WO2015129755A1

WO2015129755A1 - Novel compound and texture improver containing said compound

Info

Publication number: WO2015129755A1
Application number: PCT/JP2015/055432
Authority: WO
Inventors: 裕右網野; 優樹田原; 石渡　裕; 譲江藤; 祐子阿部; 正和中沢; 裕美子鈴木; 恵山田; 弥生河戸; 高穂田島; 佳代松本; 慧山田
Original assignee: 味の素株式会社
Priority date: 2014-02-25
Filing date: 2015-02-25
Publication date: 2015-09-03
Also published as: TW201623237A; JP2017071553A

Abstract

　Provided are: a compound having a chemical structure that was not known in the past, wherein the compound is a low-molecular-weight organic compound that is capable of imparting a tongue-coating feeling and/or a mouth-coating feeling to a food; and a food composition containing this novel compound. Provided are a low-molecular-weight organic compound such as is represented by the following formula, or a salt thereof, and a food composition containing this compound or salt thereof. (In the formula, R₁-R₈, Ra-Rd, A, B, D, X, and Y are as defined in the specification)

Description

Novel compound and texture-improving agent containing the compound

The present invention relates to a low molecular weight organic compound having a specific structure, a food composition containing the compound, a texture improving agent containing the compound, a food or drink containing the compound, or an intermediate product for producing food or drink, and food and drink The present invention relates to a method for manufacturing foods or foods.

In recent years, consumer demand for taste has increased due to diversification of eating habits, etc. With this, not only the five basic tastes expressed by sweetness, salty taste, acidity, bitterness, umami, but also texture and tongue There is a growing interest in characteristics such as sensation.
At the same time, in response to the growing interest in health, low-fat foods such as low-fat mayonnaise with a reduced fat content have been developed in fat-containing foods. The current situation is not enough to respond to interest.
On the other hand, Patent Document 1 discloses that a compound containing a linked heteroaryl moiety represented by the formula (IA) and the compound can be used as an umami flavor modifier, a taste substance, and a taste enhancer for an edible composition. It is disclosed.

Patent Document 2 includes a step of adding an aftertaste type high-potency umami substance to a raw material, and the fat content of the low-fat snack confectionery is 10% to 33%. A method for manufacturing (potato chips, etc.) is disclosed. According to this production method, compared to low-fat snack confectionery to which no aftertaste-type high-potency umami substance has been added, “strength of aftertaste”, “preference of aftertaste”, “strength of oiliness”, “ It is described that one or more parameters selected from “fat-like richness”, “satisfaction”, and “preference for overall taste” are increased.
On the other hand, it has a chemical structure different from the compounds described in the above-mentioned patent documents, and is applied to foods as “tongue-coating” (oil covers the tongue and clings to it. Development of a new compound capable of imparting a new taste such as “sensation” and “Mouth-coating” (sensation in which oil covers the oral cavity and clings) is desired.

Japanese Patent No. 4734346 JP 2013-198423 A

It is an object of the present invention to provide a low molecular weight organic compound that is a compound whose chemical structure has not been known so far, and that can provide food with a coating feeling on the tongue and / or a coating feeling in the oral cavity. .
Another object of the present invention is to provide a food composition containing the novel compound.
Another object of the present invention is to provide a texture improving agent containing the novel compound.
Another object of the present invention is to provide a method for producing a food or drink or food or drink containing the novel compound, and a method for imparting a coating feeling on the tongue and / or a coating feeling in the oral cavity to the food or drink. To do.

The present invention was made based on the knowledge that, unlike the compounds disclosed in Patent Documents 1 and 2, a novel low molecular weight organic compound having a specific structure can solve the above problems.
That is, the present invention provides a compound represented by the following general formula (I) or a salt thereof.
[1] A compound represented by the following general formula (I) or a salt thereof.
Formula (I):

(Where
A represents a 5-membered or 6-membered heteroarylene group containing one or more heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring structure;
B represents an aryl group or a heteroaryl group selected from a pyridinyl group, a thiazolyl group and an imidazolyl group;
D represents a bond, a vinylene group or a vinylene group substituted with 1 or 2 alkyl groups having 1 to 3 carbon atoms;
X represents an oxygen atom or a sulfur atom,
Y represents a carbon atom or a nitrogen atom,
L represents an integer of 0 to 3,
R1 to R3 are hydrogen atom, halogen atom, hydroxyl group, cyano group, amino group, alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, arylthio group, arylamino group, alkenyl group Alkynyl group, acyl group, carboxyl group, sulfo group, phosphono group, alkylamino group, dialkylamino group, alkylthio group, acyloxy group, acylamino group, alkoxycarbonyl group, carbamoyl group or alkylcarbamoyl group, R1 to R3 Any two of them may form a ring which may contain a substituent and may contain 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
R4 to R6 are hydrogen atom, halogen atom, hydroxyl group, cyano group, amino group, alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, arylthio group, arylamino group, arylcarbonyl Group, alkenyl group, alkynyl group, acyl group, carboxyl group, sulfo group, phosphono group, alkylamino group, dialkylamino group, alkylthio group, acyloxy group, acylamino group, alkoxycarbonyl group, alkoxyalkyl group, carbamoyl group or alkylcarbamoyl Any one of R4 to R6 may have a substituent, and may contain 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. May form a ring,
R7 and R8 represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an amino group, an alkylamino group or a dialkylamino group, but an alkyl group of a dialkylamino group May be combined to form an alkylene group having 2 to 5 carbon atoms, or may be an oxy-lower alkyleneoxy group, and both ends of the oxy group may be bonded to ring B to form a condensed ring structure. Good,
Ra to Rd each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
However, in the formula, when D is a bond, X is an oxygen atom, A is a 5-membered or 6-membered heteroarylene group containing one sulfur atom and one nitrogen atom in the ring structure, L is 2 or 3 Represents
When D represents a bond, X represents a sulfur atom and B represents a pyridinyl group, R1, R2 and R3 are not simultaneously hydrogen atoms. )
[2] In the formula, when D is a bond, X represents an oxygen atom and A represents a 5- or 6-membered heteroarylene group containing one or more sulfur atoms in the ring structure, L represents 3. [1 Or a salt thereof.
[3] In the formula, A represents one nitrogen atom, one oxygen atom, one nitrogen atom and one oxygen atom, one nitrogen atom and one sulfur atom, or two nitrogen atoms. Or a 5-membered heteroarylene group having two nitrogen atoms and one oxygen atom, or two nitrogen atoms and one sulfur atom, or a six-membered heteroarylene group having one nitrogen atom or two nitrogen atoms The compound or salt thereof according to [1] or [2], which is an arylene group.

[4] The compound or a salt thereof according to any one of [1] to [3], wherein A is a heteroarylene group represented by the following formula:

(Wherein ₁ # represents a binding site to D;
# ₂ represents a bonding site to the carbon atom to which Ra and Rb are bonded)

[5] The compound or a salt thereof according to any one of [1] to [4], wherein X is an oxygen atom.
[6] The compound or salt thereof according to any one of [1] to [5], wherein B is a pyridinyl group.
[7] The compound or salt thereof according to any one of [1] to [4], wherein X is a sulfur atom, and B is a thiazolyl group or an imidazolyl group.
[8] The compound or a salt thereof according to any one of [1] to [7], wherein at least one of Ra and Rb represents a hydrogen atom, and at least one of Rc and Rd represents a hydrogen atom.
[9] In the formula, L represents an integer of 1, 2, or 3, or when X is a sulfur atom, L represents 0, or a compound according to any one of [1] to [8] salt.
[10] In the formula, R1 to R3 represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms, or R1 The compound or a salt thereof according to any one of [1] to [9], wherein any two of -R3 are taken together to form a 5-membered or 6-membered ring containing one or two oxygen atoms.

[11] In the formula, any one of R1 to R3 is a hydrogen atom, and the remainder is a halogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms. Any one of [1] to [9], which represents an alkoxy group, or the remaining two of R1 to R3 together form a 5-membered or 6-membered ring containing one or two oxygen atoms Or a salt thereof.
[12] In the formula, any two of R1 to R3 are hydrogen atoms, and the rest are halogen atoms, hydroxyl groups, cyano groups, amino groups, aryloxy groups, alkyl groups having 1 to 4 carbon atoms, and carbon atoms 1 The compound or salt thereof according to any one of [1] to [9], which represents an alkylthio group having 3 to 3 or an alkoxy group having 1 to 3 carbon atoms.
[13] The salt is hydrochloride, sulfate, phosphate, nitrate, hydrobromide, acetate, trifluoroacetate, citrate, benzoate, maleate, fumarate, tartaric acid Salt, succinate, tannate, butyrate, hibenzate, pamoate, enanthate, decanoate, theocrate, salicylate, lactate, oxalate, mandelate, malate A salt of the compound according to any one of [1] to [12] selected from the group consisting of methanesulfonate, benzenesulfonate, and p-toluenesulfonate.
[14] A food composition containing the compound or salt thereof according to any one of [1] to [13].
[15] A texture improving agent comprising the compound or salt thereof according to any one of [1] to [13].
[16] A method for producing a food or drink comprising the step of adding and mixing the compound or salt thereof according to any one of [1] to [13] to a raw material for the food or drink.
[17] A coating feeling on the tongue of a food or drink and / or a step of adding and mixing the compound or salt thereof according to any one of [1] to [13] to the food or drink raw material or food and drink A method of imparting a feeling of coating in the oral cavity to foods and drinks.

The compound of the present invention or a salt thereof can be added to and mixed with a raw material for food or drink or a food or drink. In particular, when added to and mixed with foods in which fats and oils are dispersed or emulsified, liquid foods such as soy sauce ramen soup and non-oil dressings, when this food is eaten, a coating feeling on the tongue and a coating feeling in the oral cavity can be obtained. , Can receive a rich feeling (luxury).

1 is a view showing an optical micrograph of crystal A of the compound of Example 80. FIG. FIG. 2 is an optical micrograph of the crystal B of Example 80 compound. FIG. 3 is a diagram showing powder X-rays of crystal A and crystal B of Example 80 compound. 4 is a chart showing DSCs of crystal A and crystal B of Example 80 compound. FIG. FIG. 5 is an optical micrograph of the compound crystal of Example 85. 6 is a diagram showing a powder X-ray of the compound crystal of Example 85. FIG. 7 is a chart showing DSC of the compound crystal of Example 85. FIG.

In the above general formula (I), the “alkyl group” is preferably a linear or branched alkyl group having 1 to 12 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms. Specific examples include groups such as methyl, ethyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl and the like. Particularly preferred is a lower alkyl group, specifically an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms.
The “alkylene group” is preferably a linear or branched alkylene group having 1 to 6 carbon atoms, and more preferably an alkylene group having 1 to 3 carbon atoms. For example, methylene group, ethylene group, n-propylene group (— (CH ₂ ) ₃ —), n-butylene group (— (CH ₂ ) ₄ —), n-pentylene group (— (CH ₂ ) ₅ —), Examples thereof include n-hexylene group (— (CH ₂ ) ₆ —), isopropylene group, isobutylene group, isopentylene group and the like.
The “alkenyl group” refers to a straight or branched alkenyl group having 2 to 6 carbon atoms including each isomer. Examples thereof include a vinyl group, an allyl group, a propenyl group, a butenyl group, a pentenyl group, and a hexenyl group.
The “alkynyl group” refers to a linear or branched alkynyl group having 2 to 6 carbon atoms including each isomer. Examples include ethynyl group, 1-propynyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, pentynyl group and the like.
The “acyl group” in the “acyl group”, “acylamino group”, and “acyloxy group” is preferably an acyl group having a linear or branched or cyclic alkyl group or alkenyl group having 1 to 6 carbon atoms. A lower acyl group, that is, an acyl group having 1 to 4 carbon atoms is preferred. For example, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, acryloyl group, methacryloyl group, crotonoyl group, isocrotonoyl group, cyclopropanoyl group, cyclobutanoyl group, cyclopenta A noyl group, a cyclohexanoyl group, etc. are mentioned.

The “acylamino group” is a group in which a nitrogen atom is bonded to the carbon atom of the carbonyl group part in the aforementioned acyl group, and the acyl group part is preferably a lower acyl group. For example, an acetylamino group, a propionylamino group, etc. are mentioned.
The “acyloxy group” is a group in which an oxygen atom is bonded to a carbon atom of a carbonyl group part in the aforementioned acyl group, and preferably the acyl group part is a lower acyl group. For example, an acetyloxy group, a propionyloxy group, a butyryloxy group, etc. are mentioned.
The “alkylamino group” refers to an amino group monosubstituted with the aforementioned alkyl group. For example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, and the like can be given.
The “dialkylamino group” refers to an amino group disubstituted with the aforementioned alkyl group. Examples include a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, and an ethylmethylamino group, or a ring group in which two alkyl groups are combined to form an alkylene group having 2 to 5 carbon atoms. There may be.
The “alkylthio group” refers to an alkylthio group having an alkyl group having 1 to 6 carbon atoms. For example, methylthio group, ethylthio group, n-propylthio group and the like can be mentioned. Preferably, it is an alkylthio group having 1 to 3 carbon atoms.
The “alkylcarbamoyl group” refers to a carbamoyl group substituted with the aforementioned alkyl group.

The “cycloalkyl group” is preferably a cyclic alkyl group having 3 to 8 carbon atoms, more preferably 4 to 6 carbon atoms. Specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The “alkoxy group” is preferably an alkoxy group having 1 to 6 carbon atoms. Specifically, methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2- Methyl-1-butyloxy, 3-methyl-1-butyloxy, 2-methyl-2-butyloxy, 3-methyl-2-butyloxy, 2,2-dimethyl-1-propyloxy, 1-hexyloxy, 2-hexyloxy And groups such as 3-hexyloxy. An alkoxy group having 1 to 3 carbon atoms is preferable.
The “alkoxycarbonyl group” refers to a carbonyl group substituted with the aforementioned alkoxy group.
The “alkoxyalkyl group” refers to an alkyl group substituted with the aforementioned alkoxy group, and is preferably an alkyl group having 1 to 3 carbon atoms substituted with an alkoxy group having 1 to 3 carbon atoms. Specific examples include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group.
Examples of the “halogen atom” include fluorine, chlorine, bromine, iodine atom and the like. Of these, fluorine and chlorine are preferred.

The “aryl group” in aryl, arylcarbonyl, aryloxy, arylthio, arylamino and arylcarbonyl is preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms, and a phenyl group , A naphthyl group, a 2,3-dihydroxyindenyl group, and the like.
As the “heteroaryl group” and “heteroarylene group”, a heteroaryl group having 3 to 14 carbon atoms having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur as atoms constituting the ring, and A heteroarylene group is preferable, a heteroaryl group having 4 to 10 carbon atoms and a heteroarylene group are more preferable, and a heteroaryl group having 4 to 9 carbon atoms and a heteroarylene group are particularly preferable. Specifically, the heteroaryl group constituting the heteroaryl group and the heteroarylene group includes a furanyl group, a pyrrolyl group, an oxazolyl group, an imidazolyl group, a pyrazolyl group, a pyranyl group, an indenyl group, a thiophenyl group, a pyridinyl group, an indolyl group. Quinolinyl group, thiazolyl group and the like.

In the present invention, the salt of the compound represented by the general formula (I) may be any salt acceptable as a food additive. For a basic group in the case where a basic group is present in the formula, , Salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, Hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teocric acid, salicylic acid, salts with organic carboxylic acids such as lactic acid, oxalic acid, mandelic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Of these, salts with organic sulfonic acids are preferred, among which hydrochloric acid, acetic acid and oxalic acid are preferably used.
As a method for forming the salt, it can be obtained by mixing the compound represented by the general formula (I) and the necessary acid in an appropriate amount ratio in a solvent or a dispersant.

The compounds of the present invention also include solvates of compounds represented by general formula (I), such as hydrates, alcohol adducts and the like.
In the general formula (I), A is as defined above, but one nitrogen atom, one oxygen atom, one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom. Each, or two nitrogen atoms, or two nitrogen atoms and one oxygen atom, or five-membered heteroarylene group or nitrogen atom having two nitrogen atoms and one sulfur atom, or one nitrogen atom A 6-membered heteroarylene group having two is preferable.
Among these, it is particularly preferable that A is a heteroarylene group of any one of the following formulae.

In the general formula (I), R4 to R6 are as defined above, but a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms. It preferably represents an alkoxy group. Depending on the structure of ring A, when there are three positions where substituents can be taken, R4 to R6 exist, but when there are two or one position where substituents can be taken, R4 and R6 are respectively Only R5 and R4 will be present.
In the general formula (I), B is as defined above. The group formed by B, R7, and R8 is preferably any one of the following groups.

Among these, B is more preferably a pyridinyl group, and when X is a sulfur atom, B is preferably a thiazolyl group or an imidazolyl group.
The substituents R7 and R8 bonded to ring B are preferably a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group or an alkenyl group, and in particular, either or both of R7 and R8 are hydrogen atoms. Preferably there is.
In general formula (I), D is as defined above, and D is preferably a bond or a vinylene group. In the case of a vinylene group, a trans isomer is preferable.

In the general formula (I), X, Y, L and Ra to Rd are as defined above, but X is preferably an oxygen atom, at least one of Ra and Rb represents a hydrogen atom, Rc and It is preferred that at least one of Rd represents a hydrogen atom. It is also preferred that L represents an integer of 1, 2 or 3, or that when X is a sulfur atom, L represents 0. In addition, when Y represents a carbon atom, the ring containing Y represents a benzene ring, and when Y represents a nitrogen atom, the ring containing Y represents a pyridine ring.
Further, —C (Ra) (Rb) —X— (C (Rc) (Rd)) L— in the general formula (I) is preferably any one of the following formulae.

(Wherein ₃ # represents a binding site to A,
# ₄ represents the binding site to B)

In the general formula (I), R1 to R3 are as defined above, but R1 to R3 are each a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, an aryloxy group, or a carbon atom having 1 to 4 carbon atoms. An alkyl group, an alkylthio group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms, or any two of R1 to R3 taken together to form a 5-membered ring containing two oxygen atoms or 6 It is preferable to form a member ring. Further, any one of R1 to R3 is a hydrogen atom, and the rest represents an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, or any two of R1 to R3 are combined together To form a 5-membered or 6-membered ring containing one or two oxygen atoms. Further, any two of R1 to R3 are hydrogen atoms, and the rest are an aryloxy group, an alkyl group having 1 to 4 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms. Preferably it represents. Further, any one of R1 to R3 represents an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, and the remaining two of R1 to R3 are combined to form two oxygen atoms. It is preferable to form a 5- or 6-membered ring. When Y represents a nitrogen atom, any one of R1 to R3 may be bonded to the nitrogen atom.
The phenyl group and pyridinyl group having R1 to R3 are preferably those having the following structures.

Further, in the formula (I), when X represents an oxygen atom, A represents a 5- or 6-membered heteroarylene group containing one or more heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom in the ring structure. Preferably expressed. In Formula (I), when X represents a sulfur atom, B preferably represents a heteroaryl group selected from an aryl group, a thiazolyl group, and an imidazolyl group.
The compound represented by the general formula (I) of the present invention can be easily produced, for example, by the method shown below.
The production method of the compound represented by the formula (I) or a salt thereof is not particularly limited, and can be produced by combining known methods. Moreover, it can manufacture by the manufacturing method described below or the method which combined several of these manufacturing methods suitably in combination with the known method.
Various aromatic carboxylic acids, alcohols, thiols, and the like, which are starting materials used to produce the compound represented by the general formula (I), may be known compounds and are synthesized by methods described in the literature. Alternatively, commercially available products from various reagent suppliers can be used.
The compound represented by the general formula (I) is characterized by having the structure represented by the formula (II). The compound (I) having this structure is synthesized by the following production method 1 and production method 2. Can do.

(In the formula, each symbol is as defined above.)
Manufacturing method 1

(In the formula, each symbol is as defined above. In the formulas (III) and (I), X represents O or S. In the formula (IV), E represents chlorine, bromine, iodine, methanesulfonyloxy group. Or a p-toluenesulfonyloxy group or the like.)
Compound (I) can be produced by subjecting component (III) containing heterocycle A and having active hydrogen to component (IV) containing heterocycle B to a bond forming reaction.
The component (III) used here is an alcohol (X═O) and a thiol (X═S), and can be produced by a method described in a later example or a known method. Component (IV) can be purchased as a commercially available reagent or can be produced by a known method.
As the bond formation reaction, a general method used as a production method for ethers and thioethers may be used. For example, sodium hydride, potassium hydride, t-butoxypotassium, n-butyllithium may be used as component (III). , A method of reacting a base such as lithium diisopropylamide to form an alkoxide and a thioalkoxide and then reacting with the component (IV), in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate and the like A method of reacting with component (IV) can be used.
The amount of the base used is 1.0 to 3.0 equivalents, preferably 1.05 to 1.20 equivalents, relative to component (III).
The ratio of the component (III) and the component (IV) to be used is not limited. However, in order to cause a reaction with good yield, the component (IV) is added in an amount of 0.8 to 1.2 per 1 equivalent of the component (III). An equivalent amount may be used.

The solvent to be used is not particularly limited as long as it does not react with component (III), component (IV), and the above-mentioned base. For example, dichloromethane (DCM), N, N′-dimethylformamide (DMF), chloroform , Dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile, acetone, tetrahydrofuran (THF), and ethyl acetate or a mixed solvent thereof can be used. Of these, dichloromethane, N, N′-dimethylformamide, and THF are preferable. The amount of the solvent is 10 to 500 times by weight, preferably 15 to 100 times by weight with respect to component (III).
The reaction time is preferably about 3 to 24 hours, which depends on the reaction temperature, and the range is preferably -80 to 35 ° C.
The following example can be shown as a more specific example of the manufacturing method 1.

(In the formula, each symbol is as defined above.)
Compound (Ia) can be obtained by converting component (IIIa) to sodium alkoxide and then reacting with component (IVa).
Manufacturing method 2

(In the formula, each symbol is as defined above. In the formulas (VI) and (I), X represents O or S. In the formula (V), E represents chlorine, bromine, iodine, methanesulfonyloxy group. Or a p-toluenesulfonyloxy group or the like.)
Compound (I) can be produced by subjecting component (V) containing heterocycle A and component (VI) containing heterocycle B and active hydrogen to a bond forming reaction.
The component (V) used here can be produced by a method described in a later example or a known method. Component (VI) is an alcohol (X═O) and a thiol (X═S), which can be purchased as a commercially available reagent or produced by a known method.
As the bond formation reaction, a general method used as a production method for ethers and thioethers may be used. For example, sodium hydride, potassium hydride, t-butoxypotassium, n-butyllithium may be used as component (VI). , A method in which a base such as lithium diisopropylamide is reacted to form an alkoxide or thioalkoxide and then reacted with component (V), component (V) and component in the presence of a base such as potassium carbonate, sodium carbonate or cesium carbonate There is a method of reacting with (VI).
The amount of the base used is 1.0 to 3.0 equivalents, preferably 1.05 to 1.20 equivalents, relative to component (VI).
The ratio of the component (V) and the component (VI) to be used is not limited, but in order to react with a high yield, the component (VI) is added in an amount of 0.8 to 1.2 per 1 equivalent of the component (V). An equivalent amount may be used.

The solvent to be used is not particularly limited as long as it does not react with the component (V), component (VI) and the above-mentioned base. For example, dichloromethane (DCM), N, N′-dimethylformamide (DMF), chloroform , Dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile, acetone, tetrahydrofuran (THF), and ethyl acetate or a mixed solvent thereof can be used. Of these, dichloromethane, N, N′-dimethylformamide, and THF are preferable. The amount of the solvent is 10 to 500 times the weight, preferably 15 to 100 times the weight of the component (V).
The reaction time is preferably about 3 to 24 hours, which depends on the reaction temperature, and the range is preferably -80 to 35 ° C.
The following example can be shown as a more specific example of production method 2.

(In the formula, each symbol is as defined above.)
Compound (Ia) can be obtained by converting component (VIa) to sodium alkoxide and then reacting with component (Va).

The compounds represented by the general formulas (III), (V) and (VII), which are the raw materials for producing the compound represented by the general formula (I), can be produced by known methods described in literatures. More specifically, it can be synthesized by the following production methods 3 to 7, but the production method is not limited thereto.
Manufacturing method 3
Production method of component (VII): Production method using aromatic carbonyl compound as starting material

(In the formula, each symbol is as defined above. In Formula (VIII), Z represents a methyl group, OH, an alkoxy group, NH ₂ or the like.)
Various methods for converting various aromatic carbonyl compounds (VIII) or aromatic nitriles (IX) to heterocyclic carbonyl compounds (VII) (such as Z = OH) are known, and the heterocyclic carbonyl compounds (VII) are converted accordingly. Can be manufactured.
As a more specific example of the production method, the production method of the isoxazole derivative (VIIa) is represented by the following formula (in the above-mentioned chemical compound (VIII) and compound (VII), when D = bond).

(In the formula, each symbol is as defined above.)
Manufacturing method 4
Production method of component (III) and component (V): Production method using aromatic carbonyl compound as starting material

(In the formula, each symbol is as defined above. In formula (VIII), Z represents OH, NH _2, etc. In formula (III), X represents O, etc. In formula (V), E Represents chlorine, bromine, iodine, OH, etc.)
Various methods for converting an aromatic carbonyl compound (VIII) or aromatic nitrile (IX) to a heterocyclic compound (III) or (V) are also known, and a heterocyclic compound (III) or (V) is produced according to them. can do. As a more specific example of the production method, the production methods of the oxazole derivatives (Va) and (Vb) are shown in the following formulas (in the above compounds (VIII) and (V), D = bonded and D = vinyl group If).

(In the formula, each symbol is as defined above.)
Manufacturing method 5
Production method of component (VII): Production method using cross-coupling reaction

(In the formula, each symbol has the same meaning as above. In formula (XI), E represents chlorine, bromine, iodine, etc. In formula (V), represents Z, OH, alkoxy group, etc.)
A Suzuki-Miyaura coupling reaction using an aromatic boronic acid compound (X) is known as a method for producing a heterocyclic carbonyl compound, and the heterocyclic carbonyl compound (VII) can be produced by this method.
As a more specific example of the production method, the production method of the oxazole derivative (VIIb) is shown by the following formula (in the case of D = bond in the above compound (X) and compound (VII)).

(In the formula, each symbol is as defined above.)
Manufacturing method 6
Production method of component (VII): Production method in which an aromatic ring is introduced into the nitrogen atom of heterocycle A using a coupling reaction

(In the formula, each symbol is as defined above. In Formula (XII), D represents a bond, E represents chlorine, bromine, iodine, —B (OH) _2, etc. In Formula (XIII), H— N represents that a hydrogen atom is bonded to the nitrogen atom constituting the heterocyclic ring A. In the formula (VIIc), D represents a bond, that is, the formula (VIIc) represents an aromatic group on the nitrogen atom of the heterocyclic ring A. Indicates that the ring is directly bonded.)
As a method for producing a heterocyclic carbonyl compound, a method for introducing an aromatic ring into a nitrogen atom of a heterocyclic ring is known, and a heterocyclic carbonyl compound (VII) can be produced by this method.
As an example of a more specific production method, a production method of an imidazole derivative (VIId) is shown by the following formula (in the case of D = bond in the above compound (XII) and compound (VIIc)).

(In the formula, each symbol is as defined above.)
Manufacturing method 7
Production method of component (III, X = O): Production method starting from component (VII) (Z = alkoxy group)

(In the formula, each symbol has the same meaning as described above. In Formula (VII), Z represents a hydroxyl group or an alkoxy group having 1 to 8 carbon atoms.)

(In the formula, each symbol is as defined above. In Formula (VIIc), D represents a bond, Z represents a hydroxyl group or an alkoxy group having 1 to 8 carbon atoms, etc. In Formula (IIIa), D represents a bond. That is, the formula (VIIc) or (IIIa) represents that the aromatic ring is directly bonded to the nitrogen atom of the heterocycle A.)
The compound (VII) or (VIIc) produced in the above production methods 3, 5, and 6 can be converted to the component (III) or (IIIa) by a known method using a reduction reaction, Grignard reaction or the like.
As a reduction reaction of component (VII) or (VIIc), a general method used for a reduction reaction of a carbonyl compound may be used. For example, lithium aluminum hydride (lithium aluminum hydride, LiAlH ₄ ), sodium borohydride ( Reduction with a hydride reducing agent such as sodium borohydride, NaBH ₄ ), lithium borohydride (LiBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), sodium triacetoxyborohydride (NaBH (OAc) ₃ ), etc. Can be used. In order to produce the component (III) or (IIIa) from the component (VII) or (VIIc), once the component (VII) or (VIIc) is converted into a derivative such as aldehyde or mixed acid anhydride, the above-mentioned It can also be subjected to a reduction reaction with a reducing agent.
The amount of the reducing agent to be used is 1.0 to 5.0 equivalents, preferably 1.05 to 2.00 equivalents, relative to component (VII) or (VIIc) or a derivative thereof.

The solvent to be used is not particularly limited as long as it does not react with the component (VII) or (VIIc) and the above-mentioned reducing agent. For example, dichloromethane (DCM), chloroform, tetrahydrofuran (THF), ethyl ether or these A mixed solvent can be used. Of these, THF and ethyl ether are preferred. The amount of the solvent is 10 to 500 times by weight, preferably 15 to 100 times by weight with respect to component (VII) or (VIIc).
The reaction time is preferably about 5 minutes to 24 hours, which depends on the reaction temperature, and the range is preferably −30 to 35 ° C.
As a method for obtaining component (III) or (IIIa) from component (VII) or (VIIc) by Grignard reaction, a general method used for producing alcohol by Grignard reaction may be used. A Grignard reagent may be reacted with a derivative such as aldehyde or amide converted from (VII) or component (VIIc).
The amount of the Grignard reagent used depends on the structure of the target component (VII) or (VIIc), but is 1.0 to 5.0 equivalents, preferably 1.05 to 3.3 based on the component (VII) or (VIIc). 00 equivalents.

The solvent to be used is not particularly limited as long as it does not react with the component (VII) or (VIIc) and the Grignard reagent. For example, dichloromethane (DCM), chloroform, tetrahydrofuran (THF), ethyl ether or a mixed solvent thereof is used. Can be used. Of these, THF and ethyl ether are preferred. The amount of the solvent is 10 to 500 times by weight, preferably 15 to 100 times by weight with respect to component (VII) or (VIIc).
The reaction time is preferably about 5 minutes to 24 hours, which depends on the reaction temperature, and the range is preferably −30 to 35 ° C.
In the synthesis of each reaction and each reaction component, a known deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction or substituent exchange reaction may be performed as desired. Each substituent can be converted by carrying out alone or in combination of two or more thereof.
In each of the above reactions, when the raw material compound has an amino group, a carboxyl group, a hydroxy group or a carbonyl group as a substituent, a protective group generally used in peptide chemistry or the like may be introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction.
The method for removing the protecting group described above can be performed according to a known method, for example, a method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980).

The obtained compound represented by the formula (I) or a salt thereof can be isolated and purified by a conventional method. For example, in the case of purification by crystallization, ethyl acetate, isopropyl acetate, ethanol, methanol, acetonitrile, acetone, diethyl ether, chloroform, dichloromethane, n-hexane, n-heptane, or a mixed solvent thereof is used as a solvent. be able to. As a purification method by chromatography, preparative thin layer chromatography (PTLC) or silica gel column chromatography can be used. As the developing solvent at that time, the solvents mentioned above as the crystallization solvent can be used.

The compound represented by the general formula (I) of the present invention or a salt thereof (hereinafter abbreviated as the compound of the present invention) can be used in any form without limitation on physical properties such as dry powder, paste, and solution.
The compound of this invention can be mix | blended and used for various food-drinks, such as a foodstuff, a drink, and a seasoning.
The final amount of the compound of the present invention when used by blending the compound of the present invention in various foods and beverages such as foods, beverages and seasonings is not particularly limited as long as the desired effect can be obtained. On the basis of the total mass of the beverage or seasoning, etc., it is about 0.1 ppb to 99.9% by mass, preferably about 1 ppb to 10% by mass, and more preferably about 0.01 ppm to 1% by mass.
Various foods and beverages such as foods, beverages and seasonings in which the compound of the present invention is blended may be further blended with any solid or liquid carrier acceptable for food or beverage, suitable seasoning ingredients, and the like.
Examples of the carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, gelatin, albumin, amino acid, water, and physiological saline. Water etc. are mentioned.
The seasoning raw material may be any seasoning raw material used in the art and is not particularly limited, but more specifically, the above-mentioned ones are already mentioned.
The content of any of the above carriers and other seasoning ingredients is not particularly limited.
Among the above-mentioned seasoning raw materials, the yeast extract is not particularly limited in any of the cells from which it is derived, its culture conditions, and the extraction treatment method, and any yeast extract can be used. Further, heat treatment, enzyme treatment, concentration, powder It may be one that has been processed.

The present invention also includes a step of adding and mixing the compound of the present invention to a raw material for food or drink or a food or drink, and a method for imparting a food or food product with a coating feeling on the tongue or a coating feeling in the oral cavity. .
About the manufacturing method of the food-drinks using the compound of this invention, the process of adding the compound of this invention to food-drinks raw materials (for example, umami raw material, protein hydrolyzate, etc.), and is obtained as needed. The manufacturing method of food-drinks including the process of further cooking a food-drinks raw material mixture is preferable.
Further, the step of adding and mixing the compound of the present invention to the raw material for food and drink preferably includes the step of setting the compound concentration in the food and drink to 0.005 to 30 ppm by weight, preferably 0.05 to 10 ppm.
This invention also provides the manufacturing method of the food / beverage products characterized by including the process of adding and mixing the compound of this invention with food-drinks raw material. At this time, the compound of the present invention is preferably added to the food or drink, preferably 0.01 to 50% by weight.
In the present invention, examples of foods to which the compound of the present invention is added and mixed include all foods, but foods in which fats and oils are dispersed or emulsified in a granular form, such as mayonnaise, dressing, curry roux and stew etc. Various roux, sausages, hams, dairy products such as milk, yogurt and ice cream are preferred. In addition, liquid foods such as soy sauce ramen soup and liquid foods such as non-oil dressing that contain fats and oils in a form in which the fats and oils are not dispersed or emulsified in a granular form are listed as preferred foods.
Hereinafter, the present invention will be described in more detail with reference to examples, but these do not limit the present invention.

Hereinafter, the usefulness of the present invention will be specifically described with reference to Examples and Test Examples. However, the present invention is not limited by these. The compounds of Example compounds 1 to 101 were produced according to the methods described in the representative synthesis examples described below. That is, Example compounds 1 to 101 were synthesized by the synthesis methods A to Y described below and methods analogous thereto. In the following production examples, the structures of the synthesized compounds were identified by nuclear magnetic resonance spectrum (Bruker AVANCE 400) and ESI-MS spectrum.
[Experimental section]
Synthesis method A
Synthesis method 1 of oxazole derivative (Example 1)

Step 1: 3,4-methylenedioxyphenylboronic acid (498.5 mg, 3.00 mmol), 2-chlorooxazole-4-carboxyethyl (539.1 mg, 3.07 mmol), tetrakis (triphenylphosphine) palladium ( 0) (Pd (PPh ₃ ) ₄ , 370.8 mg, 0.32 mmol), saturated with toluene (Toluene, 30 mL) by blowing argon (Ar) gas, 2M aqueous potassium carbonate (K ₂ CO ₃ , 3 mL) ) And stirred at 80 ° C. for 3 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 2- (benzo [d] [1,3] dioxol-5-yl) oxazole-4-carboxylic acid Ethyl (648.8 mg, 2.48 mmol) was obtained.
Step 2: 2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-carboxylate (313 mg, 1.20 mmol) was dissolved in tetrahydrofuran (THF, 10 mL), and the flask was bathed in an ice-water bath. After soaking, lithium aluminum hydride (LiAlH ₄ , 68.3 mg, 1.90 mmol) was added, the ice bath was removed, and the mixture was stirred for 30 minutes. After completion of the reaction, it was quenched with 2M aqueous hydrochloric acid solution, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate, filtered, evaporated to remove the solvent, and reprecipitated with ethyl acetate and hexane to give (2- (benzo [d] [1,3] dioxol-5-yl) oxazole-4 -Yl) methanol (64.4 mg, 0.29 mmol) was obtained.

Step 3: (2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methanol (55.2 mg, 0.25 mmol) in N, N′-dimethylformamide (DMF, 5 mL) ), Sodium hydride (NaH, purity 55%, 58.0 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Thereafter, 2- (bromomethyl) pyridine bromate (82.4 mg, 0.33 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in ice water and quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 2-(((2- (benzo [d] [1,3] dioxol-5-yl) oxazole. -4-yl) methoxy) methyl) pyridine (49.7 mg, 0.16 mmol) was obtained.

Synthesis method B
Synthesis method 2 of oxazole derivative (Example 2)

Step 1: 2,3-dimethoxybenzoic acid (0.91 g, 5.00 mmol) was dissolved in THF (50 mL), triethylamine (TEA, 1.4 mL, 10.00 mmol) was added, and the mixture was stirred for 10 minutes. Thereafter, the flask was immersed in an ice bath, ethyl chloroformate (1.34 mL, 14.10 mmol) was added, the ice bath was removed, and the mixture was stirred for 1 hour. The flask was immersed in an ice bath, 28% aqueous ammonia (35 mL) was added, the ice bath was removed, and the mixture was stirred for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel column chromatography was performed to obtain 2,3-dimethoxybenzamide (746.0 mg, 4.12 mmol).

Step 2: To the total amount of 2,3-dimethoxybenzamide, xylene (Xylene, 10 mL) was added, 1,3-dichloro-2-propane (723.9 mg, 5.70 mmol) was added, and the mixture was stirred at 125 ° C. for 3 hours. After completion of the reaction, the mixture is allowed to cool, diluted with ethyl acetate, and filtered to remove the precipitate. The solvent is distilled off, and silica gel column chromatography is performed to give 4- (chloromethyl) -2- (2, 3-Dimethoxyphenyl) oxazole (439.2 mg, 1.73 mmol) was obtained.
Step 3: 5 mL of DMF was added to sodium hydride (purity 55%, 183 mg, 4.19 mmol), 2-pyridinemethanol (152.8 mg, 1.40 mmol) was added, and the mixture was stirred for 10 minutes. Thereafter, 4- (chloromethyl) -2- (2,3-dimethoxyphenyl) oxazole (438.9 mg, 1.73 mmol) was added and stirred at room temperature overnight. After completion of the reaction, the flask was immersed in ice water, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 2-((((2- (2,3-dimethoxyphenyl) oxazol-4-yl) methoxy) methyl. ) Pyridine (283.6 mg, 0.87 mmol) was obtained.

Synthesis method C
Synthesis method of thiazole derivative (Example 3)

Step 1: Add xylene (20 mL) to 4-methoxyphenylthioamide (1.678 g, 10.03 mmol) and 1,3-dichloro-2-propane (3.061 g, 24.10 mmol), and add 3 at 125 ° C. Stir for hours. After allowing to cool to room temperature, the solvent was removed with an evaporator, diluted with ethyl acetate, and filtered to remove the precipitate. The solvent was removed, and silica gel column chromatography was performed to obtain 4- (chloromethyl) -2- (4-methoxyphenyl) thiazole (1.870 g, 7.80 mmol).
Step 2: DMF (5 mL) was added to sodium hydride (purity 55%, 93.9 mg, 2.15 mmol), 2-pyridinepropanol (130 μL, 1.00 mmol) was added, and the mixture was stirred for 10 minutes. Thereafter, 4- (chloromethyl) -2- (4-methoxyphenyl) thiazole (331.8 mg, 1.38 mmol) dissolved in DMF (5 mL) was added, and the mixture was stirred at 80 ° C. overnight. The flask was immersed in ice water, quenched with 1M hydrochloric acid, basified with 2M sodium hydroxide, extracted with ethyl acetate, and washed with saturated brine. The organic layer is dried over magnesium sulfate, filtered, evaporated to remove the solvent, and subjected to silica gel column chromatography to give 2- (3-((2- (4-methoxyphenyl) thiazol-4-yl) methoxy) propyl. ) Pyridine (105.2 mg, 0.31 mmol) was obtained.

Synthesis method D
Synthesis Method 1 of Pyridine Derivative (Example 4)

Step 1: 3,4-dimethylphenylboronic acid (749.9 mg, 5.03 mmol), methyl 6-chloronicotinate (943.7 mg, 5.50 mmol), tetrakis (triphenylphosphine) palladium (0) (598. 7 mg (0.52 mmol), toluene (50 mL) saturated with Ar gas was added, and 2M aqueous potassium carbonate solution (5 mL) was added, and the mixture was stirred at 80 ° C. for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel column chromatography was performed. However, since methyl 6-chloronicotinate could not be sufficiently removed, methyl 6- (3,4-dimethylphenyl) pyridine-3-carboxylate (1.021 g) was obtained as a mixture.
Step 2: A mixture of methyl 6- (3,4-dimethylphenyl) pyridine-3-carboxylate (353.9 mg) was dissolved in THF (7 mL), the flask was immersed in an ice-water bath, and then lithium aluminum hydride ( 92.2 mg, 2.43 mmol) was added, the ice bath was removed, and the mixture was stirred at room temperature for 90 minutes. After completion of the reaction, the flask was immersed in an ice bath, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel chromatography was performed to give (6- (3,4-dimethylphenyl) pyridin-3-yl) methanol (253.2 mg, 1. 19 mmol) was obtained.

Step 3: (6- (3,4-dimethylphenyl) pyridin-3-yl) methanol (253.2 mg, 1.19 mmol) was dissolved in DMF (5 mL) and sodium hydride (purity 55%, 113.3 mg). 2.60 mmol) was added and stirred at room temperature for 20 minutes. Then, 2- (bromomethyl) pyridine bromate (269.6 mg, 1.07 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in an ice bath, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 5-(((pyridin-2-yl) methoxy) methyl) -2- (3,4-dimethyl). Phenyl) pyridine (153.9 mg, 0.51 mmol) was obtained.

Synthesis method E
Synthesis Method 2 of Pyridine Derivative (Example 5)

Step 1: 3,4-dimethylphenylboronic acid (760.8 mg, 5.07 mmol), methyl 2-chloroisonicotinate (944.0 mg, 5.44 mmol), tetrakis (triphenylphosphine) palladium (0) (599) 0.9 mg, 0.52 mmol), toluene (50 mL) saturated with Ar gas was added, and 2M aqueous potassium carbonate solution (5 mL) was added, and the mixture was stirred at 80 ° C. for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel column chromatography was performed. However, since methyl 2-chloroisonicotinate could not be sufficiently removed, methyl 2- (3,4-dimethylphenyl) pyridine-4-carboxylate (1.047 g) was obtained as a mixture.
Step 2: A mixture of methyl 2- (3,4-dimethylphenyl) pyridine-4-carboxylate (382.6 g) was dissolved in THF (5 mL), the flask was immersed in an ice-water bath, and then lithium aluminum hydride ( 92.2 mg, 2.43 mmol) was added, the ice bath was removed, and the mixture was stirred at room temperature for 90 minutes. After completion of the reaction, the flask was immersed in an ice bath, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel chromatography was performed to give (2- (3,4-dimethylphenyl) pyridin-4-yl) methanol (262.9 mg, 1. 23 mmol) was obtained.

Step 3: (2- (3,4-dimethylphenyl) pyridin-4-yl) methanol (262.9 mg, 1.23 mmol) was dissolved in DMF (5 mL) and sodium hydride (purity 55%, 123.5 mg). 2.83 mmol) was added and stirred at room temperature for 20 minutes. Thereafter, 2- (bromomethyl) pyridine bromate (272.8 mg, 1.08 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in an ice bath, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over magnesium sulfate, filtered, evaporated to remove the solvent, and subjected to silica gel column chromatography to give 2-((((2- (3,4-dimethylphenyl) pyridin-4-yl) methoxy) methyl. ) Pyridine (114.5 mg, 0.38 mmol) was obtained.

Synthesis method F
Synthesis method of pyrazine derivative (Example 6)

Step 1: Methyl 6-chloropyrazine-2-carboxylate (0.43 g, 2.50 mmol) to DMF (10 mL), 3-methoxyphenylboronic acid (0.55 g, 3.65 mmol), bistriphenylphosphine palladium (II ) Dichloride (PdCl ₂ (PPh ₃ ) ₂ , 88 mg, 0.13 mmol) and cesium carbonate (Cs ₂ CO ₃ , 1.88 g, 5.75 mmol) were added, and the mixture was stirred at 65 ° C. overnight. The reaction mixture was added to water (100 mL) and extracted three times with ethyl acetate (50 mL). The ethyl acetate layers were combined, washed with water (50 mL), 5% aqueous sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, filtered, evaporated, and purified by silica gel column chromatography to give 6- (4- Methyl methoxyphenyl) pyrazine-2-carboxylate (0.31 g, 1.27 mmol) was obtained.
Step 2: Ethanol (EtOH, 8 mL) was added to sodium borohydride (NaBH ₄ , 93.5 mg, 2.46 mmol) and suspended therein, and then methyl 6- (4-methoxyphenyl) pyrazine-2-carboxylate ( 0.30 g, 1.23 mmol) was added in THF (4 mL) and stirred at room temperature overnight. Water (5 mL) was added and adjusted to pH 5 with 2M hydrochloric acid. The organic solvent was evaporated under reduced pressure, and extraction was performed by adding ethyl acetate (25 mL) and 5% aqueous sodium hydrogen carbonate solution (6 mL). Washing with water (6 mL), evaporation of the solvent, and purification by silica gel column chromatography gave (6- (4-methoxyphenyl) pyrazin-2-yl) methanol (52.0 mg, 0.22 mmol).

Step 3: (6- (4-methoxyphenyl) pyrazin-2-yl) methanol (48.0 mg, 0.20 mmol) was dissolved in THF (4 mL), and 60% sodium hydride (17.0 mg, 0.42 mmol) was dissolved. ), 2-bromomethylpyridine hydrobromide (51.0 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature overnight. Extraction was performed by adding ice (1 g), ethyl acetate (20 mL), and 5% aqueous sodium hydrogen carbonate solution (6 ml). Insoluble matter was removed by filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2- (4-methoxyphenyl) -6- (pyridin-2-ylmethoxymethyl) pyrazine (35.0 mg, 0.11 mmol) Got.

Synthesis method G
Synthesis method of methyloxazole derivative (Example 7)

Step 1: 4-Ethylbenzoic acid (3.027 g, 20.16 mmol), Seleonine methyl ester hydrochloride (3.803 g, 22.42 mmol), 1-hydroxy-1H-benzotriazole (HOBT, 3.114 g, 23 .05 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl, WSC hydrochloride, 4.452 g, 23.23 mmol) was dissolved in DMF (80 mL) and triethylamine (10. 0 mL, 72.10 mmol) was added and stirred overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 5% -citric acid aqueous solution, 5% -sodium bicarbonate aqueous solution, and saturated brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off to obtain methyl (2S, 3R) -2- (4-ethylbenzamido) -3-hydroxybutanoate (4.929 g, 18.58 mmol). Obtained.
Step 2: Methyl (2S, 3R) -2- (4-ethylbenzamide) -3-hydroxybutanoate (4.929 g, 18.58 mmol) was dissolved in acetonitrile (100 mL), and 4-dimethylaminopyridine (DMAP, 273.4 mg, 2.24 mmol) and di-tert-butyldicarboxylic acid (Boc ₂ O, 4.934 g, 22.61 mmol) were added and stirred for 1 hour. After confirming the completion of the reaction by TLC, 1,1,3,3-tetramethylguanidine (TMG, 4 mL, 2% by volume) was added and stirred overnight. After completion of the reaction, the solvent was distilled off, diluted with ethyl acetate, and the organic layer was washed with 1M potassium potassium sulfate, 5% sodium bicarbonate, and saturated brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off to obtain methyl (E) -2- (4-ethylbenzamide) -3-hydroxyacrylate (4.287 g, 17.33 mmol). .

Step 3: THF (70 mL) was added to methyl (E) -2- (4-ethylbenzamide) -3-hydroxyacrylate (4.287 g, 17.33 mmol) and potassium carbonate (4.907 g, 35.51 mmol). In addition, the flask was immersed in an ice bath, iodine (I ₂ , 5.309 g, 20.92 mmol) dissolved in THF (30 mL) was added, the ice bath was removed, and the mixture was stirred at 75 ° C. for 3 hours. After completion of the reaction, the temperature was returned to room temperature, THF (30 mL) was added, and 1,8-diazabicyclo- [5.4.0] -7-undecene (DBU, 7.5 mL, 50.20 mmol) was added, and the mixture was heated at 75 ° C. for 3 hours. After stirring, the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off, diluted with ethyl acetate, and the organic layer was washed with sodium thiosulfate and saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel chromatography was performed to obtain methyl 2- (4-ethylphenyl) -5-methyloxazole-4-carboxylate (1.79 g, 7 Step 4: methyl 2- (4-ethylphenyl) -5-methyloxazole-4-carboxylate (504.7 mg, 2.06 mmol) was dissolved in THF (5 mL) and the flask was bathed in an ice-water bath. After soaking, lithium aluminum hydride (115.9 mg, 3.05 mmol) was added, the ice bath was removed and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, it was immersed in an ice bath, quenched with 2M hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel chromatography was performed to give (2- (4-ethylphenyl) -5-methyloxazol-4-yl) methanol (372.2 mg, 1.71 mmol) was obtained.

Step 5: (2- (4-Ethylphenyl) -5-methyloxazol-4-yl) methanol (106.9 mg, 0.49 mmol) was dissolved in DMF (5 mL) and sodium hydride (purity 55%, 91 0.5 mg, 2.10 mmol) was added and stirred at room temperature for 15 minutes. Then, 2- (bromomethyl) pyridine bromate (160.1 mg, 0.62 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in ice water and quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 2-((((2- (4-ethylphenyl) -5-methyloxazol-4-yl) methoxy. ) Methyl) pyridine (20.1 mg, 0.07 mmol) was obtained.

Synthesis method H
Synthesis method of isoxazole derivative (Example 8)

Step 1: 3,4-methylenedioxyacetophenone (1.64 g, 10.00 mmol) was dissolved in THF (55 mL), dimethyl oxalate (1.30 g, 11.00 mmol) was added, and t-butoxypotassium ( tBuOK, 1.27 g, 11.30 mmol) was dissolved in THF (11 mL) and added dropwise. The mixture was stirred at room temperature for 2 hours, 1M hydrochloric acid (11.5 mL, 11.50 mmol) was added, and the separated and aqueous layers were removed. The organic layer was concentrated and extracted by adding ethyl acetate (70 mL) and 20% aqueous sodium chloride solution (18 mL). Wash with water (18 mL), dry over anhydrous sodium sulfate, filter, evaporate the solvent and methyl 4- (benzo [d] [1,3] dioxol-5-yl) -2,4-dioxobutanoate (2.52 g, 10.00 mmol) was obtained.
Step 2: Methyl 4- (benzo [d] [1,3] dioxol-5-yl) -2,4-dioxobutanoate (2.52 g, 10.00 mmol), hydroxylamine hydrochloride in methanol (MeOH, 60 mL) (HONH ₂ .HCl, 2.08 g, 30.00 mmol) was added and stirred at 80 ° C. for 3 hours. The solvent was concentrated under reduced pressure, and extracted by adding ethyl acetate (120 mL) and water (30 mL). The organic solvent was concentrated and evaporated to dryness to give methyl 5- (benzo [d] [1,3] dioxol-5-yl) isoxazole-3-carboxylate (2.33 g, 9.40 mmol). .

Step 3: Ethanol (30 mL) was added to sodium borohydride (713 mg, 18.80 mmol) and suspended therein, and 5- (benzo [d] [1,3] dioxol-5-yl) isoxazole 3-carboxylic acid was suspended therein. Methyl acid (2.33 g, 9.40 mmol) was added in THF (30 mL) and stirred at room temperature overnight. Ice (40 g) was added, the organic solvent was distilled off under reduced pressure, ethyl acetate (120 mL) and water (40 ml) were added, and the mixture was adjusted to pH 6.3 with 1M hydrochloric acid (15.3 g) and extracted. The extract was washed with 5% aqueous sodium hydrogen carbonate solution (60 mL) and water (60 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated to remove 5- (benzo [d] [1,3] dioxole-5- Yl) isoxazol-3-yl) methanol (1.99 g, 9.10 mmol) was obtained.

Step 4: 60% sodium hydride (17 mg, 0.42 mmol) was suspended in THF (8 mL) and (5- (benzo [d] [1,3] dioxol-5-yl) isoxazol-3-yl) Methanol (1.99 g, 9.10 mmol) dissolved in THF (32 mL) was added, and further 2-bromomethylpyridine hydrobromide (2.30 g, 9.10 mmol) was added and stirred overnight at room temperature. . Ice water (20 mL) was added, the solvent was distilled off, and the mixture was extracted with ethyl acetate (60 mL). Wash with 5% aqueous sodium hydrogen carbonate (20 mL), remove the solvent, and purify by silica gel column chromatography to give 2- (5- (3,4-methylenedioxyphenyl) isooxazol-3-ylmethoxymethyl) pyridine. (1.66 g, 5.30 mmol) was obtained.

Synthesis method I
Synthesis method 1 of pyrrole derivative (Example 9)

Step 1: 1 methyl H-pyrrole-3-carboxylate (480.5 mg, 3.84 mmol), copper iodide (CuI, 36.6 mg, 0.19 mmol), tripotassium phosphate (K ₃ PO ₄ , 1.63 g) , 7.68 mmol) was dissolved in toluene (5 ml), p-iodoisopropylbenzene (1.30 g, 11.00 mmol), N, N′-dimethylethylenediamine (67.7 mg, 0.77 mmol) was added, and the mixture was added at 100 ° C. The temperature was raised to react. After completion of the reaction, the mixture was filtered through Celite, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated brine, washed with the organic layer, dried over anhydrous magnesium sulfate, filtered, and concentrated with an organic solvent. -(4-Isopropylphenyl) -1H-pyrrole-3-carboxylate methyl ester (882.5 mg, 3.63 mmol) was obtained.
Step 2: Methyl 1- (4-isopropylphenyl) -1H-pyrrole-3-carboxylate (882.5 mg, 3.63 mmol) was dissolved in THF (30 mL), the flask was immersed in an ice-water bath, and then hydrogenated. Aluminum lithium (221.9 mg, 5.45 mmol) was added, the ice bath was removed and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off to obtain (1- (4-isopropylphenyl) -1H-pyrrol-3-yl) methanol quantitatively.

Step 3: (1- (4-Isopropylphenyl) -1H-pyrrol-3-yl) methanol (215.3 mg, 1.00 mmol) was dissolved in DMF (5 mL) and sodium hydride (purity 55%, 130. 9 mg, 3.00 mmol) was added and stirred at room temperature for 10 minutes. Then, 2- (bromomethyl) pyridine bromate (379.4 mg, 1.50 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in ice water, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer is dried over magnesium sulfate, filtered, evaporated to remove the solvent, and subjected to silica gel column chromatography to give 2-((((1- (4-isopropylphenyl) -1H-pyrrol-3-yl) methoxy). Methyl) pyridine (242.2 mg, 0.79 mmol) was obtained.

Synthesis method J
Synthesis Method 1 of Pyrazole Derivative (Example 10)

Step 1: Dissolve ethyl 4-pyrazolecarboxylate (717.8 mg, 4.42 mmol), copper iodide (51.6 mg, 0.27 mmol), potassium carbonate (1.41 g, 10.19 mmol) in toluene (20 ml) 4-Bromo-1,2-methylenedioxybenzene (718 μL, 6.00 mmol) and trans-N, N′-dimethylcyclohexane 1,2-diamine (158 μL, 1.20 mmol) were added, and the temperature was raised to 100 ° C. Warm and react. After completion of the reaction, the mixture was filtered through Celite, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated brine, washed with the organic layer, dried over anhydrous magnesium sulfate, filtered, and concentrated with an organic solvent. There was obtained ethyl-(benzo [d] [1,3] dioxol-5-yl) -1H-pyrazole-4-carboxylate (193.9 mg, 0.79 mmol).
Step 2: 1- (Benzo [d] [1,3] dioxol-5-yl) -1H-pyrazole-4-carboxylate (193.9 mg, 0.79 mmol) was dissolved in THF (10 mL) and the flask was dissolved. Was immersed in an ice-water bath, lithium aluminum hydride (49.9 mg, 1.31 mmol) was added, the ice bath was removed, and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography to obtain (1- (benzo [d] [1,3] dioxol-5-yl) -1H-pyrazol-4-yl) methanol (146.7 mg, 0.67 mmol) was obtained.

Step 3: (1- (Benzo [d] [1,3] dioxol-5-yl) -1H-pyrazol-4-yl) methanol (146.7 mg, 0.67 mmol) was dissolved in DMF (5 mL), Sodium hydride (purity 55%, 88.0 mg, 2.00 mmol) was added and stirred at room temperature for 10 minutes. Then, 2- (bromomethyl) pyridine bromate (254.9 mg, 1.00 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in ice water, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 2-(((1- (benzo [d] [1,3] dioxol-5-yl)- 1H-pyrazol-4-yl) methoxy) methyl) pyridine (101.6 mg, 0.33 mmol) was obtained.

Synthesis method K
Synthesis Method of Imidazole Derivative (Example 11)

Step Methyl 1: 1H-imidazole-5-carboxylate (634.6 mg, 5.03 mmol), copper iodide (55.2 mg, 0.29 mmol), cesium carbonate (3.31 g, 10.15 mmol) in DMF (20 ml) P-iodoisopropylbenzene (1.52 g, 6.16 mmol) and trans-N, N′-dimethylcyclohexane 1,2-diamine (158 μL, 1.20 mmol) were added, and the temperature was raised to 100 ° C. , Reacted. After completion of the reaction, the mixture was filtered through Celite, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated brine, washed with the organic layer, dried over anhydrous magnesium sulfate, filtered, and concentrated with an organic solvent. Ethyl-(4-isopropylphenyl) -1H-imidazole-4-carboxylate (565.3 mg, 2.31 mmol) was obtained.

Step 2: Ethyl 1- (4-isopropylphenyl) -1H-imidazole-4-carboxylate (565.3 mg, 2.31 mmol) was dissolved in THF (20 mL), the flask was immersed in an ice-water bath, and then hydrogenated. Aluminum lithium (144.7 mg, 3.47 mmol) was added and the ice bath was removed and stirred for 30 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography to obtain (1- (4-isopropylphenyl) -1H-imidazol-4-yl) methanol (354.7 mg, 1.64 mmol).
Step 3: (1- (4-Isopropylphenyl) -1H-imidazol-4-yl) methanol (354.7 mg, 1.64 mmol) was dissolved in DMF (10 mL) and sodium hydride (purity 55%, 215. 0 mg, 4.92 mmol) was added and stirred at room temperature for 10 minutes. Thereafter, 2- (bromomethyl) pyridine bromate (622.0 mg, 2.46 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in ice water, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer is dried over magnesium sulfate, filtered, evaporated to remove the solvent, and subjected to silica gel column chromatography to obtain 2-(((1- (4-isopropylphenyl) -1H-imidazol-4-yl) methoxy). Methyl) pyridine (315.6 mg, 1.03 mmol) was obtained.

Synthesis method L
Synthesis Method 2 of Pyrazole Derivative (Example 12)

Step 1: 1 methyl 1H-pyrazole-3-carboxylate (629.0 mg, 4.99 mmol), copper iodide (62.9 mg, 0.33 mmol), cesium carbonate (3.26 g, 10.00 mmol) in toluene (15 ml) 4-bromo-1,2-methylenedioxybenzene (718 μL, 6.00 mmol), trans-N, N′-dimethylcyclohexane 1,2-diamine (158 μL, 1.20 mmol) was added, and 100 The temperature was raised to 0 ° C. and reacted. After completion of the reaction, the mixture was filtered through celite, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated brine, washed with the organic layer, dried over anhydrous magnesium sulfate, filtered, and the organic solvent was concentrated. The obtained crude product was purified by silica gel column chromatography to obtain methyl 1- (benzo [d] [1,3] dioxol-5-yl) -1H-pyrazole-carboxylate (47.1 mg, 0.4 mg). 19 mmol) was obtained.
Step 2: 1- (Benzo [d] [1,3] dioxol-5-yl) -1H-pyrazole-3-carboxylate methyl (80.0 mg, 0.40 mmol) was dissolved in THF (10 mL) Was immersed in an ice-water bath, lithium aluminum hydride (29.9 mg, 0.80 mmol) was added, the ice bath was removed, and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography to obtain (1- (benzo [d] [1,3] dioxol-5-yl) -1H-pyrazol-3-yl) methanol (63.0 mg, 0.29 mmol) was obtained.

Step 3: (1- (Benzo [d] [1,3] dioxol-5-yl) -1H-pyrazol-3-yl) methanol (63.0 mg, 0.29 mmol) was dissolved in DMF (5 mL), Sodium hydride (purity 55%, 19.1 mg, 0.44 mmol) was added and stirred at room temperature for 10 minutes. Thereafter, 2- (bromomethyl) pyridine bromate (111.3 mg, 0.44 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in ice water, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 2-(((1- (benzo [d] [1,3] dioxol-5-yl)- 1H-pyrazol-3-yl) methoxy) methyl) pyridine (52.6 mg, 0.17 mmol) was obtained.

Synthesis method M
Synthesis Method of Oxadiazole Derivative (Example 13)

Step 1: Ethyl chloroglyoxylate (2.46 g, 18.00 mmol) was dissolved in toluene (20 mL) and DMF (5 mL), and 5- (1,3-benzodioxol-5-yl) -2H- Tetrazole (2.85 g, 15.00 mmol) was added and heated to reflux. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 1N hydrochloric acid and saturated brine. The organic layer is dried over magnesium sulfate, filtered, evaporated to remove the solvent, and recrystallized to give 5- (benzo [d] [1,3] dioxol-5-yl) -1,3,4-oxadi Obtained ethyl azole-2-carboxylate (2.30 g, 8.80 mmol).
Step 2: 5- (Benzo [d] [1,3] dioxol-5-yl) -1,3,4-oxadiazole-2-carboxylate (786.7 g, 3.00 mmol) in THF (20 mL) And the flask was immersed in an ice-water bath, sodium borohydride (283.7 mg, 7.50 mmol) was added, and the mixture was stirred at room temperature. After completion of the reaction, the reaction was quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off. The obtained crude product was recrystallized to give (5- (benzo [d] [1,3] dioxol-5-yl) -1,3,4-oxadiazol-2-yl) methanol (294. 6 mg, 1.34 mmol).
Step 3: (5- (Benzo [d] [1,3] dioxol-5-yl) -1,3,4-oxadiazol-2-yl) methanol (294.6 mg, 1.34 mmol) in DMF ( 5 mL), sodium hydride (purity 55%, 175.4 mg, 4.02 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Then, 2- (bromomethyl) pyridine bromate (508.4 mg, 2.00 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in ice water, quenched with 1N hydrochloric acid, diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 2-(((5- (benzo [d] [1,3] dioxol-5-yl)- 1,3,4-oxadiazol-2-yl) methoxy) methyl) pyridine (306.1 mg, 0.98 mmol) was obtained.

Synthesis method N
Synthesis Method of Furan Derivative (Example 14)

Step 1: 3,4-dimethylphenylboronic acid (496.8 g, 3.00 mmol), methyl 5-bromofuran-2-carboxylate (620.6 mg, 3.00 mmol), tetrakis (triphenylphosphine) palladium (0) (366.2 mg, 0.300 mmol) was added with degassed toluene (20 mL) and 2M aqueous potassium carbonate solution (3 mL), and the mixture was stirred at 80 ° C. for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off to obtain a crude product of methyl 5- (benzo [d] [1,3] dioxol-5-yl) furan-2-carboxylate. .
Step 2: 5- (benzo [d] [1,3] dioxol-5-yl) furan-2-carboxylate crude product (925.2 mg) was dissolved in THF (10 mL) and the flask was bathed in an ice-water bath. After soaking, lithium aluminum hydride (166.9 mg, 4.50 mmol) was added, the ice bath was removed and the mixture was stirred for 30 minutes. After completion of the reaction, it was quenched with 2M aqueous hydrochloric acid solution, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate, filtered, evaporated to remove the solvent, and purified by silica gel column chromatography to obtain (5- (benzo [d] [1,3] dioxol-5-yl) furan-2-yl. ) Methanol (268.0 mg, 1.23 mmol) was obtained.
Step 3: (5- (Benzo [d] [1,3] dioxol-5-yl) furan-2-yl) methanol (268.0 mg, 1.23 mmol) was dissolved in DMF (5 mL) and sodium hydride was dissolved. (Purity 55%, 65.5 mg, 1.50 mmol) was added and stirred at room temperature for 10 minutes. Then, 2- (bromomethyl) pyridine bromate (379.4 mg, 1.50 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in ice water, quenched with 1N hydrochloric acid, diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel column chromatography was performed to give 2-(((5- (benzo [d] [1,3] dioxol-5-yl) furan. -2-yl) methoxymethyl) pyridine (276.9 mg, 0.86 mmol) was obtained.

Synthesis method O
Synthesis method 2 of pyrrole derivative (Example 15)

Step 1: 1 methyl H-pyrrole-3-carboxylate (627.8 mg, 5.00 mmol), copper iodide (71.3 mg, 0.25 mmol), tripotassium phosphate (2.15 g, 10.00 mmol) in toluene (15 mL), 2-iodopyridine (622 μL, 6.00 mmol) and N, N′-dimethylethylenediamine (108 μL, 1.00 mmol) were added, and the mixture was heated to 90 ° C. for reaction. After completion of the reaction, the mixture was filtered through Celite, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated brine, washed with the organic layer, dried over anhydrous magnesium sulfate, filtered, and concentrated with an organic solvent. Obtained methyl-(pyridin-2-yl) -1H-pyrrole-3-carboxylate (816.7 mg, 4.04 mmol).
Step 2: Dissolve methyl 1- (pyridin-2-yl) -1H-pyrrole-3-carboxylate (816.7 mg, 4.04 mmol) in THF (30 mL), immerse the flask in an ice-water bath, Lithium aluminum halide (278.9 mg, 6.06 mmol) was added, the ice bath was removed and the mixture was stirred for 15 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off to give (1- (pyridin-2-yl) -1H-pyrrol-3-yl) methanol quantitatively.
Step 3: (1- (Pyridin-2-yl) -1H-pyrrol-3-yl) methanol (174.2 mg, 1.00 mmol) was dissolved in DMF (5 mL) and sodium hydride (purity 55%, 130% .9 mg, 3.00 mmol) was added and stirred at room temperature for 10 minutes. Thereafter, 4-isopropylbenzyl bromide (319.7 mg, 1.50 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in ice water, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer is dried over magnesium sulfate, filtered, evaporated to remove the solvent, and subjected to silica gel column chromatography to give 2- (3-((4-isopropylbenzyloxy) methyl) -1H-pyrrol-1-yl). Pyridine (244.1 mg, 0.80 mmol) was obtained.

Synthesis method P
Synthesis method of thioether derivative (Example 16)

Step 1: 3,4-dimethylbenzamide (746.0 mg, 5.00 mmol), 1,3-dichloro-2-propane (761.8 mg, 6.00 mmol) were dissolved in xylene (10 mL) and dissolved at 125 ° C. for 7 Stir for hours. After completion of the reaction, the reaction mixture was allowed to cool, diluted with ethyl acetate, and filtered to remove the precipitate. The solvent was distilled off, and silica gel column chromatography was performed to obtain 4- (chloromethyl) -2- (3,4-dimethylphenyl) oxazole (769.4 mg, 3.47 mmol).
Step 2: 4- (chloromethyl) -2- (3,4-dimethylphenyl) oxazole (110.8 mg, 0.50 mmol), 2-mercaptopyridine (83.4 mg, 0.75 mmol), potassium carbonate (138. 2 mg, 1.00 mmol) was dissolved in DMF (5 mL) and stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel column chromatography was performed to give 2-((2- (3,4-dimethylphenyl) oxazol-4-yl) methylthio) pyridine ( 123.6 mg, 0.42 mmol).

Synthesis method Q
Synthesis method of α-methyloxazole derivative (Example 17)

Step 1: 4-methoxyphenylboronic acid (868.9 mg, 5.72 mmol), ethyl 2-chlorooxazole-4-carboxylate (1.002 g, 5.70 mmol), tetrakis (triphenylphosphine) palladium (0) ( Toluene (60 mL) saturated with Ar gas and 2M-potassium carbonate aqueous solution (5.7 mL) were added to 668.9 mg (0.58 mmol), and the mixture was stirred at 90 ° C. for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel column chromatography was performed to obtain ethyl 2- (4-methoxyphenyl) oxazole-4-carboxylate (557.7 mg, 2.26 mmol). Got.
Step 2: Dissolve ethyl 2- (4-methoxyphenyl) oxazole-4-carboxylate (557.7 mg, 2.26 mmol) in THF (15 mL), add 1M aqueous sodium hydroxide solution (15 mL), and stir for 1 hour. did. After completion of the reaction, 2N-hydrochloric acid was added to make it acidic, diluted with ethyl acetate to remove the aqueous solution, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off to obtain 2- (4-methoxyphenyl) oxazole-4-carboxylic acid (467.0 g, 2.13 mmol).

Step 3: 2- (4-methoxyphenyl) oxazole-4-carboxylic acid (464.7 g, 2.12 mmol), N, O-dimethylhydroxylamine hydrochloride (2.243 g, 23.00 mmol), HOBT (885. 9 mg, 6.56 mmol) and WSC hydrochloride (1.11 g, 5.79 mmol) were dissolved in DMF (30 mL), triethylamine (9.0 mL, 64.90 mmol) was added, and the mixture was stirred overnight. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with 5% -citric acid aqueous solution, 5% -sodium hydrogencarbonate aqueous solution, and saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to obtain N-methoxy-2- (4-methoxyphenyl) -N-methyloxazole-4-carboxamide. It was.
Step 4: The total amount of N-methoxy-2- (4-methoxyphenyl) -N-methyloxazole-4-carboxamide was dissolved in THF (50 mL), the flask was immersed in an ice bath, and then 2M-n-propylmagnesium bromide. A solution (20 mL) of (n-PrMgBr) in THF was added and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was immersed in an ice bath and quenched with a saturated aqueous ammonium chloride solution, THF was distilled off, the aqueous solution was extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, evaporated to remove the solvent, and subjected to silica gel column chromatography to give 1- (2- (4-methoxyphenyl) oxazol-4-yl) butan-1-one (236 .6 mg, 0.96 mmol).

Step 5: 1- (2- (4-methoxyphenyl) oxazol-4-yl) butan-1-one (236.6 mg, 0.96 mmol) was dissolved in methanol (10 mL) and the flask was immersed in an ice bath. Thereafter, sodium borohydride (203.1 mg, 5.37 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was immersed in an ice bath, quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, evaporated to remove the solvent, and subjected to silica gel column chromatography to give 1- (2- (4-methoxyphenyl) oxazol-4-yl) butan-1-ol (233 .8 mg, 0.95 mmol).
Step 6: 1- (2- (4-methoxyphenyl) oxazol-4-yl) butan-1-ol (77.9 mg, 0.32 mmol) was dissolved in DMF (5 mL) and sodium hydride (purity 55% 90.0 mg, 2.06 mmol) was added and stirred at room temperature for 10 minutes. Thereafter, 2- (bromomethyl) pyridine bromate (106.5 mg, 0.42 mmol) was added and stirred overnight. After completion of the reaction, the flask was immersed in an ice bath, quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over magnesium sulfate, filtered, evaporated to remove the solvent, and subjected to silica gel column chromatography to give 2-((1- (2- (4-methoxyphenyl) oxazol-4-yl) butoxy) methyl. ) Pyridine (76.3 mg, 0.23 mmol) was obtained.

Synthesis method R
Synthesis method of α-dimethyloxazole derivative (Example 18)

Step 1: 3,4- (methylenedioxy) phenylboronic acid (3.320 g, 20.01 mmol), ethyl 2-chlorooxazole-4-carboxylate (3.554 g, 20.24 mmol), tetrakis (triphenylphosphine) ) To palladium (0) (2.443 g, 2.11 mmol) was added toluene (150 mL) saturated with Ar gas, and 2M aqueous potassium carbonate (20 mL), and the mixture was stirred at 80 ° C. for 5 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 2- (benzo [d] [1,3] dioxol-5-yl) oxazole-4-carboxylic acid Ethyl (3.944 g, 15.10 mmol) was obtained.
Step 2: 2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-carboxylate (264.3 mg, 1.07 mmol) was dissolved in THF (10 mL) and immersed in an ice bath. After that, 20 mL of 1M-methylmagnesium bromide (MeMgBr) in THF was added and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was immersed in an ice bath, quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer is dried over magnesium sulfate, filtered, the solvent is distilled off, and silica gel column chromatography is performed to give 2- (2- (benzo [d] [1,3] dioxol-5-yl) oxazole-4 -Yl) propan-2-ol (166.4 mg, 0.67 mmol) was obtained.

Step 3: 2- (2- (benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) propan-2-ol (166.4 mg, 0.67 mmol) in DMF (10 mL) After dissolution, sodium hydride (purity 55%, 174.2 mg, 3.9721 mmol) was added and stirred at room temperature for 10 minutes. Then, 2- (bromomethyl) pyridine bromate (205.2 mg, 0.81 mmol) was added and stirred for 3 hours. After completion of the reaction, the flask was immersed in ice water and quenched with distilled water, diluted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate, filtered, evaporated to remove the solvent, and subjected to silica gel column chromatography to give 2-((2- (benzo [d] [1,3] dioxol-5-yl. ) Oxazol-4-yl) propan-2-yloxy) methyl) pyridine (172.5 mg, 0.51 mmol) was obtained.

Synthesis method S
Synthesis Method of Oxazole Derivative (Another Method of Synthesis Method B) (Example 80)

Step 1 (Thionyl chloride (SOCl ₂ ) method): Piperonic acid (41.5 g, 0.25 mol) was suspended in toluene (325 mL), and N, N-dimethylformamide (96 μl, 1.25 mmol), thionyl chloride (27 .2 ml, 0.375 mol) was added and stirred at 50 ° C. overnight. The reaction solution was concentrated under reduced pressure, and toluene (300 mL) was added to the residue to dissolve it. 28% aqueous ammonia (NH ₄ OH, 125 mL) was added to water (425 mL), and the mixture was cooled to 5 ° C. The previous toluene solution was added and stirred. The precipitated crystals were separated and slurry washed with water (300 mL). The crystals were separated and dried at 50 ° C. under reduced pressure to obtain piperonylamide (39.4 g, 0.24 mol).

Step 1 (1-hydroxy-1H-benzotriazole (HOBT) method): piperonic acid (16.6 g, 0.1 mol) to acetonitrile (CH ₃ CN, 100 mL), 1-hydroxy-1H-benzotriazole monohydrate (15.3 g, 0.1 mol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (WSC.HCl, WSC hydrochloride, 21.0 g, 0.11 mol) was added at room temperature. Stir overnight. 28% aqueous ammonia (20 mL) was added to the reaction mixture and stirred, and then water (400 mL) was added and stirred at 5 ° C. for 3 hours. The precipitated crystals were separated, washed with water (100 mL), and dried at 40 ° C. under reduced pressure to obtain piperonylamide (15.0 g, 0.09 mol).

Step 1 (N-hydroxysuccinimide (HOSu) method): acetonitrile (10.5 L) with piperonic acid (3.00 Kg, 17.88 mol) and N-hydroxysuccinimide (2.08 Kg, 17.88 mol) The mixture was further stirred, cooled to 10 ° C., 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (3.81 Kg, 19.67 mol) was added, and the mixture was stirred overnight at room temperature. The mixture was cooled to 5 ° C., 28% aqueous ammonia (3.70 L, 53.64 mol) was added over 1.5 hours, and the mixture was stirred at the same temperature for 2 hours. Water (42 L) was added and stirred at 10 ° C. overnight. The crystals were separated, washed with water (12 L), and dried overnight at 50 ° C. under reduced pressure to obtain piperonylamide (2.54 Kg, 15.25 mol).

Step 2: Add 1,3-dichloroacetone (2.91 Kg, 22.67 mol) to isopropanol (21.2 L) and stir, add piperonylamide (2.5 Kg, 15.01 mol) and stir at 75 ° C. for 22 hours. . Water (2.13 L) was added, and an oxazole compound (seed crystal: 0.013 Kg) was added, followed by crystallization at 25 ° C. overnight. The crystals were separated, washed with a mixed solvent of water and isopropanol (IPA) (9: 1, 7.50 L), dried at 40 ° C. under reduced pressure, and 2- (1,3-benzodioxol-5-yl)- 4- (Chloromethyl) oxazole (2.58 Kg, 10.82 mol) was obtained.

Step 3: Sodium t-butoxy (tBuONa, 1.27 Kg, 13.10 mol) was added to THF (20.8 L), cooled to 10 ° C., and 2-pyridinemethanol (1.44 kg, 13.10 mol) was added. . 2- (1,3-benzodioxol-5-yl) -4- (chloromethyl) oxazole (2.08 Kg, 8.73 mol) was added, and the mixture was stirred at 40 ° C. overnight. Cold water (20.8 L) was added and adjusted to pH 6.7 with 6M hydrochloric acid (0.68 L). The THF was distilled off by concentration under reduced pressure, and ethyl acetate (16.7 L) was added for extraction. After separation, the ethyl acetate layer was concentrated under reduced pressure to about 4.4 Kg. After dissolution by heating at 45 ° C., seed crystals (crystal B: ground product) were added at 30 ° C., and the mixture was stirred overnight at 10 ° C. n-Heptane (11.08 L) was added dropwise over 3 hours and crystallized overnight at 10 ° C. The crystals were separated, washed with a mixed solvent of ethyl acetate and n-heptane (2: 3, 3.17 Kg) and dried overnight at 40 ° C. under reduced pressure to give 2-(((2- (benzo [d] [1 , 3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine (2.33 Kg, 7.42 mol).

Method for preparing crystal A (Form A):
2-(((2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine (0.51 g, 1.64 mmol) to ethyl acetate (0.77 mL ) And heated to 55 ° C. to dissolve. After confirming dissolution, the mixture was cooled to 40 ° C. and stirred overnight for crystallization. At the same temperature, n-heptane (1.54 ml) was added, cooled to room temperature, and crystallized. The crystals were separated and dried at 40 ° C. under reduced pressure to obtain crystal A (0.36 g, 1.16 mmol).

B crystal (Form B) preparation method:
2-(((2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine (0.51 g, 1.64 mmol) to ethyl acetate (1.11 mL ) And heated to 55 ° C. to dissolve. After confirming dissolution, it was cooled to 40 ° C. and it was confirmed that there was no precipitation of crystals. Crystallization was performed by adding n-heptane (2.22 mL) at the same temperature. After cooling to room temperature, the crystals were separated and dried at 40 ° C. under reduced pressure to obtain B crystals (0.41 g, 1.32 mmol).

Synthesis method T
Synthesis method 2 of isoxazole derivative (Example 81)

Step 1: 50% hydroxyamine (2.0 mL) was added to an ethanol solution (20 mL) of piperonal (750 mg, 5.00 mmol), heated to reflux for 5 hours, and then added with 50% hydroxylamine (2.0 mL). Refluxed overnight. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to quantitatively obtain 1,3-benzodioxole-5-carbaldehyde oxime (832 mg, 5.04 mmol).

Step 2: 1,3-benzodioxole-5-carbaldehyde oxime (832 mg, 5.04 mmol) was suspended in chloroform (20 mL), and N-chlorosuccinimide (NCS, 734 mg, 5.50 mmol) was added. After stirring at room temperature for 1 hour, propargyl alcohol (0.380 mL, 6.44 mmol) and triethylamine (TEA, 0.906 mL, 6.50 mmol) were added, and the mixture was stirred overnight at room temperature. The insoluble material was filtered off, the filtrate was evaporated under reduced pressure, and the resulting residue was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. did. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel chromatography to obtain [3- (1,3-benzodioxol-5-yl) isoxazol-5-yl] methanol (313 mg, 1 .43 mmol) was obtained.

Step 3: [3- (1,3-benzodioxol-5-yl) isoxazole-5 was added to a DMF suspension (2 mL) of sodium hydride (NaH, purity 55%, 64.3 mg, 1.47 mmol). -Yl] Methanol (80.8 mg, 0.369 mmol) in DMF (3 mL) was added and stirred at room temperature for 10 minutes. 2- (Bromomethyl) pyridine hydrobromide (103 mg, 0406 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours, and further 2- (bromomethyl) pyridine hydrobromide (46.7 mg, 0.185 mmol). And stirred at room temperature overnight. The reaction mixture was ice-cooled, water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to give 2-((3- (1,3-benzodioxole-5 -Yl) isoxazol-5-yl) methoxymethyl) pyridine (25.8 mg, 0.0831 mmol) was obtained.

Synthesis method U
Synthesis Method 1 of Oxadiazole Derivative (Example 82)

Step 1: 4-Isopropyloxybenzonitrile (1.23 g, 7.49 mmol) was dissolved in ethanol (38 mL) and hydroxylamine hydrochloride (1.06 g, 15.0 mmol) was added. Next, sodium carbonate (3.98 g, 37.6 mmol) was added, and the slurry-like reaction liquid was heated to 75 ° C. and stirred as it was overnight. After returning to room temperature and concentrating under reduced pressure, dichloromethane (25 mL) was added to the residue, and the remaining salt was removed by filtration. The mother liquor was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane: methanol) to obtain the desired (4-isopropoxyphenyl) hydroxyaminoimine (1.06 g, 5.44 mmol) as an oil.
Step 2: (4-Isopropoxyphenyl) hydroxyaminoimine (1.05 g, 5.42 mmol) was dissolved in pyridine (25 mL) and ethyl chloroglyoxylate (0.92 mL, 8.12 mmol) was added. This was heated to 90 ° C. and reacted for 3 hours, then returned to room temperature and concentrated under reduced pressure. The residue was extracted with ethyl acetate (25 mL) and water (20 mL), and the organic layer was washed twice with 1N hydrochloric acid (20 mL), saturated brine (20 mL) and concentrated. The obtained residue was purified by silica gel chromatography (dichloromethane: methanol) to give the desired 3- (4-isopropoxyphenyl) -1,2,4-oxadiazole-5-carboxylic acid ethyl ester (1.19 g, 4 .31 mmol) was obtained as an oil.
Step 3: 3- (4-Isopropoxyphenyl) -1,2,4-oxadiazole-5-carboxylic acid ethyl ester (0.71 g, 2.56 mmol) was dissolved in tetrahydrofuran (15 mL) and ice-cooled. Sodium borohydride (0.26 g, 6.22 mmol) was added. After returning to room temperature and reacting for 2 hours, disappearance of the raw material was confirmed by TLC. Under cooling, water (10 mL) was slowly added to quench, and then the mixture was returned to room temperature and extracted with ethyl acetate (25 mL). The organic layer was washed with saturated brine (15 mL), the solvent was distilled off, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain the desired (3- (4-isopropoxyphenyl) -1 , 2,4-oxadiazol-5-yl) methanol (0.39 g, 1.66 mmol) was obtained as a solid.
Step 4: To a suspension of sodium hydride (55%, 0.16 g, 3.62 mmol) in DMF (8 mL), (3- (4-isopropoxyphenyl) -1,2,4-oxadi Azol-5-yl) methanol (0.38 g, 1.64 mmol) was added in several portions. The reaction mixture was cooled, 2- (bromomethyl) pyridine bromate (0.47 g, 1.80 mmol) was added, and the mixture was warmed to room temperature and stirred for 2 hours. Water (8 mL) and 1N hydrochloric acid (4 mL) were combined and cooled in another container, and the reaction solution was added dropwise thereto. After returning to room temperature and neutralizing with 1N sodium hydroxide (4.4 mL), the mixture was extracted with ethyl acetate (25 mL). The organic layer was washed with saturated brine (15 mL) and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain the desired 2-((((3- (4-isopropoxyphenyl)). -1,2,4-oxadiazol-5-yl) methoxy) methyl) pyridine (0.25 g, 0.76 mmol) was obtained as a light pink solid.

Synthesis method V
Synthesis Method 2 of Oxadiazole (Example 83)

Step 1: 4-Isopropoxybenzoic acid (4.50 g, 25.0 mmol) was suspended in methylene chloride (80 mL), and DMF (140 μl, 1.81 mmol) and thionyl chloride (12.1 mL, 167.00 mmol) were added. added. The reaction was stirred at 30-50 ° C. for 22 hours under nitrogen atmosphere. The reaction mixture was allowed to cool, concentrated under reduced pressure, and azeotroped twice with toluene (10 mL) to give 4-isopropoxybenzoic acid chloride (5.11 g) as a colorless liquid.
Step 2: 4-Isopropoxybenzoic acid chloride (5.11 g) was dissolved in methylene chloride (80 ml), and the reaction solution was ice-cooled after being placed in a nitrogen atmosphere. Ethyl-2-oximinooxamate (3.30 g, 25.00 mmol) and triethylamine (4.20 mL, 30.10 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature overnight. Methylene chloride (50 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) were added to the reaction solution for extraction. The aqueous layer was further extracted once with methylene chloride (20 mL) and twice with ethyl acetate (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 2-[(4-isopropoxybenzoyl) amino] -2- (hydroxyimino) acetic acid ethyl ester (7.05 g, 24.00 mmol) as a white powder. It was.
Step 3: 2-[(4-Isopropoxybenzoyl) amino] -2- (hydroxyimino) acetic acid ethyl ester (7.05 g, 24.00 mmol) was dissolved in DMF (40 mL) and heated to reflux for 4 hours. The reaction mixture was allowed to cool and extracted with ethyl acetate (100 mL) and water (50 mL). The organic layer was washed 3 times with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The sodium sulfate was filtered, and the filtrate was concentrated under reduced pressure to give 5- (4-isopropoxyphenyl) -1,2,4-oxadiazole-3-carboxylic acid ethyl ester composition (6.29 g). This composition was purified by medium pressure chromatography (silica gel 200 g, eluted with hexane: ethyl acetate = 95: 5 to 85:15) to give 5- (4-isopropoxyphenyl) -1,2,4-oxadiazole. -3-Carboxylic acid ethyl ester (5.53 g, 20.00 mmol) was obtained as a white solid.
Step 4: 5- (4-Isopropoxyphenyl) -1,2,4-oxadiazole-3-carboxylic acid ethyl ester (0.55 g, 2.00 mmol) was dissolved in tetrahydrofuran (12 mL) and ice-cooled. Sodium borohydride (0.19 g, 4.71 mmol) was added. After returning to room temperature and reacting for 4 hours, disappearance of the raw material was confirmed by TLC. Under cooling, water (12 mL) was slowly added to quench, and then the mixture was returned to room temperature and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (15 mL), and then the solvent was distilled off to obtain the desired product as a white solid. (5- (4-Isopropoxyphenyl) -1,2,4-oxadiazol-3-yl) methanol (0.45 g, 1.94 mmol) was used as such in the next reaction.
Step 5: Sodium hydride (55%, 0.18 g, 4.21 mmol) was suspended in DMF (10 mL), and (5- (4-isopropoxyphenyl) -1,2,4-oxadiazole was added under cooling. -3-yl) methanol (0.45 g, 1.94 mmol) was added. 2- (Bromomethyl) pyridine bromate (0.54 g, 2.09 mmol) was added and the mixture was warmed to room temperature and stirred for 2 hours. Water (10 mL) and 1N hydrochloric acid (5 mL) were combined and cooled in another container, and the reaction solution was added dropwise thereto. After returning to room temperature and neutralizing with 1N sodium hydroxide (5.5 mL), the mixture was extracted with ethyl acetate (25 mL). The organic layer was washed with saturated brine (15 mL), the solvent was distilled off, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate) to obtain the desired 2-(((5- (4-isopropoxy Phenyl) -1,2,4-oxadiazol-3-yl) methoxy) methyl) pyridine (0.45 g, 1.40 mmol) was obtained as a colorless oil.

Synthesis method W
Synthesis method of thiadiazole (Example 84)

Step 1: Suspend ethyl oxamate (30.0 g, 256.00 mmol) in toluene (250 mL), add chlorothioformyl chloride (21.0 mL, 253.00 mmol), and add 7.5% at 100 ° C. under a nitrogen atmosphere. Stir for hours. After allowing the reaction solution to cool, the precipitate was removed by filtration, and the filtrate was washed with water (300 mL), saturated aqueous sodium hydrogen carbonate solution (300 mL), and saturated brine (300 mL). The organic layer was dried over anhydrous sodium sulfate, sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 2-oxo-1,3,4-oxathiazole-5-carboxylic acid ethyl ester (20.99 g, 120. 00 mmol) as a yellow oil.
Step 2: 4-isopropoxybenzonitrile (42.1 g, 261.00 mmol) and 2-oxo-1,3,4-oxathiazole-5-carboxylic acid ethyl ester (13.1 g, 74.60 mmol) Dissolved in 2-dichlorobenzene (180 mL) and stirred at 170 ° C. for 4 days. The reaction solution was purified by silica gel column chromatography (silica gel 500 g, eluted with hexane: ethyl acetate = 1: 0 to 4: 1) to give 5- (4-isopropoxyphenyl) -1,2,4-thiadiazole-3- The carboxylic acid ethyl ester (2.76 g, 9.44 mmol) was obtained as a brown oil.
Step 3: 5- (4-Isopropoxyphenyl) -1,2,4-thiadiazole-3-carboxylic acid ethyl ester (0.59 g, 2.00 mmol) was dissolved in tetrahydrofuran (12 mL), cooled with ice, and hydrogenated. Sodium boron (0.21 g, 5.02 mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. Under cooling, water (12 mL) was slowly added to quench, and then the mixture was returned to room temperature and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (15 mL), and the solvent was evaporated to obtain the desired product as a yellow solid. (5- (4-Isopropoxyphenyl) -1,2,4-thiadiazol-3-yl) methanol (0.49 g, 1.96 mmol) was directly used in the next reaction.
Step 4: Sodium hydride (55%, 0.19 g, 4.28 mmol) was suspended in DMF (5 mL), and under cooling, (5- (4-isopropoxyphenyl) -1,2,4-thiadiazole-3 -Yl) methanol (0.49 g, 1.95 mmol) was added dissolved in dimethylformamide (3 mL). 2- (Bromomethyl) pyridine bromate (0.55 g, 2.14 mmol) was added and the mixture was warmed to room temperature and stirred for 2 hours. Water (10 mL) and 1N hydrochloric acid (4.5 mL) were combined and cooled in another container, and the reaction solution was added dropwise thereto. After returning to room temperature and neutralizing with 1N sodium hydroxide (5 mL), the mixture was extracted with ethyl acetate (25 mL). The organic layer was washed with saturated brine (15 mL) and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate) to give the desired 2-((((5- (4-isopropoxyphenyl)). -1,2,4-thiadiazol-3-yl) methoxy) methyl) pyridine (0.32 g, 0.93 mmol) was obtained as a yellow oil.

Synthesis method X
Preparation of oxalate (Example 85)

2-((((2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine (0.50 g, 1.62 mmol) in acetone (acetone, 10 mL) The oxalic acid dihydrate (0.49 g, 3.90 mmol) was added, and it stirred at room temperature for 30 minutes. The solid residue obtained by concentrating the reaction solution under reduced pressure was dissolved in ethanol (5 mL), but crystals were precipitated by stirring slowly at room temperature. In order to improve the stirring ability, ethanol (2 mL) was added and stirring was continued for 1 hour. The crystals were filtered, washed with ethanol (2 mL × 2 times), and dried under reduced pressure at 40 ° C. The crystal recovery was 77%, and the purity by HPLC was 75.6%. Since the theoretical purity of monooxalate is close to 77.5%, 2-(((2- (benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) Presumed to be methyl) pyridine monooxalate.

Synthesis method Y
Synthesis method 3 of oxazole derivative (Example 86)

Step 1: 3,4-methylenedioxycinnamic acid (1.0 g, 5.20 mmol) and thionyl chloride (4.0 mL, 52.00 mmol) were dissolved in toluene (10 mL) and stirred at 100 ° C. for 2 hours. After completion of the reaction, the solvent was distilled off to obtain a crude product of 3- (1,3-benzodioxol-5-yl)-(2E) -2-propenioyl chloride.
Step 2: The crude product of 3- (1,3-benzodioxol-5-yl)-(2E) -2-propenyloyl chloride was dissolved in an aqueous ammonia solution (40 mL) and dimethylformamide (10 mL). And stirred at 40 ° C. for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off to obtain a crude product of 3- (1,3-benzodioxol-5-yl)-(2E) -2-propenamide.
Step 3: Crude product of 3- (1,3-benzodioxol-5-yl)-(2E) -2-propenamide, 1,3-dichloro-2-propane (761.8 mg, 6.00 mmol) ) Was dissolved in xylene (Xylene, 10 mL) and stirred at 125 ° C. for 12 hours. After completion of the reaction, the mixture was allowed to cool and then the solvent was distilled off, followed by silica gel column chromatography to give 2-((1E) -2- (benzo [d] [1,3] dioxol-5-yl) ethenyl) -4. -Chloromethyloxazole (912.7 mg, 3.47 mmol) was obtained.
Step 4: 2-((1E) -2- (benzo [d] [1,3] dioxol-5-yl) ethenyl) -4-chloromethyloxazole (912.7 mg, 3.47 mmol), 2-pyridinemethanol (301.6 mg, 3.12 mmol) and sodium hydride (272.3 mg, 6.24 mmol) were dissolved in DMF (5 mL) and stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, stopped by adding ice-cold water, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off, and silica gel column chromatography was performed to give 2-(((((1E) -2- (benzo [d] [1,3] dioxole). -5-yl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine (933.0 mg, 2.78 mmol) was obtained.

The following compounds were synthesized by the above synthesis method. Both chemical structural formulas and identification data are shown below.

Example 1 and Example 80: Synthesis Method A or Synthesis Method S

2-(((2- (benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.55 (s, 2H), 4.65 (s, 2H), 6.13 (s, 2H), 7.07 (d, J = 8.1 Hz, 1H), 7.24-7.59 ( m, 4H), 7.77-7.85 (m, 1H), 8.17 (s, 1H), 8.46-8.56 (m, 1H)
MS (ESI) m / z: 311.2 (M + H)

Optical micrographs of the crystal A and B of the Example 80 compound are shown in FIGS. 1 and 2, respectively. The measurement conditions of the optical micrograph were as follows.
* Optical microscope Measuring device: Olympus BX61
Objective lens = UPlan FI 20X / 0.50
Eyepiece lens = WH10X / 22

FIG. 3 shows powder X-rays of the crystal A and B of the compound of Example 80. The measurement conditions of the powder X-ray were as follows.
* Powder X-ray measuring device: BRUKER D2 PHASER, a tabletop powder X-ray diffractometer manufactured by Bruker AXS Co., Ltd.
<Measurement conditions>
Radiation: CuKα Time per step (s): 0.20
Generator tension: 30kV Step size (2θ): 0.02417
Generator current: 10mA Peak angle: 4-30 °
2θ value:
Crystal A: 4.54, 15.27, 24.24
Crystal B: 15.46, 16.90, 24.58

FIG. 4 shows DSCs of the crystal A and B of the compound of Example 80. The DSC measurement conditions were as follows.
* DSC
Measuring device: NETZSCH Japan Co., Ltd. Differential scanning calorimeter DSC3100SA
<Measurement conditions>
Reference: Air
Sample Pan: Al
Sample amount: 5-10mg
Temperature increase rate: 5 ℃ / K
Measurement temperature range: 50 to 300 ° C
The melting point and heat of fusion were as shown in the table below.

Example 2: Synthesis method B

2-(((2- (2,3-dimethoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-((((2- (2,3-Dimethoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.80 (s, 3H), 3.85 (s, 3H), 4.59 (s, 2H), 4.68 (s, 2H), 7.15-7.55 (m, 5H), 7.75-7.86 (m, 1H), 8.20-8.26 (m, 1H), 8.46-8.58 (m, 1H)
MS (ESI) m / z: 327.2 (M + H)

Example 3: Synthesis method C

2- (3-((2- (4-methoxyphenyl) thiazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (4-Methoxyphenyl) thiazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.91-2.02 (m, 2H), 2.75-2.87 (m, 2H), 3.50-3.59 (m, 2H), 3.83 (s, 3H), 4.57 (s , 2H), 7.00-7.29 (m, 4H), 7.50 (s, 1H), 7.60-7.70 (m, 1H), 7.82-7.89 (m, 2H), 8.42-8.49 (m, 1H)
MS (ESI) m / z: 341.2 (M + H)

Example 4: Synthesis method D

5-((((pyridin-2-yl) methoxy) methyl) -2- (3,4-dimethylphenyl) pyridine
5-((((Pyridin-2-yl) methoxy) methyl) -2- (3,4-dimethylphenyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.28 (s, 3H), 2.31 (s, 3H), 4.66 (s, 2H), 4.68 (s, 2H), 7.22-7.39 (m, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.78-7.98 (m, 5H), 8.50-8.70 (m, 2H)
MS (ESI) m / z: 305.2 (M + H)

Example 5: Synthesis method E

2-(((2- (3,4-dimethylphenyl) pyridin-4-yl) methoxy) methyl) pyridine
2-((((2- (3,4-Dimethylphenyl) pyridin-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.28 (s, 3H), 2.31 (s, 3H), 4.70 (s, 2H), 4.73 (s, 2H), 7.22-7.39 (m, 3H), 7.54 (d, J = 7.8 Hz, 1H), 7.74-7.92 (m, 4H), 8.51-8.63 (m, 2H)
MS (ESI) m / z: 305.2 (M + H)

Example 6: Synthesis method F

2- (4-Methoxyphenyl) -6- (pyridin-2-ylmethoxymethyl) pyrazine
2- (4-Methoxyphenyl) -6- (pyridin-2-ylmethoxymethyl) pyrazine
¹ H NMR (CDCl ₃ ) δ = 3.88 (s, 3H), 4.85 (s, 2H), 4.87 (s, 2H), 7.01 (s, 1H), 7.03 (s, 1H), 7.20-7,24 ( m, 1H), 7.54 (d, J = 7.8Hz, 1H), 7.73 (ddd, J = 6.9, 6.9, 1.5, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 8.58 (d, J = 4.8Hz, 1H), 8.66 (s, 1H), 8.90 (s, 1H)
MS (DART) m / z: 308.2 [M + H] ⁺

Example 7: Synthesis method G

2-(((2- (4-ethylphenyl) -5-methyloxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Ethylphenyl) -5-methyloxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.21 (t, J = 7.6 Hz, 3H), 2.41 (s, 3H), 3.64-3.76 (m, 2H), 4.52 (s, 2H), 4.62 ( s, 2H), 7.28-7.81 (m, 4H), 7.78-7.92 (m, 3H), 8.50-8.57 (m, 1H)
MS (ESI) m / z: 309.2 (M + H)

Example 8: Synthesis method H

2- (5- (3,4-Methylenedioxyphenyl) -isoxazol-3-ylmethoxymethyl) pyridine
2- (5- (3,4-Methylenedioxyphenyl) isooxazol-3-ylmethoxymethyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 4.73 (s, 2H), 4.75 (s, 2H), 6.04 (s, 2H), 6.50 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 7.20 -7.22 (m, 1H), 7.22 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 8.1, 1.7 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.70 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 8.57-8.59 (m, 1H)
MS (DART) m / z: 311.1 [M + H] ⁺

Example 9: Synthesis Method I

2-(((1- (4-isopropylphenyl) -1H-pyrrol-3-yl) methoxy) methyl) pyridine
2-((((1- (4-Isopropylphenyl) -1H-pyrrol-3-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.21 (s, 3H), 1.22 (s, 3H), 2.83-3.00 (m, 1H), 4.49 (s, 2H), 4.58 (s, 2H), 6.24-6.33 (m, 1H), 7.23-7.52 (m, 8H), 7.73-7.84 (m, 1H), 8.47-8.55 (m, 1H)
MS (ESI) m / z: 307.0 (M + H)

Example 10: Synthesis method J

2-(((1- (benzo [d] [1,3] dioxol-5-yl) -1H-pyrazol-4-yl) methoxy) methyl) pyridine
2-(((1- (Benzo [d] [1,3] dioxol-5-yl) -1H-pyrazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.54 (s, 2H), 4.60 (s, 2H), 6.09 (s, 2H), 7.01 (d, J = 8.4 Hz, 1H), 7.23-7.34 ( m, 2H), 7.40-7.52 (m, 2H), 7.69-7.87 (m, 2H), 8.38-8.57 (m, 2H)
MS (ESI) m / z: 310.2 (M + H)

Example 11: Synthesis method K

2-(((1- (4-isopropylphenyl) -1H-imidazol-4-yl) methoxy) methyl) pyridine
2-((((1- (4-Isopropylphenyl) -1H-imidazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.22 (s, 3H), 1.23 (s, 3H), 2.89-3.03 (m, 1H), 4.53 (s, 2H), 4.64 (s, 2H), 7.26-7.51 (m, 6H), 7.72-7.88 (m, 2H), 8.18-8.20 (m, 1H), 8.49-8.55 (m, 1H)
MS (ESI) m / z: 308.1 (M + H)

Example 12: Synthesis method L

2-(((1- (benzo [d] [1,3] dioxol-5-yl) -1H-pyrazol-3-yl) methoxy) methyl) pyridine
2-(((1- (Benzo [d] [1,3] dioxol-5-yl) -1H-pyrazol-3-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.62 (s, 2H), 4.63 (s, 2H), 6.09 (s, 2H), 6.54 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 7.27-7.32 (m, 2H), 7.42 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.79-7.83 (m, 1H), 8.36 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 4.1 Hz, 1H)
MS (ESI) m / z: 310.0 (M + H)

Example 13: Synthesis method M

2-((((5- (benzo [d] [1,3] dioxol-5-yl) -1,3,4-oxadiazol-2-yl) methoxy) methyl) pyridine
2-(((5- (Benzo [d] [1,3] dioxol-5-yl) -1,3,4-oxadiazol-2-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.74 (s, 2H), 4.91 (s, 2H), 6.17 (s, 2H), 7.13 (d, J = 8.1 Hz, 1H), 7.30-7.33 ( m, 1H), 7.46-7.47 (m, 2H), 7.53-7.56 (m, 1H), 7.79-7.83 (m, 1H), 8.53 (d, J = 4.2 Hz, 1H)
MS (ESI) m / z: 312.1 (M + H)

Example 14 Synthesis Method N

2-((((5- (benzo [d] [1,3] dioxol-5-yl) furan-2-yl) methoxy) methyl) pyridine
2-(((5- (Benzo [d] [1,3] dioxol-5-yl) furan-2-yl) methoxymethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.59 (s, 2H), 4.62 (s, 2H), 6.06 (s, 2H), 6.55 (d, J = 3.3 Hz, 1H), 6.79 (d, J = 3.3 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 7.19-7.22 (m, 1H), 7.26-7.30 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.76-7.81 (m, 1H), 8.52 (d, J = 4.1 Hz, 1H)
MS (ESI) m / z: 310.2 (M + H)

Example 15: Synthesis method O

2- (3-((4-isopropylbenzyloxy) methyl) -1H-pyrrol-1-yl) pyridine
2- (3-((4-Isopropylbenzyloxy) methyl) -1H-pyrrol-1-yl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.19 (d, J = 6.9 Hz, 1H), 2.85-2.88 (m, 1H), 4.42 (s, 2H), 4.46 (s, 2H), 6.31- 6.32 (m, 1H), 7.20-7.27 (m, 5H), 7.66-7.70 (m, 3H), 7.88-7.90 (m, 1H), 8.41-8.43 (m, 1H)
MS (ESI) m / z: 307.2 (M + H)

Example 16: Synthesis method P

2-((2- (4-isopropylphenyl) oxazol-4-yl) methylthio) pyridine
2-((2- (4-Isopropylphenyl) oxazol-4-yl) methylthio) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.21 (s, 3H), 1.23 (s, 3H), 2.88-3.02 (m, 1H), 4.37 (s, 2H), 7.09-7.19 (m, 1H ), 7.31-7.42 (m, 3H), 7,61-7.71 (m, 1H), 7.82-7.91 (m, 2H), 8.01-8.07 (m, 1H), 8.42-8.51 (m, 1H)
MS (ESI) m / z: 311.0 (M + H)

Example 17: Synthesis method Q

2-((1- (2- (4-methoxyphenyl) oxazol-4-yl) butoxy) methyl) pyridine
2-((1- (2- (4-Methoxyphenyl) oxazol-4-yl) butoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 0.82-0.98 (m, 3H), 1.20-1.49 (m, 2H), 1.73-1.98 (m, 2H), 3.83 (s, 3H), 4.42-4.63 (m, 3H), 7.01-7.12 (m, 2H), 7.22-7.33 (m, 1H), 7.42-7.51 (m, 1H), 7.71-7.97 (m, 3H), 8.12 (s, 1H), 8.44 -8.52 (m, 1H)
MS (ESI) m / z: 339.1 (M + H)
Example 18: Synthesis method R

2-((2- (2- (benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) propan-2-yloxy) methyl) pyridine
2-((2- (2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) propan-2-yloxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.59 (s, 6H), 4.40 (s, 2H), 6.13 (s, 2H), 7.06 (d, J = 8.1 Hz, 1H), 7.19-7.28 ( m, 1H), 7.39-7.57 (m, 3H), 7.71-7.81 (m, 1H), 8.15 (s, 1H), 8.39-8.47 (m, 1H)
MS (ESI) m / z: 339.2 (M + H)

Example 19: Synthesis method A

2-(((2- (4-methoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-((((2- (4-Methoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.83 (s, 3H), 4.56 (s, 2H), 4.66 (s, 2H), 7.00-7.50 (m, 4H), 7.77-7.98 (m, 3H ), 8.16 (s, 1H), 8.48-8.58 (m, 1H)
MS (ESI) m / z: 297.0 (M + H)

Example 20: Synthesis method A

2- (2-((2- (4-methoxyphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
2- (2-((2- (4-Methoxyphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.00 (t, J = 6.8 Hz, 2H), 3.82-3.86 (m, 2H), 4.42 (d, J = 0.8 Hz, 2H), 7.07-7.09 ( m, 2H), 7.21-7.23 (m, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.67-7.71 (m, 1H), 7.89-7.91 (m, 2H), 8.03 (s, 1H) , 8.47-8.49 (m, 1H)
MS (ESI) m / z: 311.2 (M + H)

Example 21: Synthesis method A

2- (3-((2- (4-methoxyphenyl) oxazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (4-Methoxyphenyl) oxazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.89-1.99 (m, 2H), 2.74-2.82 (m, 2H), 3.50 (t, J = 6.5 Hz, 2H), 3.83 (s, 3H), 4.40 (s, 2H), 7.00-7.28 (m, 4H), 7.62-7.68 (m, 1H), 7.88-7.93 (m, 2H), 8.07 (s, 1H), 8.42-8.50 (m, 1H)
MS (ESI) m / z: 325.5 (M + H)

Example 22: Synthesis method B

2-(((2- (3,4-dimethylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-((((2- (3,4-Dimethoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.24-2.38 (m, 6H), 4.57 (s, 2H), 4.66 (s, 2H), 7.23-7.53 (m, 3H), 7.66-7.88 (m , 3H), 8.19 (s, 1H), 8.49-8.55 (m, 1H)
MS (ESI) m / z: 295.5 (M + H)

Example 23 Synthesis Method B

2- (2-((2- (3,4-dimethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
2- (2-((2- (3,4-Dimethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.88 (s, 3H), 2.30 (s, 3H), 2.98-3.08 (m, 2H), 3.78-3.90 (m, 2H), 4.43 (s, 2H ), 7.18-7.39 (m, 3H), 7.63-7.79 (m, 3H), 8.06 (s, 1H), 8.42-8.52 (m, 1H)
MS (ESI) m / z: 309.2 (M + H)

Example 24 Synthesis Method B

2- (3-((2- (3,4-dimethylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (3,4-Dimethylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.89-2.00 (m, 2H), 2.28 (s, 3H), 2.30 (s, 3H), 2.73-2.82 (m, 2H), 3.47-3.56 (m , 2H), 4.40 (s, 2H), 7.12-7.33 (m, 3H), 7.61-7.79 (m, 3H), 8.09 (s, 1H), 8.42-8.50 (m, 1H)
MS (ESI) m / z: 322.7 (M + H)

Example 25 Synthesis Method B

2-(((2- (4-ethylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Ethylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.21 (t, J = 7.6 Hz, 3H), 2.62-2.73 (m, 2H), 4.57 (s, 2H), 4.66 (s, 2H), 7.28- 7.52 (m, 4H), 7.78-7.96 (m, 3H), 8.20 (s, 1H), 8.53 (d, J = 4.0 Hz, 1H)
MS (ESI) m / z: 295.1 (M + H)

Example 26 Synthesis Method B

2- (2-((2- (4-ethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
2- (2-((2- (4-Ethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.21 (t, J = 7.6 Hz, 3H), 2.57-2.73 (m, 2H), 3.01 (t, J = 6.8 Hz, 2H), 3.85 (t, J = 6.8 Hz, 2H), 4.44 (s, 2H), 7.15-7.43 (m, 4H), 7.60-7.97 (m, 3H), 8.07 (s, 1H), 8.41-8.52 (m, 1H)
MS (ESI) m / z: 309.1 (M + H)

Example 27: Synthesis method B

2- (3-((2- (4-ethylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (4-Ethylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.21 (t, J = 7.6 Hz, 3H), 1.89-2.05 (m, 2H), 2.61-2.74 (m, 2H), 2.78 (t, J = 7.8 Hz, 2H), 3.50 (t, J = 6.5 Hz, 2H), 4.11 (s, 2H), 7.11-7.43 (m, 4H), 7.59-7.71 (m, 1H), 7.83-7.97 (m, 2H) , 8.11 (s, 1H), 8.43-8.51 (m, 1H)
MS (ESI) m / z: 323.1 (M + H)

Example 28: Synthesis method B

2-(((2- (2,4-dimethylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-((((2- (2,4-Dimethylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.33 (s, 3H), 2.60 (s, 3H), 4.58 (d, J = 0.8 Hz, 2H), 4.68 (s, 2H), 7.11-7.38 ( m, 3H), 7.48-7.54 (m, 1H), 7.74-7.87 (m, 2H), 8.21 (s, 1H), 8.50-8.58 (m, 1H)
MS (ESI) m / z: 295.2 (M + H)

Example 29 Synthesis Method B

2- (2-((2- (2,4-dimethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
2- (2-((2- (2,4-Dimethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.33 (s, 3H), 2.58 (s, 3H), 3.01 (t, J = 6.8 Hz, 2H), 3.86 (t, J = 6.8 Hz, 2H) , 4.45 (s, 2H), 7.11-7.39 (m, 4H), 7.65-7.85 (m, 2H), 8.08 (s, 1H), 8.46-8.51 (m, 1H)
MS (ESI) m / z: 309.2 (M + H)

Example 30: Synthesis method B

2- (3-((2- (2,4-dimethylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (2,4-Dimethylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.90-2.01 (m, 2H), 2.33 (s, 3H), 2.58 (s, 3H), 2.78 (t, J = 7.8 Hz, 2H), 3.52 ( t, J = 6.4 Hz, 2H), 4.42 (s, 2H), 7.12-7.28 (m, 4H), 7.60-7.69 (m, 1H), 7.80 (d, J = 7.9 Hz, 1H), 8.12 (s , 1H), 8.42-8.50 (m, 1H)
MS (ESI) m / z: 323.0 (M + H)

Example 31 Synthesis Method C

2- (2-((2- (4-methoxyphenyl) thiazol-4-yl) methoxy) ethyl) pyridine
2- (2-((2- (4-Methoxyphenyl) thiazol-4-yl) methoxy) ethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.03 (t, J = 6.8 Hz, 2H), 3.82 (s, 3H), 3.88 (t, J = 6.8 Hz, 2H), 4.59 (d, J = 0.7 Hz, 2H), 7.04-7.06 (m, 2H), 7.20-7.23 (m, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.43 (s, 1H), 7.67-7.72 (m, 1H ), 7.84-7.87 (m, 2H), 8.46-8.51 (m, 1H)
MS (ESI) m / z: 327.2 (M + H)

Example 32 Synthesis Method A

2-(((2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.22-4.38 (m, 4H), 4.55 (s, 2H), 4.65 (s, 2H), 6.98-7.03 (m, 1H), 7.23-7.50 (m , 4H), 7.78-7.87 (m, 1H), 8.15 (s, 1H), 8.48-8.58 (m, 1H)
MS (ESI) m / z: 325.3 (M + H)

Example 33 Synthesis Method A

2-(((2- (4-phenoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Phenoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.57 (s, 2H), 4.66 (s, 2H), 7.04-7.53 (m, 9H), 7.78-8.04 (m, 3H), 8.20 (s, 1H ), 8.50-8.58 (m, 1H)
MS (ESI) m / z: 359.2 (M + H)

Example 34 Synthesis Method B

2-(((2- (3-phenoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (3-phenoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.56 (s, 2H), 4.64 (s, 2H), 7.09-7.62 (m, 10H), 7.70-7.86 (m, 2H), 8.51 (s, 1H ), 8.49-8.56 (m, 1H)
MS (ESI) m / z: 359.2 (M + H)

Example 35: Synthesis method B

2-(((2- (4-isopropylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Isopropylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.23 (s, 3H), 1.24 (s, 3H), 2.88-3.08 (m, 1H), 4.57 (s, 2H), 4.66 (s, 2H), 7.20-7.50 (m, 4H), 7.72-7.96 (m, 3H), 8.20 (s, 1H), 8.48-8.59 (m, 1H)
MS (ESI) m / z: 309.1 (M + H)

Example 36 Synthesis Method B

2-(((2- (4-tert-butylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (4-tert-Butylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.32 (s, 9H), 4.57 (s, 2H), 4.66 (s, 2H), 7.27-7.62 (m, 4H), 7.73-7.94 (m, 3H ), 8.21 (s, 1H), 8.49-8.58 (m, 1H)
MS (ESI) m / z: 323.4 (M + H)

Example 37 Synthesis Method B

2- (3-((2- (4-isopropylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (4-Isopropylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.23 (s, 3H), 1.24 (s, 3H), 1.85-2.02 (m, 2H), 2.70-2.82 (m, 2H), 2.89-3.00 (m , 1H), 3.43-3.57 (m, 2H), 4.41 (s, 2H), 7.11-7.28 (m, 2H), 7.34-7.48 (m, 2H), 7.57-7.71 (m, 1H), 7.83-7.97 (m, 2H), 8.11 (s, 1H), 8.42-8.51 (m, 1H)
MS (ESI) m / z: 337.2 (M + H)

Example 38 Synthesis Method B

2-(((2- (4-propylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-((((2- (4-propylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 0.91 (t, J = 7.4 Hz, 3H), 1.56-1.70 (m, 2H), 2.62 (t, J = 7.8 Hz, 2H), 4.57 (s, 2H), 4.66 (s, 2H), 7.28-7.52 (m, 4H), 7.79-7.94 (m, 3H), 8.20 (s, 1H), 8.49-8.59 (m, 1H)
MS (ESI) m / z: 309.2 (M + H)

Example 39 Synthesis Method B

2- (3-((2- (4-propylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (4-propylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 0.91 (t, J = 7.4 Hz, 3H), 1.54-1.69 (m, 2H), 1.89-2.00 (m, 2H), 2.62 (t, J = 7.7 Hz, 2H), 2.78 (t, J = 7.8 Hz, 2H), 3.50 (t, J = 6.5 Hz, 2H), 4.41 (s, 2H), 7.11-7.40 (m, 4H), 7.59-7.69 (m , 1H), 7.83-7.92 (m, 2H), 8.11 (s, 1H), 8.42-8.50 (m, 1H)
MS (ESI) m / z: 337.2 (M + H)

Example 40 Synthesis Method B

2-(((2- (4-isopropoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Isopropoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.20-1.37 (m, 6H), 4.55 (s, 2H), 4.65 (s, 2H), 4.70-4.79 (m, 1H), 6.99-7.10 (m , 2H), 7.24-7.36 (m, 1H), 7.47-7.53 (m, 1H), 7.80-7.97 (m, 3H), 8.15 (s, 1H), 8.51-8.57 (s, 1H)
MS (ESI) m / z: 325.2 (M + H)

Example 41 Synthesis Method G

2-(((2- (4-methoxyphenyl) -5-methyloxazol-4-yl) methoxy) methyl) pyridine
2-((((2- (4-methoxyphenyl) -5-methoxyoxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.39 (s, 3H), 3.82 (s, 3H), 4.50 (s, 2H), 4.62 (m, 2H), 7.06 (d, J = 8.9 Hz, 1H), 7.28-7.31 (m, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.78-7.82 (m, 1H), 7.86-7.88 (m, 2H), 8.52 (d, J = 4.1 Hz , 1H)
MS (ESI) m / z: 311.0 (M + H)

Example 42 Synthesis Method G

2-(((5-methyl-2- (3,4-dimethylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((5-Methyl-2- (3,4-dimethylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.27 (s, 3H), 2.29 (s, 3H), 2.40 (s, 3H), 4.51 (s, 2H), 4.62 (m, 2H), 7.26- 7.31 (m, 2H), 7.46 (d, J = 7.8 Hz, 1H), 7.64-7.66 (m, 1H), 7.72 (S, 1H), 7.78-7.83 (m, 1H), 8.51-8.53 (m, 1H)
MS (ESI) m / z: 309.2 (M + H)

Example 43 Synthesis Method G

2-(((2- (4-isopropylphenyl) -5-methyloxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Isopropylphenyl) -5-methyloxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.22 (s, 3H), 1.24 (s, 3H), 2.41 (s, 3H), 2.89-3.04 (m, 1H), 4.52 (s, 2H), 4.62 (s, 2H), 7.22-7.52 (m, 4H), 7.77-7.91 (m, 3H), 8.48-8.58 (m, 1H)
MS (ESI) m / z: 323.3 (M + H)

Example 44 Synthesis Method B

2-(((2- (3,4-dimethoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-((((2- (3,4-Dimethoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.83 (s, 3H), 3.85 (s, 3H), 4.56 (s, 2H), 4.65 (s, 2H), 7.11 (d, J = 8.5 Hz, 1H), 7.23-7.34 (m, 1H), 7.46-7.60 (m, 3H), 7.78-7.89 (m, 1H), 8.17 (s, 1H), 8.49-8.59 (m, 1H)
MS (ESI) m / z: 327.1 (M + H)

Example 45 Synthesis Method B

2- (3-((2- (3,4-dimethoxyphenyl) oxazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (3,4-Dimethoxyphenyl) oxazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.91-2.01 (m, 2H), 2.73-2.85 (m, 2H), 3.50 (t, J = 6.5 Hz, 2H), 3.83 (s, 3H), 3.85 (s, 3H), 4.40 (s, 2H), 7.08-7.28 (m, 3H), 7.48-7.71 (m, 3H), 8.08 (s, 1H), 8.43-8.52 (m, 1H)
MS (ESI) m / z: 355.0 (M + H)

Example 46 Synthesis Method B

2-(((2- (2,4-dimethoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-((((2- (2,4-Dimethoxyphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.84 (s, 3H), 3.87 (s, 3H), 4.55 (s, 2H), 4.65 (s, 2H), 6.62-6.74 (m, 2H), 7.23-7.34 (m, 1H), 7.42-7.52 (m, 1H), 7.77-7.89 (m, 2H), 8.13 (s, 1H), 8.50-8.58 (m, 1H)
MS (ESI) m / z: 327.2 (M + H)

Example 47: Synthesis method B

2- (3-((2- (2,4-dimethoxyphenyl) oxazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (2,4-Dimethoxyphenyl) oxazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.89-1.99 (m, 2H), 2.71-2.82 (m, 2H), 3.48-3.54 (m, 2H), 3.84 (s, 3H), 3.86 (s , 3H), 4.39 (s, 2H), 6.62-6.73 (m, 2H), 7.14-7.29 (m, 2H), 7.60-7.80 (m, 2H), 8.04 (s, 1H), 8.40-8.50 (m , 1H)
MS (ESI) m / z: 354.8 (M + H)

Example 48 Synthesis Method A

2-(((2- (benzo [d] [1,3] dioxol-4-yl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (Benzo [d] [1,3] dioxol-4-yl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.58 (s, 2H), 4.65 (s, 2H), 6.18 (s, 2H), 6.92-7.12 (m, 2H), 7.28-7.57 (m, 3H ), 7.75-7.88 (m, 1H), 8.25 (s, 1H), 8.48-8.59 (m, 1H)
MS (ESI) m / z: 311.0 (M + H)

Example 49 Synthesis Method B

2-((R) -1-((2- (4-methoxyphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
2-((R) -1-((2- (4-methoxyphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.42 (d, J = 6.5 Hz, 1H), 3.83 (s, 3H), 4.35 (d, J = 10.0 Hz, 1H), 4.40 (d, J = 10.0 Hz, 1H), 4.64-4.69 (m, 1H), 7.09 (d, J = 9.0 Hz, 2H), 7.29-7.32 (m, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.81- 7.83 (m, 1H), 7.91 (d, J = 9.0 Hz, 2H), 8.08 (s, 1H), 8.51-8.56 (m, 1H)
MS (ESI) m / z: 311.1 (M + H)

Example 50: Synthesis method B

2-((R) -1-((2- (3,4-dimethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
2-((R) -1-((2- (3,4-dimethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.42 (d, J = 6.5 Hz, 1H), 2.28 (s, 3H), 2.30 (s, 3H), 4.34-4.43 (m, 2H), 4.64- 4.69 (m, 1H), 7.28-7.32 (m, 2H), 7.51 (d, J = 7.9 Hz, 1H), 7.67-7.70 (m, 1H), 7.76 (s, 1H), 7.81-7.85 (m, 1H), 8.11 (s, 1H), 8.52-8.56 (m, 1H)
MS (ESI) m / z: 308.8 (M + H)

Example 51 Synthesis Method B

2-((S) -1-((2- (4-methoxyphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
2-((S) -1-((2- (4-methoxyphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.42 (d, J = 6.5 Hz, 3H), 3.83 (s, 3H), 4.41-4.47 (m, 2H), 4.62-4.72 (m, 1H), 7.09-7,13 (m, 2H), 7.28-7.32 (m, 1H), 7.48-7.55 (m, 1H), 7.80-7.96 (m, 3H), 8.08 (s, 1H), 8.52-8.58 (m , 1H)
MS (ESI) m / z: 310.7 (M + H)

Example 52 Synthesis Method B

2-((S) -1-((2- (3,4-dimethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
2-((S) -1-((2- (3,4-dimethylphenyl) oxazol-4-yl) methoxy) ethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.43 (d, J = 6.5 Hz, 3H), 2.28 (s, 3H), 2.30 (s, 3H), 4.31-4.47 (m, 2H), 4.63- 4.70 (m, 1H), 7.20-7.37 (m, 2H), 7.49-7.56 (m, 1H), 7.64-7.79 (m, 3H), 8.10 (s, 1H), 8.51-8.58 (m, 1H)
MS (ESI) m / z: 308.7 (M + H)

Example 53 Synthesis Method B

4-(((thiazol-2-yl) methoxy) methyl) -2- (4-methoxyphenyl) oxazole
4-(((thiazol-2-yl) methoxy) methyl) -2- (4-methoxyphenyl) oxazole
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.83 (s, 3H), 4.59 (d, J = 0.6 Hz, 2H), 4.88 (s, 2H), 7.07-7.12 (m, 2H), 7.71- 7.82 (m, 2H), 7.88-7.96 (m, 2H), 8.16 (s, 1H)
MS (ESI) m / z: 302.7 (M + H)

Example 54 Synthesis Method B

4-((((thiazol-2-yl) methoxy) methyl) -2- (3,4-dimethylphenyl) oxazole
4-(((thiazol-2-yl) methoxy) methyl) -2- (3,4-dimethylphenyl) oxazole
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.29 (s, 3H), 2.30 (s, 3H), 4.60 (d, J = 0.7 Hz, 2H), 4.88 (s, 2H), 7.30 (d, J = 7.9 Hz, 1H), 7.66-7.84 (m, 4H), 8.19 (s, 1H)
MS (ESI) m / z: 301.0 (M + H)

Example 55 Synthesis Method P

2-((2- (3,4-dimethylphenyl) oxazol-4-yl) methylthio) pyridine
2-((2- (3,4-Dimethylphenyl) oxazol-4-yl) methylthio) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.27 (s, 3H), 2.29 (s, 3H), 4.36 (d, J = 0.9 Hz, 3H), 7.13-7.16 (m, 1H), 7.28 ( d, J = 7.9 Hz, 1H), 7.34-7.37 (m, 1H), 7.65-7.67 (m, 2H), 7.73 (s, 1H), 8.03 (s, 1H), 8.47-8.49 (m, 1H)
MS (ESI) m / z: 297.0 (M + H)

Example 56 Synthesis Method P

2-((2- (4-ethylphenyl) oxazol-4-yl) methylthio) pyridine
2-((2- (4-Ethylphenyl) oxazol-4-yl) methylthio) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.20 (t, J = 7.6 Hz, 3H), 2.67 (q, J = 7.6 Hz, 2H), 4.36 (d, J = 0.9 Hz, 2H), 7.14 -7.16 (m, 1H), 7.35-7.38 (m, 3H), 7.65-7.67 (m, 1H), 7,85-7.87 (m, 2H), 8.04 (s, 1H), 8.47-8.49 (m, 1H)
MS (ESI) m / z: 297.2 (M + H)

Example 57 Synthesis Method P

2- (3,4-dimethylphenyl) -4-((thiazol-2-ylthio) methyl) oxazole
2- (3,4-Dimethylphenyl) -4-((thiazol-2-ylthio) methyl) oxazole
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.27 (s, 3H), 2.29 (s, 3H), 4.43 (d, J = 0.78 Hz, 2H), 6.98 (d, J = 1.3 Hz, 1H) , 7.28 (d, J = 7.9 Hz, 1H), 7.65-7.67 (m, 1H), 7.69 (d, J = 3.4 Hz, 1H), 7.74 (s, 1H), 7.77 (d, J = 3.4 Hz, 1H), 8.05 (s, 1H)
MS (ESI) m / z: 303.2 (M + H)

Example 58 Synthesis Method P

2-((2- (3,4-dimethylphenyl) oxazol-4-yl) methylthio) -1-methyl-1H-imidazole
2-((2- (3,4-Dimethylphenyl) oxazol-4-yl) methylthio) -1-methyl-1H-imidazole
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.27 (s, 3H), 2.28 (s, 3H), 3.52 (s, 3H), 4.13 (d, J = 0.75 Hz, 2H), 6.98 (d, J = 1.3 Hz, 1H), 7.24 (d, J = 1.3 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.64-7.66 (m, 1H), 7.73 (s, 1H), 7.85 ( s, 1H)
MS (ESI) m / z: 300.0 (M + H)

Example 59 Synthesis Method B

2-(((2- (4-methoxy-3-methylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Methoxy-3-methylphenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.22 (s, 3H), 3.86 (s, 3H), 4.55 (s, 2H), 4.66 (s, 2H), 7.09 (d, J = 8.5 Hz, 1H), 7.26-7.37 (m, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.74-7.88 (m, 3H), 8.15 (s, 1H), 8.49-8.59 (m, 1H)
MS (ESI) m / z: 311.1 (M + H)

Example 60: Synthesis method B

2- (3-((2- (4-methoxy-3-methylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
2- (3-((2- (4-Methoxy-3-methylphenyl) oxazol-4-yl) methoxy) propyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.88-2.01 (m, 2H), 2.22 (s, 3H), 2.71-2.82 (m, 2H), 3.50 (t, J = 6.5 Hz, 2H), 3.86 (s, 3H), 4.39 (d, J = 0.8 Hz, 2H), 7.04-7.29 (m, 3H), 7.60-7.83 (m, 3H), 8.06 (s, 1H), 8.43-8.51 (m, 1H)
MS (ESI) m / z: 339.4 (M + H)

Example 61 Synthesis Method Q

2-((1- (2- (benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) ethoxy) methyl) pyridine
2-((1- (2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) ethoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.51 (d, J = 6.5 Hz, 3H), 4.59 (s, 2H), 4.62-4.72 (m, 1H), 6.13 (s, 2H), 7.06 ( d, J = 8.2 Hz, 1H), 7.22-7.59 (m, 4H), 7.72-7.84 (m, 1H), 8.09-8.17 (m, 1H), 8.43-8.55 (m, 1H)
MS (ESI) m / z: 325.2 (M + H)

Example 62 Synthesis Method B

2-(((2- (4-methoxybenzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Methoxybenzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.91 (s, 3H), 4.55 (s, 2H), 4.65 (s, 2H), 6.11 (s, 2H), 7.04-7.58 (m, 4H), 7.71-7.91 (m, 1H), 8.09-8.27 (m, 1H), 8.45-8.63 (m, 1H)
MS (ESI) m / z: 341.1 (M + H)

Example 63 Synthesis Method D

5-(((pyridin-2-yl) methoxy) methyl) -2- (4-methoxyphenyl) pyridine
5-((((Pyridin-2-yl) methoxy) methyl) -2- (4-methoxyphenyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.82 (s, 3H), 4.66 (s, 2H), 4.67 (s, 2H), 7.02-7.09 (m, 2H), 7.29-7.38 (m, 1H ), 7.50 (d, J = 7.8 Hz, 1H), 7.79-7.96 (m, 3H), 8.00-8.10 (m, 2H), 8.49-8.57 (m, 1H), 8.59-8.68 (m, 1H)
MS (ESI) m / z: 307.0 (M + H)

Example 64 Synthesis Method E

2-(((2- (4-methoxyphenyl) pyridin-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Methoxyphenyl) pyridin-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.82 (s, 3H), 4.70 (s, 2H), 4.73 (s, 2H), 7.02-7.10 (m, 2H), 7.29-7.39 (m, 2H ), 7.52-7.58 (m, 1H), 7.80-7.89 (m, 2H), 8.02-8.10 (m, 2H), 8.50-8.61 (m, 2H)
MS (ESI) m / z: 307.2 (M + H)

Example 65 Synthesis Method D

5-(((pyridin-2-yl) methoxy) methyl) -2- (4-ethylphenyl) pyridine
5-((((Pyridin-2-yl) methoxy) methyl) -2- (4-ethylphenyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.22 (t, J = 7.6 Hz, 3H), 2.59-2.73 (m, 2H), 4.67 (s, 2H), 4.69 (s, 2H), 7.27- 7.57 (m, 4H), 7.77-8.08 (m, 5H), 8.49-8.68 (m, 2H)
MS (ESI) m / z: 305.0 (M + H)

Example 66 Synthesis Method E

2-(((2- (4-ethylphenyl) pyridin-4-yl) methoxy) methyl) pyridine
2-(((2- (4-Ethylphenyl) pyridin-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.22 (t, J = 7.6 Hz, 3H), 2.61-2.77 (m, 2H), 4.70 (s, 2H), 4.74 (s, 2H), 7.29- 7.39 (m, 4H), 7.51-7.59 (m, 1H), 7.79-8.07 (m, 4H), 8.48-8.68 (m, 2H)
MS (ESI) m / z: 305.0 (M + H)

Example 67 Synthesis Method D

5-(((pyridin-2-yl) methoxy) methyl) -2- (4-isopropylphenyl) pyridine
5-((((Pyridin-2-yl) methoxy) methyl) -2- (4-isopropylphenyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.19-1.29 (m, 6H), 2.88-3.02 (m, 1H), 4.67 (s, 2H), 4.69 (s, 2H), 7.29-7.54 (m , 4H), 7.79-8.04 (m, 5H), 8.50-8.57 (m, 1H), 8.61-8.69 (m, 1H)
MS (ESI) m / z: 319.4 (M + H)

Example 68 Synthesis Method E

2-(((2- (4-isopropylphenyl) pyridin-4-yl) methoxy) methyl) pyridine
2-((((2- (4-Isopropylphenyl) pyridin-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.24 (s, 3H), 1.25 (s, 3H), 2.90-3.02 (m, 1H), 4.70 (s, 2H), 4.74 (s, 2H), 7.29-7.40 (m, 4H), 7.54 (d, J = 7.8 Hz, 1H), 7.80-7.94 (m, 2H), 7.98-8.07 (m, 2H), 8.51-8.59 (m, 1H), 8.61- 8.68 (m, 1H)
MS (ESI) m / z: 319.2 (M + H)

Example 69 Synthesis Method D

5-(((pyridin-2-yl) methoxy) methyl) -2- (benzo [d] [1,3] dioxol-5-yl) pyridine
5-(((Pyridin-2-yl) methoxy) methyl) -2- (benzo [d] [1,3] dioxol-5-yl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.66 (s, 2H), 4.67 (s, 2H), 6.09 (s, 2H), 7.03 (d, J = 8.7 Hz, 1H), 7.27-7.39 ( m, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.60-7.70 (m, 2H), 7.78-7.93 (m, 3H), 8.49-8.68 (m, 2H)
MS (ESI) m / z: 321.1 (M + H)

Example 70 Synthesis Method H

2-(((5- (4-methoxyphenyl) isoxazol-3-yl) methoxy) methyl) pyridine
2-((((5- (4-Methoxyphenyl) isoxazol-3-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.83 (s, 3H), 4.67 (s, 2H), 4.71 (s, 2H), 6.99 (s, 1H), 7.05-7.14 (m, 2H), 7.28-7.39 (m, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.79-7.92 (m, 3H), 8.50-8.59 (m, 1H)
MS (ESI) m / z: 297.2 (M + H)

Example 71 Synthesis Method H

2- (5- (4-Ethylphenyl) -isoxazol-3-ylmethoxymethyl) pyridine
2- (5- (4-Ethylphenyl) isooxazol-3-ylmethoxymethyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 1.26 (t, J = 7.6 Hz, 3H), 2.68 (q, J = 7.6 Hz, 2H), 4.74 (s, 2H), 4.76 (s, 2H), 6.59 (s , 1H), 7.18-7.22 (m, 1H), 7.27 (s, 1H), 7.29 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.67-7.72 (m, 3H), 8.57- 8.59 (m, 1H)
MS (DART) m / z: 295.2 [M + H] ⁺

Example 72 Synthesis Method A

2-(((3- (4-methoxyphenyl) isoxazol-5-yl) methoxy) methyl) pyridine
2-((((3- (4-Methoxyphenyl) isooxazol-5-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.82 (s, 3H), 4.69 (s, 2H), 4.79 (s, 2H), 7.02-7.11 (m, 3H), 7.27-7.38 (m, 1H ), 7.43-752 (m, 1H), 7.78-7.89 (m, 3H), 8.51-8.60 (m, 1H)
MS (ESI) m / z: 297.0 (M + H)

Example 73 Synthesis Method F

2- (4-Isopropylphenyl) -5- (pyridin-2-ylmethoxymethyl) pyrazine
2- (4-Isopropylphenyl) -5- (pyridin-2-ylmethoxymethyl) -pyrazine
¹ H NMR (CDCl ₃ ) δ = 1.30 (d, J = 6.9 Hz, 6H), 2.95-3.02 (m, 1H), 4.83 (s, 2H), 4.85 (s, 2H), 7.20-7.23 (m, 1H), 7.36 (s, 1H), 7.39 (s, 1H), 7.53 (d, J = 7.8Hz, 1H), 7.72 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.94 (s, 1H ), 7.96 (s, 1H), 8.57-8.59 (m, 1H), 8.80 (d, J = 1.4 Hz, 1H), 8.95 (d, J = 1.5 Hz, 1H)
MS (DART) m / z: 320.2 [M + H] ⁺

Example 74 Synthesis Method F

2- (2,4-Dimethoxyphenyl) -5- (pyridin-2-ylmethoxymethyl) pyrazine
2- (2,4-Dimethoxyphenyl) -5- (pyridin-2-ylmethoxymethyl) -pyrazine
¹ H NMR (CDCl ₃ ) δ = 3.87 (s, 3H), 3.88 (s, 3H), 4.83 (s, 2H), 4.84 (s, 2H), 6.57 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 8.6, 2.4 Hz, 1H), 7.20-7.23 (m, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.72 (ddd, J = 9.5, 9.5, 1.8 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 8.57-8.59 (m, 1H), 8.78 (d, J = 1.5 Hz, 1H), 9.09 (d, J = 1.5 Hz, 1H)
MS (DART) m / z: 338.2 [M + H] ⁺

Example 75 Synthesis Method F

2- (3,4-methylenedioxyphenyl) -5- (pyridin-2-ylmethoxymethyl) pyrazine
2- (3,4-Methylenedioxyphenyl) -5- (pyridin-2-ylmethoxymethyl) -pyrazine
¹ H NMR (CDCl ₃ ) δ = 4.82 (s, 2H), 4.83 (s, 2H), 6.04 (s, 2H), 6.93 (dd, J = 7.6, 1.1 Hz, 1H), 7.20-7.24 (m, 1H), 7.51-7.53 (m, 2H), 7.54 (s, 1H), 7.72 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 8.58 (d, J = 4.4 Hz, 1H), 8.76 (m , 1H), 8.88 (d, J = 1.5 Hz, 1H)
MS (DART) m / z: 322.1 [M + H] ⁺

Example 76 Synthesis Method F

2- (4-Isopropylphenyl) -4- (pyridin-2-ylmethoxymethyl) pyrazine
2- (4-Isopropylphenyl) -6- (pyridin-2-ylmethoxymethyl) -pyrazine
¹ H NMR (CDCl ₃ ) δ = 1.29 (d, J = 6.9 Hz, 6H), 2.94-3.01 (m, 1H), 4.85 (s, 2H), 4.89 (s, 2H), 7.20-7.24 (m, 1H), 7.35 (s, 1H), 7.37 (s, 1H), 7.54 (d, J = 7.8Hz, 1H), 7.72 (ddd, J = 7.7, 7.7, 1.8, 1H), 7.93 (s, 1H) , 7.95 (s, 1H), 8.58-8.59 (m, 1H), 8.71 (s, 1H), 8.92 (s, 1H)
MS (DART) m / z: 320.2 [M + H] ⁺

Example 77 Synthesis Method F

2- (3,4-methylenedioxyphenyl) -6- (pyridin-2-ylmethoxymethyl) pyrazine
2- (3,4-Methylenedioxyphenyl) -6- (pyridin-2-ylmethoxymethyl) -pyrazine
¹ H NMR (CDCl ₃ ) δ = 4.85 (s, 2H), 4.86 (s, 2H), 6.04 (s, 2H), 6.92 (dd, J = 7.4, 1.2 Hz, 1H), 7.20-7.24 (m, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.54 (s, 2H), 7.55 (s, 1H), 7.73 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 8.57-8.59 (m , 1H), 8.67 (m, 1H), 8.86 (s, 1H)
MS (DART) m / z: 322.1 [M + H] ⁺

Example 78 Synthesis Method O

2- (3-(((benzo [d] [1,3] dioxol-5-yl) methoxy) methyl) -1H-pyrrol-1-yl) pyridine
2- (3-(((Benzo [d] [1,3] dioxol-5-yl) methoxy) methyl) -1H-pyrrol-1-yl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.39 (s, 2H), 4.40 (s, 2H), 6.00 (s, 2H), 6.30-6.32 (m, 1H), 6.83-6.90 (m, 3H ), 7.21-7.24 (m, 1H), 7.65-7.70 (m, 3H), 7.88-7.89 (m, 1H), 8.41-8.43 (m, 1H)
MS (ESI) m / z: 309.2 (M + H)

Example 79 Synthesis Method K

2-(((1- (benzo [d] [1,3] dioxol-5-yl) -1H-pyrrol-3-yl) methoxy) methyl) pyridine
2-(((1- (Benzo [d] [1,3] dioxol-5-yl) -1H-pyrrol-3-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.47 (s, 2H), 4.57 (s, 2H), 6.07 (s, 2H), 6.21-6.31 (m, 1H), 6.92-7.07 (m, 2H ), 7.20-7.37 (m, 4H), 7.43-7.50 (m, 1H), 7.73-7.86 (m, 1H), 8.47-8.57 (m, 1H)
MS (ESI) m / z: 309.2 (M + H)

Example 81 Synthesis Method T

2-((3- (1,3-benzodioxsol-5-yl) isoxazol-5-yl) methoxymethyl) pyridine
2-((3- (1,3-Benzodioxol-5-yl) isoxazol-5-yl) methoxymethyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 4.79 (s, 2H), 4.80 (s, 2H), 6.05 (s, 2H), 6.56 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 7.24 -7.30 (m, 2H), 7.34-7.35 (m, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.74-7.78 (m, 1H), 8.60 (d, J = 4.1 Hz, 1H).
MS (ESI) m / z: 311 [M + H] ⁺

Example 82 Synthesis Method U

2-(((3- (4-isopropoxy-phenyl) -1,2,4-oxadiazol-5-yl) methoxy) methyl) pyridine
2-(((3- (4-Isopropoxyphenyl) -1,2,4-oxadiazol-5-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.30 (d, J = 6.0Hz, 6H), 4.73 (m, 1H), 4.78 (s, 2H), 5.02 (s, 2H), 7.07-7.11 ( m, 2H), 7.32-7.35 (m, 1H), 7.50 (d, J = 7.6Hz, 1H), 7.84 (td, J = 1.6, 7.6Hz, 1H), 7.92-7.95 (m, 2H), 8.54 -8.55 (m, 1H)
MS (ESI) m / z: 326.2 (M + H)

Example 83 Synthesis Method V

2-(((5- (4-isopropoxy-phenyl) -1,2,4-oxadiazol-3-yl) methoxy) methyl) pyridine
2-((((5- (4-Isopropoxyphenyl) -1,2,4-oxadiazol-3-yl) methoxy) methyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 1.40 (d, J = 6.0Hz, 6H), 4.65-4.71 (m, 1H), 4.83 (s, 2H), 4.87 (s, 2H), 6.98-7.02 (m, 2H), 7.21-7.24 (m, 1H), 7.55 (d, J = 8.0Hz, 1H), 7.71-7.75 (m, 1H), 8.08-8.12 (m, 2H), 8.58-8.60 (m, 1H)
MS (ESI) m / z: 348.3 (M + Na)

Example 84 Synthesis Method W

2-(((5- (4-isopropoxy-phenyl) -1,2,4-thiadiazol-3-yl) methoxy) methyl) pyridine
2-((((5- (4-Isopropoxyphenyl) -1,2,4-thiadiazol-3-yl) methoxy) methyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 1.39 (d, J = 6.0Hz, 6H), 4.63-4.69 (m, 1H), 4.90 (s, 2H), 4.96 (s, 2H), 6.95-6.98 (m, 2H), 7.19-7.22 (m, 1H), 7.59 (d, J = 7.6Hz, 1H), 7.72 (td, J = 1.6, 7.6Hz, 1H), 7.89-7.93 (m, 2H), 8.57-8.59 (m, 1H)
MS (ESI) m / z: 364.2 (M + Na)

Example 85 (Example 1 compound / oxalate): Synthesis method X

2-(((2- (benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine oxalic acid salt
2-(((2- (Benzo [d] [1,3] dioxol-5-yl) oxazol-4-yl) methoxy) methyl) pyridine monooxalate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.55 (s, 2H), 4.66 (s, 2H), 6.13 (s, 2H), 7.07 (d, J = 8.0Hz, 1H), 7.30-7.33 ( m, 1H), 7.44 (d, J = 1.6Hz, 1H), 7.48-7.55 (m, 2H), 7.80-7.85 (m, 1H), 8.17 (s, 1H), 8.52-8.54 (m, 1H)

An optical micrograph of the compound crystal of Example 85 is shown in FIG. The measurement conditions of the optical micrograph were as follows.
* Optical microscope Measuring device: Olympus BX61
Objective lens = UPlan FI 20X / 0.50
Eyepiece lens = WH10X / 22

Example 85 A powder X-ray of the compound crystal is shown in FIG. The measurement conditions of the powder X-ray were as follows.
* Powder X-ray measuring device: BRUKER D2 PHASER
<Measurement conditions>
Radiation: CuKα Time per step (s): 0.20
Generator tension: 30kV Step size (2θ): 0.02417
Generator current: 10mA Peak angle: 4-30 °
2θ value: 4.20, 16.83, 22.92

Example 85 The DSC of the compound crystal is shown in FIG. DSC measurement conditions were as follows.
* DSC
Measuring device: NETZSCH Japan Co., Ltd., differential scanning calorimeter DSC3100SA
<Measurement conditions>
Reference: Air
Sample Pan: Al
Sample amount: 5-10mg
Temperature increase rate: 5 ℃ / K
Measurement temperature range: 50 to 300 ° C
The melting point and heat of fusion were as shown in the table below.

Example 86 Synthesis Method Y

2-(((2-((1E) -2- (benzo [d] [1,3] dioxol-5-yl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2-((1E) -2- (benzo [d] [1,3] dioxol-5-yl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 4.52 (s, 2H), 4.64 (s, 2H), 6.07 (s, 2H), 6.94-7.04 (m, 2H), 7.16 (dd, 1H), 7.29-32 (m, 1H), 7.42-7.48 (m, 3H), 7.79-7.83 (m, 1H), 8.10 (s, 1H), 8.51-8.53 (m, 1H)
MS (ESI) m / z: 337.1 (M + H)

Example 87 Synthesis Method F

2- (2,4-dimethylphenyl) -5- (pyridin-2-ylmethoxymethyl) pyrazine
2- (2,4-Dimethylphenyl) -5- (pyridin-2-ylmethoxymethyl) pyrazine
¹ H NMR (CDCl ₃ ) δ = 2.40 (s, 6H), 4.88 (m, 4H), 7.14 (s, 1H), 7.16 (s, 1H), 7.23-7.27 (m, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.73-7.78 (m, 1H), 8.60-8.62 (m, 1H), 8.67 (s, 1H), 8.85 (s, 1H ).
MS (ESI) m / z: 306 [M + H] ⁺

Example 88 Synthesis Method H

2- (5- (4-isopropoxyphenyl) -isoxazol-3-ylmethoxymethyl) pyridine
2- (5- (4-Isopropoxyphenyl) isooxazol-3-ylmethoxymethyl) pyridine
1H NMR ((CD ₃ ) ₂ SO) δ = 1.29 (s, 3H), 1.30 (s, 3H), 4.62-4.79 (m, 5H), 6.98 (s, 1H), 7.00-7.09 (m, 2H) , 7.28-7.38 (m, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.78-7.89 (m, 3H), 8.51-8.59 (m, 1H)
MS (ESI) m / z: 325.3 (M + H)

Example 89 Synthesis Method H

2- (5- (4-ethoxyphenyl) -isoxazol-3-ylmethoxymethyl) pyridine
2- (5- (4-Ethoxyphenyl) -isoxazol-3-ylmethoxymethyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 1.46 (t, J = 7.0 Hz, 3H), 4.11 (q, J = 7.0 Hz, 2H), 4.77 (s, 2H), 4.78 (s, 2H), 6.54 (s , 1H), 6.97-6.99 (m, 1H), 7.23-7.28 (m, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.72-7.75 (m, 3H), 8.61 (d, J = 4.3 Hz, 1H).
MS (ESI) m / z: 311 [M + H] ⁺

Example 90 Synthesis Method H

2- (5- (2,3-dihydrobenzofuran-5-yl) -isoxazol-3-ylmethoxymethyl) pyridine
2- (5- (2,3-Dihydrobenzofuran-5-yl) -isoxazol-3-ylmethoxymethyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 3.29 (t, J = 8.8 Hz, 2H), 4.67 (t, J = 8.8 Hz, 2H), 4.78 (s, 2H), 4.79 (s, 2H), 6.51 (s , 1H), 6.87 (d, J = 8.3 Hz, 1H), 7.25-7.28 (m, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.75 -7.79 (m, 1H), 8.61 (d, J = 4.2 Hz, 1H).
MS (ESI) m / z: 309 [M + H] ⁺

Example 91 Synthesis Method H

2- (5- (4-methylsulfanylphenyl) -isoxazol-3-ylmethoxymethyl) pyridine
2- (5- (4-Methylsulfanyl) -isoxazol-3-ylmethoxymethyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 2.30-2.62 (m, 3H), 4.68 (s, 2H), 4.72 (s, 2H), 7.10 (s, 1H), 7.29-7.56 (m, 4H ), 7.67-7.91 (m, 3H), 8.49-8.59 (m, 1H)
MS (ESI) m / z: 313 [M + H] ⁺

Example 92 Synthesis Method K

2-((1- (1,3-benzodioxol-5-yl) -1H-imidazol-4-yl) methoxymethyl) pyridine
2-((1- (1,3-Benzodioxol-5-yl) -1H-imidazol-4-yl) methoxymethyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 4.66 (s, 2H), 4.78 (s, 2H), 6.05 (s, 2H), 6.83-6.85 (m, 3H), 7.15-7.19 (m, 1H), 7.22 ( s, 1H), 7.51-7.55 (m, 1H), 7.68-7.71 (m, 2H), 8.55-8.57 (m, 1H).
MS (ESI) m / z: 310 [M + H] ⁺

Example 93 Synthesis Method K

2-((1- (4-methoxyphenyl) -1H-imidazol-4-yl) methoxymethyl) pyridine
2-((1- (4-Methoxyphenyl) -1H-imidazol-4-yl) methoxymethyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 3.85 (s, 3H), 4.67 (s, 2H), 4.78 (s, 2H), 6.97, (s, 1H), 6.99 (s, 1H), 7.15-7.19 (m , 1H), 7.24-7.30 (m, 3H), 7.53-7.56 (m, 1H), 7.67-7.73 (m, 2H), 8.50-8.56 (m, 1H).
MS (ESI) m / z: 296 [M + H] ⁺

Example 94 Synthesis Method K

2-((1- (4-isopropoxyphenyl) -1H-imidazol-4-yl) methoxymethyl) pyridine
2-((1- (4-Isopropoxyphenyl) -1H-imidazol-4-yl) methoxymethyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 1.38 (d, J = 6.1 Hz, 6H), 4.59 (sept, J = 6.1 Hz, 1H), 4.69 (s, 2H), 4.80 (s, 2H), 6.96-6.99 (m, 2H), 7.18-7.21 (m, 1H), 7.26-7.30 (m, 3H), 7.56 (d, J = 7.8 Hz, 1H), 7.69-7.76 (m, 2H), 8.57 (d, J = 4.9 Hz, 1H).
MS (ESI) m / z: 324 [M + H] ⁺

Example 95 Synthesis Method K

2-((1- (2,3-dihydrobenzofuran-5-yl) -1H-imidazol-4-yl) methoxymethyl) pyridine
2-((1- (2,3-Dihydrobenzofuran-5-yl) -1H-imidazol-4-yl) methoxymethyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 3.30 (t, J = 8.7 Hz, 2H), 4.67 (d, = 8.7 Hz, 2H), 4.71 (s, 2H), 4.82 (s, 2H), 6.86 (d, J = 8.4 Hz, 1H), 7.12-7.14 (m, 1H), 7.22-7.25 (m, 3H), 7.58 (d, J = 7.8 Hz, 1H), 7.72-7.78 (m, 1H), 7.79 (s , 1H), 8.58 (d, J = 4.4 Hz, 1H).
MS (ESI) m / z: 308 [M + H] ⁺

Example 96 Synthesis Method U

2-(((3- (4-tert-butylphenyl) -1,2,4-oxadiazol-5-yl) methoxy) methyl) pyridine
2-(((3- (4-tert-Butylphenyl) -1,2,4-oxadiazol-5-yl) methoxy) methyl) pyridine
¹ H NMR (CDCl ₃ ) δ = 1.38 (s, 9H), 4.89 (s, 2H), 4.95 (s, 2H), 7.23-7.27 (m, 1H), 7.51-7.54 (m, 3H), 7.73- 7.77 (m, 1H), 8.03-8.06 (m, 2H), 8.59-8.61 (m, 1H)
MS (ESI) m / z: 323.7 (M + H)

Example 97 Synthesis Method X

2-(((5- (4-isopropoxy-phenyl) -1,2,4-thiadiazol-3-yl) methoxy) methyl) pyridine oxalic acid salt
2-((((5- (4-Isopropoxyphenyl) -1,2,4-thiadiazol-3-yl) methoxy) methyl) pyridine oxalate
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.31 (d, J = 6.0Hz, 6H), 4.73-4.78 (m, 3H), 4.89 (s, 2H), 7.08-7.11 (m, 2H), 7.31-7.34 (m, 1H), 7.52 (d, J = 8.0Hz, 1H), 7.84 (td, J = 2.0, 7.6Hz, 1H), 7.94-7.97 (m, 2H), 8.53-8.54 (m, 1H)

Example 98 Synthesis Method Y

2-(((2-((1E) -2- (4-methoxyphenyl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2-((1E) -2- (4-methoxyphenyl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 3.80 (s, 3H), 4.52 (s, 2H), 4.64 (s, 2H), 6.69-7.01 (m, 3H), 7.29-7.32 (m, 1H ), 7.45-7.49 (m, 2H), 7.66 (d, J = 20 Hz, 2H), 7.79-7.83 (m, 1H), 8.09 (s, 1H), 8.51-8.53 (m, 1H)
MS (ESI) m / z: 323.1 (M + H)

Example 99 Synthesis Method Y

2-(((2-((1E) -2- (4- (1-methylethoxy) phenyl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2-((1E) -2- (4- (1-methylethoxy) phenyl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.24 (d, J = 8.1 Hz, 6H), 4.52 (s, 2H), 4.66 (s, 2H), 4.67 (m, 1H), 6.93-6.99 ( m, 3H), 7.28-7.32 (m, 1H), 7.43-7.48 (m, 2H), 7.63 (d, J = 12 Hz, 2H), 7.79-7.83 (m, 2H), 8.09 (s, 1H) , 8.51-8.53 (m, 1H)
MS (ESI) m / z: 351.0 (M + H)

Example 100: Synthesis method Y

2-(((2-((1E) -2- (4- (1-methylethyl) phenyl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2-((1E) -2- (4- (1-methylethyl) phenyl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.20 (d, J = 8.1 Hz, 6H), 2.87-2.94 (m, 1H), 4.53 (s, 2H), 4.64 (s, 2H), 7.08 ( d, J = 16.0 Hz, 1H), 7.27-7.32 (m, 3H), 7.46-7.51 (m, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.79-7.83 (m, 1H), 8.12 (s, 1H), 8.51-8.53 (m, 1H)
MS (ESI) m / z: 335.2 (M + H)

Example 101 Synthesis Method Y

2-(((2-((1E) -2- (4- (1,1-dimethylethyl) phenyl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
2-(((2-((1E) -2- (4- (1,1-dimethylethyl) phenyl) ethenyl) oxazol-4-yl) methoxy) methyl) pyridine
¹ H NMR ((CD ₃ ) ₂ SO) δ = 1.31 (s, 9H), 4.53 (s, 2H), 4.64 (s, 2H), 7.09 (d, J = 16 Hz, 1H), 7.28-7.32 ( m, 1H), 7.42-7.51 (m, 4H), 7.63 (d, J = 8.0 Hz, 2H), 7.79-7.83 (m, 1H), 8.12 (s, 1H), 8.51-8.53 (m, 1H)
MS (ESI) m / z: 349.2 (M + H)

The effects of various compounds on the oral sensation of low-fat mayonnaise were investigated by sensory evaluation on the effects of various compounds on the oral sensation of low-fat mayonnaise. Each compound was added to low-fat mayonnaise (“Pure Select” Koku-Uma, manufactured by Ajinomoto Co., Inc., with a fat content of 22%), and the sensory evaluation was conducted by three professional evaluation panels on the strength of the oral sensation. The evaluation items were “mouth-coating feeling” and “tongue-coating feeling”. In addition, “Mouth-coating” means “the degree to which there is a leftover resedues, a slick, powdery or fating in the feelings of the mouth”. Defined. “Tonge-coating” means “the degree to what the is restorative, a slick, powdered or fating to the food.” defined). In addition, the score of the additive-free product was evaluated as 0, and the score of mayonnaise with a fat content of 72% (“Pure Select” mayonnaise manufactured by Ajinomoto Co., Inc.) was evaluated as 4. The results are shown in the table.
table. Effects of various compounds on oral sensation of low-fat mayonnaise

As shown in the table, all of the compounds of Examples 70, 67, 1, 34, 62, and 8 exhibited “Mouth-coating” and “Tonge-coating” on the tongue. Strengthened. From the above results, it was shown that by adding the compound of the present invention to a low-fat mayonnaise, the texture such as a coating feeling in the oral cavity and tongue is improved.

The effects of various compounds on the oral sensation of potage soup were investigated by sensory evaluation on the effects of various compounds on the oral sensation of potage soup. Specializing in the strength of oral sensation by adding each compound to potage soup (Ajinomoto Co. Cup soup "Potage": after removing croutons with a sieve and dissolving one bag in 150 mL of hot water) Sensory evaluation was performed by three evaluation panels. The evaluation items were “mouth-coating feeling” and “tongue-coating feeling”. In addition, “Mouth-coating” means “the degree to which there is a leftover resedues, a slick, powdery or fating in the feelings of the mouth”. Defined. “Tonge-coating” means “the degree to what the is restorative, a slick, powdered or fating to the food.” defined). The score for additive-free products is 0, 1 is “slightly strong”, 2 is “slightly strong”, 3 is “strong”, 4 is “very strong”, 5 is “imaginary” It was evaluated by a scoring method in increments of 0.1. The results are shown in the table. The evaluation results are shown as an average value ± standard error.
table. Effects of potage of each compound on oral sensation

As shown in the table, all of the compounds of Examples 67, 1, 34, 62, and 8 enhanced “Mouth-coating” and “Tonge-coating”. . Among these, Example 1 particularly enhanced “the coating feeling in the oral cavity” and “the coating feeling on the tongue”. From the above results, it was shown that by adding the compound of the present invention to the potage soup, the texture such as a coating feeling in the oral cavity and the tongue is improved.

The effect of various compounds on the oral sensation of pork bone ramen soup was investigated by sensory evaluation on the effect of various compounds on the oral sensation of pork bone ramen soup. One bag of powdered soup attached to a commercial instant pork bone ramen (“Maru-chan Masamen, Tonkotsu” manufactured by Toyo Suisan Co., Ltd.) was dissolved in 500 mL of hot water to prepare a pork bone ramen soup. Each compound was added to this pork bone ramen soup, and the sensory evaluation was performed by three professional evaluation panels on the intensity of oral sensation. The evaluation items were “mouth-coating feeling” and “tongue-coating feeling”. In addition, “Mouth-coating” means “the degree to which there is a leftover resedues, a slick, powdery or fating in the feelings of the mouth”. Defined. “Tonge-coating” means “the degree to what the is restorative, a slick, powdered or fating to the food.” defined). The score for additive-free products is 0, 1 is “slightly strong”, 2 is “slightly strong”, 3 is “strong”, 4 is “very strong”, 5 is “imaginary” It was evaluated by a scoring method in increments of 0.1. The results are shown in the table. The evaluation results are shown as an average value ± standard error.
table. Effects of various compounds on the oral sensation of pork bone ramen soup

As shown in the table, all of the compounds of Examples 67, 1, 34, 62, and 8 enhanced “Mouth-coating” and “Tonge-coating”. . Among these, the compound of Example 1 particularly enhanced the “coating feeling in the oral cavity” and the “coating feeling on the tongue”. From the above results, it was shown that by adding the compound of the present invention to pork bone ramen soup, the texture such as the coating feeling in the oral cavity and tongue is improved.

Claims

A compound represented by the following general formula (I) or a salt thereof.
Formula (I):

(Where
A represents a 5-membered or 6-membered heteroarylene group containing one or more heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring structure;
B represents an aryl group or a heteroaryl group selected from a pyridinyl group, a thiazolyl group and an imidazolyl group;
D represents a bond, a vinylene group or a vinylene group substituted with 1 or 2 alkyl groups having 1 to 3 carbon atoms;
X represents an oxygen atom or a sulfur atom,
Y represents a carbon atom or a nitrogen atom,
L represents an integer of 0 to 3,
R1 to R3 are hydrogen atom, halogen atom, hydroxyl group, cyano group, amino group, alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, arylthio group, arylamino group, alkenyl group Alkynyl group, acyl group, carboxyl group, sulfo group, phosphono group, alkylamino group, dialkylamino group, alkylthio group, acyloxy group, acylamino group, alkoxycarbonyl group, carbamoyl group or alkylcarbamoyl group, R1 to R3 Any two of them may form a ring which may contain a substituent and may contain 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
R4 to R6 are hydrogen atom, halogen atom, hydroxyl group, cyano group, amino group, alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, arylthio group, arylamino group, arylcarbonyl Group, alkenyl group, alkynyl group, acyl group, carboxyl group, sulfo group, phosphono group, alkylamino group, dialkylamino group, alkylthio group, acyloxy group, acylamino group, alkoxycarbonyl group, alkoxyalkyl group, carbamoyl group or alkylcarbamoyl Any one of R4 to R6 may have a substituent, and may contain 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. May form a ring,
R7 and R8 represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an amino group, an alkylamino group or a dialkylamino group, but an alkyl group of a dialkylamino group May be combined to form an alkylene group having 2 to 5 carbon atoms, or may be an oxy-lower alkyleneoxy group, and both ends of the oxy group may be bonded to ring B to form a condensed ring structure. Good,
Ra to Rd each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
However, in the formula, when D is a bond, X is an oxygen atom, A is a 5-membered or 6-membered heteroarylene group containing one sulfur atom and one nitrogen atom in the ring structure, L is 2 or 3 Represents
When D represents a bond, X represents a sulfur atom and B represents a pyridinyl group, R1, R2 and R3 are not simultaneously hydrogen atoms. )
Where D is a bond,
The compound or a salt thereof according to claim 1, wherein when X represents a 5-membered or 6-membered heteroarylene group containing an oxygen atom and A contains one or more sulfur atoms in the ring structure, L represents 3.
In the formula, A is one nitrogen atom, one oxygen atom, one nitrogen atom and one oxygen atom, one nitrogen atom and one sulfur atom, two nitrogen atoms, or nitrogen A 5-membered heteroarylene group having 2 atoms and 1 oxygen atom, or 2 nitrogen atoms and 1 sulfur atom, or a 6-membered heteroarylene group having 1 nitrogen atom or 2 nitrogen atoms Item 3. The compound according to Item 1 or 2, or a salt thereof.
The compound or a salt thereof according to any one of claims 1 to 3, wherein A is a heteroarylene group of the following formula.

(Wherein 1 # represents a binding site to D;
# 2 represents a bonding site to the carbon atom to which Ra and Rb are bonded)
The compound or a salt thereof according to any one of claims 1 to 4, wherein X is an oxygen atom.
The compound or a salt thereof according to any one of claims 1 to 5, wherein B is a pyridinyl group.
The compound or a salt thereof according to any one of claims 1 to 4, wherein X is a sulfur atom, and B is a thiazolyl group or an imidazolyl group.
The compound or a salt thereof according to any one of claims 1 to 7, wherein at least one of Ra and Rb represents a hydrogen atom, and at least one of Rc and Rd represents a hydrogen atom.
The compound or a salt thereof according to any one of claims 1 to 8, wherein L represents an integer of 1, 2, or 3, or when X is a sulfur atom, L represents 0.
In the formula, R1 to R3 each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms, or R1 to R3 The compound or a salt thereof according to any one of claims 1 to 9, wherein any two of them together form a 5- or 6-membered ring containing one or two oxygen atoms.
In the formula, any one of R1 to R3 is a hydrogen atom, and the remainder is a halogen atom, a hydroxyl group, a cyano group, an amino group, an alkyl group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms. The compound according to any one of claims 1 to 9, wherein the remaining two of R1 to R3 are combined to form a 5-membered ring or a 6-membered ring containing one or two oxygen atoms, or Its salt.
In the formula, any two of R1 to R3 are hydrogen atoms, and the rest are halogen atoms, hydroxyl groups, cyano groups, amino groups, aryloxy groups, alkyl groups having 1 to 4 carbon atoms, and having 1 to 3 carbon atoms. The compound or a salt thereof according to any one of claims 1 to 9, which represents an alkylthio group or an alkoxy group having 1 to 3 carbon atoms.
The salt is hydrochloride, sulfate, phosphate, nitrate, hydrobromide, acetate, trifluoroacetate, citrate, benzoate, maleate, fumarate, tartrate, succinate Acid salt, tannate, butyrate, hybenzate, pamoate, enanthate, decanoate, theocrate, salicylate, lactate, oxalate, mandelate, malate, methanesulfone The salt of the compound according to any one of claims 1 to 12, which is selected from the group consisting of acid salts, benzene sulfonates, and p-toluene sulfonates.
A food composition comprising the compound or salt thereof according to any one of claims 1 to 13.
A texture improving agent comprising the compound or salt thereof according to any one of claims 1 to 13.
A method for producing a food or drink comprising the step of adding and mixing the compound or salt thereof according to any one of claims 1 to 13 to a raw material for the food or drink.
A coating feeling on the tongue of the food and drink and / or a coating feeling in the oral cavity, comprising the step of adding and mixing the compound or salt thereof according to any one of claims 1 to 13 to the raw material or food or drink. A method of giving to food and drink.