WO2017164173A1 - Imidazole compound and medicine comprising same - Google Patents

Abstract

Provided is a novel compound which has an excellent Aβ aggregation-inhibiting activity and is useful as a medicine. An imidazole compound represented by general formula (1) (wherein A, B and C may be the same as or different from one another and independently represent a nitrogen atom or a carbon atom; X¹ and X² may be the same as or different from each other and independently represent -CH₂-, -O- or -S-; R¹ and R² may be the same as or different from each other and independently represent an aromatic hydrocarbon group that may have a substituent, or the like; R³ represents a hydrogen atom or a linear or branched alkyl group, and R⁴ represents a linear or branched alkyl group or a cyclic alkyl group, wherein R³ and R⁴ may together form a saturated heterocyclic ring in conjunction with an adjacent nitrogen atom; R⁵ represents a linear or branched alkyl group or a cyclic alkyl group; either one of R⁶ and R⁷ represents a hydrogen atom or an alkyl group; and the broken line in the imidazole ring means the presence of one double bond) or a salt thereof.

Description

Imidazole compound and pharmaceutical containing the same

The present invention relates to an imidazole compound and a pharmaceutical for preventing or treating a disease involving amyloid deposition such as Alzheimer's disease containing the imidazole compound.

Alzheimer's disease is a neurodegenerative disease having the pathological features of senile plaque formation and neurofibrillary tangles along with the degeneration and loss of nerve cells. Alzheimer's disease causes cognitive symptoms that result in progressive loss of memory, cognition, thinking, judgment, etc., and ultimately leads to death.
The main protein constituting senile plaques deposited in the brain is amyloid β peptide (Aβ), which consists of 39-43 amino acids. Aβ exhibits cytotoxicity, which is thought to cause Alzheimer's disease (Non-patent Document 1). Aβ secreted from cells is a polypeptide composed mainly of 40 or 42 amino acids, and in particular, Aβ consisting of 42 is more cohesive and deposits early in the brain and is highly cytotoxic. Is known (Non-Patent Document 2). Therefore, a drug that inhibits Aβ aggregation is expected as a preventive or therapeutic drug for Alzheimer's disease.

L- [Lys-Leu-Val-Phe-Phe], which is a partial sequence of Aβ, is known to have aggregation inhibitory activity against Aβ (Non-patent Document 3). In addition, the present inventor has reported that cyclic oligopeptides and picolinic acid amide derivatives have Aβ aggregation inhibitory activity (Non-patent Document 4).

However, since the Aβ aggregation inhibitory activity of the pentapeptide is extremely weak and is composed of natural amino acids, there is a concern about low metabolic stability. Moreover, the Aβ aggregation inhibitory action of cyclic oligopeptides and picolinic acid amides is not yet sufficient, and there is a problem that water solubility is low.
Therefore, an object of the present invention is to provide a new compound having an excellent Aβ aggregation inhibitory action and useful as a medicine.

Therefore, the present inventor has conducted various studies to find a low molecular compound having an Aβ aggregation inhibitory activity superior to that of the pentapeptide and the like. As a result, the imidazole compound represented by the following general formula (1) or a salt thereof is excellent. It has been found that it has aggregation inhibitory activity, has high water solubility, and is useful as a prophylactic and therapeutic agent for various diseases caused by amyloid deposition such as Alzheimer's disease.

That is, the present invention provides the following [1] to [22].
[1] The following general formula (1)

Wherein A, B and C are the same or different and each represents a nitrogen atom or a carbon atom;
X ¹ and X ² are the same or different and each represents —CH ₂ —, —O— or —S—;
R ¹ and R ² are the same or different and each represents a cyclic alkyl group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, or a heterocycle that may have a substituent. Represents a cyclic group;
R ³ represents a hydrogen atom or a linear or branched alkyl group;
R ⁴ represents a linear or branched alkyl group or a cyclic alkyl group;
R ³ and R ⁴ together with the adjacent nitrogen atom may form a saturated heterocyclic ring;
R ⁵ represents a linear or branched alkyl group or a cyclic alkyl group;
One of R ⁶ and R ⁷ represents a hydrogen atom or an alkyl group;
The dashed line in the imidazole ring indicates that there is one double bond. )
Or an salt thereof.
[2] The ring containing A, B and C is the following (a), (c), (d) or (e)

The imidazole compound or the salt thereof according to [1], which is a ring represented by the formula:
[3] The ring containing A, B and C is the following (c), (d) or (e)

The imidazole compound or salt thereof according to [1] or [2], which is a ring represented by
[4] The ring containing A, B and C is the following (c)

The imidazole compound or salt thereof according to any one of [1] to [3], which is a ring represented by the formula:
[5] The imidazole compound or salt thereof according to any one of [1] to [4], wherein X ¹ and X ² are the same or different and are —CH ₂ — or —O—.
[6] The imidazole compound or salt thereof according to any one of [1] to [5], wherein one of X ¹ and X ² is —O— and the other is —CH ₂ — or —O—.
[7] The imidazole compound or salt thereof according to any one of [1] to [6], wherein X ¹ and X ² are both —O—.
[8] R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, a nitro group, an amino group, mono C _1-4 1 to 5 selected from an alkylamino group, a di-C _1-4 alkylamino group and a halogeno C _1-4 alkyl group may be substituted, an aromatic hydrocarbon group having 6 to 14 carbon atoms, 8. The imidazole compound or salt thereof according to any one of [1] to [7], which is a cyclic alkyl group or a heterocyclic group.
[9] R ³ is a hydrogen atom or a linear or branched alkyl group having 1 to 12 carbon atoms; R ⁴ and R ⁵ are the same or different and are a hydrogen atom or a linear chain having 1 to 12 carbon atoms. Or a branched alkyl group or a cyclic alkyl group having 3 to 8 carbon atoms; R ³ and R ⁴ may form a saturated heterocyclic ring together with an adjacent nitrogen atom, [1] to [8 ] The imidazole compound or its salt in any one of.
[10] The imidazole compound or the imidazole compound according to any one of [1] to [9], wherein R ³ is a hydrogen atom, and R ⁴ and R ⁵ are the same or different and are a branched alkyl group having 3 to 8 carbon atoms. salt.
[11] The imidazole ring in the general formula (1) has one of the following structures:

The imidazole compound or salt thereof according to any one of [1] to [10], wherein one of R ⁶ and R ⁷ is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.
[12] The imidazole compound or salt thereof according to any one of [1] to [11] selected from the following compounds or salts thereof.

[13] An amyloid β peptide aggregation inhibitor comprising the imidazole compound or salt thereof according to any one of [1] to [12] as an active ingredient.
[14] A medicament comprising the imidazole compound or salt thereof according to any one of [1] to [12].
[15] The medicament according to [14], which is an Alzheimer's disease preventive or therapeutic drug.
[16] A pharmaceutical composition comprising the imidazole compound or a salt thereof according to any one of [1] to [12] and a pharmaceutically acceptable carrier.
[17] Use of the imidazole compound or salt thereof according to any one of [1] to [12] for the production of an amyloid β peptide aggregation inhibitor.
[18] Use of the imidazole compound or a salt thereof according to any one of [1] to [12] for the manufacture of an agent for preventing or treating Alzheimer's disease.
[19] The imidazole compound or salt thereof according to any one of [1] to [12] for inhibiting amyloid β peptide aggregation.
[20] The imidazole compound or salt thereof according to any one of [1] to [12] for preventing or treating Alzheimer's disease.
[21] A method for inhibiting amyloid β peptide aggregation, comprising administering the imidazole compound or salt thereof according to any one of [1] to [12].
[22] A method for preventing or treating Alzheimer's disease, comprising administering the imidazole compound or a salt thereof according to any one of [1] to [12].

The imidazole compound represented by the formula (1) or a salt thereof has an extremely excellent Aβ aggregation inhibitory activity and is excellent in water solubility, and therefore prevents or treats diseases caused by amyloid deposition such as Alzheimer's disease and Down's syndrome. It is useful as a medicinal product.

The Aβ aggregation inhibitory activity of the compound of the present invention is shown. 2 shows the concentration dependency of the Aβ aggregation inhibitory activity of compound (1-3).

In the formula (1), A, B and C are the same or different and represent a nitrogen atom or a carbon atom. Therefore, the ring containing A, B and C includes the following benzene rings and heterocycles.

Of these rings, (a), (c), (d) and (e) are more preferred, (c), (d) and (e) are more preferred, and (c) is more preferred.

In formula (1), X ¹ and X ² are the same or different and represent —CH ₂ —, —O— or —S—. Of these, —CH ₂ — or —O— is preferable. Furthermore, one of X ¹ and X ² is -O-, the other is -CH ₂ - and more preferably from or -O-, further preferably both X ¹ and X ² is -O- .

In formula (1), R ¹ and R ² are the same or different and have a cyclic alkyl group which may have a substituent, an aromatic hydrocarbon group which may have a substituent or a substituent. The heterocyclic group which may be carried out is shown. Examples of the aromatic hydrocarbon group include aromatic hydrocarbon groups having 6 to 14 carbon atoms, and specific examples include a phenyl group, an indenyl group, a naphthyl group, a biphenyl group, a phenanthrenyl group, and an anthracenyl group. Among these, a phenyl group, a naphthyl group, and a biphenyl group are more preferable, and a phenyl group is more preferable. As the cyclic alkyl group, a cyclic alkyl group having 5 to 8 carbon atoms is preferable, and a cyclic alkyl group having 5 to 6 carbon atoms is more preferable. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. The heterocyclic group is preferably a heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specific examples include pyrrolyl group, imidazolyl group, thienyl group, furyl group, pyridyl group, pyrimidyl group, triazinyl group, quinolyl group, morpholinyl group, piperidinyl group, piperazinyl group and the like.
Examples of the group which can be substituted with an aromatic hydrocarbon group, a cyclic alkyl group or a heterocyclic group include an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, a nitro group, amino _1-5 selected from a group, a mono C _1-4 alkylamino group, a di C _1-4 alkylamino group and a halogeno C _1-4 alkyl group. Here, examples of the alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and tert-butyl group. Examples of the alkoxy group having 1 to 4 carbon atoms include methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, and n-butyloxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the mono C _1-4 alkylamino group include a methylamino group, an ethylamino group, and an isopropylamino group. Examples of the diC _1-4 alkylamino group include a dimethylamino group, a diethylamino group, and a diisopropylamino group. Examples of the halogeno C _1-4 alkyl group include a chloromethyl group, a trichloromethyl group, and a trifluoromethyl group.

R ³ represents a hydrogen atom or a linear or branched alkyl group. R ⁴ and R ⁵ are the same or different and each represents a linear or branched alkyl group or a cyclic alkyl group. Here, examples of the linear or branched alkyl group include a linear or branched alkyl group having 1 to 12 carbon atoms, preferably a linear or branched alkyl group having 1 to 8 carbon atoms, More preferred are 8 branched alkyl groups. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, an isohexyl group, an isooctyl group, and a 2-ethylhexyl group.
Examples of the cyclic alkyl group include cyclic alkyl groups having 3 to 8 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

R ³ and R ⁴ may be combined with an adjacent nitrogen atom to form a saturated heterocyclic ring. The saturated heterocycle formed by R ³ , R ⁴ and a nitrogen atom is preferably a 5- or 6-membered saturated heterocycle containing one nitrogen atom and further containing an oxygen atom. For example, pyrrolidine, piperidine And morpholine.

R ³ is preferably a hydrogen atom, and R ⁴ and R ⁵ are preferably the same or different and are a linear or branched alkyl group or a cyclic alkyl group. More preferably, R ³ is a hydrogen atom, and R ⁴ and R ⁵ are the same or different and are a linear or branched alkyl group having 3 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms. More preferably, R ³ is a hydrogen atom, R ⁴ and R ⁵ are the same or different, and are a branched alkyl group having 3 to 8 carbon atoms.

One of R ⁶ and R ⁷ represents a hydrogen atom or an alkyl group. Here, the alkyl group is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group. The dashed line of the imidazole ring indicates that there is one double bond. This imidazole ring may have the following structure depending on the position of the double bond.

Of the imidazole compounds of the formula (1), compounds in which A and C are carbon atoms and B is a nitrogen atom (the structure of (c) above) are preferred. X ¹ and X ² are preferably —CH ₂ — or —O—, and particularly preferably both X ¹ and X ² are —O—. R ¹ and R ² are preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms, and more preferably a phenyl group. R ³ is a hydrogen atom, R ⁴ and R ⁵ are the same or different and are preferably a branched alkyl group having 3 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, and R ³ is a hydrogen atom More preferably, R ⁴ and R ⁵ are the same or different and are branched alkyl groups having 3 to 8 carbon atoms.

Of the imidazole compounds of formula (1), A and C are carbon atoms, B is a nitrogen atom; X ¹ and X ² are —O—; R ¹ and R ² are phenyl groups; More preferred are compounds wherein ³ is a hydrogen atom; and R ⁴ and R ⁵ are branched alkyl groups having 3 to 8 carbon atoms.

Examples of the salt of the imidazole compound of the formula (1) include pharmaceutically acceptable salts such as inorganic acid salts such as hydrochloride, sulfate, nitrate, carbonate, phosphate, trifluoroacetate, acetate, Acid addition salts such as organic acid salts such as acid salts and succinic acid salts.

The imidazole compound of the formula (1) or a salt thereof may have an asymmetric carbon atom, and in this case, each optically active substance and a mixture thereof are included.

Particularly preferred examples of the imidazole compound or a salt thereof of the present invention are the compounds or salts thereof described in Examples described later.

The imidazole compound or salt thereof of the present invention can be produced, for example, according to the following reaction formula.

(In the formula, Hal represents a halogen atom, Bpin represents a pinacolboranyl group, R ^a , R ^b and R ^c are the same or different and represent an amino protecting group, and A, B, C, X ¹ , X ² And R ¹ to R ⁷ are the same as the above, but only one of R ^a and R ^b is present.

That is, compound (4) is obtained by cross-coupling compound (2) and compound (3), and compound (1) is obtained by removing the amino protecting group.

Compound (2) can be produced according to a known method. Compound (3) can be produced from imidazole, for example, according to the following reaction formula.

(Wherein R ^b , R ^c , R ⁴ and Bpin are the same as above)

First, the amino group of imidazole (5) is protected to obtain compound (6). Examples of amino protecting groups include protecting groups that can be removed under acidic conditions such as trifluoroacetic acid, for example, silylalkyl groups such as trimethylsilylethoxymethyl group, and tert-butoxycarbonyl groups. The reaction for bonding the protecting group can be carried out, for example, by reacting a halogenated protecting group with imidazole (5) in the presence of a strong base. Specifically, the reaction may be performed at room temperature for 10 to 24 hours in the presence of a strong base such as sodium hydride.

Compound (6) is reacted with n-butyllithium and a copper bromide dimethylsulfide complex, and then reacted with an alkyl halide such as methylallyl bromide to obtain compound (7). This reaction is performed, for example, by reacting compound (6) with n-butyllithium, reacting with a copper bromide dimethylsulfide complex, and then reacting with methylallyl bromide. Specifically, the reaction may be carried out in an ether solvent such as tetrahydrofuran at a temperature of −80 to −150 ° C. for 1 hour to 10 hours.

Compound (8) is obtained by reducing Compound (7). This reaction is carried out by hydrogenation in the presence of a catalyst such as palladium / carbon. Specifically, the reaction may be carried out in an alcohol solvent such as methanol at room temperature for 10 to 48 hours.

Compound (9) is obtained by reacting Compound (8) with a halogenating agent such as N-bromosuccinimide. Halogenation may be carried out with chlorine as well as bromine. The halogenation reaction may be performed in a solvent such as chloroform at room temperature for 5 to 30 minutes.

Compound (10) is obtained by reacting compound (9) with n-butyllithium and then with a formylating agent. As the formylating agent, dimethylformamide, orthoformate, N-ethoxymethyleneaniline and the like can be used. The reaction may be performed in a solvent such as tetrahydrofuran at −80 ° C. to room temperature for 30 minutes to 3 hours.

Compound (11) is obtained by reducing compound (10). For the reduction reaction, for example, diisobutylaluminum hydride, lithium aluminum hydride, sodium borohydride and the like can be used. The reaction may be carried out in an ether solvent such as tetrahydrofuran at room temperature for 30 minutes to 3 hours.

Compound (12) is obtained by halogenating the imidazole ring of compound (11). The halogenation reaction can be performed using a halogenating agent such as N-bromosuccinimide. The reaction can be carried out at room temperature in a solvent such as chloroform.

Compound (13) is obtained by halogenating the hydroxy group of compound (12). The halogenation reaction of the hydroxy group is performed using a halogenating agent such as thionyl chloride. The reaction can be performed at room temperature in a solvent such as toluene.

Compound (14) is obtained by amination of compound (13). The amination reaction can be performed by reacting an N-protected alkylamine such as N-benzylisopropylamine. Examples of the amino-protecting group used herein include protecting groups that can be eliminated by a hydrogenation reaction such as a benzyl group or a benzyloxycarbonyl group. The reaction may be performed in a solvent such as dimethylformamide at room temperature for 10 to 36 hours.

Compound (15) is obtained by reacting compound (14) with a boron compound such as pinacol borane. As the boron compound, in addition to pinacol borane, an organic boron compound used for Suzuki Miyaura cross-coupling reaction is used. Here, the compound (15) is an example of the compound (3), and R ⁴ and R ⁵ can be appropriately changed. The reaction can be carried out in a solvent such as tetrahydrofuran at −80 ° C. to room temperature.

The reaction of the compound (2) and the compound (3) in the above reaction formula is a Suzuki Miyaura cross-coupling reaction, and is performed in the presence of a palladium catalyst and a base. Examples of the palladium catalyst include Pd (PPh ₃ ) ₄ , PdCl ₂ (dppf), and the like. As the base, potassium phosphate or the like is used. The reaction can be carried out at 30 to 100 ° C. in a solvent such as water and toluene.

Compound (1) is obtained by removing the amino protecting group of compound (4). The elimination reaction of the amino protecting group varies depending on the type of the protecting group. In the case of a protecting group that is eliminated by a reduction reaction such as a benzyl group or a benzyloxycarbonyl group, hydrogenation is performed under a palladium / carbon catalyst. It can be eliminated by the method. On the other hand, in the case of a protecting group such as a silylalkyl group or a t-butoxycarbonyl group that can be eliminated under acidic conditions, it can be eliminated by reacting with trifluoroacetic acid.

Also, the compound (1) can be produced by the following reaction formula.

(In the formula, THP represents a tetrahydropyranyl group, and R ¹ to R ⁷ , A, B, C, X ¹ , X ² , Hal, Bpin, and R ^b are the same as described above.)

In the above reaction formula, the compound (16) is obtained by reacting the compound (12) with 3,4-dihydropyran in the presence of an acid to tetrahydropyranylate, and then reacting this with pinacolborane. can get.

Compound (17) is obtained by coupling compound (2) and compound (16). This reaction is a Suzuki Miyaura cross-coupling reaction, and is performed in the same manner as the reaction of the compound (2) and the compound (3).

By removing the hydroxy protecting group (THP) and amino protecting group (R ^b ) of compound (17), compound (18) is obtained. This reaction can be performed by reacting an acid such as trifluoroacetic acid. Specifically, it can be performed at room temperature in a solvent such as dichloromethane.

Compound (19) is obtained by Dess-Martin oxidation of compound (18). For the Dess-Martin oxidation reaction, Dess-Martin periodinane (DMP) can be used. The reaction can be easily carried out at room temperature in a solvent such as dichloromethane.

Compound (20) and compound (21) are obtained by reacting compound (19) with an alkylating agent typified by a methylating agent such as methyl trifluoromethanesulfonate. This reaction proceeds easily at −80 ° C. to room temperature in a solvent such as dichloromethane.

Compound (1a) and Compound (1b) can be obtained by reacting Compound (20) or Compound (21) with alkylamine or the like. This reaction can be performed at room temperature by adding decaborane or the like in a solvent such as methanol.

The imidazole compound of the present invention or a salt thereof has an excellent Aβ aggregation inhibitory activity as shown in the examples below, and as an Aβ aggregation inhibitor, and diseases involving amyloid deposition and Aβ aggregation in animals including humans, such as It is useful as a preventive and therapeutic drug for Alzheimer's disease, Down's syndrome and the like.

When the imidazole compound of the present invention or a salt thereof is used as a medicine for the human body, the dosage is 1 mg to 1 g per day for an adult, preferably 10 mg to 300 mg.

The pharmaceutical composition containing the imidazole compound or a salt thereof of the present invention can be prepared by selecting an appropriate preparation according to the administration method and preparing various preparations using a pharmaceutically acceptable carrier. As the dosage form of the pharmaceutical composition mainly comprising the amide compound of the present invention or a salt thereof, for example, tablets, powders, granules, capsules, liquids, syrups, elixirs, oily or aqueous suspensions and the like are used orally. It can be illustrated as a formulation.

As injections, stabilizers, preservatives, and solubilizing aids may be used in the preparation. After storing a solution that may contain these adjuvants in a container, it may be prepared as a solid preparation by lyophilization or the like. It is good also as a formulation. Further, a single dose may be stored in one container, and multiple doses may be stored in one container.

Also, liquid preparations, suspensions, emulsions, ointments, gels, creams, lotions, sprays, patches and the like can be exemplified as external preparations.

The solid preparation includes amide compounds of the present invention or salts thereof and pharmaceutically acceptable additives. For example, fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants Agents and the like can be selected and mixed as necessary to prepare a formulation.
Examples of liquid preparations include solutions, suspensions, emulsions and the like, but additives may include suspending agents, emulsifiers and the like.

Hereinafter, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited to the following examples.

Synthesis example 1
1-((2- (Trimethylsilyl) ethoxy) methyl) -1H-imidazole (6-1)

According to the literature report (Chem. Eur. J. 2013, 19, 11301), colorless oily compound (6-1) was obtained in one step from 9.25 g of imidazole (22.1 g, yield 82%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.61 (1H, s), 7.12 (1H, s), 7.06 (1H, s), 3.49 (2H, t, J = 8. 2 Hz), 0.92 (2 H, t, J = 8.2 Hz), 0.00 (9 H, s)
ESI MS (positive): [M + H] ⁺ Found m / z 199

Synthesis example 2
2- (2-Methylallyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (7-1)

Compound (6-1) (9.69 g, 48.9 mmol) and tetrahydrofuran (490 mL) were added to an eggplant flask (1 L), stirred and cooled to −78 ° C., then 20.2 mL (2.66 M hexane) of normal butyl lithium. Solution, 53.7 mmol) was added dropwise and stirred for 30 minutes. Subsequently, copper (I) bromide dimethyl sulfide complex (1.00 g, 4.89 mmol) was added and stirred for 15 minutes, and then 3-bromo-2-methylprop-1-ene (5.50 mL, 53.7 mmol). Was added dropwise, and the mixture was warmed to room temperature and stirred for 5 hours. A saturated aqueous solution of ethylenediaminetetraacetic acid / trisodium salt was added to complete the reaction. Water and ethyl acetate were added to carry out a liquid separation operation, and the collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain a colorless oily compound (7-1) (7.96 g, yield 65%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.99 (1H, s), 6.95 (1H, s), 5.21 (2H, s), 4.88 (1H, s), 4.67 (1H, s), 3.54 (2H, s), 3.48 (2H, t, J = 8.4 Hz), 1.76 (3H, s), 0.91 (2H, t, J = 8) .4Hz), 0.00 (9H, s)
ESI MS (positive): [M + H] ⁺ Found m / z 253

Synthesis example 3
2-Isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (8-1)

Compound (7-1) (7.96 g, 31.6 mmol), palladium on carbon (10% w / w, 1.34 g, 1.26 mmol) and methanol (315 mL) were added to an eggplant flask (1 L) under a hydrogen atmosphere. Stir at room temperature for 24 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain a colorless oily compound (8-1) (7.61 g). Compound (8-1) was used in the next reaction without purification.

Synthesis example 4
5-Bromo-2-isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (9-1)

Compound (8-1) (7.60 g, 30.0 mmol) and chloroform (300 mL) were added to an eggplant flask (1 L), and the mixture was stirred at room temperature. N-bromosuccinimide (5.34 g, 30.0 mmol) was added and stirred for 5 minutes. A saturated aqueous sodium thiosulfate solution was added and stirred for 10 minutes, and water and chloroform were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a colorless oily compound (9-1) (9.79 g, yield 98% (2 steps) )).
¹ H NMR (400 MHz, CDCl ₃ ): δ 6.94 (1H, s), 5.26 (2H, s), 3.54 (2H, t, J = 8.4 Hz), 2.63 (2H, d, J = 7.6 Hz), 2.20 (1H, m), 0.98 (6H, d, J = 6.8 Hz), 0.90 (2H, t, J = 8.4 Hz),. 00 (9H, s)
ESI MS (positive): [M + H] ⁺ Found m / z 333,335 (1: 1)

Synthesis example 5
2-Isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole-5-carbaldehyde (10-1)

Compound (9-1) (9.79 g, 29.5 mmol) and tetrahydrofuran (300 mL) were added to an eggplant flask (1 L), and the mixture was stirred and cooled to -78 ° C. Normal butyl lithium (13.3 mL, 2.66 M hexane solution, 35.3 mmol) was added dropwise and stirred for 10 minutes. Subsequently, NN′-dimethylformamide (11.4 mL, 147.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 50 minutes. A saturated aqueous ammonium chloride solution was added to complete the reaction, and water and ethyl acetate were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain a colorless oily compound (10-1) (5.52 g, yield 66%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 9.70 (1H, s), 7.77 (1H, s), 5.77 (2H, s), 3.59 (2H, t, J = 8. 0 Hz), 2.71 (2H, d, J = 6.5 Hz), 2.31 (1H, m), 1.03 (6H, d, J = 6.4 Hz), 0.91 (2H, t, J = 8.0Hz), 0.00 (9H, s)
ESI MS (positive): [M + H] ⁺ Found m / z 283

Synthesis Example 6
(2-Isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-5-yl) methanol (11-1)

Compound (10-1) (5.52 g, 19.6 mmol) and tetrahydrofuran (200 mL) were added to an eggplant flask (1 L) and stirred, and diisobutylaluminum hydride (19.6 mL, 1.0 M hexane solution, 19.6 mmol) was added. Was added dropwise and stirred for 1 hour. A saturated aqueous solution of sodium potassium tartrate (Rochelle salt) was added to complete the reaction, and water and ethyl acetate were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was distilled off under reduced pressure to obtain a colorless oily compound (11-1) (4.19 g). Compound (11-1) was used in the next reaction without purification.

Synthesis example 7
(4-Bromo-2-isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-5-yl) methanol (12-1)

Compound (11-1) (1.28 g) and chloroform (45 mL) were added to an eggplant flask (200 mL), and the mixture was stirred at room temperature. Subsequently, N-bromosuccinimide (843 mg, 4.73 mmol) was added and stirred for 5 minutes. A saturated aqueous sodium thiosulfate solution was added and stirred for 10 minutes, and water and chloroform were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was distilled off under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a colorless oily compound (12-1) (1.66 g, yield 76% (2 steps) )).
¹ H NMR (500 MHz, CDCl ₃ ): δ 5.29 (2H, s), 4.63 (2H, s), 3.54 (2H, t, J = 7.6 Hz), 2.57 (2H, d, J = 7.5 Hz), 2.13 (1 H, m), 0.96 (3 H, d, J = 7.0 Hz), 0.92 (2 H, t, J = 7.6 Hz), 0. 00 (9H, s)
ESI MS (positive): [M + H] ⁺ Found m / z 363, 365 (1: 1)

Synthesis example 8
4-Bromo-5- (chloromethyl) -2-isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (13-1)

Compound (12-1) (773 mg, 2.12 mmol) and toluene (21 mL) were added to an eggplant flask (100 mL), and the mixture was stirred at room temperature. Thionyl chloride (185 μL, 2.55 mmol) was added and stirred for 15 minutes at room temperature. After completion of the reaction, the reaction solution was distilled off under reduced pressure to obtain a yellow solid compound (13-1) (777 mg). Compound (13-1) was used in the next reaction without purification.

Synthesis Example 9
N-benzyl-N-((4-bromo-2-isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-5-yl) methyl) propan-2-amine (14-1)

Compound (13-1) (777 mg) and dimethylformamide (18 mL) were added to an eggplant flask (100 mL), and the mixture was stirred at room temperature. N-benzylisopropylamine (3.0 mL, 18.6 mmol) was added and stirred at room temperature for 24 hours, and water and ethyl acetate were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was distilled off under reduced pressure, and then residual dimethylformamide and excess N-benzylisopropylamine were distilled off by lyophilization. The residue was washed with hexane, and the filtrate was distilled off under reduced pressure to obtain a yellow oily compound (14-1) (816 mg, yield 76% (2 steps)).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.23-7.30 (5H, m), 5.17 (2H, s), 3.61 (2H, s), 3.52 (2H, s) 3.16 (2H, t, J = 8.2 Hz), 2.94 (1H, m), 2.51 (2H, d, J = 6.0 Hz), 2.15 (1H, m), 1 .15 (6H, d, J = 6.4 Hz), 0.96 (6H, d, J = 6.8 Hz) 0.78 (2H, t, J = 8.2 Hz), 0.00 (9H, s )
ESI MS (positive): [M + Na] ⁺ Found m / z 516,518 (1: 1)

Synthesis Example 10
N-benzyl-N-((2-isobutyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-((2- (trimethylsilyl) ethoxy) Methyl) -1H-imidazol-5-yl) methyl) propan-2-amine (15-1)

The compound (14-1) (816 mg, 1.65 mmol) and tetrahydrofuran (17 mL) were added to an eggplant flask (100 mL), and the mixture was stirred and cooled to -78 ° C. Normal butyl lithium (745 μL, 2.66 M hexane solution, 1.98 mmol) was added dropwise and stirred for 10 minutes. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (600 μL, 2.97 mmol) was added, and the mixture was warmed to room temperature and stirred for 20 minutes. The reaction solution was evaporated under reduced pressure, the residue was washed with dichloromethane, and the filtrate was evaporated under reduced pressure to give a yellow oily compound (15-1) (1.10 g). Compound (15-1) was used in the next reaction without purification.

Synthesis Example 11
4-Bromo-2-isobutyl-5-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (16-1)

Compound (12-1) (43.2 mg, 120 μmol), paratoluenesulfonic acid (2.3 mg, 12.0 μmol) and tetrahydrofuran (1.2 mL) were added to an eggplant flask (20 mL), and the mixture was stirred at room temperature. Thereafter, 3,4-dihydro-2H-pyran (11.0 μL, 130 μmol) was added and stirred for 2 hours. The mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and subjected to liquid separation with water and ethyl acetate. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was distilled off under reduced pressure and purified by column chromatography with alumina (hexane: ethyl acetate = 1: 1) to obtain a yellow oily compound (16-1) (28.7 mg, 54%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 5.29-5.32 (2H, m), 4.52-4.73 (2H, m), 3.91 (1H, m), 3.46- 3.58 (3H, m), 2.58 (2H, d, J = 7.6 Hz), 2.19 (1H, m), 1.51-1.56 (6H, m), 0.97 ( 6H, d, J = 7.0 Hz), 0.91 (2H, t, J = 10.2 Hz), 0.00 (9H, s),
ESI MS (positive): [M + Na] ⁺ Found m / z 469,471 (1: 1)

Synthesis Example 12
2-Isobutyl-5-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (16-2)

Compound (16-1) (344 mg, 770 μmol) and tetrahydrofuran (7.7 mL) were added to an eggplant flask (50 mL), and the mixture was stirred and cooled to −78 ° C. Normal butyl lithium (345 μL, 2.66 M hexane solution, 0.92 mmol) was added dropwise and stirred for 10 minutes. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (280 μL, 1.39 mmol) was added, and the mixture was warmed to room temperature and stirred for 50 minutes. The solvent was distilled off under reduced pressure, the residue was washed with dichloromethane, and the filtrate was distilled off under reduced pressure to obtain a yellow oily compound (16-2) (468 mg). Compound (16-2) was used in the next reaction without purification.

Synthesis Example 13
2- (Methylthio) -4,6-diphenoxypyrimidine (2-a)

To an eggplant flask (50 mL) were added potassium tert-butoxide (1.18 g, 10.5 mmol), phenol (988 mg, 10.5 mmol), and tetrahydrofuran (5.0 mL), and the mixture was stirred for 5 minutes. Thereto was added 4,6-dichloro-2- (methylthio) pyrimidine (976 mg, 5.0 mmol) dissolved in 10 mL of tetrahydrofuran, followed by stirring for 10 hours. Thereafter, the mixture was stirred at 60 ° C. for 9 hours and cooled to room temperature. Water and ethyl acetate were added to carry out a liquid separation operation, and the collected organic layer was washed with 1M aqueous sodium hydroxide solution and saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was distilled off under reduced pressure to obtain a white solid compound (2-a) (1.60 g, yield 103%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.41 (4H, t, J = 8.0 Hz), 7.25 (2H, t, J = 8.0 Hz), 7.15 (4H, d, J = 8.0 Hz), 5.82 (1H, s), 2.30 (3H, s)
ESI MS (positive): [M + Na] ⁺ Found m / z 333

Synthesis Example 14
2- (Methylsulfonyl) -4,6-diphenoxypyrimidine (2-b)

Compound (2-a) (1.20 g, 3.87 mmol) and dichloromethane (40 mL) were added to an eggplant flask (100 mL), and the mixture was stirred for 5 minutes. Metachloroperbenzoic acid (purity <77%, 2.60 g, about 11.6 mmol) was added thereto and stirred for 20 minutes. A saturated aqueous sodium thiosulfate solution was added and stirred for 10 minutes, and then water and dichloromethane were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was distilled off under reduced pressure and purified by recrystallization in diethyl ether to obtain a white solid compound (2-b) (1.42 g, yield 107%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.45 (4H, t, J = 8.0 Hz), 7.31 (2H, t, J = 8.0 Hz), 7.17 (4H, d, J = 8.0 Hz), 6.32 (1H, s), 3.09 (3H, s)
ESI MS (positive): [M + Na] ⁺ Found m / z 365

Synthesis Example 15
4,6-Diphenoxypyrimidin-2-ol (2-c)

To the eggplant flask (100 mL) were added compound (2-b) (1.42 g, 4.15 mmol), tert-butyl alcohol (20 mL), and 1M aqueous sodium hydroxide solution (20 mL), and the mixture was stirred for 90 minutes with heating under reflux. After cooling to room temperature, 21 mL of a 1M hydrochloric acid aqueous solution was added, and then water and ethyl acetate were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was distilled off under reduced pressure to obtain a white solid compound (2-c) (1.07 g, yield 92%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.41 (4H, t, J = 8.0 Hz), 7.27 (2H, t, J = 8.0 Hz), 7.14 (4H, d, J = 8.0 Hz), 5.23 (1H, s)
ESI MS (positive): [M + Na] ⁺ Found m / z 303

Synthesis Example 16
2-Chloro-4,6-diphenoxypyrimidine (2-d)

Compound (2-c) (400 mg, 1.43 mmol) and dimethylformamide (14 mL) were added to an eggplant flask (50 mL), and phosphoryl chloride (663 μL, 7.14 mmol) was added dropwise thereto. The mixture was heated to 100 ° C., stirred for 90 minutes, cooled to 0 ° C., and then neutralized with a saturated aqueous sodium hydrogen carbonate solution. Water and ethyl acetate were added to carry out a liquid separation operation, and the collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain a colorless oily compound (2-d) (304 g, yield 71%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.44 (4H, t, J = 8.0 Hz), 7.29 (2H, t, J = 8.0 Hz), 7.15 (4H, d, J = 8.0 Hz), 6.09 (1H, s)
ESI MS (positive): [M + Na] ⁺ Found m / z 321

Synthesis Example 17
N-benzyl-N-((4- (4,6-diphenoxypyrimidin-2-yl) -2-isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-5-yl) Methyl) propan-2-amine (4-1)

In a test tube (15 mL) with a thread, compound (2-d) (10.9 mg, 36.6 μmmol), compound (15-1) (36.6 μmmol), dichloro [1,1′-bis (diphenylphosphino) ferrocene ] Palladium (2.7 mg, 3.66 μmol) and tripotassium phosphate (31.1 mg, 146 μmol) were added and dissolved in toluene (1.0 mL) and water (100 μL). The temperature was raised to 40 ° C., the mixture was stirred for 4 hours, cooled to room temperature, and water and ethyl acetate were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by preparative chromatography (hexane: ethyl acetate = 1: 2) to give a colorless oily compound (4-1) (1.5 mg, yield 6%). .
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.47 (4H, t, J = 8.0 Hz), 7.33-7.13 (11H, m), 5.91 (1H, s), 5. 20 (1H, s), 3.78 (2H, m), 3.12 (2H, s), 2.96 (2H, t, J = 8.4 Hz), 2.58 (3H, m), 2 .19 (1H, m), 0.91 (6H, d, J = 7.4 Hz), 0.80 (6H, d, J = 7.4 Hz), 0.63 (2H, t, J = 8. 4Hz), -0.08 (9H, s)
ESI MS (positive): [M + H] ⁺ Found m / z 678

Synthesis Example 18
N-((4- (4,6-Diphenoxypyrimidin-2-yl) -2-isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-5-yl) methyl) propane- 2-Amine (4-2)

Add compound (4-1) (1.5 mg, 2.21 μmmol), palladium on carbon (10% w / w, 0.2 mg, 0.221 μmmol), tetrahydrofuran (1.0 mL) to a test tube (15 mL) with a thread The mixture was stirred for 7 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain a colorless oily compound (4-2) (1.2 mg, yield 92%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.40 (4H, t, J = 8.0 Hz), 7.23 (2H, t, J = 8.0 Hz), 7.16 (4H, t, J = 8.0 Hz), 5.87 (1H, s), 5.30 (2H, s), 3.85 (2H, s), 3.50 (2H, t, J = 8.4 Hz), 2. 63 (2H, d, J = 7.2 Hz), 2.25 (2H, m), 0.96 (6H, d, J = 6.5 Hz), 0.89 (8H, m), −0.02 (9H, s)
ESI MS (positive): [M + H] ⁺ Found m / z 588

Synthesis Example 19
N-((5- (4,6-Diphenoxypyrimidin-2-yl) -2-isobutyl-1H-imidazol-4-yl) methyl) propan-2-amine bistrifluoroacetate (1-1)

Compound (4-2) (30.2 mg, 51.4 μmol), dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 mL) were added to an eggplant flask (20 mL), and the mixture was stirred at room temperature for 9 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to obtain white powdery compound (1-1) as a trifluoroacetate salt (27.9 mg, yield 79%).
¹ H NMR (400 MHz, CD ₃ CN): δ 7.49 (4H, t, J = 8.0 Hz), 7.33 (2H, t, J = 8.0 Hz), 7.23 (4H, t , J = 8.0 Hz), 6.21 (1H, s), 4.30 (2H, s), 2.80 (1H, m), 2.72 (2H, d, J = 7.6 Hz), 2.06 (1H, m), 1.15 (6H, d, J = 6.3 Hz), 0.90 (6H, d, J = 6.7 Hz)
ESI MS (positive): [M + H] ⁺ Found m / z 458

Synthesis Example 20
2- (2-Isobutyl-5-(((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-4-yl)- 4,6-Diphenoxypyrimidine (17-1)

An eggplant flask (50 mL) was charged with compound (2-d) (400 mg, 1.34 mmol), compound (16-2) (1.34 mmol), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (98 0.0 mg, 134 μmol) and tripotassium phosphate (1.14 g, 5.36 mmol) were added and dissolved in toluene (13.4 mL) and water (1.34 mL). The mixture was heated to 60 ° C., stirred for 1 hour, cooled to room temperature, and water and ethyl acetate were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 1: 1) to obtain a colorless oily compound (17-1) (430 mg, yield 51 %).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.43 (4H, t, J = 8.0 Hz), 7.27 (2H, t, J = 8.0 Hz), 7.19 (4H, d, J = 8.0 Hz), 5.91 (1 H, s), 5.38 (1 H, d, J = 10.3 Hz), 5.27 (1 H, d, J = 10.3 Hz), 4.95 (1 H) , D, J = 12.6 Hz), 4.73 (1H, d, J = 12.6 Hz), 4.09 (1 H, m), 3.78 (1 H, m), 3.49 (2 H, m) ), 3.39 (1H, m), 2.65 (2H, d, J = 7.2 Hz), 2.27 (1H, m), 1.73 (1H, m), 1.44-1. 56 (4H, m), 1.38 (1H, m), 0.962 (3H, d, J = 7.0 Hz), 0.957 (3H, d, J = 7.0 Hz), 0.89 ( 2H, m),- .02 (9H, s)
ESI MS (positive): M + Na] ⁺ Found m / z 653

Synthesis Example 21
(4- (4,6-Diphenoxypyrimidin-2-yl) -2-isobutyl-1H-imidazol-5-yl) methanol (18-1)

Compound (17-1) (104 mg, 165 μmol), dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL) were added to an eggplant flask (20 mL), and the mixture was stirred at room temperature for 9 hours. The solvent was distilled off under reduced pressure, dichloromethane was added to the residue, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and a liquid separation operation was performed. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by preparative chromatography (ethyl acetate) to obtain a colorless oily compound (18-1) (59.3 mg, yield 86%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.47 (4H, t, J = 8.0 Hz), 7.33 (2H, t, J = 8.0 Hz), 7.16 (4H, d, J = 8.0 Hz), 5.98 (1 H, s), 4.43 (2 H, s), 2.52 (2 H, d, J = 7.4 Hz), 2.03 (1 H, m),. 91 (6H, d, J = 6.5 Hz)
ESI MS (positive): [M + Na] ⁺ Found m / z 439

Synthesis Example 22
4- (4,6-Diphenoxypyrimidin-2-yl) -2-isobutyl-1H-imidazole-5-carbaldehyde (19-1)

Compound (18-1) (41.2 mg, 98.9 μmol), dichloromethane (1.0 mL) and Dess-Martin periodinane (62.9 mg, 148 μmol) were added to an eggplant flask (20 mL), and the mixture was stirred at room temperature for 15 minutes. did. The mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and subjected to a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a colorless oily compound (19-1) (38.6 mg, 94% yield). .
¹ H NMR (500 MHz, CDCl ₃ ): Major tatoomer δ 10.65 (1H, brs), 9.56 (1H, s), 7.45 (4H, m), 7.30 (2H, m), 7 .16 (4H, m), 6.04 (1H, s), 2.68 (2H, d, J = 7.4 Hz), 2.17 (1H, m), 0.94 (6H, d, J = 6.5 Hz), Minor tautomer δ 9.94 (1H, s), 9.88 (1H, brs), 7.45 (4H, m), 7.30 (2H, m), 7.16 (4H) M), 6.14 (1H, s), 2.59 (2H, d, J = 7.4 Hz), 2.07 (1H, m), 0.92 (6H, d, J = 6.5 Hz) )
(Major: Minor = 1.2: 1.0)
ESI MS (positive): [M + Na] ⁺ Found m / z 437

Synthesis Example 23
4- (4,6-Diphenoxypyrimidin-2-yl) -2-isobutyl-1-methyl-1H-imidazole-5-carbaldehyde (20-1), 5- (4,6-diphenoxypyrimidine-2 -Yl) -2-isobutyl-1-methyl-1H-imidazole-4-carbaldehyde (21-1)

Compound (19-1) (96.2 mg, 232 μmol) and dichloromethane (4.6 mL) were added to an eggplant flask (30 mL), and the mixture was cooled to −78 ° C. Methyl trifluoromethanesulfonate (28.1 μL, 255 μmol) was added dropwise, and the mixture was stirred for 3 hours while gradually warming to room temperature. The mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and subjected to a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by preparative chromatography (hexane: diethyl ether = 1: 1) to give a colorless oily compound (20-1) (27.5 mg, yield 28%), and colorless Oily compound (21-1) (9.5 mg, yield 10%) was obtained.
Compound (20-1): ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.93 (1H, s), 7.45 (4H, t, J = 8.0 Hz), 7.30 (2H, t, J = 8.0 Hz), 7.16 (4H, t, J = 8.0 Hz), 6.02 (1H, s), 3.82 (3H, s), 2.65 (2H, d, J = 7.4 Hz), 2.22 (1 H, m), 0.96 (6 H, d, J = 6.5 Hz)
ESI MS (positive): [M + H] ⁺ Found m / z 429
Compound (21-1): ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.92 (1H, s), 7.46 (4H, t, J = 8.0 Hz), 7.31 (2H, t, J = 8.0 Hz), 7.16 (4H, t, J = 8.0 Hz), 6.37 (1H, s), 3.41 (3H, s), 2.55 (2H, d, J = 7.4 Hz), 2.09 (1 H, m), 0.91 (6 H, d, J = 6.5 Hz)
ESI MS (positive): [M + H] ⁺ Found m / z 429

Synthesis Example 24
N-((4- (4,6-Diphenoxypyrimidin-2-yl) -2-isobutyl-1-methyl-1H-imidazol-5-yl) methyl) propan-2-amine bistrifluoroacetate (1a- 1)

Compound (20-1) (9.6 mg, 22.4 μmol), isopropylamine (7.7 μL, 89.6 μL) and methanol (2 mL) were added to an eggplant flask (20 mL), and the mixture was stirred for 5 minutes. Decaborane (2.7 mg, 22.4 mg) was added thereto, and the mixture was stirred at room temperature for 90 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel 60 (spherical) NH ₂ (Kanto Chemical), ordinary silica gel column chromatography, and preparative HPLC to obtain a white powdery compound (1a-1 ) As the trifluoroacetate salt (5.1 mg, 32% yield).
¹ H NMR (500 MHz, CD ₃ OD): δ 7.50 (4H, t, J = 8.0 Hz), 7.34 (2H, t, J = 8.0 Hz), 7.21 (4H, t, J = 8.0 Hz), 6.02 (1H, s), 4.60 (2H, s), 3.88 (3H, s), 2.93 (2H, d, J = 7.4 Hz), 2 .86 (1H, m), 2.13 (1H, m), 1.31 (6H, d, J = 7.0 Hz), 1.02 (6H, d, J = 6.9 Hz)
ESI MS (positive): [M + H] ⁺ Found m / z 472

Synthesis Example 25
N-((5- (4,6-Diphenoxypyrimidin-2-yl) -2-isobutyl-1-methyl-1H-imidazol-4-yl) methyl) propan-2-amine bistrifluoroacetate (1b- 1)

In the same manner as for compound (1a-1), white powdery compound (1b-1) was obtained as a trifluoroacetate salt from compound (21-1) (9.5 mg, 22.2 μmol) (7.1 mg). Yield 45%).
¹ H NMR (500 MHz, CD ₃ OD): δ 7.51 (4H, t, J = 8.0 Hz), 7.35 (2H, t, J = 8.0 Hz), 7.24 (4H, t, J = 8.0 Hz), 6.30 (1H, s), 4.20 (2H, s), 3.46 (3H, s), 3.03 (1H, m), 2.62 (2H, d) , J = 6.9 Hz), 2.02 (1H, m), 1.26 (6H, d, J = 7.0 Hz), 0.94 (6H, d, J = 6.9 Hz)
ESI MS (positive): [M + H] ⁺ Found m / z 472

Synthesis Example 26
((5-Bromo-1,3-phenylene) bis (oxy)) dibenzene (2-e)

According to a literature report (Angew. Chem. Int. Ed. 2015, 54, 13581), 1-bromo-3,5-difluorobenzene (1.93 g, 10.0 mmol) was used as a colorless oily compound (2- e) was obtained (2.20 g, 64% yield).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.38 (4H, t, J = 8.0 Hz), 7.17 (2H, t, J = 8.0 Hz), 7.05 (4H, t, J = 8.0 Hz), 6.82 (2 H, t, J = 2.0 Hz), 6.61 (1 H, t, J = 2.0 Hz)
DART (positive): [M + H] ⁺ Found m / z 341, 343 (1: 1)

Synthesis Example 27
N-benzyl-N-((4- (3,5-diphenoxyphenyl) -2-isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-5-yl) methyl) propane- 2-Amine (4-3)

In an eggplant flask (10 mL), compound (2-e) (40.8 mg, 120 μmol), compound (15-1) (73 mg), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (8. 8 mg, 12.0 μmol), tripotassium phosphate (102 mg, 480 μmol), toluene (2.0 mL), and water (0.2 mL) were added, and the mixture was stirred at 60 ° C. for 90 minutes. After cooling to room temperature, water and ethyl acetate were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain a yellow oily compound (4-3) (11.3 mg, 12% yield). .
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.40 (4H, t, J = 8.0 Hz), 7.11-7.30 (11H, m), 7.07 (2H, s), 6. 68 (1H, t, J = 0.8 Hz), 5.32 (2H, s), 3.72 (2H, s), 3.37 (2H, s), 3.25 (2H, t, J = 8.0 Hz), 2.83 (1 H, m), 2.58 (2 H, d, J = 7.5 Hz), 2.17 (1 H, m), 0.98 (6 H, d, J = 2. 0 Hz) 0.97 (6 H, d, J = 2.0 Hz), 0.82 (2 H, d, J = 8.0 Hz), 0.00 (9 H, s)
ESI MS (positive): [M + H] ⁺ Found m / z 676

Synthesis Example 28
N-((4- (3,5-diphenoxyphenyl) -2-isobutyl-1H-imidazol-5-yl) methyl) propan-2-amine bistrifluoroacetate (1-2)

In a recovery flask (10 mL), compound (4-3) (11.3 mg, 17.0 μmol), palladium on carbon (10% w / w, 8.9 mg, 8.50 μmol), methanol (170 μL), tetrahydrofuran (340 μL) were added. The mixture was further stirred for 15 hours. The reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. Dichloromethane (450 μL) and trifluoroacetic acid (450 μL) were added to the residue, and the mixture was stirred at 40 ° C. for 36 hours. The reaction solution was distilled off under reduced pressure, and the residue was purified by preparative HPLC to obtain white amorphous compound (1-2) as a trifluoroacetate salt (2.54 mg, yield 2 steps, 33%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.36 (3H, t, J = 8.0 Hz), 7.16 (2H, t, J = 7.5 Hz), 7.05 (5H, m), 6.78 (2H, d, J = 2.0 Hz), 6.63 (1H, s), 4.02 (2H, s), 3.08 (1H, m), 2.58 (2H, d, J = 7.0 Hz), 2.03 (1H, m), 1.31 (6H, d, J = 6.5 Hz), 0.87 (6H, d, J = 7.0 Hz)
ESI MS (positive): [M + H] ⁺ Found m / z 456

Synthesis Example 29
2,4,6-tribromopyridine

According to a literature report (Dyes and Pigments 2013, 96, 705), 2,4-dibromopyridine (11.4 g, 17.4 mmol) was obtained as a white solid 2,4,6-tribromopyridine from four steps. (5.49 g, yield 36%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.66 (2H, s)
DART (positive): [M + H] ⁺ Found m / z 316, 318 (1: 1)

Synthesis Example 30
4-bromo-2,6-diphenoxypyridine (4-3), 2-bromo-4,6-diphenoxypyridine (4-4)

Phenol (20 g) and sodium metal (300 mg, 12.5 mmol) were placed in a thick vial for a microwave synthesizer and stirred at 60 ° C. for 1 hour. After cooling to 0 ° C., 2,4,6-tribromopyridine (2.00 g, 6.33 mmol) was added and stirred at 80 ° C. for 1 hour, then set in a microwave synthesizer and 195 ° C. under microwave irradiation. For 24 hours. The mixture was cooled to 80 ° C., dropped into 100 mL of 1M aqueous sodium hydroxide solution, and stirred until the supernatant became transparent. The solution was filtered, the residue was washed with water and dried, and then purified by column chromatography (hexane: diethyl ether = 50: 1 to 20: 1) to give a white solid compound (4-3) (1.91 g, Yield 89%) and white solid compound (4-4) (118 mg, yield 5%).
Compound 4-3: ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.35 (4H, t, J = 8.0 Hz), 7.20 (2H, t, J = 8.0 Hz), 7.11 ( 4H, d, J = 8.0 Hz), 6.67 (2H, s)
ESI MS (positive): [M + Na] ⁺ Found m / z 364, 366 (1: 1)
Compound 4-4: ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.34 (2H, t, J = 8.0 Hz), 7.29 (2H, t, J = 8.0 Hz), 7.18 ( 1H, t, J = 8.0 Hz), 7.11 (1H, t, J = 8.0 Hz), 7.04 (2H, d, J = 8.0 Hz), 7.00 (2H, d, J = 8.0 Hz), 6.63 (1H, d, J = 1.7 Hz), 6.19 (1H, d, J = 1.7 Hz)
ESI MS (positive): [M + Na] ⁺ Found m / z 364, 366 (1: 1)

Synthesis Example 31
N-benzyl-N-((4- (4,6-diphenoxypyridin-2-yl) -2-isobutyl-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-5-yl) Methyl) propan-2-amine (4-5)

In an eggplant flask (10 mL), compound (4-4) (41.0 mg, 120 μmol), compound (15-1) (120 μmol), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (8. 8 mg, 12.0 μmol), tripotassium phosphate (102 mg, 480 μmol), toluene (2.0 mL), and water (0.2 mL) were added, and the mixture was stirred at 60 ° C. for 90 minutes. After cooling to room temperature, water and ethyl acetate were added to carry out a liquid separation operation. The collected organic layer was washed with saturated brine, dehydrated with sodium sulfate, and the solution was filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain a yellow oily compound (4-5) (26.6 mg, yield 32%). .
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.50 (4H, m), 7.20-7.38 (12 H, m), 6.28 (1 H, d, J = 2.0 Hz), 5. 26 (2H, s), 3.90 (2H, s), 3.22 (2H, s), 3.08 (2H, t, J = 8.0 Hz), 2.70 (1H, m), 2 .58 (2H, d, J = 7.5 Hz), 2.18 (1H, m), 1.00 (6H, d, J = 7.0 Hz), 0.90 (6H, d, J = 7. 0 Hz), 0.74 (2H, t, J = 8.0 Hz), 0.00 (9H, s)
ESI MS (positive): [M + H] ⁺ Found m / z 677

Synthesis Example 32
N-((5- (4,6-Diphenoxypyridin-2-yl) -2-isobutyl-1H-imidazol-4-yl) methyl) propan-2-amine bistrifluoroacetic acid (1-3)

In a recovery flask (10 mL), compound (4-5) (26.6 mg, 39.0 μmol), palladium on carbon (10% w / w, 20.8 mg, 19.5 μmol), methanol (390 μL), tetrahydrofuran (780 μL) were added. The mixture was further stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were added to the residue, and the mixture was stirred at 40 ° C. for 36 hours. After cooling to room temperature, the reaction solution was distilled off under reduced pressure and purified by preparative HPLC to obtain amorphous compound (1-3) as a trifluoroacetate salt (16.2 mg, yield 2 steps 90%).
¹ H NMR (500 MHz, CDCl ₃ ): δ 7.38 (5H, m), 7.22 (2H, m), 7.08 (2H, d, J = 8.0 Hz), 7.02 (2H, d, J = 7.5 Hz), 6.20 (1H, s), 4.33 (2H, s), 2.87 (1H, m), 2.70 (2H, d, J = 7.5 Hz) , 2.03 (1H, m), 1.23 (6H, d, J = 5.5 Hz), 0.86 (6H, d, J = 6.5 Hz)
ESI MS (positive): [M + H] ⁺ Found m / z 457

Test Example 1 (Aβ aggregation inhibition test)
To a 0.1 M phosphate buffer solution (pH 7.4, 50 μL) containing Aβ O-acyl isopeptide (10 μM), a test sample solution (DMSO solution) was added (sample final concentration 50 μM, 1% DMSO), 37 After incubating at 0 ° C. for an arbitrary time, a part of the reaction solution (10 μL) is added to a mixed solution of thioflavin T solution (50 μM thioflavin T, 10 μL) and 50 mM glycine-NaOH buffer (pH 8.5, 396 μL) and immediately mixed. The fluorescence intensity of thioflavin T was measured. In the fluorescence intensity measurement, an excitation wavelength of 440 nm and a fluorescence wavelength of 480 nm were used.

The obtained results are shown in FIG. 1 as the aggregation inhibition ratio when the activity of the DMSO solution used for the control is 100.
As a result, the compound (1b-1), the compound (1-2) and the compound (1-3) of the present invention are more excellent in inhibiting Aβ aggregation than the cyclic oligopeptides and picolinic acid amides described in Non-Patent Document 4. showed that.

In addition, FIG. 2 shows the concentration dependency of the Aβ aggregation inhibitory activity of the compound (1-3).

Claims (22)

1. The following general formula (1)
   

   

   Wherein A, B and C are the same or different and each represents a nitrogen atom or a carbon atom;
   X ¹ and X ² are the same or different and each represents —CH ₂ —, —O— or —S—;
   R ¹ and R ² are the same or different and each represents a cyclic alkyl group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, or a heterocycle that may have a substituent. Represents a cyclic group;
   R ³ represents a hydrogen atom or a linear or branched alkyl group;
   R ⁴ represents a linear or branched alkyl group or a cyclic alkyl group;
   R ³ and R ⁴ together with the adjacent nitrogen atom may form a saturated heterocyclic ring;
   R ⁵ represents a linear or branched alkyl group or a cyclic alkyl group;
   One of R ⁶ and R ⁷ represents a hydrogen atom or an alkyl group;
   The dashed line in the imidazole ring indicates that there is one double bond. )
   Or an salt thereof.
2. The ring containing A, B and C is the following (a), (c), (d) or (e)
   

   

   The imidazole compound or a salt thereof according to claim 1, which is a ring represented by the formula:
3. The ring containing A, B and C is the following (c), (d) or (e)
   

   

   The imidazole compound or a salt thereof according to claim 1 or 2, which is a ring represented by
4. The ring containing A, B and C is the following (c)
   

   

   The imidazole compound or a salt thereof according to any one of claims 1 to 3, which is a ring represented by the formula:
5. The imidazole compound or a salt thereof according to any one of claims 1 to 4, wherein X ¹ and X ² are the same or different and are -CH ₂ -or -O-.
6. 6. The imidazole compound or a salt thereof according to claim 1, wherein one of X ¹ and X ² is —O— and the other is —CH ₂ — or —O—.
7. The imidazole compound or a salt thereof according to any one of claims 1 to 6, wherein X ¹ and X ² are both -O-.
8. R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a halogen atom, a nitro group, an amino group, or a mono C _1-4 alkylamino group. 1-6 selected from di-C _1-4 alkylamino group and halogeno C _1-4 alkyl group, an optionally substituted aromatic hydrocarbon group having 6 to 14 carbon atoms, cyclic group having 5 to 8 carbon atoms The imidazole compound or a salt thereof according to any one of claims 1 to 7, which is an alkyl group or a heterocyclic group.
9. R ³ is a hydrogen atom, or a linear or branched alkyl group having 1 to 12 carbon atoms; R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a linear or branched chain having 1 to 12 carbon atoms; The alkyl group or a cyclic alkyl group having 3 to 8 carbon atoms; R ³ and R ⁴ may be combined with an adjacent nitrogen atom to form a saturated heterocyclic ring. Or an salt thereof.
10. The imidazole compound or a salt thereof according to any one of claims 1 to 9, wherein R ³ is a hydrogen atom, and R ⁴ and R ⁵ are the same or different and are a branched alkyl group having 3 to 8 carbon atoms.
11. The imidazole ring in the general formula (1) has one of the following structures:
    

    

    The imidazole compound or a salt thereof according to any one of claims 1 to 10, wherein one of R ⁶ and R ⁷ is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.
12. The imidazole compound or salt thereof according to any one of claims 1 to 11, which is selected from the following compounds or salts thereof.
    

    
13. An amyloid β peptide aggregation inhibitor comprising the imidazole compound or salt thereof according to any one of claims 1 to 12 as an active ingredient.
14. A pharmaceutical comprising the imidazole compound or a salt thereof according to any one of claims 1 to 12.
15. The medicament according to claim 14, which is an Alzheimer's disease preventive or therapeutic drug.
16. A pharmaceutical composition comprising the imidazole compound or a salt thereof according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier.
17. Use of the imidazole compound or a salt thereof according to any one of 1 to 12 for producing an amyloid β peptide aggregation inhibitor.
18. Use of the imidazole compound or salt thereof according to any one of 1 to 12 for the manufacture of an Alzheimer's disease preventive or therapeutic drug.
19. The imidazole compound or salt thereof according to any one of 1 to 12, which inhibits amyloid β peptide aggregation.
20. The imidazole compound or a salt thereof according to any one of 1 to 12, for preventing or treating Alzheimer's disease.
21. A method for inhibiting amyloid β peptide aggregation, comprising administering the imidazole compound or a salt thereof according to any one of claims 1 to 12.
22. A method for preventing or treating Alzheimer's disease, comprising administering the imidazole compound or a salt thereof according to any one of claims 1 to 12.

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