), 129.6(t), 128.7(q), 126.8(t), 126.6(q), 118.6(q), 111.2(t), 64.5(d), 54.8(d), 44.3(s), 34.9(d), 30.2(t), 29.4(d), 20.6(s).

[0709] Example 136: 2-(3,5-dimethyl-2-(3-morpholinopropyl)phenoxy)benzonitrile

[0710] Example 136a: 1-(Allyloxy)-3,5-dimethylbenzene

[0711] A mixture of 3,5-dimethylphenol (25.0 g, 205 mmol), 3-bromoprop-1-ene (32.2 g, 266 mmol) and potassium carbonate (56.6 g, 409 mmol) in acetone (400 mL) was heated to reflux overnight. The solvent was removed by rotary evaporation, water (200 mL) was added, and the mixture was extracted with MTBE (100 mL × 3). The combined organic phases were washed with MgSO 4 Drying and rotary evaporation to remove the solvent gave the title product (33.0 g, yield 96%) as a colorless liquid. GC / MS (EI): m / z (%): 162 (100) [M + ],147(98),119(60),107(30),91(75),77(50),65(15).

[0712] Example 136b: 1-(Allyloxy)-3,5-dimethylbenzene

[0713] Pure 1-(allyloxy)-3,5-dimethylbenzene (5.0 g, 29.3 mmol) was heated to 200°C for half an hour under Ar. After the reaction was cooled to room temperature, it was purified by silica gel column chromatography (PE:MTBE=92:8) to obtain the title product (3.6 g, yield 72%) as a colorless liquid. GC / MS (EI): m / z (%): 162 (85) [M + ],147(100),135(25),119(50),91(55),77(35),65(20).

[0714] Example 136c: 2-(2-allyl-3,5-dimethylphenoxy)benzonitrile

[0715] To a mixture of 2-allyl-3,5-dimethylphenol (2.0 g, 11.7 mmol), 2-iodobenzonitrile (4.0 g, 17.5 mmol), potassium phosphate (5.0 g, 23.4 mmol) and picolinic acid (0.4 g, 3.5 mmol) in DMSO (40 mL) was added copper (I) iodide (0.34 g, 1.8 mmol) under Ar. The mixture was evacuated and flushed with Ar three times, and the resulting mixture was heated to 90 ° C overnight. After the reaction mixture was cooled to room temperature, dilute NaCl solution (100 mL) was added, the solution was extracted with MTBE (100 mL × 3), and the combined organic phase was washed with MgSO 4 After drying, the solvent was removed and the residue was purified by silica gel column chromatography (PE:MTBE=9:1) to give the title product (2.5 g, yield 77%) as a colorless liquid. GC / MS (EI): m / z (%): 263 (75) [M +],248(100),231(40),220(25),128(40),115(35),91(25).

[0716] Example 136d: 2-(2-(3-hydroxypropyl)-3,5-dimethylphenoxy)benzonitrile To a solution of 2-(2-allyl-3,5-dimethylphenoxy)benzonitrile (0.5 g, 1.9 mmol) in tetrahydrofuran (20 mL) was added dropwise BH 3 ·Me 2 S (2M THF solution, 2.4 mL, 4.8 mmol). After the mixture was stirred at room temperature for 2 h, it was cooled to 0 °C and carefully treated with NaOH solution (3 M, 3 mL, 6.6 mmol), followed by the addition of H 2 O 2 (30% solution, 2.6 g, 22.8 mmol). The solution was stirred at room temperature for 15 minutes and then heated to reflux for 2 hours. After the solution was cooled to room temperature, water (30 mL) was added and the solution was extracted with ethyl acetate (40 mL × 3). The combined organic phases were precipitated with MgSO 4 After drying, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (PE:MTBE=3:2) to obtain the title product (0.19 g, yield 36%) as a white solid. GC / MS (EI): m / z (%): 281 (1) [M + ],250(5),236(100),220(15),208(65),193(15),165(10),115(10),103(5),91(20).

[0717] Example 136e: 2-(3,5-dimethyl-2-(3-oxopropyl)phenoxy)benzonitrile

[0718] To a suspension of 2-(2-(3-hydroxypropyl)-3,5-dimethylphenoxy)benzonitrile (0.18 g, 0.6 mmol), sodium acetate (0.10 g, 1.2 mmol) and silica gel (0.5 g) in dichloromethane (25 mL) was added pyridinium chlorochromate (0.26 g, 1.2 mmol) in portions at 0°C. The resulting mixture was then stirred at room temperature for 2 hours. The reaction solution was diluted with MTBE (60 mL), the mixture was filtered through a small silica gel pad, the solvent was removed by rotary evaporation and the residue was purified by silica gel column chromatography (PE:MTBE=4:1) to give the title product (0.12 g, yield 67%) as a colorless liquid. GC / MS (EI): m / z (%): 279 (10) [M +],260(25),236(30),222(100),208(45),193(15),165(10),115(25),103(10),91(35).

[0719] Example 136f: 2-(3,5-dimethyl-2-(3-morpholinopropyl)phenoxy)benzonitrile

[0720] To a solution of 2-(3,5-dimethyl-2-(3-oxopropyl)phenoxy)benzonitrile (0.11 g, 0.38 mmol) and morpholine (0.040 g, 0.4 mmol) in dichloromethane (10 mL) was added sodium triacetoxyborohydride (0.11 g, 0.5 mmol) at 0°C under argon. The resulting mixture was then stirred at room temperature overnight. After the reaction mixture was cooled to 5°C, dilute NaHCO 3 The solution was extracted with MTBE (30 mL × 3) and the combined organic phases were precipitated with MgSO 4 The residue was dried, concentrated by rotary evaporation, and then purified by silica gel column chromatography (PE:MTBE=7:3) to obtain the title product (0.06 g, yield 42%) as a liquid. GC / MS (EI): m / z (%): 350 (8) [M + ],207(15),193(3),127(11),115(15),100(100),91(10),56(10). 1 H NMR (300 MHz, CDCl 3 )δ7.64 (d, J=7.6Hz, 1H), 7.42 (t, J=7.5Hz, 1H), 7.08 (t, J=7.5Hz, 1H), 6.87 (s, 1H), 6.73 (d, J=8.5Hz, 1H), 6.63 (s, 1H), 3.83-3.50 (m, 4H), 2.74-2.49 (m, 2H), 2.45-2.35 (m, 6H), 2.33 (s, 3H), 2.26 (s, 3H), 1.77-1.58 (m, 2H). 13 CNMR (75MHz, 13 C NMR (75 MHz, CDCl 3)δ160.4(s), 152.5(s), 138.5(s), 136.8(s), 134.2(d), 133.8(d), 129.8(s), 128.3(d), 122.1(d), 118.7(d) , 116.1(s), 115.7(d), 102.7(s), 67.0(t), 58.8(t), 53.6(t), 29.8(s), 26.3(d), 24.4(d), 20.9(q), 19.4(q).

[0721] Example 137: 4-(3-(2-(2-fluorophenoxy)-4,6-dimethylphenyl)propyl)morpholine

[0722] Prepared by a similar sequence as described in Example 136: 3-(2-(2-fluorophenoxy)-4,6-dimethylphenyl)propanal (0.17 g, 0.59 mmol), NaBH(AcO) 3 (0.19 g, 0.89 mmol) and morpholine (0.070 g, 0.77 mmol) were reacted in dichloromethane (10 mL) to give the title product (0.17 g, yield 79%) as a brown viscous liquid. GC / MS (EI): m / z (%): 343 (20) [M + ],256(5),227(5),165(4),127(8),100(100),91(5),56(6). 1 H NMR (300 MHz, CDCl 3 )δ7.21-7.10(m, 1H), 7.08-7.00(m, 2H), 6.96-6.88(m, 1H), 6.76(s, 1H), 6.45(s, 1H), 3.85 -3.50(m, 4H), 2.87-2.57(m, 2H), 2.40(s, 6H), 2.32(s, 3H), 2.20(s, 3H), 1.88-1.60(m, 2H). 13 C NMR (75 MHz, CDCl 3 )δ155.3(s), 154.6(s), 152.1(s), 145.1(s), 144.8(s), 137.9(s), 136.3(s), 128.3(s), 126.5(d), 124.5(d), 124.0(d), 123. 7(d), 123.6(d), 120.3(d), 117.0(d), 116.8(d), 115.8(d), 67.0(t), 58.9(t), 53.7(t), 26.3(t), 24.2(t), 21.0(q), 19.4(q).

[0723] Example 138: 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile

[0724] Example 138a: 2-(3-Hydroxypropyl)-5-methylphenol

[0725] At 0°C, LiAlH 4 To a suspension of 7-methyl-2H-benzopyran-2-one (3.8 g, 100 mmol) in tetrahydrofuran (150 mL) was carefully added dropwise a solution of 7-methyl-2H-benzopyran-2-one (10.0 g, 62.4 mmol) in tetrahydrofuran (30 mL). After addition, the resulting mixture was stirred at room temperature for 2 hours. The reaction was carefully quenched by adding dilute HCl solution (100 mL), the solution was extracted with ethyl acetate (100 mL×2), and the combined organic phases were washed with Na 2 SO 4 After drying, the solvent was removed and the residue was purified by silica gel column chromatography (PE:MTBE=1:1) to give the title product (2.8 g, yield 26%) as a white solid. GC / MS (EI): m / z (%): 166 (40) [M + ],148(25),133(45),121(100),105(15),91(50),77(35),65(10).

[0726] Example 138b: 2-(2-(3-Hydroxypropyl)-5-methylphenoxy)benzonitrile

[0727] The entire mixture of 2-(3-hydroxypropyl)-5-methylphenol (0.8 g, 4.67 mmol), 2-iodobenzonitrile (1.6 g, 7.0 mmol), potassium phosphate (1.98 g, 9.3 mmol), copper (I) iodide (0.13 g, 0.7 mmol) and picolinic acid (0.17 g, 1.4 mmol) in DMSO (25 mL) was evacuated and flushed with Ar three times. Then it was stirred at 90 ° C overnight. Water (100 mL) was added, the solution was extracted with EA (100 mL×3), and the organic phase was washed with MgSO 4 After drying, the solvent was removed and the residue was purified by silica gel column chromatography (PE:MTBE=2:3) to give the title product (0.70 g, yield 56%) as a white solid. GC / MS (EI): m / z (%): 267 (4) [M + ], 249(100), 234(90), 222(30), 206(40), 194(35), 115(20), 91(35), 77(20), 65(10).

[0728] Example 138c: 2-(5-methyl-2-(3-oxopropyl)phenoxy)benzonitrile

[0729] To a suspension of pyridinium chlorochromate (0.39 g, 1.8 mmol), sodium acetate (0.15 g, 1.8 mmol) and 1.0 g of silica gel in dichloromethane (25 mL) was added 2-(2-(3-hydroxypropyl)-5-methylphenoxy)benzonitrile (0.25 g, 0.91 mmol) in portions at 0°C and the resulting mixture was stirred at room temperature for 3 hours. MTBE (60 mL) was added, the mixture was filtered through a small pad of silica gel, the pad was rinsed with MTBE (50 mL), and the solvent was removed to give the title product (0.26 g, yield 65%) as a viscous liquid, which was used directly in the next step. GC / MS (EI): m / z (%): 265 (45) [M + ], 236(100), 222(75), 208(100), 194(40), 121(50), 115(20), 91(35), 77(20), 65(10).

[0730] Example 138d: 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile

[0731] A flask was charged with 2-(5-methyl-2-(3-oxopropyl)phenoxy)benzonitrile (0.22 g, 0.50 mmol) and 1-methylpiperazine (0.05 g, 0.5 mmol) in dichloromethane (15 mL). Sodium triacetoxyborohydride (0.13 g, 0.60 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was cooled to 5 °C and diluted NaHCO was added dropwise. 3 The solution (30 mL) was added, the mixture was extracted with dichloromethane (30 mL×3), the organic phase was concentrated and the residue was purified by silica gel column chromatography (DCM: methanol = 10: 1) to obtain the title product (0.14 g, yield 78%) as a viscous liquid. GC / MS (EI): m / z (%): 349 (7) [M + ], 293(6), 248(2), 194(5), 160(6), 127(45), 113(100), 98(5), 85(8), 70(40). 1 H NMR (300 MHz, CDCl 3)δ7.63 (dd, J=7.7, 1.5Hz, 1H), 7.46-7.38 (m, 1H), 7.16 (d, J=7.7Hz, 1H), 7.07 (t, J=7.5Hz, 1H), 6.97 (d, J=7 .8Hz, 1H), 6.76 (s, 1H), 6.69 (d, J=8.5Hz, 1H), 2.67-2.34 (m, 12H), 2.30 (d, J=5.9Hz, 6H), 1.86-1.69 (m, 2H). 13 C NMR (75 MHz, CDCl 3 )δ160.3(q), 152.3(q), 137.9(q), 134.3(t), 133.9(t), 130.9(q), 130.9(t), 126.5(t), 122.3(t), 121. 2(t), 116.2(q), 115.8(t), 102.8(q), 57.7(d), 54.6(d), 52.5(d), 45.6(s), 27.6(d), 27.1(d), 21.1(s).

[0732] Example 139: 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile hydrochloride

[0733] To a solution of 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile (0.53 g, 1.44 mmol) in methanol (25 mL) was added hydrogen chloride (0.75 g, 7.20 mmol) and the resulting mixture was stirred at room temperature for half an hour. The solvent was then removed and the mixture was dried under reduced pressure at 90° C. to give the title product (550 mg, 1.35 mmol, yield 94%) as a white solid. GC / MS (EI): m / z (%): 349 (10) [M + ], 293(8), 235(5), 194(6), 160(7), 127(42), 113(100), 98(5), 85(8), 70(39).

[0734] Example 140: 2-(4-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile

[0735] Prepared in a similar sequence as described in Example 138 (starting from 6-methyl-2H-benzopyran-2-one instead of 7-methyl-2H-benzopyran-2-one): In the last step, a flask was charged with 2-(4-methyl-2-(3-oxopropyl)phenoxy)benzonitrile (0.18 g, 0.54 mmol) and 1-methylpiperazine (0.050 g, 0.54 mmol) in dichloromethane (15 mL). Sodium triacetoxyborohydride (0.14 g, 0.65 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was cooled to 5°C and NaHCO was added dropwise. 3 The solution was added, the mixture was extracted with DCM, the organic phase was concentrated and the residue was purified by silica gel column chromatography (DCM: methanol = 10: 1) to give the title product (0.14 g, yield 72%) as a viscous liquid. GC / MS (EI): m / z (%): GC / MS (EI): m / z (%): 349 (25) [M + ],293(11),194(5),160(15),127(60),113(100),85(10),70(40). 1 H NMR (300 MHz, CDCl 3 )δ7.63 (d, J=7.7, 1H), 7.45-7.36 (m, 1H), 7.13-6.99 (m, 3H), 6.86 (d, J=8.2Hz, 1H), 6.68 (d, J=8.5Hz, 1H), 2.73-2.36 (m, 12H), 2.34 (s, 6H), 1.88-1.72 (m, 2H). 13 C NMR (75 MHz, CDCl 3 )δ160.5(q), 150.1(q), 135.5(q), 134.4(q), 133.9(t), 133.9(t), 131.7(t), 128.4(t), 122.2(t), 120. 7(t), 116.3(q), 115.4(t), 102.7(q), 57.7(d), 54.6(d), 52.5(d), 45.7(s), 27.9(d), 27.1(d), 21.0(s).

[0736] Example 141: 2-(2-(2-Hydroxy-3-morpholinopropyl)-5-methylphenoxy)benzonitrile

[0737] A mixture of 2-(5-methyl-2-(oxiran-2-ylmethyl)phenoxy)benzonitrile (0.20 g, 0.72 mmol) (obtained by preparing 2-(2-allyl-5-methylphenoxy)benzonitrile in a similar sequence as described in Example 136a-c and then epoxidizing as described in Example 63) and morpholine (0.19 g, 2.15 mmol) in ethanol (20 mL) was heated to reflux overnight. The solvent was then removed, water was added, the solution was extracted with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (PE:MTBE=3:7) to give the title product (0.20 g, 0.57 mmol, yield 71%) as a viscous liquid. GC / MS (EI): m / z (%): 352 (1) [M + ], 281(1), 223(1), 207(4), 194(1), 152(1), 130(4), 100(100), 77(2), 56(5). 1 H NMR (300 MHz, CDCl 3 )δ7.65 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 7.18-7.05 (m, 2H), 6.92-6.62 (m, 2H), 3.95 (d, J=23.6Hz, 1H), 3.67 (s, 4H), 3.50 (s, 1H), 2 .85 (d, J=13.6Hz, 1H), 2.69 (d, J=4.3Hz, 1H), 2.59 (s, 2H), 2.47 (d, J=13.8Hz, 3H), 2.35 (d, J=11.7Hz, 4H), 1.26 (s, 2H), 0.87 (s, 1H). 13 C NMR (75 MHz, CDCl 3 )δ159.8(s), 152.9(s), 140.2(s), 134.2(d), 133.9(d), 132.1(d), 129.1(s), 127.5(d), 126.4(d), 122.4(d), 121.0(d), 118.0(d), 115.9(d), 102.9(s), 67.1(t), 66.2(d), 64.2(t), 53.5(t), 35.2(s), 32.1(t), 21.1(q).

[0738] Example 142: 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile

[0739] Example 142a: Ethyl 2-(2-(2-cyanobenzyl)-4,6-dimethylphenoxy)propanoate

[0740] A solution of 2-(2-hydroxy-3,5-dimethylbenzyl)benzonitrile (0.50 g, 2.1 mmol) in DMF (10 mL) was treated with potassium carbonate (0.87 g, 6.3 mmol), and then ethyl 2-bromopropionate (0.57 g, 3.2 mmol) was added. The suspension was stirred at room temperature overnight. Water (50 mL) was added, the solution was extracted with MTBE (30 mL×3), the solvent was removed and the residue was purified by silica gel column chromatography (PE:MTBE=8:1) to give the title product (0.65 g, yield 90%) as a viscous liquid. GC / MS (EI): m / z (%): 337 (30) [M + ],291(5),264(25),236(100),220(10),208(75),182(55),121(10),91(5),77(4).

[0741] Example 142b: 2-(2-((1-hydroxypropan-2-yl)oxy)-3,5-dimethylbenzyl)benzonitrile

[0742] Sodium borohydride (0.20 g, 5.3 mmol) was added in portions to a solution of ethyl 2-(2-(2-cyanobenzyl)-4,6-dimethylphenoxy)propanoate (0.60 g, 1.9 mmol) in methanol (10 mL) at 0°C and the resulting mixture was stirred at room temperature overnight. The solvent was removed, water (50 mL) was added, the solution was extracted with EA (40 mL×3), the mixture was concentrated and the residue was purified by silica gel column chromatography (PE:MTBE=1:1) to give the title product (0.52 g, yield 94%) as a viscous liquid. GC / MS (EI): m / z (%): 295 (10) [M + ],264(8),237(100),222(15),208(55),194(30),182(55),121(25). 1 H NMR (300 MHz, CDCl 3 )δ7.63 (d, J=7.7Hz, 1H), 7.50-7.41 (m, 1H), 7.33-7.24 (m, 1H), 7.18 (d, J=7.8Hz, 1H), 6.89 (s, 1H ), 6.68 (s, 1H), 4.35-4.10 (m, 3H), 3.77 (s, 2H), 2.28 (s, 3H), 2.21 (s, 3H), 1.19 (d, J=6.4Hz, 3H). 13 C NMR (75 MHz, CDCl 3)δ151.3(q), 145.4(q), 133.4(q), 132.9(t), 132.8(t), 132.1(q), 131.3(t), 131.2(q), 130.1(t), 129.1(t), 126.7(t), 118.6(q), 112.6(q), 78.5(t), 66.9(d), 34.8(d), 20.8(s), 17.5(s), 16.2(s).

[0743] Example 142c: 2-(3,5-dimethyl-2-((1-oxopropan-2-yl)oxy)benzyl)benzonitrile

[0744] To a solution of oxalyl chloride (0.50 g, 3.94 mmol) in dichloromethane (volume: 15 mL) at -78°C was added (methylsulfinyl)methane (0.513 g, 6.6 mmol) dropwise. Then, after 5 minutes of reaction, a solution of 2-(2-((1-hydroxypropan-2-yl)oxy)-3,5-dimethylbenzyl)benzonitrile (0.17 g, 0.55 mmol) in dichloromethane (5 mL) was added dropwise via a syringe. The solution was stirred at -78°C for 30 minutes. Triethylamine (1.33 g, 13 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 30 minutes. Water (25 mL) was added and the solution was extracted with dichloromethane (3×25 mL). The combined organic phases were washed with 0.1 M aqueous HCl (100 mL), H 2 O (100 mL), and then saturated with NaHCO 3 The organic phase was washed with MgSO 4 Dry and filter through a small silica gel pad. Remove the solvent to give the title product (0.18 g, yield 95%) as a colorless liquid. GC / MS (EI): m / z (%): 293 (65) [M + ],264(98),236(45),221(20),208(100),190(35),165(24),116(20).

[0745] Example 142d: 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile

[0746] A flask was charged with 2-(3,5-dimethyl-2-((1-oxopropan-2-yl)oxy)benzyl)benzonitrile (0.17 g, 0.49 mmol) and 1-methylpiperazine (0.060 g, 0.64 mmol) in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.13 g, 0.59 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was cooled to 5 °C and NaHCO was added dropwise. 3 The solution (30 mL) was added, the mixture was extracted with DCM (30 mL×3), the organic phase was concentrated and the residue was purified by silica gel column chromatography (DCM: methanol: TEA = 95: 5: 1) to obtain the title product (0.12 g, yield 61%) as a viscous liquid. GC / MS (EI): m / z (%): 377 (1) [M + ], 261(1), 208(3), 190(3), 165(2), 141(26), 113(100), 98(6), 84(1), 70(28). 1 H NMR (300 MHz, CDCl 3 )δ7.62 (d, J=7.7Hz, 1H), 7.45-7.41 (m, 1H), 7.29-7.22 (m, 1H), 7.16 (d, J=7.9Hz, 1H), 6.86 (s, 1H), 6.69 (s, 1H), 4.25 (s, 2H), 2.78-2.66 (m, 1H), 2.62-2.34 (m, 8H), 2.27 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 1.19 (d, J=6.2Hz, 3H). 13 CNMR (75MHz, CDCl 3 )δ152.2(q), 145.7(q), 132.9(t), 132.6(t), 132.1(q), 131.0(q), 131.0(t), 130.1(t), 129.1(t), 126.5(t) , 118.6(q), 112.5(q), 76.2(t), 64.4(d), 55.2(d), 54.1(d), 46.1(s), 34.8(d), 20.8(s), 18.9(s), 17.5(s).

[0747] Example 143: 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile hydrochloride

[0748] To 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile (0.050 g, 0.13 mmol) in methanol (10 mL) was added hydrogen chloride (0.065 g, 0.63 mmol) and the resulting mixture was allowed to stand for half an hour. The solvent was then removed by rotary evaporation and the residue was dried on a Kugelrohde (90° C., 0.1 mbar) to give the title product (0.050 mg, yield 91%) as a solid. GC / MS (EI): m / z (%): 377 (1) [M + ],237(2),208(5),141(35),113(100),98(8),84(1),70(30).

[0749] Example 144: (1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperidin-4-yl)methanol

[0750] A flask was charged with 2-(2-benzyl-4-methylphenoxy)acetaldehyde (0.4 g, 1.17 mmol) and piperidin-4-yl-methanol (0.17 g, 1.52 mmol) in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.37 g, 1.75 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was cooled to 5 °C and NaHCO was added dropwise. 3 The solution was added, the mixture was extracted with DCM, the organic phase was concentrated and the residue was purified by silica gel column chromatography (DCM: methanol = 90: 10) to obtain the title product (0.24 g, 0.64 mmol, yield 54.6%) as a viscous liquid. GC / MS (EI): m / z (%): 339 (15) [M + ], 224(5), 195(5), 165(5), 142(4), 128(100), 115(4), 91(10), 67(4). 1 H NMR (300 MHz, CDCl 3 )δ7.25-7.10 (m, 5H), 6.95 (d, J=8.2Hz, 1H), 6.89 (s, 1H), 6.73 (d, J=8.2H z, 1H), 4.05 (t, J=5.9Hz, 2H), 3.92 (s, 2H), 3.45 (d, J=6.4Hz, 2H), 2.96 (d , J=11.6Hz, 2H), 2.75(t, J=5.8Hz, 2H), 2.22(s, 3H), 2.12-2.00(m, 2H), 1 .97 (s, 1H), 1.68 (d, J=13.1Hz, 2H), 1.54-1.36 (m, 1H), 1.35-1.20 (m, 2H). 13C NMR (75 MHz, CDCl 3 )δ154.5(q), 141.4(q), 131.4(t), 129.9(q), 129.6(q), 128.9(t), 128.3(t), 127.8(t), 125. 8(t), 111.6(t), 67.9(d), 66.6(d), 57.7(d), 54.0(d), 38.4(t), 36.2(d), 28.9(d), 20.6(s).

[0751] Example 145: 1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperidin-4-ol

[0752] A flask was charged with 2-(2-benzyl-4-methylphenoxy)acetaldehyde (0.50 g, 1.5 mmol) and piperidin-4-ol (0.19 g, 1.9 mmol) in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was cooled to 5 °C and NaHCO was added dropwise. 3 The solution was added, the mixture was extracted with DCM, the organic phase was concentrated and the residue was purified by silica gel column chromatography (DCM: methanol = 90: 10) to give the title product (0.43 g, yield 82%) as a viscous liquid. GC / MS (EI): m / z (%): 325 (10) [M + ],224(10),195(10),165(11),128(8),114(100),91(13),70(2). 1 H NMR (300 MHz, CDCl 3 )δ7.26-7.19 (m, 2H), 7.14 (t, J=8.6Hz, 3H), 6.98 (d, J=8.2Hz, 1H), 6.92 (s, 1H), 6.73 (d, J=8.2Hz, 1H), 5.41 (s, 1H), 4.16 (t, J=5.0Hz, 2H), 3.92 (s, 2H), 3.10-2.84 (m, 4H), 2.66-2.46 (m, 2H), 2.24 (s, 3H), 2.03-1.92 (m, 3H), 1.72-1.55 (m, 2H). 13 C NMR (75 MHz, CDCl 3)δ154.0(q), 141.3(q), 131.9(t), 130.4(q), 128.9(q), 128.7(t), 128.4(t), 128.1 (t), 125.9(t), 111.4(t), 64.9(d), 56.5(d), 50.1(d), 36.3(d), 32.5(d), 20.6(s).

[0753] Example 146: 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)piperazine

[0754] A flask was charged with 2-(2-benzyl-4-methylphenoxy)acetaldehyde (0.33 g, 0.96 mmol) and piperazine (0.17 g, 1.92 mmol) in dichloromethane (volume: 10 mL). Sodium triacetoxyborohydride (0.27 g, 1.25 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was cooled to 5 °C and NaHCO was added dropwise. 3 The solution was added, the mixture was extracted with DCM, the organic phase was concentrated and the residue was purified by silica gel column chromatography (DCM: methanol = 80: 20) to give the title product (0.10 g, 0.31 mmol, yield 31.8%) as a viscous colorless liquid. GC / MS (EI): m / z (%): 310 (25) [M + ],268(10),195(10),165(20),152(10),113(30),99(100),86(20),70(30),56(50).

[0755] Example 147: 1-(2-(2-Benzyl-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine

[0756] At room temperature, 2-benzyl-4,6-dimethylphenol (1.00 g, 4.5 mmol), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.58 g, 6.7 mmol) and potassium iodide (0.15 g, 0.89 mmol) were added to a mixture of sodium hydride (1.34 g, 31.3 mmol, 56% purity) in DMF (20 mL), and the mixture was stirred at 70 ° C overnight. The mixture was then heated to 100 ° C for 1 hour. Water (60 mL) was added to quench the reaction, and the solution was extracted 3 times with EA (50 mL×3), the solvent was carefully removed and the residue was purified by silica gel column chromatography (DCM: methanol = 10: 1) to obtain the title product (0.32 g, yield 21%) as a viscous liquid. GC / MS (EI): m / z (%): 338 (4) [M +], 295(1), 209(5), 178(4), 165(7), 127(52), 113(100), 100(19), 84(7), 70(41). 1 H NMR (300 MHz, CDCl 3 )δ7.25-7.10(m, 5H), 6.83(s, 1H), 6.71(s, 1H), 3.97(s, 2H), 3.77(t, J=5.9Hz, 2H), 2.70 (t, J=5.9Hz, 2H), 2.56 (s, 8H), 2.28 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.6(q), 141.4(q), 133.4(q), 133.3(q), 130.7(q), 130.2(t), 129.3(t), 128.9(t), 128. 4(t), 125.9(t), 70.2(d), 58.1(d), 55.0(d), 53.5(d), 45.9(s), 35.8(d), 20.8(s), 16.5(s).

[0757] Example 148: 1-Methyl-4-(2-(4-methyl-2-(3-methylbenzyl)phenoxy)ethyl)piperazine

[0758] To a mixture of sodium hydride (1.20 g, 28.0 mmol) in DMF (20 mL) was added 4-methyl-2-(3-methylbenzyl)phenol (1.00 g, 4.0 mmol), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.41 g, 6.0 mmol) and potassium iodide (0.13 g, 0.80 mmol) at room temperature. The resulting mixture was stirred at 40 ° C for two days. It was heated to 100 ° C for 1 hour. The reaction was quenched by adding water, the solution was extracted 3 times with EA, the solvent was removed, and the residue was purified by silica gel column chromatography (PE: MTBE = 1: 1 to MTBE to DCM: methanol = 10: 1) to give the title product (0.28 g, yield 20%), which was a light yellow viscous liquid. GC / MS (EI): m / z (%): 338 (3) [M + ], 295(1), 209(2), 178(3), 165(6), 127(43), 113(100), 100(6), 84(4), 70(37). 1 H NMR (300 MHz, CDCl 3)δ7.20-7.10 (m, 1H), 7.06-6.87 (m, 5H), 6.74 (d, J=8.2Hz, 1H), 4.06 (t, J=5.7Hz, 2H), 3.9 0 (s, 2H), 2.77 (t, J=5.7Hz, 2H), 2.75-2.41 (m, 8H), 2.32 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ154.5(q), 141.2(q), 137.7(q), 131.4(t), 129.9(q), 129.7(t), 129.6(t), 128.2(t), 127.7(t), 126. 5(t), 125.9(t), 111.6(t), 66.7(d), 57.3(d), 55.0(d), 53.3(d), 45.8(s), 36.1(d), 21.5(s), 20.6(s).

[0759] Example 149: 1-(2-(2-isobutyl-4-methylphenoxy)ethyl)-4-methylpiperazine

[0760] 2-isobutyl-4-methylphenol (0.30 g, 1.8 mmol) and 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.45 g, 1.8 mmol) were added to a suspension of sodium hydride (0.22 g, 9.1 mmol) in DMF (10 mL) at 0°C and the reaction mixture was stirred overnight at room temperature. It was then poured into ice water, the mixture was extracted with EA, the solvent was removed, and the residue was purified by silica gel column chromatography (DCM: methanol = 3: 1) to give the title product (0.13 g, yield 23%) as a viscous brown liquid. GC / MS (EI): m / z (%): 290 (1) [M + ], 275(1), 207(2), 176(1), 147(1), 127(38), 113(100), 98(5), 84(4), 70(31). 1 H NMR (300 MHz, CDCl 3 )δ6.94-6.84 (m, 2H), 6.69 (d, J=8.1Hz, 1H), 4.05 (t, J=5.7Hz, 2H), 2.80 (t, J=5.7Hz, 2H), 2.68-2.55 (m, 8H ), 2.52 (s, 4H), 2.42 (d, J = 7.1Hz, 2H), 2.32 (s, 3H), 2.24 (s, 3H), 1.95-1.80 (m, 1H), 0.87 (d, J = 6.6Hz, 6H). 13C NMR (75 MHz, CDCl 3 )δ154.8(q), 131.8(t), 130.2(q), 129.4(q), 127.1(t), 111.3(t), 66.6(d), 57.4 (d), 55.1(d), 53.5(d), 45.9(s), 39.7(d), 29.9(s), 28.9(t), 22.7(s), 20.6(s).

[0761] Example 150: 1-(2-(2-isobutyl-4-methylphenoxy)ethyl)-4-methylpiperazine dihydrochloride

[0762] 2-isobutyl-4-methylphenol (0.30 g, 1.8 mmol) and 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.45 g, 1.8 mmol) were added to a suspension of sodium hydride (0.22 g, 9.1 mmol) in DMF (10 mL) at 0°C and the reaction mixture was stirred overnight at room temperature. It was then poured into ice water, the mixture was extracted with EA, the solvent was removed, and the residue was purified by silica gel column chromatography (DCM: methanol = 3: 1) to give the title product (0.13 g, yield 23%) as a viscous brown liquid. GC / MS (EI): m / z (%): 331 (5) [M + ], 244(8), 207(10), 171(2), 145(3), 114(15), 100(100), 91(3), 70(4). GC / MS(EI): m / z(%): 290(1)[M + ], 275(1), 147(1), 127(40), 113(100), 98(5), 84(5), 70(35).

[0763] Example 151: 1-(2-(2-(2-iodobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine

[0764] A solution of 1-(2-(2-(2-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine (0.15 g, 0.36 mmol), sodium 2,2,2-trifluoroacetate (0.29 g, 2.2 mmol) and copper (I) iodide (0.41 g, 2.16 mmol) in DMF (10 mL) and toluene (3 mL) was heated to reflux for 6 hours. The mixture was then kept at 150° C. for two days. Water (50 mL) was added, the solution was extracted with DCM (50 mL×3), the solvent was removed and the residue was purified by silica gel column chromatography (DCM: methanol = 10: 1) to give the title product (0.089 g, yield 27%) as a viscous liquid. GC / MS (EI): m / z (%): 464 (5) [M + ],209(10),195(8),179(11),165(10),152(5),127(74),113(100),100(20). 1 H NMR (300 MHz, CDCl 3 )δ7.88-7.50 (m, 1H), 7.23-7.18 (m, 1H), 7.11-6.85 (m, 3H), 6.64 (d, J=5.7Hz, 1H), 4.04 (d, J=1 2.8Hz, 2H), 3.79 (t, J=5.3Hz, 2H), 2.99-2.66 (m, 10H), 2.54 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ153.5(q), 143.7(q), 140.5(q), 139.3(t), 133.7(q), 132.6(t), 131.9(q ), 131.6(q), 130.8(q), 130.7(t), 130.7(t), 130.6(t), 129.9(t), 129.3(t) , 128.5(t), 128.1(t), 127.9(t), 127.6(t), 124.8(q), 101.5(q), 70.0(d), 57.7(d), 54.4(d), 51.6(d), 44.8(s), 41.4(d), 36.2(d), 20.9(s), 16.5(s).

[0765] Example 152: 2-(2-Hydroxy-5-methylbenzylidene)cyclohexan-1-one

[0766] A solution of 2-hydroxy-5-methylbenzaldehyde (5.00 g, 36.7 mmol) in 4% aqueous sodium hydroxide solution (5.88 g, 147 mmol) was added dropwise to a mixture of 4% aqueous sodium hydroxide solution (1.47 g, 36.7 mmol) and cyclohexanone (18.02 g, 184 mmol) under stirring. The reaction mixture was stirred at room temperature for 40 hours and then neutralized with HCl 6N (40 mL). HCl solution was added dropwise to avoid heating. The product was extracted into CHCl 3 (100 mL), washed with water (4 × 100 mL) and washed with Na 2 SO 4 Dry. Evaporate the chloroform and extract the resulting dark brown liquid with hot petroleum ether. The crude product was purified by Biotage to obtain the title product (3.60 g, yield 45%). GC / MS (EI): m / z (%): 210 (1) [M + ],197(100),183(40),168(10),152(10),91(10),76(8).

[0767] Example 153: 2-(2-Hydroxy-5-methylbenzyl)cyclohexan-1-one

[0768] To a suspension of Pd-C (palladium on carbon) (0.050 g, 0.46 mmol) in MeOH (50 mL) was added (E)-2-(2-hydroxy-5-methylbenzylidene)cyclohexan-1-one (1.00 g, 4.6 mmol) under stirring, and the mixture was placed under a hydrogen atmosphere (5 bar). The reaction mixture was stirred at room temperature for 40 hours. The product was extracted into CHCl 3 (100 mL), washed with water (4 × 100 mL) and washed with Na 2 SO 4 The chloroform was evaporated and the resulting brown liquid was purified by silica gel column to obtain the title product (0.84 g, yield 82%). GC / MS (EI): m / z (%): 218 (40) [M + ],199(20),171(40),121(100),108(40),91(20),77(20).

[0769] Example 154: (E)-2-(5-methyl-2-(2-morpholinoethoxy)benzylidene)cyclohexan-1-one

[0770] According to the general method of Example 80: a mixture of (E)-2-(2-hydroxy-5-methylbenzylidene)cyclohexan-1-one (0.30 g, 1.4 mmol), 4-(2-chloroethyl)morpholine dihydrochloride (0.62 g, 2.8 mmol), potassium carbonate (0.58 g, 4.2 mmol) and potassium iodide (0.046 g, 0.28 mmol) in DMF (20 mL) was reacted to give the title product (0.21 g, yield 46%) as a viscous liquid. GC / MS (EI): m / z (%): 329 (10) [M + ],242(2),199(5),171(3),145(5),114(5),100(100),91(4),70(5). 1 H NMR (300 MHz, CDCl 3 )δ7.61 (s, 1H), 7.13-7.00 (m, 2H), 6.79 (d, J = 8.2Hz, 1H), 4.09 (t, J = 5.9Hz, 2H), 3.75-3.69 (m, 4H), 2.83-2.70(m, 4H), 2.59-2.48(m, 6H), 2.29(s, 3H), 1.94-1.84(m, 2H), 1.79-1.68(m, 2H). 13 C NMR (75 MHz, CDCl 3 )δ201.9(q), 155.6(q), 136.8(q), 131.4(t), 130.9(t), 130.5(t), 129.5(q), 124.9(q) , 112.1(t), 67.1(d), 57.7(d), 54.3(d), 40.6(d), 29.3(d), 24.2(d), 23.8(d), 20.7(s).

[0771] Example 155: (E)-2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)-cyclohexan-1-one

[0772] A mixture of (E)-2-(2-hydroxy-5-methylbenzylidene)cyclohexan-1-one (0.30 g, 1.4 mmol), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.65 g, 2.8 mmol), potassium carbonate (0.58 g, 4.2 mmol) and potassium iodide (0.046 g, 0.28 mmol) in DMF (20 mL) was heated to 100° C. for 4 h. It was then diluted with water (50 mL) and then washed with CH 2 Cl 2 (50 mL × 2) extraction. The combined organic layer was washed with Na 2 SO 4The mixture was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography and eluted with (hexane: MTBE = 20: 1 → 10: 1) to obtain the title product (0.13 g, 0.38 mmol, yield 27.1%) as a colorless liquid. GC / MS (EI): m / z (%): 365 (8) [M + ],350(5),319(3),290(11),262(100),235(11),207(24),75(9). 1 H NMR (300 MHz, CDCl 3 )δ6.91 (d, J=9.0Hz, 2H), 6.68 (d, J=8.0Hz, 1H), 4.11-3.95 (m, 2H), 3.15 (dd, J=13.5, 4.6Hz, 1H), 2.76 (t, J=5.7Hz , 2H), 2.70-2.44(m, 8H), 2.39-2.28(m, 5H), 2.22(s, 3H), 2.09-1.86(m, 2H), 1.82-1.45(m, 3H), 1.40-1.21(m, 1H). 13 C NMR (75 MHz, CDCl 3 )δ213.2(q), 154.6(q), 132.0(t), 129.6(q), 128.7(q), 127.5(t), 111.3(t), 66.3(d), 57.3(d) , 55.0(d), 53.4(d), 50.8(t), 45.9(s), 42.2(d), 33.6(d), 30.3(d), 28.2(d), 25.1(d), 20.5(s).

[0773] Example 156: 2-(5-methyl-2-(2-morpholinoethoxy)benzyl)cyclohexan-1-one

[0774] According to the general method of Example 80: a mixture of 2-(2-hydroxy-5-methylbenzyl)cyclohexan-1-one (0.30 g, 1.4 mmol), 4-(2-chloroethyl)morpholine dihydrochloride (0.61 g, 2.8 mmol), potassium carbonate (0.95 g, 6.9 mmol) and potassium iodide (0.046 g, 0.28 mmol) in DMF (20 mL) was reacted to give the title product (0.24 g, yield 53%) as a viscous liquid. GC / MS (EI): m / z (%): 331 (5) [M + ],244(8),207(10),171(2),145(3),114(15),100(100),91(3),70(4). 1H NMR (300 MHz, CDCl 3 )δ6.92 (d, J=8.0Hz, 1H), 6.90 (s, 1H), 6.69 (d, J=8.0Hz, 1H), 4.12-3.95 (m, 2H), 3.74-3.64 (m, 4H), 3.20-3.15 (m, 1H), 2.75 (t, J=5.6Hz, 2H), 2.67-2.48 (m, 5H), 2.45-2.17 (m, 6H), 2.10-1.91 (m, 2H), 1.84-1.46 (m, 3H), 1.41-1.30 (m, 1H). 13 C NMR (75 MHz, CDCl 3 )δ212.9(q), 154.6(q), 132.0(t), 129.6(q), 128.6(q), 127.5(t), 111.2(t), 67.0(d), 66. 1(d), 57.9(d), 54.1(d), 50.8(t), 42.2(d), 33.6(d), 30.3(d), 28.1(d), 25.1(d), 20.5(s).

[0775] Example 157: (5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)(phenyl)methanol

[0776] LiAlH 4 (0.17 g, 4.4 mmol) (5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)(phenyl)methanone (0.15 g, 0.44 mmol) was added to a suspension of (0.17 g, 4.4 mmol) in THF (20 mL) and the resulting mixture was stirred at room temperature for 1 hour. Water was added to quench the reaction, the solution was extracted with DCM, the solvent was removed, and the residue was purified by silica gel column chromatography (DCM: methanol = 10: 1) to give the title product (0.10 g, yield 63%) as a viscous liquid. GC / MS (EI): m / z (%): 340 (30) [M + ], 296(5), 252(4), 195(8), 127(4), 127(55), 113(100), 100(15), 84(10), 70(55). 1 H NMR (300 MHz, CDCl 3)δ7.42-7.35(m, 2H), 7.32-7.28(m, 2H), 7.25-7.17(m, 1H), 7.02(d, J=8.1Hz, 1H), 6.93(s, 1H), 6. 78 (d, J=8.2Hz, 1H), 5.87 (s, 1H), 4.16-3.98 (m, 2H), 2.73-2.41 (m, 10H), 2.32 (s, 3H), 2.25 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ154.5(q), 144.1(q), 133.8(q), 130.6(q), 129.7(t), 129.0(t), 128.0(t), 126.7(t), 126.3(t), 113.5(t), 73.4(t), 65.4(d), 57.3(d), 54.6(d), 52.9(d), 45.8(s), 20.7(s).

[0777] Example 158: 1-Methyl-4-(2-(4-methyl-2-(1-phenylvinyl)phenoxy)ethyl)piperazine

[0778] Example 158a: p-Toluene benzoate

[0779] To a solution of p-cresol (200 g, 1.85 mol) in DCM (volume: 150 mL) was added triethylamine (387 mL, 2774 mmol) and DMAP (0.23 g, 1.85 mmol) at 0°C, followed by benzoyl chloride (312 g, 2.22 mol). The reaction mixture was warmed to room temperature and stirred for 3 hours. At this point, the reaction mixture was diluted with 500 mL of DCM and washed with NH 4 The product was quenched with 500 mL of aqueous Cl solution. The aqueous layer was extracted with DCM (2×100), and the combined organic layers were then washed with water and brine and concentrated in vacuo. The resulting residue was recrystallized in 300 mL of PE to give the title product (347 g, yield 87%) as a white powder. GC / MS (EI): m / z (%): 212 (15) [M + ],105(100),77(35),51(5).

[0780] Example 158b: (2-Hydroxy-5-methylphenyl)(phenyl)methanone

[0781] A mixture of p-tolyl benzoate (300 g, 1.41 mol) and aluminum chloride (283 g, 2.12 mol) was slowly (approximately 0.5 h) heated to 120-125° C. in chlorobenzene (volume: 200 mL). The mixture was stirred at this temperature for 20 h, then HCl (172 mL, 5.65 mol) 2M HCl was added at 0° C. The product was extracted with 3×200 mL DCM, and the combined extracts were purified by Na 2 SO 4 Drying and then evaporation to dryness. This method afforded the title product (240 g, 1.07 mol, yield 76%) which was used further without additional purification. GC / MS (EI): m / z (%): 212 (75) [M + ],211(100),135(40),105(25),77(35).

[0782] Example 158c: 2-(1-Hydroxy-1-phenylethyl)-4-methylphenol

[0783] To methylmagnesium bromide (3M ether solution, 14.2 mmol, 4.7 mL) in THF (volume: 10 mL) at 0°C was added (2-hydroxy-5-methylphenyl)(phenyl)methanone (1.00 g, 4.7 mmol) and the resulting mixture was stirred at room temperature for 1 hour. 4 The reaction was quenched with Cl solution (50 mL), and the solution was extracted with MTBE (30 mL×3). The solvent was removed and the residue was directly used as the title product (1.10 g, yield 87%). GC / MS (EI): m / z (%): 211 (100) [M + ],210(100),195(95),165(55),152(20),77(20).

[0784] Example 158d: 4-methyl-2-(1-phenylvinyl)phenol

[0785] 2-(1-Hydroxy-1-phenylethyl)-4-methylphenol (1.10 g, 4.8 mmol) and MgSO 4 Acetic acid (0.060 g, 0.96 mmol) was added to the stirred solution in DCM (30 mL). The resulting mixture was then stirred at room temperature overnight. After completion, the reaction mixture was filtered and washed with DCM. The filtrate was concentrated and the residue was purified by silica gel chromatography (PE: MTBE = 10: 1) to give the title product (1.00 g, yield 96%) as a viscous liquid. GC / MS (EI): m / z (%): 210 (100) [M +],209(100),195(95),178(15),165(50),152(20),115(13),103(10),77(20).

[0786] Example 158e: 1-Methyl-4-(2-(4-methyl-2-(1-phenylvinyl)phenoxy)ethyl)piperazine

[0787] According to the general method of Example 80: a mixture of 4-methyl-2-(1-phenylvinyl)phenol (0.25 g, 1.2 mmol), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.56 g, 2.4 mmol), potassium carbonate (1.64 g, 12 mmol) and potassium iodide (0.040 g, 0.24 mmol) in DMF (10 mL) was reacted to give the title product (0.20 g, yield 47%) as a viscous liquid. GC / MS (EI): m / z (%): 336 (98) [M + ],209(10),195(5),178(12),165(20),127(35),113(100),98(20),70(85). 1 H NMR (300 MHz, CDCl 3 ) δ7.31-7.20 (m, 5H), 7.13-7.06 (m, 2H), 6.79-6.72 (m, 1H), 5.62 (s, 1H), 5.29 (s, 1H), 3.89 (t, J=5.7Hz, 2H), 2.45-2.32 (m, 13H), 2.25 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ154.3(q), 147.8(q), 141.8(q), 132.0(t), 131.4(q), 130.2(q), 129.4(t), 128.1(t), 127.3 (t), 126.5(t), 115.3(d), 112.6(t), 67.3(d), 57.0(d), 55.1(d), 53.4(d), 46.1(s), 20.6(s).

[0788] Example 159: 1-Methyl-4-(2-(4-methyl-2-(1-phenylethyl)phenoxy)ethyl)piperazine

[0789] Example 159a: 4-Methyl-2-(1-phenylethyl)phenol

[0790] A mixture of 4-methyl-2-(1-phenylvinyl)phenol (0.40 g, 1.9 mmol) and 10% Pd / C (0.15 g) in MeOH (30 mL) was stirred at 4 °C for 1 h. 2 The mixture was stirred overnight. The mixture was filtered through a small pad of silica gel and the solvent was removed to obtain the title product (0.40 g, yield 94%) as a viscous liquid, which was used directly in the next step. GC / MS (EI): m / z (%): 212 (98) [M + ],197(100),182(50),165(20),134(30),91(40),77(40),65(15).

[0791] Example 159b: 1-Methyl-4-(2-(4-methyl-2-(1-phenylethyl)phenoxy)ethyl)piperazine

[0792] According to the general method of Example 80: a mixture of 4-methyl-2-(1-phenylethyl)phenol (0.25 g, 1.2 mmol), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.56 g, 2.4 mmol), potassium carbonate (1.63 g, 11 mmol) and potassium iodide (0.040 g, 0.24 mmol) in DMF (10 mL) was reacted to give the title product (0.20 g, yield 48%) as a viscous liquid. GC / MS (EI): m / z (%): 338 (25) [M + ],209(5),195(10),165(12),127(90),113(100),100(20),84(10),70(80). 1 H NMR (300 MHz, CDCl 3 )δ7.25-7.17(m, 4H), 7.16-7.09(m, 1H), 7.00(s, 1H), 6.95(d, J=8.2Hz, 1H), 6.70(d, J=8.2Hz, 1H), 4.50(q, J=7.3Hz, 1H), 4 .10-3.88 (m, 2H), 2.76-2.65 (m, 2H), 2.59-2.55 (m, 4H), 2.54-2.45 (m, 4H), 2.30 (s, 3H), 2.26 (s, 3H), 1.56 (d, J=7.3Hz, 3H). 13 C NMR (75 MHz, CDCl 3)δ154.1(q), 146.8(q), 134.5(q), 129.8(q), 128.6(t), 128.1(t), 127.7(t), 127.4(t), 125. 7(t), 111.7(t), 66.7(d), 57.3(d), 55.1(d), 53.4(d), 46.0(s), 37.8(t), 21.2(s), 20.9(s).

[0793] Example 160: 4-(2-(2-(1-(2-fluorophenyl)ethyl)-4,6-dimethylphenoxy)ethyl)morpholine

[0794] A mixture of 2-(1-(2-fluorophenyl)ethyl)-4,6-dimethylphenol (0.37 g, 1.51 mmol) (prepared in a similar order as described in Examples 158 and 159a), 4-(2-chloroethyl)morpholine hydrochloride (0.85 g, 4.54 mmol), potassium carbonate (1.26 g, 9.09 mmol) and potassium iodide (0.03 g, 0.15 mmol) in DMF (20 mL) was heated to reflux for 3 hours. Water was added to the cooled solution, the solution was extracted with DCM, the solvent was removed and the residue was purified by silica gel column chromatography (PE:MTBE=1:1) to give the title product (0.46 g, 1.25 mmol, yield 82%) as a light yellow liquid. GC / MS (EI): m / z (%): 357 (10) [M + ],270(30),255(15),241(5),227(5),114(30),100(100),91(3),70(10),56(15).

[0795] Example 161: 4-(2-(2-(1-(2-fluorophenyl)vinyl)-4,6-dimethylphenoxy)ethyl)morpholine

[0796] A mixture of 2-(1-(2-fluorophenyl)vinyl)-4,6-dimethylphenol (0.5 g, 2.06 mmol) (prepared in a similar order as described in Example 158), 4-(2-chloroethyl)morpholine hydrochloride (1.15 g, 6.19 mmol), potassium carbonate (1.71 g, 12.38 mmol) and potassium iodide (0.03 g, 0.21 mmol) in DMF (20 mL) was heated to reflux for 3 hours. GCMS showed that the starting material was completely consumed, and a mixture of =7:3 was observed in GCMS. Water was added to the cooled solution, the mixture was extracted with DCM, the solvent was removed and the residue was purified by silica gel column chromatography (PE:MTBE=5:1) to give the title product (0.43 g, 1.25 mmol, yield 57%) as a light yellow liquid. GC / MS (EI): m / z (%): 355 (20) [M + ],270(30),255(35),241(10),183(10),114(20),100(100),85(3),70(10),56(15).

[0797] Example 162: (5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)(phenyl)methanone

[0798] A mixture of (2-hydroxy-5-methylphenyl)(phenyl)methanone (0.50 g, 2.4 mmol), 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (1.11 g, 4.7 mmol), potassium carbonate (3.26 g, 23 mmol) and potassium iodide (0.080 g, 0.47 mmol) in DMF (volume: 10 mL) was heated to reflux for 3 hours. Water was added, the solution was extracted 3 times with DCM, the solvent was removed and the residue was purified by silica gel column chromatography (DCM: methanol = 10: 1) to give the title product (0.58 g, 1.54 mmol, yield 65.5%) as a viscous liquid. GC / MS (EI): m / z (%): 338 (3) [M + ], 282(3), 268(5), 211(10), 165(5), 127(55), 113(100), 98(10), 70(85). 1 H NMR (300 MHz, CDCl 3)δ7.79-7.71(m, 2H), 7.55-7.50(m, 1H), 7.44-7.35(m, 2H), 7.24-7.15(m, 2H), 6.81(d, J= 6.3Hz, 1H), 3.97 (t, J=5.6Hz, 2H), 2.39 (t, J=5.6Hz, 2H), 2.35-2.24 (m, 11H), 2.21 (s, 3H). 13 C NMR (75 MHz, CDCl 3 )δ197.1(q), 154.6(q), 138.4(q), 132.8(t), 132.5(t), 130.4(q), 130.1(t), 129.7(t), 129.1(q), 128.2(t), 112.6(t), 67.5(d), 56.8(d), 55.0(d), 53.4(d), 46.0(s), 20.5(s).

[0799] Example 163: 1-(2-((2-benzyl-4-methylcyclohexyl)oxy)ethyl)-4-methylpiperazine

[0800] Sodium hydride (489 mg, 12.24 mmol) was added to 2-benzyl-4-methylcyclohexanol (0.50 mg, 2.5 mmol) in DMF (15 mL) in an ice bath for 2 hours, and 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride (0.87 g, 3.7 mmol) was added dropwise to the above solution. After the addition was completed, the reaction was allowed to proceed at room temperature for 12 hours. After the reaction was completed, the reaction was washed twice with water. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain the title product (0.20 g, yield 25%). GC / MS (EI): m / z (%): 330 (3) [M + ],127(35),113(100),98(50),84(4),70(20),56(5).

[0801] Example 164: 1-(2-((2-benzyl-4-methylcyclohexyl)oxy)ethyl)-4-methylpiperazine dihydrochloride

[0802] According to the method described in Example 96, prepared from 1-(2-((2-benzyl-4-methylcyclohexyl)oxy)ethyl)-4-methylpiperazine, the title product (0.15 g, yield 18%) was obtained as a brown solid. GC / MS (EI): m / z (%): 330 (2) [M + ],127(40),113(100),98(50),84(4),70(20),56(5).

[0803] Example 165: 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)aniline

[0804] A mixture of 4-(2-(2,4-dimethyl-6-(2-nitrobenzyl)phenoxy)ethyl)morpholine (0.45 g, 0.85 mmol) and 10% Pd / C (150 mg) in methanol (15 mL) was stirred at 4 ℃ for 2 h. 2 The mixture was stirred overnight. The mixture was filtered, the solvent was removed and the residue was purified by silica gel column chromatography (DCM: methanol = 95: 5) to obtain the title product (0.21 g, 0.06 mmol, yield 36.3%) as a viscous liquid. GC / MS (EI): m / z (%): 340 (3) [M + ],253(13),227(29),210(14),194(4),165(2),114(26),100(100),87(1),70(5).

[0805] Example 166: TRPM8 modulator assay

[0806] A HEK293 cell line stably expressing hTRPM8 was generated according to Klein et al. (Chem. Senses 36: 649-658, 2011), and receptor activation was monitored by calcium imaging in a Flexstation. For Ca imaging assays of TRPM8 channel activation, cells were seeded at a density of 12,000 cells per well on day 0 in Dulbecco's modified Eagle's medium (DMEM) containing 9% fetal bovine serum in a black clear bottom 96-well plate coated with 0.001% polyethyleneimine (molecular weight = 60,000, Acros Organics). On day 2, agonists were assessed by calcium imaging using Fluo-4. Briefly, the growth medium was discarded and the cells were incubated in 50 μL of loading buffer at 37°C in the dark for 1 h, which consisted of 2.7 μM Fluo-4 AM (Invitrogen) and 2.5 μM probenecid (Sigma-Aldrich) in DMEM (serum-free). After incubation, the cells were washed with 100 μL of detection buffer (unit: mM: 130 NaCl, 5 KCl, 10 HEPES, 2 CaCl 2The plates were washed five times with 10 μL of 10% glucose, pH 7.4) and then further incubated for 30 min in the dark at room temperature. The cells were then washed five times with 100 μL of assay buffer and the calcium influx of serial dilutions of compounds of the invention were measured in a Flexstation 3 (Molecular Devices). Receptor activation was initiated upon addition of 20 μL of a 10-fold concentrated ligand stock solution, also prepared in assay buffer. Fluorescence was monitored continuously for 15 s before addition of the ligand and for 105 s after addition of the ligand, for a total of 120 s. The maximum receptor activation relative to the solvent control and relative to 31.6 μM menthol was determined. The data from the serial dilutions were processed using the KNIME workflow to fit sigmoidal dose-response curves and infer the EC 50 value.

[0807] Exhibits an EC lower than 35 μM 50 The TRPM8 agonists with the highest values ​​are listed in Table 1 below.

[0808] Table 1:

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817] ++++EC 50 Values ​​in the range of 0.05 μM and below

[0818] +++EC 50 Values ​​are in the range of 0.05-0.3 μM

[0819] ++EC 50 Values ​​are in the range of 0.3-1.00 μM

[0820] +EC 50 Values ​​range from 1.00-35 μM

[0821] Example 167: Sensory Studies in Aqueous Solutions

[0822] The compounds listed in Table 2 below were dissolved in propylene glycol at a concentration of 1 wt-%. These solutions were then dispensed in appropriate amounts into a mixture containing 0.5 wt-% Poloxamer 407 (which is a hydrophilic nonionic surfactant, available, for example, from Sigma Aldrich) and 0.25 wt-% RH40 (obtained from BASF) as solubilizer in deionized water to obtain the desired final concentration of 40 ppm (parts per million) of the corresponding compound.

[0823] Well-trained panelists evaluated the aqueous solution containing the test compound by sipping 20mL solution in the mouth for 60 seconds, then spitting it out, and then not rinsing the mouth during the evaluation period. Panelists evaluated and recorded cooling performance and other sensory and organoleptic properties at different time points within two hours. Cooling performance was rated on a scale of 0 to 10, with 0 representing no effect and 10 representing extreme cold. All panelists were scored averaged, and cooling intensity was divided into "N", representing "none" (score of 0), "L", representing "low" (score higher than 0, up to 1), "M", representing "medium" (score higher than 1, up to 4), "S", representing "strong" (score higher than 4, up to 8) and "E", representing "extreme" (score higher than 8), which are provided in Table 2. None of the tested compounds showed any statistically significant bitterness or negative organoleptic characteristics.

[0824] Table 2:

[0825]

[0826]

[0827] Column A: Maximum Coolness

[0828] Column B: Maximum cooling time, in minutes

[0829] Column C: Cooling after 1 hour

[0830] Example 168: Sensory Study in Model Dentifrice

[0831] The compounds listed in Table 3 were dissolved in propylene glycol at a concentration of 1 wt-%. These solutions were then dispersed in appropriate amounts to obtain the desired final concentration of 100 ppm (parts per million) of the test compound into a model unscented dentifrice, the formulation of which is shown below (the ingredients obtained from the supplier are indicated in parentheses).

[0832]

[0833] Well-trained panelists evaluated the dentifrice containing the compound of formula (I) by brushing their teeth with 1g of dentifrice using a toothbrush for 60 seconds, spitting it out subsequently, and not rinsing their mouths during the evaluation period afterwards. Panelists evaluated and recorded cooling performance and other sensations and sensory attributes at different time points within two hours. Cooling performance was rated on a scale of 0 to 10, with 0 representing no effect and 10 representing extreme cold. All panelists were scored averaged, and cooling intensity was divided into "N", representing "none" (score of 0), "L", representing "low" (score higher than 0, up to 1), "M", representing "medium" (score higher than 1, up to 4), "S", representing "strong" (score higher than 4, up to 8) and "E", representing "extreme" (score higher than 8), which are summarized in Table 3 below. The tested compounds did not show any statistically significant bitterness or negative sensory characteristics.

[0834] Table 3:

[0835]

[0836]

[0837] Column A: Maximum Coolness

[0838] Column B: Maximum cooling time, in minutes

[0839] Column C: Cooling after 1 hour

Claims

1. A non-medical method for regulating transient receptor potential channel melastatin member 8 (TRPM8), comprising contacting the receptor with a compound of formula (Ia) or a salt thereof (him) in Ring A represents a phenyl ring, a cyclohexyl ring or a cyclohexenyl ring; R1 is selected from hydrogen, C1-C6 alkyl and C1-C6 alkoxy, R2 is attached to the 3, 4 or 5 position of ring A and is selected from C1-C6 alkyl, C1-C6 alkoxy and C(O)O-C1-C3-alkyl, R3 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, OH and =0, and R4 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl and OH, provided that at least one of R3 and R4 is hydrogen, or R3 and R1 together with the carbon atoms to which they are attached form a six-membered ring system, and R4 is hydrogen, R5 is selected from hydrogen, F and C1-C6 alkyl, R6 is selected from hydrogen, F and C1-C6 alkyl, m is 0, p is 1, W is selected from -CH2-, -O- and >NR 13 , where R 13 is selected from hydrogen and C1-C3 alkyl, V is selected from >CH- and >N-, Z is selected from -O-, >CHR 12 、>NR 12 , where R 12 is hydrogen, C1-C3 alkyl, OH or CH2OH, Ring B represents a phenyl, furan or pyridine ring, R 11 is selected from CN, halogen, CH2CN, NO2, NH2, CF3, C(O)OC2H5, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkenyl and OH, and n is an integer from 0 to 5, provided that if n>1, then R 11 Can be the same or different, X is selected from -CH2-, -O-, >CH-CH3, >C=CH2 and >CHOH.

2. The method according to claim 1, wherein ring B represents a phenyl ring.

3. The method according to claim 1, wherein the compound of formula (Ia) is selected from the group consisting of: (1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperidin-4-yl)methanol; (5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)(phenyl)methanol; (E)-1-(2-((6-benzylidene-2,4-dimethylcyclohex-1-en-1-yl)oxy)ethyl)-4-methylpiperazine; 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine; (E)-2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)cyclohexan-1-one; (E)-2-(5-methyl-2-(2-morpholinoethoxy)benzylidene)cyclohexan-1-one; 2-(3,5-dimethyl-2-(2-morpholinopropoxy)benzyl)benzonitrile; 2-(3,5-dimethyl-2-((1-morpholinoprop-2-yl)oxy)benzyl)benzonitrile; 1-((8-Benzylchroman-2-yl)methyl)-4-methylpiperazine; 1-(2-((2-benzyl-4-methylcyclohexyl)oxy)ethyl)-4-methylpiperazine; 1-(2-((2-benzyl-4-methylcyclohexyl)oxy)ethyl)-4-methylpiperazine dihydrochloride; 1-(2-(2-(2-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-(2-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-(2-fluorobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-(2-iodobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-(3-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-(3-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-(4-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride; 1-(2-(2-(Furan-2-ylmethyl)-4-methylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2,4-dimethyl-6-(2-(trifluoromethyl)benzyl)phenoxy)ethyl)-4-methylpiperazine; 1-(2-(2,4-dimethyl-6-(pyridin-2-ylmethyl)phenoxy)ethyl)-4-methylpiperazine; 1-(2-(2,4-dimethyl-6-(pyridin-3-ylmethyl)phenoxy)ethyl)-4-methylpiperazine; 1-(2-(2,4-dimethyl-6-(pyridin-4-ylmethyl)phenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-benzyl-3,6-dimethylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-benzyl-3-methoxyphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-benzyl-3-methylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-benzyl-4-(tert-butyl)-6-methoxyphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-benzyl-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-Benzyl-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine dihydrochloride; 1-(2-(2-Benzyl-4-ethylphenoxy)ethyl)-4-methylpiperazine hydrochloride; 1-(2-(2-benzyl-4-isopropylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-ethylpiperazine hydrochloride; 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine 2,3-dihydroxysuccinate; 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine 2-hydroxypropane-1,2,3-tricarboxylate; 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2,2,2-trifluoroacetate); 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2-hydroxysuccinate); 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(phosphate); 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimaleate; 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimethanesulfonate; 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride; 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine oxalate; 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine sulfate; 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)piperazine; 1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperidin-4-ol; 1-(2-(2-benzyl-4-methylphenoxy)propyl)-4-methylpiperazine; 1-(2-(2-Benzyl-4-methylphenoxy)propyl)-4-methylpiperazine hydrochloride; 1-(2-(2-Benzyl-6-methylphenoxy)ethyl)-4-methylpiperazine; 1-(2-(2-Benzylphenoxy)ethyl)-4-methylpiperazine hydrochloride; 1-(2-Benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-ol; 1-(2-Benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-one; 1-(3-(2-Benzyl-4-methylphenoxy)propyl)-4-methylpiperazine hydrochloride; 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine; 1-Methyl-4-(2-(4-methyl-2-(1-phenylethyl)phenoxy)ethyl)piperazine; 1-Methyl-4-(2-(4-methyl-2-(1-phenylethenyl)phenoxy)ethyl)piperazine; 1-Methyl-4-(2-(4-methyl-2-(2-methylbenzyl)phenoxy)ethyl)piperazine; 1-Methyl-4-(2-(4-methyl-2-(3-methylbenzyl)phenoxy)ethyl)piperazine; 2-(2-(2-hydroxy-3-morpholinopropyl)-5-methylphenoxy)benzonitrile; 2-(2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)phenyl)acetonitrile; 2-(2,4-dimethyl-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile; 2-(2,6-difluorobenzyl)-4-methyl-N-(2-morpholinoethyl)aniline; 2-(2,6-difluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline; 2-(2,6-difluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline; 2-(2-Fluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline; 2-(2-Fluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline; 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile; 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile hydrochloride; 2-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile; 2-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile hydrochloride; 2-(3,5-dimethyl-2-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)benzyl)benzonitrile; 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)-3-fluorobenzonitrile; 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)aniline; 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile; 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile hydrochloride; 2-(3,5-dimethyl-2-(3-morpholinopropoxy)benzyl)benzonitrile; 2-(3,5-dimethyl-2-(3-morpholinopropyl)phenoxy)benzonitrile; 2-(3,5-dimethyl-2-(methyl(2-morpholinoethyl)amino)benzyl)benzonitrile; 2-(4-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile; 2-(5-methyl-2-(2-(1-methylpiperidin-4-yl)ethoxy)benzyl)benzonitrile; 2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile; 2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile dihydrochloride; 2-(5-methyl-2-(2-morpholinoethoxy)benzyl)cyclohexan-1-one; 2-(5-methyl-2-(2-morpholinopropoxy)benzyl)benzonitrile; 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile; 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile hydrochloride; 2-Benzyl-4-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline; 2-Benzyl-4-methylphenyl 2-(4-methylpiperazin-1-yl)acetate; 2-Benzyl-N,4-dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline; 2-Benzyl-N,4-dimethyl-N-(2-morpholinoethyl)aniline; 3-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile dihydrochloride; 3-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)aniline; 3-Bromo-2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile; 3-Chloro-2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile; 4-(1-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)propan-2-yl)morpholine; 4-(2-(2-(1-(2-fluorophenyl)ethyl)-4,6-dimethylphenoxy)ethyl)morpholine; 4-(2-(2-(1-(2-fluorophenyl)vinyl)-4,6-dimethylphenoxy)ethyl)morpholine; 4-(2-(2-(2,4-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine; 4-(2-(2-(2,5-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine; 4-(2-(2-(2,6-dichlorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine; 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine; 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)propyl)morpholine; 4-(2-(2-(2,6-difluorobenzyl)-4-methylphenoxy)ethyl)morpholine; 4-(2-(2-(2-chlorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine; 4-(2-(2-(2-fluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine; 4-(2-(2-(3,5-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine; 4-(2-(2,4-dimethyl-5-((perfluorophenyl)methyl)phenoxy)ethyl)morpholine; 4-(2-(2,4-dimethyl-6-(2,4,5-trifluorobenzyl)phenoxy)ethyl)morpholine; 4-(2-(2,4-dimethyl-6-(2-nitrobenzyl)phenoxy)ethyl)morpholine; 4-(2-(2-Benzyl-4-methylphenoxy)ethyl)-1,2,6-trimethylpiperazine; 4-(2-(2-Benzyl-4-methylphenoxy)ethyl)morpholine hydrochloride; 4-(2-(2-ethyl-6-(2-fluorobenzyl)-4-methylphenoxy)ethyl)morpholine; 4-methyl-2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)phenol; 4-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzoic acid ethyl ester dihydrochloride; and Methyl 3-benzyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate.

4. 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 (Ia) or a salt thereof as defined in any one of claims 1 to 3.

5. A non-medical 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 (Ia) as defined in any one of claims 1 to 3.

6. Consumer product comprising one or more compounds of formula (Ia) as defined in any one of claims 1 to 3.

7. A compound of formula (Ia) as defined in any one of claims 1 to 3 for use in providing a cooling sensation.

8. A composition providing a cooling sensation, wherein the composition comprises a compound of formula (Ia) as defined in any one of claims 1 to 3.

9. A compound of formula (Ia) or a salt thereof (him) in Ring A represents a phenyl ring, a cyclohexyl ring or a cyclohexenyl ring; R1 is selected from hydrogen, C1-C6 alkyl and C1-C6 alkoxy, R2 is attached to the 3, 4 or 5 position of ring A and is selected from C1-C6 alkyl, C1-C6 alkoxy and C(O)O-C1-C3-alkyl, R3 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, OH and =0, and R4 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl and OH, provided that at least one of R3 and R4 is hydrogen, or R3 and R1 together with the carbon atoms to which they are attached form a six-membered ring system, and R4 is hydrogen, R5 is selected from hydrogen, F and C1-C6 alkyl, R6 is selected from hydrogen, F and C1-C6 alkyl, m is 0, p is 1, W is selected from -CH2-, -O- and >NR 13 , where R 13 is selected from hydrogen and C1-C3 alkyl, V is selected from >CH- and >N-, Z is selected from -O-, >CHR 12 、>NR 12 , where R 12 is hydrogen, C1-C3 alkyl, OH or CH2OH, Ring B represents a phenyl, furan or pyridine ring, R 11 is selected from CN, halogen, CH2CN, NO2, NH2, CF3, C(O)OC2H5, C1-C3 alkyl, C1-C3 alkoxy, C2-C3 alkenyl and OH, and n is an integer from 0 to 5, provided that if n>1, then R 11 Can be the same or different, X is selected from -CH2-, -O-, >CH-CH3, >C=CH2 and >CHOH, Provided that the compound of formula (Ia) is not 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine, and is not 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine, and is not N-(2-benzyl-4-methoxyphenyl)-2-(piperidin-4-yl)acetamide.

10. A compound of formula (Ia) according to claim 9 or a salt thereof, selected from (1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperidin-4-yl)methanol, (5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)(phenyl)methanol, (E)-1-(2-((6-benzylidene-2,4-dimethylcyclohex-1-en-1-yl)oxy)ethyl)-4-methylpiperazine, (E)-2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)cyclohexan-1-one, (E)-2-(5-methyl-2-(2-morpholinoethoxy)benzylidene)cyclohexan-1-one, 2-(3,5-dimethyl-2-(2-morpholinopropoxy)benzyl)benzonitrile, 2-(3,5-dimethyl-2-((1-morpholinoprop-2-yl)oxy)benzyl)benzonitrile, 1-((8-Benzylchroman-2-yl)methyl)-4-methylpiperazine, 1-(2-((2-benzyl-4-methylcyclohexyl)oxy)ethyl)-4-methylpiperazine, 1-(2-((2-benzyl-4-methylcyclohexyl)oxy)ethyl)-4-methylpiperazine dihydrochloride, 1-(2-(2-(2-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-(2-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-(2-fluorobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-(2-iodobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-(3-bromobenzyl)-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-(3-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-(4-chlorobenzyl)-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride, 1-(2-(2-(Furan-2-ylmethyl)-4-methylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2,4-dimethyl-6-(2-(trifluoromethyl)benzyl)phenoxy)ethyl)-4-methylpiperazine, 1-(2-(2,4-dimethyl-6-(pyridin-2-ylmethyl)phenoxy)ethyl)-4-methylpiperazine, 1-(2-(2,4-dimethyl-6-(pyridin-3-ylmethyl)phenoxy)ethyl)-4-methylpiperazine, 1-(2-(2,4-dimethyl-6-(pyridin-4-ylmethyl)phenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-benzyl-3,6-dimethylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-benzyl-3-methoxyphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-benzyl-3-methylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-benzyl-4-(tert-butyl)-6-methoxyphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-benzyl-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-benzyl-4,6-dimethylphenoxy)ethyl)-4-methylpiperazine dihydrochloride, 1-(2-(2-benzyl-4-ethylphenoxy)ethyl)-4-methylpiperazine hydrochloride, 1-(2-(2-benzyl-4-isopropylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-ethylpiperazine hydrochloride, 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine 2,3-dihydroxysuccinate, 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine 2-hydroxypropane-1,2,3-tricarboxylate, 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2,2,2-trifluoroacetate), 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(2-hydroxysuccinate), 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine di(phosphate), 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimaleate, 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine dimethanesulfonate, 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine hydrochloride, 1-(2-(2-benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine oxalate, 1-(2-(2-Benzyl-4-methylphenoxy)ethyl)-4-methylpiperazine sulfate, 1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperazine, 1-(2-(2-benzyl-4-methylphenoxy)ethyl)piperidin-4-ol, 1-(2-(2-benzyl-4-methylphenoxy)propyl)-4-methylpiperazine, 1-(2-(2-benzyl-4-methylphenoxy)propyl)-4-methylpiperazine hydrochloride, 1-(2-(2-benzyl-6-methylphenoxy)ethyl)-4-methylpiperazine, 1-(2-(2-Benzylphenoxy)ethyl)-4-methylpiperazine hydrochloride, 1-(2-Benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-ol, 1-(2-Benzyl-4-methylphenyl)-3-(4-methylpiperazin-1-yl)propan-2-one, 1-(3-(2-Benzyl-4-methylphenoxy)propyl)-4-methylpiperazine hydrochloride, 1-(3-(2-benzyl-4-methylphenyl)propyl)-4-methylpiperazine, 1-methyl-4-(2-(4-methyl-2-(1-phenylethyl)phenoxy)ethyl)piperazine, 1-methyl-4-(2-(4-methyl-2-(1-phenylvinyl)phenoxy)ethyl)piperazine, 1-methyl-4-(2-(4-methyl-2-(2-methylbenzyl)phenoxy)ethyl)piperazine, 1-methyl-4-(2-(4-methyl-2-(3-methylbenzyl)phenoxy)ethyl)piperazine, 2-(2-(2-hydroxy-3-morpholinopropyl)-5-methylphenoxy)benzonitrile, 2-(2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)phenyl)acetonitrile, 2-(2,4-dimethyl-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile, 2-(2,6-difluorobenzyl)-4-methyl-N-(2-morpholinoethyl)aniline, 2-(2,6-difluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline, 2-(2,6-difluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline, 2-(2-Fluorobenzyl)-N,4,6-trimethyl-N-(2-morpholinoethyl)aniline, 2-(2-Fluorobenzyl)-N,4-dimethyl-N-(2-morpholinoethyl)aniline, 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile, 2-(3,5-dimethyl-2-((1-(4-methylpiperazin-1-yl)propan-2-yl)oxy)benzyl)benzonitrile hydrochloride, 2-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile, 2-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile hydrochloride, 2-(3,5-dimethyl-2-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)benzyl)benzonitrile, 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)-3-fluorobenzonitrile, 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)aniline, 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile, 2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile hydrochloride, 2-(3,5-dimethyl-2-(3-morpholinopropoxy)benzyl)benzonitrile, 2-(3,5-dimethyl-2-(3-morpholinopropyl)phenoxy)benzonitrile, 2-(3,5-dimethyl-2-(methyl(2-morpholinoethyl)amino)benzyl)benzonitrile, 2-(4-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile, 2-(5-methyl-2-(2-(1-methylpiperidin-4-yl)ethoxy)benzyl)benzonitrile, 2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile, 2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile dihydrochloride, 2-(5-methyl-2-(2-morpholinoethoxy)benzyl)cyclohexan-1-one, 2-(5-methyl-2-(2-morpholinopropoxy)benzyl)benzonitrile, 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile, 2-(5-methyl-2-(3-(4-methylpiperazin-1-yl)propyl)phenoxy)benzonitrile hydrochloride, 2-Benzyl-4-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline, 2-Benzyl-4-methylphenyl 2-(4-methylpiperazin-1-yl)acetate, 2-Benzyl-N,4-dimethyl-N-(2-(4-methylpiperazin-1-yl)ethyl)aniline, 2-Benzyl-N,4-dimethyl-N-(2-morpholinoethyl)aniline, 3-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzonitrile dihydrochloride, 3-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)aniline, 3-Bromo-2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile, 3-Chloro-2-(3,5-dimethyl-2-(2-morpholinoethoxy)benzyl)benzonitrile, 4-(1-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)prop-2-yl)morpholine, 4-(2-(2-(1-(2-fluorophenyl)ethyl)-4,6-dimethylphenoxy)ethyl)morpholine, 4-(2-(2-(1-(2-fluorophenyl)vinyl)-4,6-dimethylphenoxy)ethyl)morpholine, 4-(2-(2-(2,4-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine, 4-(2-(2-(2,5-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine, 4-(2-(2-(2,6-dichlorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine, 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine, 4-(2-(2-(2,6-difluorobenzyl)-4,6-dimethylphenoxy)propyl)morpholine, 4-(2-(2-(2,6-difluorobenzyl)-4-methylphenoxy)ethyl)morpholine, 4-(2-(2-(2-chlorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine, 4-(2-(2-(2-fluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine, 4-(2-(2-(3,5-difluorobenzyl)-4,6-dimethylphenoxy)ethyl)morpholine, 4-(2-(2,4-dimethyl-5-((perfluorophenyl)methyl)phenoxy)ethyl)morpholine, 4-(2-(2,4-dimethyl-6-(2,4,5-trifluorobenzyl)phenoxy)ethyl)morpholine, 4-(2-(2,4-dimethyl-6-(2-nitrobenzyl)phenoxy)ethyl)morpholine, 4-(2-(2-benzyl-4-methylphenoxy)ethyl)-1,2,6-trimethylpiperazine, 4-(2-(2-benzyl-4-methylphenoxy)ethyl)morpholine hydrochloride, 4-(2-(2-ethyl-6-(2-fluorobenzyl)-4-methylphenoxy)ethyl)morpholine, 4-methyl-2-(5-methyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)phenol, 4-(3,5-dimethyl-2-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)benzoic acid ethyl ester dihydrochloride, and Methyl 3-benzyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzoate.

11. A pharmaceutical composition comprising one or more compounds of formula (Ia) as defined in claim 9 or 10.

12. A compound of formula (Ia) as defined in claim 9 or 10 for use as a medicament.

Images