JP2017066078A - Imidazo pyridine derivative and pharmaceutical use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound having an imidazo pyridine structure having 5-HT2C receptor agonistic action.SOLUTION: The present invention provides an imidazo pyridine derivative represented by the following compound or a pharmacologically acceptable acid addition salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a novel imidazopyridine derivative and its pharmaceutical use.

  The serotonin (hereinafter 5-HT) 2 receptor is one of seven transmembrane G protein-coupled receptors and is classified into three subtypes: 5-HT2A, 5-HT2B and 5-HT2C. Among them, 5-HT2C receptor has been reported to be expressed in the central nervous system mainly in the spinal cord (Non-patent Document 1).

［式中、
Ｒ^１は、Ｈ又はＣ１〜８アルキルであり、
Ｒ^２は、Ｃ１〜４アルキル、−ＣＨ_２−Ｏ−（Ｃ１〜４アルキル）、−ＣＨ_２−Ｏ−（Ｃ１〜４ハロアルキル）又は−ＣＨ_２ＯＨであり、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６はそれぞれ独立して、Ｈ、Ｃ１〜４アルキル、アミノ、シアノ、ハロゲン、Ｃ１〜４ハロアルキル、ニトロ又はＯＨである、
ただしＲ^２がＣ１〜４アルキル、−ＣＨ_２−Ｏ−（Ｃ１〜４アルキル）及び−ＣＨ_２ＯＨの場合は、Ｒ^３及びＲ^６はどちらも水素ではない。］ Here, as a conventionally known 5-HT2C receptor agonist, a benzazepine derivative represented by the following general formula (A) is disclosed, and a benzazepine derivative represented by the general formula (A) is obesity and It has been reported that it can be used as a therapeutic or prophylactic agent for related disorders (Patent Document 1).

[Where:
R ¹ is H or C 1-8 alkyl;
R ² is, C1 -4 _alkyl, -CH 2 -O- _{(C1~4 alkyl),} - CH 2 -O- is (C1 -4 haloalkyl) or _{^{-CH 2 OH, R 3, R}} 4, R 5 And R ⁶ are each independently H, C 1-4 alkyl, amino, cyano, halogen, C 1-4 haloalkyl, nitro or OH.
However, if ^{R 2} is a C1 -4 _alkyl, -CH 2 -O- (C1~4 alkyl) and _-CH 2 OH, ^{R 3} and ^{R 6} are not both hydrogen. ]

  In addition, as a specific action of a benzazepine derivative that is a 5-HT2C receptor agonist, an antifeedant action is known (Non-Patent Documents 2 and 3). As a benzazepine derivative targeting the 5-HT2C receptor marketed so far, lorcaserine approved in the United States in 2012 has been reported (Non-patent Document 4).

  5-HT2C receptor is also involved in peripheral nerve function, and administration of a piperazine derivative, which is a 5-HT2C receptor agonist, increases urethral resistance when rat abdominal pressure increases (Non-Patent Document 5). ), Prolongation of time from insertion to ejaculation in the mating behavior test of monkeys (Non-patent Document 6) and efficacy against rat neuropathic pain model by intrathecal administration (Non-patent Document 7) have been reported Yes. Similarly, induction of penile erection in rats by administration of furindazole derivative, which is a 5-HT2C receptor agonist (Non-patent Document 8), and efficacy for rat inflammatory pain model by intrathecal administration of indole derivatives Sexuality has been reported (Non-Patent Document 9).

［式中、
Ｒ^５は水素原子、塩素原子、メチル基又はトリフルオロメチル基から選択され、
Ｒ^６は水素原子、メチル基又はトリフルオロメチル基から選択される。］ On the other hand, as a compound having an imidazopyridine structure, a compound represented by the following general formula (B) as a dopamine D3 receptor antagonist and a compound represented by the following general formula (C) as its synthesis intermediate have been reported ( Non-patent document 10).

[Where:
R ⁵ is selected from a hydrogen atom, a chlorine atom, a methyl group or a trifluoromethyl group;
R ⁶ is selected from a hydrogen atom, a methyl group or a trifluoromethyl group. ]

International Publication No. 2005/003096

L. A. Helton et al., NeuroReport, 1994, Volume 5, p. 2617-2620 S. R. Smith et al., Obesity, 2008, 17, p. 494-503 W. J. et al. Thomsen et al., The Journal of Pharmacology and Experimental Therapeutics, 2008, Vol. 325, p. 577-587 L. E. Miller, Journal of The Academy of Nutrition and Dietetics, 2013, Vol. 113, p. 25-30 M.M. Miyazaki et al., American Journal of Physiology, Renal Physiology, 2009, 297, p. F1024-1031 S. M.M. Pomerantz et al., Psychopharmacology, 1993, 111, p. 47-54 H. Obata et al., Pain, 2004, 108, p. 163-169 Y. Kimura et al., European Journal of Pharmacology, 2004, 483, p. 37-43 S. Hao et al., Annesthesia and Analgesia, 2003, 96, p. 1072-1078 F. Micheli et al., Bioorganic and Medicinal Chemistry Letters, 2008, Vol. 18, p. 908-912

  However, Patent Document 1 and Non-Patent Documents 1 to 9 only describe the function of 5-HT2C receptor and benzazepine derivatives, piperazine derivatives, furindazole derivatives and indole derivatives as 5-HT2C receptor agonists.

  Further, Non-Patent Document 10 discloses a compound having an imidazopyridine structure, but only describes a function as an antagonist of dopamine D3 receptor, and it does not have any effect on 5-HT2C receptor. Not listed.

  That is, the prior art has neither suggested nor disclosed a compound having an imidazopyridine structure that is 5-HT2C receptor agonistic.

  Then, an object of this invention is to provide the compound which has the imidazopyridine structure which shows 5-HT2C receptor operation | movement.

［式中、ｍは、１又は２を表し、
ｍが１を表す場合、Ｒ^１及びＲ^２は、それぞれ独立して、水素原子、プロピル基、ブチル基又はシクロプロピル基を表し、Ｒ^３及びＲ^４は、水素原子を表し、
ｍが２を表す場合、Ｒ^１は、水素原子、臭素原子、プロピル基又はシクロプロピル基を表し、Ｒ^２及びＲ^３は、それぞれ独立して、水素原子、臭素原子又はプロピル基を表し、Ｒ^４は、水素原子、臭素原子又はトリフルオロメチル基を表し、
Ｒ^１〜Ｒ^４はいずれか１つのみが水素原子以外を表す。］ As a result of intensive studies to achieve the above object, a novel imidazopyridine derivative exhibiting high 5-HT2C receptor agonist activity has been found and the present invention has been completed. That is, the present invention provides an imidazopyridine derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof.

[Wherein m represents 1 or 2,
When m represents 1, R ¹ and R ² each independently represent a hydrogen atom, a propyl group, a butyl group or a cyclopropyl group, R ³ and R ⁴ represent a hydrogen atom,
When m represents 2, R ¹ represents a hydrogen atom, bromine atom, propyl group or cyclopropyl group, R ² and R ³ each independently represent a hydrogen atom, bromine atom or propyl group, R ⁴ represents a hydrogen atom, a bromine atom or a trifluoromethyl group,
Only one of R ^{1 to} R ⁴ represents other than a hydrogen atom. ]

  These compounds are particularly useful as 5-HT2C receptor agonists because of their high 5-HT2C receptor agonistic properties.

  The present invention also provides a medicament comprising as an active ingredient an imidazopyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof.

  Furthermore, the present invention provides a 5-HT2C receptor agonist containing the imidazopyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

  The imidazopyridine derivative of the present invention or a pharmacologically acceptable acid addition salt thereof has high 5-HT2C receptor agonist activity, and is used as a therapeutic or prophylactic agent for diseases related to 5-HT2C receptor. be able to.

［式中、
ｍは、１又は２を表し、
ｍが１を表す場合、Ｒ^１及びＲ^２は、それぞれ独立して、水素原子、プロピル基、ブチル基又はシクロプロピル基を表し、Ｒ^３及びＲ^４は、水素原子を表し、
ｍが２を表す場合、Ｒ^１は、水素原子、臭素原子、プロピル基又はシクロプロピル基を表し、Ｒ^２及びＲ^３は、それぞれ独立して、水素原子、臭素原子又はプロピル基を表し、Ｒ^４は、水素原子、臭素原子又はトリフルオロメチル基を表し、
Ｒ^１〜Ｒ^４は、いずれか１つのみが水素原子以外を表す。］、 The imidazopyridine derivative of the present invention is characterized by being represented by the following general formula (I).

[Where:
m represents 1 or 2,
When m represents 1, R ¹ and R ² each independently represent a hydrogen atom, a propyl group, a butyl group or a cyclopropyl group, R ³ and R ⁴ represent a hydrogen atom,
When m represents 2, R ¹ represents a hydrogen atom, bromine atom, propyl group or cyclopropyl group, R ² and R ³ each independently represent a hydrogen atom, bromine atom or propyl group, R ⁴ represents a hydrogen atom, a bromine atom or a trifluoromethyl group,
Any ^{one of} R ^{1 to} R ⁴ represents other than a hydrogen atom. ],

Here, preferred specific examples of m and R ^{1 to} R ⁴ in the general formula (I) are shown below.

When m represents 1, R ² is preferably a hydrogen atom or a propyl group, R ¹ is preferably a cyclopropyl group, and R ² is more preferably a hydrogen atom.

When m represents 2, R ¹ is preferably a hydrogen atom, bromine atom or propyl group, R ¹ is a hydrogen atom or propyl group, R ² is a hydrogen atom, and R ³ is a hydrogen atom or propyl group. , R ⁴ is more preferably a hydrogen atom or a bromine atom.

  Examples of the pharmacologically acceptable acid addition salt of the imidazopyridine derivative represented by the above general formula (I) include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphorus. Inorganic acid salts such as acid salts, acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate or phthalate Organic carboxylates such as acid salts or organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, etc. Hydrochloride, phosphate, tartrate or methanesulfonate are preferred, and hydrochloride, tartrate or methanesulfonate are more preferred.

  Specific examples of preferable compounds of the imidazopyridine derivative represented by the above general formula (I) are shown in Table 1, but the present invention is not limited thereto.

  The imidazopyridine derivative represented by the above general formula (I) can be produced, for example, by the method exemplified in the examples described later. The starting materials and reagents used in this production are generally available and can be synthesized by known methods.

  The imidazopyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has 5-HT2C receptor agonist activity. For example, Jerman et al. (European Journal of Pharmacology). 2001, vol. 414, p. 23-30), and can be confirmed in an in vitro experimental system using cells expressing the human 5-HT2C receptor. Specifically, for example, human 5-HT2C receptor can be forcibly expressed in HEK-293 cells derived from human fetal kidney, and the increase in intracellular calcium concentration due to the operability of the compound can be measured.

  Since the imidazopyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has 5-HT2C receptor agonist activity, it can be used as a medicine based on the agonist activity. For example, the above medicament can be used as a therapeutic and prophylactic agent for obesity, stress urinary incontinence, male erectile dysfunction, premature ejaculation, neuropathic pain or inflammatory pain.

  The imidazopyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is a mammal (eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human). In particular, it can be used as a useful medicament when administered to humans.

  When the imidazopyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is used clinically as a pharmaceutical, the imidazopyridine derivative represented by the above general formula (I) or The pharmacologically acceptable acid addition salt may be used as it is, or additives such as excipients, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents or isotonic agents. May be appropriately mixed. Moreover, said pharmaceutical can be manufactured by a normal method using these pharmaceutical carriers as appropriate. Examples of the above-mentioned pharmaceutical administration forms include oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or liquids, or topical administration. Examples include ointments, creams, patches, and the like. Further, it may be a known continuous preparation.

  The medicament preferably contains 0.00001 to 90% by weight of the imidazopyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof. It is more preferable to contain by weight. The dose is appropriately selected according to the patient's symptom, age and weight, and administration method. As an amount of the active ingredient for an adult, 0.1 μg to 1 g per day for an injection, 1 μg to 10 g for an oral formulation, In the case of a patch, 1 μg to 10 g is preferable and can be administered once or several times.

  Examples of the pharmaceutically acceptable carrier or diluent of the above-mentioned pharmaceutical include, for example, binders (syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride, tragacanth, etc.), excipients (sugar, lactose, corn starch, calcium phosphate, Sorbitol or glycine) or a lubricant (magnesium stearate, polyethylene glycol, talc, silica, etc.).

  The above medicines may be used in combination with or in combination with other drugs in order to supplement or enhance the therapeutic effect or preventive effect or to reduce the dose.

  EXAMPLES Hereinafter, although an Example and a reference example are shown and this invention is explained in full detail, this invention is not limited to these.

  In addition, about the compound which is not described in the synthesis method among the compounds used for the synthesis | combination of a compound, the commercially available compound was used. The solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (manufactured by JEOL Ltd.). The chemical shift is represented by δ (unit: ppm) with reference to tetramethylsilane, and the signals are s (single line), brs (wide single line), d (double line), t (triple line), dd, respectively. (Double double line), dt (double triple line), tq (triple quadruple line), m (multiple line). The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology). The silica gel was thin layer chromatography (hereinafter TLC) Silica gel 60 F254 (Merck KGaA) and YFLC W-prep2XY (Yamazen) was used for the chromatography. Monowave 300 (manufactured by Anton-Paar) was used as the microwave reaction apparatus.

１０ｍＬフラスコに、２−アミノ−４−ブロモピリジン（２０ｍｇ、０．１２ｍｍｏｌ）、ｔｅｒｔ−ブチル ３−ブロモ−４−オキソピペリジン−１−カルボキシラート（３２ｍｇ、０．１２ｍｍｏｌ）及び炭酸水素ナトリウム（１２ｍｇ、０．１４ｍｍｏｌ）を量り取り、２−プロパノール（０．５ｍＬ）を加え、８０℃で９０時間撹拌した。反応混合物を濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９８／２）で精製し、ｔｅｒｔ−ブチル ７−ブロモ−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、参考例１の化合物）（２５ｍｇ、７２μｍｏｌ）を白色固体として得た（収率６２％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.74 (1H, d, J = 1.2 Hz), 7.66 (1H, d, J = 7.1 Hz), 6.92 (1H, dd, J = 7.1, 2.0 Hz), 4.68 (2H, brs), 3.82 (2H, brs), 2.92 (2H, brs), 1.51 (9H, s).
MS (ESI): m/z 352 ([M+H]⁺). Reference Example 1 Synthesis of tert-butyl 7-bromo-3,4-dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate:

To a 10 mL flask was added 2-amino-4-bromopyridine (20 mg, 0.12 mmol), tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (32 mg, 0.12 mmol) and sodium bicarbonate (12 mg, 0.14 mmol) was weighed, 2-propanol (0.5 mL) was added, and the mixture was stirred at 80 ° C. for 90 hours. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (chloroform only to chloroform / methanol = 98/2), and tert-butyl 7-bromo-3,4-dihydroimidazo [1, 2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter, the compound of Reference Example 1) (25 mg, 72 μmol) was obtained as a white solid (yield 62%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.74 (1H, d, J = 1.2 Hz), 7.66 (1H, d, J = 7.1 Hz), 6.92 (1H, dd, J = 7.1, 2.0 Hz) , 4.68 (2H, brs), 3.82 (2H, brs), 2.92 (2H, brs), 1.51 (9H, s).
MS (ESI): m / z 352 ([M + H] ⁺ ).

１０ｍＬマイクロウェーブ反応容器に、２−アミノ−３−ブロモピリジン（０．１０ｇ、０．５８ｍｍｏｌ）及びｔｅｒｔ−ブチル ３−ブロモ−４−オキソピペリジン−１−カルボキシラート（０．１６ｇ、０．５８ｍｍｏｌ）を量り取り、１，２−ジメトキシエタン（２ｍＬ）を加えた後、ジイソプロピルエチルアミン（以下、ＤＩＰＥＡ）（７５ｍｇ、０．５８ｍｍｏｌ）を加え、マイクロウェーブ反応装置を用い１４０℃で９０分間撹拌した。反応混合物を濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサンのみ〜ｎ−ヘキサン／酢酸エチル＝３４／６６）で精製し、ｔｅｒｔ−ブチル ６−ブロモ−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、参考例２の化合物）（２９ｍｇ、８１μｍｏｌ）を淡黄色油状物として得た（収率１４％）。
¹H-NMR (400MHz, CD₃OD) δ: 7.78 (1H, d, J = 6.6 Hz), 7.45 (1H, d, J = 7.3 Hz), 6.72 (1H, t, J = 7.0 Hz), 4.71 (2H, brs), 3.83 (2H, brs), 2.99 (2H, brs), 1.60 (9H, s).
MS (ESI): m/z 352 ([M+H]⁺). (Reference Example 2)
Synthesis of tert-butyl 6-bromo-3,4-dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate:

In a 10 mL microwave reaction vessel, add 2-amino-3-bromopyridine (0.10 g, 0.58 mmol) and tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.16 g, 0.58 mmol). After adding 1,2-dimethoxyethane (2 mL), diisopropylethylamine (hereinafter, DIPEA) (75 mg, 0.58 mmol) was added, and the mixture was stirred at 140 ° C. for 90 minutes using a microwave reactor. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (n-hexane only to n-hexane / ethyl acetate = 34/66), and tert-butyl 6-bromo-3,4- Dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter referred to as the compound of Reference Example 2) (29 mg, 81 μmol) was obtained as a pale yellow oil (yield) 14%).
¹ H-NMR (400MHz, CD ₃ OD) δ: 7.78 (1H, d, J = 6.6 Hz), 7.45 (1H, d, J = 7.3 Hz), 6.72 (1H, t, J = 7.0 Hz), 4.71 (2H, brs), 3.83 (2H, brs), 2.99 (2H, brs), 1.60 (9H, s).
MS (ESI): m / z 352 ([M + H] ⁺ ).

１０ｍＬフラスコに、参考例１の化合物（２０ｍｇ、５７μｍｏｌ）及びＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２（４．６ｍｇ、５．７μｍｏｌ）を量り取り、１，４−ジオキサン（０．６ｍＬ）を加えた。ここにジメチル亜鉛（１．０Ｍ ｎ−ヘキサン溶液、０．２３ｍＬ、０．２３ｍｍｏｌ）を加えた後、５５℃で１４時間撹拌した。反応混合物を室温まで冷却した後、水及び飽和塩化アンモニウム水溶液を加え、酢酸エチルで３回抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（アンモニア飽和クロロホルムのみ〜アンモニア飽和クロロホルム／メタノール＝９０／１０）で精製し、ｔｅｒｔ−ブチル ７−メチル−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、中間体１）（１２ｍｇ、４２μｍｏｌ）を黄色固体として得た（収率７４％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.66 (1H, d, J = 6.8 Hz), 7.31 (1H, s), 6.65 (1H, dd, J = 6.8, 1.0 Hz), 4.67 (2H, brs), 3.82 (2H, brs), 2.91 (2H, brs), 2.40 (3H, s), 1.51 (9H, s).
MS (ESI): m/z 288 ([M+H]⁺). Reference Example 3 Synthesis of 7-methyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride:

In a 10 mL flask, weigh the compound of Reference Example 1 (20 mg, 57 μmol) and PdCl ₂ (dppf) · CH ₂ Cl ₂ (4.6 mg, 5.7 μmol), and add 1,4-dioxane (0.6 mL). It was. Dimethyl zinc (1.0 M n-hexane solution, 0.23 mL, 0.23 mmol) was added thereto, followed by stirring at 55 ° C. for 14 hours. The reaction mixture was cooled to room temperature, water and a saturated aqueous ammonium chloride solution were added, the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by flash silica gel column chromatography (ammonia saturated chloroform only-ammonia saturated chloroform / methanol = 90/10), and tert-butyl 7- Methyl-3,4-dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter intermediate 1) (12 mg, 42 μmol) was obtained as a yellow solid ( Yield 74%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.66 (1H, d, J = 6.8 Hz), 7.31 (1H, s), 6.65 (1H, dd, J = 6.8, 1.0 Hz), 4.67 (2H, brs), 3.82 (2H, brs), 2.91 (2H, brs), 2.40 (3H, s), 1.51 (9H, s).
MS (ESI): m / z 288 ([M + H] ⁺ ).

The obtained intermediate 1 (12 mg, 42 μmol) was dissolved in 1,4-dioxane (0.1 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 7-methyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride (Hereinafter, the compound of Reference Example 3) (10 mg, 43 μmol) was obtained as a white solid (yield 100%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.57 (1H, d, J = 7.1 Hz), 7.78 (1H, s), 7.46 (1H, dd, J = 7.0, 1.3 Hz), 4.72 (2H , s), 3.75 (2H, t, J = 6.0 Hz), 3.28 (2H, t, J = 6.0 Hz), 2.63 (3H, s).
MS (ESI): m / z 188 ([M + H] ⁺ ).
mp: 255-260 ° C.

１０ｍＬマイクロウェーブ反応容器に、２−アミノ−３−メチルピリジン（７０ｍｇ、０．６５ｍｍｏｌ）及びｔｅｒｔ−ブチル ３−ブロモ−４−オキソピペリジン−１−カルボキシラート（０．１８ｇ、０．６５ｍｍｏｌ）を量り取り、エタノール（２ｍＬ）を加え、マイクロウェーブ反応装置を用い１４０℃で７５分間撹拌した。反応混合物を濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサンのみ〜ｎ−ヘキサン／酢酸エチル＝３４／６６）で精製し、ｔｅｒｔ−ブチル ６−メチル−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、中間体２）を無色油状物として得た。 Reference Example 4 Synthesis of 6-methyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride:

In a 10 mL microwave reaction vessel weigh 2-amino-3-methylpyridine (70 mg, 0.65 mmol) and tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.18 g, 0.65 mmol). And ethanol (2 mL) was added and stirred for 75 minutes at 140 ° C. using a microwave reactor. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (n-hexane only to n-hexane / ethyl acetate = 34/66), and tert-butyl 6-methyl-3,4- Dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter intermediate 2) was obtained as a colorless oil.

The obtained intermediate 2 was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at room temperature for 2 hours. The crude product obtained by concentrating the reaction mixture was purified by preparative TLC (chloroform / ammonia saturated chloroform / methanol = 6/6/1), and then the obtained solid was dissolved in methanol (1 mL). % Hydrogen chloride-methanol (0.17 mL) was added, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 6-butyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride (Hereinafter, the compound of Reference Example 4) (16 mg, 84 μmol) was obtained as a white solid (two-stage yield 13%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.53 (1H, d, J = 6.8 Hz), 7.86 (1H, d, J = 7.3 Hz), 7.49 (1H, t, J = 7.1 Hz), 4.74 (2H, s), 3.77 (2H, t, J = 6.1 Hz), 3.34 (2H, t, J = 6.1 Hz), 2.67 (3H, s).
MS (ESI): m / z 188 ([M + H] ⁺ ).
mp: 269-274 ° C.

１０ｍＬフラスコに、テトラヒドロフラン（以下、ＴＨＦ）（０．５ｍＬ）を加え、０℃に冷却した後、ｎ−プロピルマグネシウムクロリド（２Ｍ ＴＨＦ溶液、０．１３ｍＬ、０．２６ｍｍｏｌ）及びジクロロ亜鉛（１．９Ｍ ２−メチルＴＨＦ溶液、９０μＬ、０．１７ｍｍｏｌ）を加え、室温で３０分撹拌した。ここにＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２（４．６ｍｇ、５．７μｍｏｌ）及びＴＨＦ（０．５ｍＬ）に溶解した参考例１の化合物（２０ｍｇ、５７μｍｏｌ）を加え、５５℃で１３時間撹拌した。反応混合物を室温まで冷却した後、水及び飽和塩化アンモニウム水溶液を加え、酢酸エチルで３回抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（アンモニア飽和クロロホルムのみ〜アンモニア飽和クロロホルム／メタノール＝９０／１０）で精製し、ｔｅｒｔ−ブチル ７−プロピル−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、中間体３）（１１ｍｇ、３５μｍｏｌ）を黄色油状物として得た（収率６１％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.68 (1H, d, J = 6.8 Hz), 7.32 (1H, s), 6.67 (1H, dd, J = 7.0, 1.3 Hz), 4.68 (2H, brs), 3.81 (2H, brs), 2.91 (2H, brs), 2.63 (2H, t, J = 7.4 Hz), 1.68 (2H, tq, J = 7.4, 7.4 Hz), 1.51 (9H, s), 0.96 (3H, t, J = 7.3 Hz).
MS (ESI): m/z 316 ([M+H]⁺). Example 1 Synthesis of 7-propyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride:

Tetrahydrofuran (hereinafter referred to as THF) (0.5 mL) was added to a 10 mL flask, cooled to 0 ° C., and then n-propylmagnesium chloride (2M THF solution, 0.13 mL, 0.26 mmol) and dichlorozinc (1.9 M). 2-methyl THF solution, 90 μL, 0.17 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To this was added PdCl ₂ (dppf) · CH ₂ Cl ₂ (4.6 mg, 5.7 μmol) and the compound of Reference Example 1 (20 mg, 57 μmol) dissolved in THF (0.5 mL), and the mixture was stirred at 55 ° C. for 13 hours. did. The reaction mixture was cooled to room temperature, water and a saturated aqueous ammonium chloride solution were added, the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by flash silica gel column chromatography (ammonia saturated chloroform only-ammonia saturated chloroform / methanol = 90/10), and tert-butyl 7- Propyl-3,4-dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter intermediate 3) (11 mg, 35 μmol) was obtained as a yellow oil. (Yield 61%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.68 (1H, d, J = 6.8 Hz), 7.32 (1H, s), 6.67 (1H, dd, J = 7.0, 1.3 Hz), 4.68 (2H, brs), 3.81 (2H, brs), 2.91 (2H, brs), 2.63 (2H, t, J = 7.4 Hz), 1.68 (2H, tq, J = 7.4, 7.4 Hz), 1.51 (9H, s), 0.96 (3H, t, J = 7.3 Hz).
MS (ESI): m / z 316 ([M + H] ⁺ ).

The obtained intermediate 3 (11 mg, 35 μmol) was dissolved in 1,4-dioxane (0.1 mL), 4M hydrogen chloride-1,4-dioxane solution (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. . The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 7-propyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride (Hereinafter, the compound of Example 1) (5.5 mg, 22 μmol) was obtained as a white solid (yield 63%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.54 (1H, d, J = 6.3 Hz), 7.74 (1H, s), 7.45 (1H, d, J = 7.3 Hz), 4.70 (2H, s ), 3.74 (2H, t, J = 6.1 Hz), 3.28 (2H, t, J = 6.2 Hz), 2.87 (2H, t, J = 7.6 Hz), 1.78 (2H, tq, J = 7.3, 7.3 Hz) ), 1.02 (3H, t, J = 7.4 Hz).
MS (ESI): m / z 216 ([M + H] ⁺ ).
mp: 163-167 ° C.

１０ｍＬフラスコに、ＴＨＦ（０．１ｍＬ）を加え、０℃に冷却した後、ｎ−ブチルマグネシウムクロリド（０．９４Ｍ ＴＨＦ溶液、０．２７ｍＬ、０．２６ｍｍｏｌ）及びジクロロ亜鉛（１．９Ｍ ２−メチルＴＨＦ溶液、９０μＬ、０．１７ｍｍｏｌ）を加え、室温で３０分撹拌した。ここにＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２（４．６ｍｇ、５．７μｍｏｌ）及びＴＨＦ（０．５ｍＬ）に溶解した参考例１の化合物（２０ｍｇ、５７μｍｏｌ）を加え、５５℃で１５時間撹拌した。反応混合物を室温まで冷却した後、水及び飽和塩化アンモニウム水溶液を加え、酢酸エチルで３回抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝３５／６５〜０／１００）で精製し、ｔｅｒｔ−ブチル ７−ブチル−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、中間体４）（１２ｍｇ、３７μｍｏｌ）を無色油状物として得た（収率６５％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.68 (1H, d, J = 6.8 Hz), 7.32 (1H, s), 6.67 (1H, dd, J = 6.8, 1.5 Hz), 4.68 (2H, brs), 3.81 (2H, brs), 2.91 (2H, brs), 2.66 (2H, t, J = 7.6 Hz), 1.67-1.59 (2H, m), 1.51 (9H, s), 1.37 (2H, m), 0.93 (3H, t, J = 7.3 Hz).
MS (ESI): m/z 330 ([M+H]⁺). Example 2 Synthesis of 7-butyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride:

After adding THF (0.1 mL) to a 10 mL flask and cooling to 0 ° C., n-butylmagnesium chloride (0.94 M THF solution, 0.27 mL, 0.26 mmol) and dichlorozinc (1.9 M 2-methyl) were added. (THF solution, 90 μL, 0.17 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To this was added PdCl ₂ (dppf) · CH ₂ Cl ₂ (4.6 mg, 5.7 μmol) and the compound of Reference Example 1 (20 mg, 57 μmol) dissolved in THF (0.5 mL), and the mixture was stirred at 55 ° C. for 15 hours. did. The reaction mixture was cooled to room temperature, water and a saturated aqueous ammonium chloride solution were added, the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by flash silica gel column chromatography (n-hexane / ethyl acetate = 35 / 65-0 / 100) to give tert-butyl 7- Butyl-3,4-dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter intermediate 4) (12 mg, 37 μmol) was obtained as a colorless oil. (Yield 65%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.68 (1H, d, J = 6.8 Hz), 7.32 (1H, s), 6.67 (1H, dd, J = 6.8, 1.5 Hz), 4.68 (2H, brs), 3.81 (2H, brs), 2.91 (2H, brs), 2.66 (2H, t, J = 7.6 Hz), 1.67-1.59 (2H, m), 1.51 (9H, s), 1.37 (2H, m ), 0.93 (3H, t, J = 7.3 Hz).
MS (ESI): m / z 330 ([M + H] ⁺ ).

Intermediate 4 (12 mg, 37 μmol) obtained was dissolved in 1,4-dioxane (0.1 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hr. The crude product obtained by concentrating the reaction mixture was purified by preparative TLC (ammonia saturated chloroform / methanol = 10/1), and the obtained solid was dissolved in 1,4-dioxane (0.1 mL). 4M Hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 7-butyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride (Hereinafter, the compound of Example 2) (5.2 mg, 23 μmol) was obtained as a white solid (yield 62%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.59 (1H, d, J = 7.1 Hz), 7.77 (1H, d, J = 0.7 Hz), 7.49 (1H, dd, J = 6.8, 1.5 Hz ), 4.73 (2H, s), 3.75 (2H, t, J = 6.1 Hz), 3.33-3.31 (2H, m), 2.91 (2H, t, J = 7.8 Hz), 1.78-1.70 (2H, m) , 1.49-1.39 (2H, m), 0.99 (3H, t, J = 7.4 Hz).
MS (ESI): m / z 230 ([M + H] ⁺ ).
mp: 122-128 ° C.

２０ｍＬフラスコに、参考例１の化合物（２０ｍｇ、５７μｍｏｌ）、シクロプロピルボロン酸（１２ｍｇ、０．１４ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１．９ｍｇ、８．５μｍｏｌ）、トリシクロヘキシルホスフィン（４．８ｍｇ、１７μｍｏｌ）及びリン酸カリウム（１２ｍｇ、５７μｍｏｌ）を量り取り、トルエン（１ｍＬ）及び水（０．１ｍＬ）を加え、８０℃で１４時間撹拌した。反応混合物を室温まで冷却した後、水を加え、酢酸エチルで３回抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濃縮して得られた粗生成物をプレパラティブＴＬＣ（ｎ−ヘキサン／酢酸エチル ＝１０／１）で精製し、ｔｅｒｔ−ブチル ７−シクロプロピル−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、中間体５）（９．１ｍｇ、２９μｍｏｌ）を無色油状物として得た（収率５１％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.65 (1H, d, J = 7.1 Hz), 7.24 (1H, s), 6.54 (1H, dd, J = 7.1, 1.2 Hz), 4.67 (2H, brs), 3.81 (2H, brs), 2.90 (2H, brs), 1.97-1.91 (1H, m), 1.51 (9H, s), 1.06-1.01 (2H, m), 0.78-0.74 (2H, m).
MS (ESI): m/z 314 ([M+H]⁺). Example 3 Synthesis of 7-cyclopropyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride:

In a 20 mL flask, the compound of Reference Example 1 (20 mg, 57 μmol), cyclopropylboronic acid (12 mg, 0.14 mmol), Pd (OAc) ₂ (1.9 mg, 8.5 μmol), tricyclohexylphosphine (4.8 mg, 17 μmol) and potassium phosphate (12 mg, 57 μmol) were weighed, toluene (1 mL) and water (0.1 mL) were added, and the mixture was stirred at 80 ° C. for 14 hours. The reaction mixture was cooled to room temperature, water was added, the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by preparative TLC (n-hexane / ethyl acetate = 10/1) and tert-butyl 7-cyclopropyl-3,4. -Dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter, intermediate 5) (9.1 mg, 29 μmol) was obtained as a colorless oil (yield) 51%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.65 (1H, d, J = 7.1 Hz), 7.24 (1H, s), 6.54 (1H, dd, J = 7.1, 1.2 Hz), 4.67 (2H, brs), 3.81 (2H, brs), 2.90 (2H, brs), 1.97-1.91 (1H, m), 1.51 (9H, s), 1.06-1.01 (2H, m), 0.78-0.74 (2H, m) .
MS (ESI): m / z 314 ([M + H] ⁺ ).

The obtained intermediate 5 (9.1 mg, 29 μmol) was dissolved in 1,4-dioxane (0.1 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. did. The crude product obtained by concentrating the reaction mixture was purified by preparative TLC (ammonia saturated chloroform / methanol = 10/1), and then the obtained solid was dissolved in 1,4-dioxane (0.1 mL). 4M Hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 7-cyclopropyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride. Salt (hereinafter, the compound of Example 3) (6.4 mg, 22 μmol) was obtained as a white solid (yield 77%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.52 (1H, dd, J = 7.1, 0.7 Hz), 7.65 (1H, d, J = 0.7 Hz), 7.27 (1H, dd, J = 7.1, 1.7 Hz), 4.70 (2H, t, J = 1.5 Hz), 3.74 (2H, t, J = 6.1 Hz), 3.29-3.27 (2H, m), 2.28-2.22 (1H, m), 1.34-1.29 ( 2H, m), 1.06-1.02 (2H, m).
MS (ESI): m / z 214 ([M + H] ⁺ ).
mp: 235-240 ° C.

５０ｍＬフラスコに、ＴＨＦ（０．５ｍＬ）を加え、０℃に冷却した後、ｎ−プロピルマグネシウムクロリド（２Ｍ ＴＨＦ溶液、０．３１ｍＬ、０．６２ｍｍｏｌ）及びジクロロ亜鉛（１．９Ｍ ２−メチルＴＨＦ溶液、０．２２ｍＬ、０．４１ｍｍｏｌ）を加え、室温で３０分撹拌した。ここにＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２（６．７ｍｇ、８．２μｍｏｌ）及びＴＨＦ（１ｍＬ）に溶解した参考例２の化合物（２９ｍｇ、８２μｍｏｌ）を加え、６０℃で１６時間撹拌した。反応混合物を室温まで冷却した後、水及び飽和塩化アンモニウム水溶液を加え、酢酸エチルで３回抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサンのみ〜ｎ−ヘキサン／酢酸エチル＝５０／５０）で精製し、ｔｅｒｔ−ブチル ７−プロピル−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、中間体６）を得た。 Example 4 Synthesis of 6-propyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride:

After adding THF (0.5 mL) to a 50 mL flask and cooling to 0 ° C., n-propylmagnesium chloride (2 M THF solution, 0.31 mL, 0.62 mmol) and dichlorozinc (1.9 M 2-methyl THF solution) were added. , 0.22 mL, 0.41 mmol) and stirred at room temperature for 30 minutes. PdCl ₂ (dppf) · CH ₂ Cl ₂ (6.7 mg, 8.2 μmol) and the compound of Reference Example 2 (29 mg, 82 μmol) dissolved in THF (1 mL) were added thereto, and the mixture was stirred at 60 ° C. for 16 hours. The reaction mixture was cooled to room temperature, water and a saturated aqueous ammonium chloride solution were added, the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by flash silica gel column chromatography (n-hexane only to n-hexane / ethyl acetate = 50/50), and tert-butyl 7 -Propyl-3,4-dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter, intermediate 6) was obtained.

The obtained intermediate 6 was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.1 mL) was added, and the mixture was stirred at room temperature for 2 hr. The crude product obtained by concentrating the reaction mixture was purified by preparative TLC (chloroform / ammonia saturated chloroform / methanol = 6/6/1), and then the obtained solid was dissolved in methanol (1 mL). % Hydrogen chloride-methanol (38 μL) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 6-propyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride (Hereinafter, the compound of Example 4) (4.2 mg, 20 μmol) was obtained as a white solid (two-stage yield 23%).
LCMS (ESI): 216 (M + H) ⁺ .
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.53 (1H, d, J = 6.6 Hz), 7.87 (1H, d, J = 7.3 Hz), 7.52 (1H, t, J = 7.0 Hz), 4.74 (2H, s), 3.77 (2H, t, J = 6.0 Hz), 3.34-3.32 (2H, m), 2.99 (2H, t, J = 7.6 Hz), 1.85-1.78 (2H, m), 1.07 (3H, t, J = 7.4 Hz).
mp: 226-236 ° C.

２５ｍＬフラスコに、ＴＨＦ（０．５ｍＬ）を加え、０℃に冷却した後、ｎ−ブチルマグネシウムクロリド（０．９４Ｍ ＴＨＦ溶液、０．４３ｍＬ、０．４１ｍｍｏｌ）及びジクロロ亜鉛（１．９Ｍ ２−メチルＴＨＦ溶液、０．１４ｍＬ、０．２７ｍｍｏｌ）を加え、室温で３０分撹拌した。ここにＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２（４．４ｍｇ、５．４μｍｏｌ）及びＴＨＦ（１ｍＬ）に溶解した参考例２の化合物（１９ｍｇ、５４μｍｏｌ）を加え、６０℃で１５時間撹拌した。反応混合物を室温まで冷却した後、水及び飽和塩化アンモニウム水溶液を加え、酢酸エチルで３回抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝５０／５０）で精製し、ｔｅｒｔ−ブチル ６−ブチル−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、中間体７）（１１ｍｇ、４８μＬ）を白色固体として得た（収率６５％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.64 (1H, d, J = 6.8 Hz), 6.97 (1H, d, J = 6.8 Hz), 6.76 (1H, t, J = 6.8 Hz), 4.69 (2H, s), 3.83 (2H, brs), 3.03-2.96 (4H, m), 1.82-1.74 (2H, m), 1.51 (9H, s), 1.49-1.40 (2H, m), 0.95 (3H, t, J = 7.3 Hz).
MS (ESI) : 330 (M+H)⁺.
mp: 135-136℃. Example 5 Synthesis of 6-butyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride:

After adding THF (0.5 mL) to a 25 mL flask and cooling to 0 ° C., n-butylmagnesium chloride (0.94 M THF solution, 0.43 mL, 0.41 mmol) and dichlorozinc (1.9 M 2-methyl) were added. (THF solution, 0.14 mL, 0.27 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To this was added PdCl ₂ (dppf) · CH ₂ Cl ₂ (4.4 mg, 5.4 μmol) and the compound of Reference Example 2 (19 mg, 54 μmol) dissolved in THF (1 mL), and the mixture was stirred at 60 ° C. for 15 hours. The reaction mixture was cooled to room temperature, water and a saturated aqueous ammonium chloride solution were added, the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by flash silica gel column chromatography (n-hexane / ethyl acetate = 50/50), and tert-butyl 6-butyl-3, 4-Dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter intermediate 7) (11 mg, 48 μL) was obtained as a white solid (yield 65%). ).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.64 (1H, d, J = 6.8 Hz), 6.97 (1H, d, J = 6.8 Hz), 6.76 (1H, t, J = 6.8 Hz), 4.69 (2H, s), 3.83 (2H, brs), 3.03-2.96 (4H, m), 1.82-1.74 (2H, m), 1.51 (9H, s), 1.49-1.40 (2H, m), 0.95 (3H , t, J = 7.3 Hz).
MS (ESI): 330 (M + H) ⁺ .
mp: 135-136 ° C.

The obtained intermediate 7 (11 mg, 48 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.1 mL) was added, and the mixture was stirred at room temperature for 2 hr. The crude product obtained by concentrating the reaction mixture was purified by preparative TLC (chloroform / ammonia saturated chloroform / methanol = 6/6/1), and the obtained oil was dissolved in methanol (1 mL). 10% hydrogen chloride-methanol (35 μL) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated, and 6-butyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride (hereinafter referred to as the compound of Example 5) (4 0.2 mg, 18 μmol) was obtained as amorphous (58% yield).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.48 (1H, d, J = 6.6 Hz), 7.81 (1H, d, J = 7.3 Hz), 7.46 (1H, t, J = 7.1 Hz), 4.72 (2H, s), 3.76 (2H, t, J = 6.1 Hz), 3.33-3.31 (2H, m), 3.01 (2H, t, J = 7.8 Hz), 1.81-1.73 (2H, m), 1.51 -1.44 (2H, m), 1.00 (3H, t, J = 7.3 Hz).
MS (ESI): m / z 230 ([M + H] ⁺ ).

５０ｍＬフラスコに、参考例２の化合物（２０ｍｇ、５７μｍｏｌ）、シクロプロピルボロン酸（１２ｍｇ、０．１４ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（１．９ｍｇ、８．５μｍｏｌ）、トリシクロヘキシルホスフィン（４．８ｍｇ、１７μｍｏｌ）及びリン酸カリウム（４２ｍｇ、０．２０ｍｍｏｌ）を量り取り、ＴＨＦ（１ｍＬ）及び水（０．１ｍＬ）を加え、９０℃で１５時間撹拌した。反応混合物を室温まで冷却した後、濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサンのみ〜ｎ−ヘキサン／酢酸エチル ＝６６／３４）で精製し、ｔｅｒｔ−ブチル ６−シクロプロピル−３，４−ジヒドロイミダゾ［１，２−ａ：５，４−ｃ’］ジピリジン−２（１Ｈ）−カルボキシラート（以下、中間体８）（９．４ｍｇ、３０μｍｏｌ）を黄色油状物として得た（収率５３％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.61 (1H, d, J = 6.3 Hz), 6.74 (1H, t, J = 6.8 Hz), 6.66 (1H, d, J = 7.3 Hz), 4.69 (2H, s), 3.83 (2H, brs), 2.98 (2H, brs), 2.62-2.56 (1H, m), 1.51 (9H, s), 1.14-1.09 (2H, m), 0.88-0.84 (2H, m).
MS (ESI): m/z 314 ([M+H]⁺). Example 6 Synthesis of 6-cyclopropyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride:

In a 50 mL flask, the compound of Reference Example 2 (20 mg, 57 μmol), cyclopropylboronic acid (12 mg, 0.14 mmol), Pd (OAc) ₂ (1.9 mg, 8.5 μmol), tricyclohexylphosphine (4.8 mg, 17 μmol) and potassium phosphate (42 mg, 0.20 mmol) were weighed, THF (1 mL) and water (0.1 mL) were added, and the mixture was stirred at 90 ° C. for 15 hours. After cooling the reaction mixture to room temperature, the crude product obtained by concentration was purified by flash silica gel column chromatography (n-hexane only to n-hexane / ethyl acetate = 66/34), and tert-butyl 6- Cyclopropyl-3,4-dihydroimidazo [1,2-a: 5,4-c ′] dipyridine-2 (1H) -carboxylate (hereinafter intermediate 8) (9.4 mg, 30 μmol) (Yield 53%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.61 (1H, d, J = 6.3 Hz), 6.74 (1H, t, J = 6.8 Hz), 6.66 (1H, d, J = 7.3 Hz), 4.69 (2H, s), 3.83 (2H, brs), 2.98 (2H, brs), 2.62-2.56 (1H, m), 1.51 (9H, s), 1.14-1.09 (2H, m), 0.88-0.84 (2H , m).
MS (ESI): m / z 314 ([M + H] ⁺ ).

The obtained intermediate 8 (9.4 mg, 30 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.1 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. The crude product obtained by concentrating the reaction mixture was purified by preparative TLC (chloroform / ammonia saturated chloroform / methanol = 6/6/1), and then the obtained solid was dissolved in methanol (1 mL). % Hydrogen chloride-methanol (47 μL) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 6-cyclopropyl-1,2,3,4-tetrahydroimidazo [1,2-a: 5,4-c ′] dipyridine dihydrochloride. Salt (hereinafter, the compound of Example 6) (3.0 mg, 25 μmol) was obtained as a white solid (yield 84%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.31 (1H, s), 7.36 (1H, s), 7.26 (1H, s), 4.67 (2H, s), 3.73 (2H, t, J = 6.1 Hz), 3.35-3.31 (2H, m), 2.37-2.28 (1H, m), 1.22-1.18 (2H, m), 0.94-0.89 (2H, m).
MS (ESI): m / z 214 ([M + H] ⁺ ).

１０ｍＬマイクロウェーブ反応容器に、２−アミノ−３−ブロモピリジン（０．１５ｇ、０．８７ｍｍｏｌ）及びｔｅｒｔ−ブチル ４−ブロモ−５−オキソアゼパン−１−カルボキシラート（０．２５ｇ、０．８７ｍｍｏｌ）を量り取り、エタノール（４ｍＬ）及びＤＩＰＥＡ（０．１５ｍＬ、０．８７ｍｍｏｌ）を加え、マイクロウェーブ反応装置を用い１４０℃で２時間撹拌した。反応混合物を濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝５５／４５〜４５／５５）で精製し、ｔｅｒｔ−ブチル ７−ブロモ−４，５−ジヒドロ−１Ｈ−ピリド［１’，２’：１，２］イミダゾ［４，５−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（以下、中間体９）（３１ｍｇ、８５μｍｏｌ）を黄色油状物として得た（収率１０％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.83 (1H, d, J = 6.8 Hz), 7.40 (1H, d, J = 7.1 Hz), 6.70 (1H, t, J = 7.1 Hz), 3.79 (2H, dt, J = 15.1, 5.6 Hz), 3.73-3.67 (2H, m), 3.23 (2H, dt, J = 12.9, 5.7 Hz), 3.00 (2H, dt, J = 18.5, 5.4 Hz), 1.48 (9H, s).
MS (ESI): m/z 366 ([M+H]⁺). Example 7 Synthesis of 7-bromo-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride:

In a 10 mL microwave reaction vessel, 2-amino-3-bromopyridine (0.15 g, 0.87 mmol) and tert-butyl 4-bromo-5-oxoazepan-1-carboxylate (0.25 g, 0.87 mmol). Weighed out, added ethanol (4 mL) and DIPEA (0.15 mL, 0.87 mmol), and stirred at 140 ° C. for 2 hours using a microwave reactor. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (n-hexane / ethyl acetate = 55 / 45-45 / 55), and tert-butyl 7-bromo-4,5-dihydro −1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine-3 (2H) -carboxylate (hereinafter intermediate 9) (31 mg, 85 μmol) was obtained as a yellow oil. (Yield 10%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.83 (1H, d, J = 6.8 Hz), 7.40 (1H, d, J = 7.1 Hz), 6.70 (1H, t, J = 7.1 Hz), 3.79 (2H, dt, J = 15.1, 5.6 Hz), 3.73-3.67 (2H, m), 3.23 (2H, dt, J = 12.9, 5.7 Hz), 3.00 (2H, dt, J = 18.5, 5.4 Hz), 1.48 (9H, s).
MS (ESI): m / z 366 ([M + H] ⁺ ).

The obtained intermediate 9 (5.0 mg, 14 μmol) was dissolved in 1,4-dioxane (0.1 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. did. The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 7-bromo-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5 -D] Azepine dihydrochloride (hereinafter, the compound of Example 7) (3.1 mg, 8.3 μmol) was obtained as a white solid (yield 57%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.75 (1H, dd, J = 6.8, 0.7 Hz), 8.24 (1H, dd, J = 7.6, 0.7 Hz), 7.46 (1H, dd, J = 7.7, 7.0 Hz), 3.70-3.65 (4H, m), 3.53 (2H, t, J = 5.6 Hz), 3.48 (2H, t, J = 5.7 Hz).
MS (ESI): m / z 266 ([M + H] ⁺ ).
mp: 237-243 ° C.

１０ｍＬフラスコに、２−アミノ−４−ブロモピリジン（０．１０ｍｇ、０．５８ｍｍｏｌ）、ｔｅｒｔ−ブチル ４−ブロモ−５−オキソアゼパン−１−カルボキシラート（０．１７ｇ、０．５８ｍｍｏｌ）及び炭酸水素ナトリウム（４９ｍｇ、０．５８ｍｍｏｌ）を量り取り、２−プロパノール（２ｍＬ）を加え、８０℃で９０時間撹拌した。反応混合物を濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝５０／５０）で精製し、ｔｅｒｔ−ブチル ８−ブロモ−４，５−ジヒドロ−１Ｈ−ピリド［１’，２’：１，２］イミダゾ［４，５−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（以下、中間体１０）（０．１３ｇ、０．３６ｍｍｏｌ）を白色固体として得た（収率６２％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.71-7.69 (2H, m), 6.90 (1H, dd, J = 7.3, 2.0 Hz), 3.81-3.75 (2H, m), 3.72-3.67 (2H, m), 3.15 (2H, dt, J = 15.4, 5.7 Hz), 2.97 (2H, dt, J = 18.4, 5.3 Hz), 1.48 (9H, s).
MS (ESI): m/z 366 ([M+H]⁺). Example 8 Synthesis of 8-bromo-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride:

To a 10 mL flask was added 2-amino-4-bromopyridine (0.10 mg, 0.58 mmol), tert-butyl 4-bromo-5-oxoazepan-1-carboxylate (0.17 g, 0.58 mmol) and sodium bicarbonate. (49 mg, 0.58 mmol) was weighed, 2-propanol (2 mL) was added, and the mixture was stirred at 80 ° C. for 90 hours. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (n-hexane / ethyl acetate = 50/50), and tert-butyl 8-bromo-4,5-dihydro-1H-pyrido. [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine-3 (2H) -carboxylate (hereinafter, intermediate 10) (0.13 g, 0.36 mmol) was obtained as a white solid. (Yield 62%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.71-7.69 (2H, m), 6.90 (1H, dd, J = 7.3, 2.0 Hz), 3.81-3.75 (2H, m), 3.72-3.67 (2H , m), 3.15 (2H, dt, J = 15.4, 5.7 Hz), 2.97 (2H, dt, J = 18.4, 5.3 Hz), 1.48 (9H, s).
MS (ESI): m / z 366 ([M + H] ⁺ ).

The obtained intermediate 10 (5.0 mg, 14 μmol) was dissolved in 1,4-dioxane (0.2 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. did. The reaction mixture was concentrated and subsequently recrystallized with methanol-diethyl ether to give 8-bromo-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5 -D] Azepine dihydrochloride (hereinafter, the compound of Example 8) (3.7 mg, 8.4 μmol) was obtained as a white solid (yield 60%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.63 (1H, dd, J = 7.3, 0.7 Hz), 8.20 (1H, dd, J = 1.7, 0.7 Hz), 7.71 (1H, dd, J = 7.3, 2.0 Hz), 3.68-3.63 (4H, m), 3.50 (2H, t, J = 5.6 Hz), 3.41 (2H, t, J = 5.7 Hz).
MS (ESI): m / z 266 ([M + H] ⁺ ).
mp: 285-291 ° C.

１０ｍＬマイクロウェーブ反応容器に、２−アミノ−５−ブロモピリジン（０．１０ｍｇ、０．５８ｍｍｏｌ）及びｔｅｒｔ−ブチル ４−ブロモ−５−オキソアゼパン−１−カルボキシラート（０．１７ｇ、０．５８ｍｍｏｌ）を量り取り、エタノール（２ｍＬ）及びＤＩＰＥＡ（０．１０ｍＬ、０．５８ｍｍｏｌ）を加え、マイクロウェーブ反応装置を用い１４０℃で２時間撹拌した。反応混合物を濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝７５／２５〜５０／５０）で精製し、ｔｅｒｔ−ブチル ９−ブロモ−４，５−ジヒドロ−１Ｈ−ピリド［１’，２’：１，２］イミダゾ［４，５−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（以下、中間体１１）（３０ｍｇ、８２μｍｏｌ）を黄色油状物として得た（収率１４％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.98 (1H, s), 7.42 (1H, d, J = 9.3 Hz), 7.18 (1H, dd, J = 9.5, 1.2 Hz), 3.81-3.77 (2H, m), 3.72-3.66 (2H, m), 3.16 (2H, dt, J = 11.2, 5.8 Hz), 2.98 (2H, dt, J = 15.2, 5.4 Hz), 1.48 (9H, s).
MS (ESI): m/z 366 ([M+H]⁺). Example 9 Synthesis of 9-bromo-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride:

In a 10 mL microwave reaction vessel, 2-amino-5-bromopyridine (0.10 mg, 0.58 mmol) and tert-butyl 4-bromo-5-oxoazepan-1-carboxylate (0.17 g, 0.58 mmol). Weighed out, added ethanol (2 mL) and DIPEA (0.10 mL, 0.58 mmol), and stirred at 140 ° C. for 2 hours using a microwave reactor. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (n-hexane / ethyl acetate = 75 / 25-50 / 50), and tert-butyl 9-bromo-4,5-dihydro −1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine-3 (2H) -carboxylate (hereinafter, intermediate 11) (30 mg, 82 μmol) was obtained as a yellow oil. (Yield 14%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.98 (1H, s), 7.42 (1H, d, J = 9.3 Hz), 7.18 (1H, dd, J = 9.5, 1.2 Hz), 3.81-3.77 ( 2H, m), 3.72-3.66 (2H, m), 3.16 (2H, dt, J = 11.2, 5.8 Hz), 2.98 (2H, dt, J = 15.2, 5.4 Hz), 1.48 (9H, s).
MS (ESI): m / z 366 ([M + H] ⁺ ).

The obtained intermediate 11 (4.0 mg, 11 μmol) was dissolved in 1,4-dioxane (0.2 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. did. The crude product obtained by concentrating the reaction mixture was purified by preparative TLC (ammonia saturated chloroform / methanol = 10/1), and then the obtained solid was dissolved in 1,4-dioxane (0.2 mL). 4M Hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 9-bromo-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5 -D] Azepine dihydrochloride (hereinafter, the compound of Example 9) (2.6 mg, 7.7 μmol) was obtained as a white solid (yield 70%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 9.07 (1H, dd, J = 1.7, 0.7 Hz), 8.10 (1H, dd, J = 9.5, 1.7 Hz), 7.86 (1H, dd, J = 9.5, 0.7 Hz), 3.68-3.63 (4H, m), 3.51 (2H, t, J = 5.5 Hz), 3.43 (2H, t, J = 5.6 Hz).
MS (ESI): m / z 266 ([M + H] ⁺ ).
mp: 211-216 ° C.

１０ｍＬマイクロウェーブ反応容器に、２−アミノ−６−ブロモピリジン（０．１０ｍｇ、０．５８ｍｍｏｌ）及びｔｅｒｔ−ブチル ４−ブロモ−５−オキソアゼパン−１−カルボキシラート（０．１７ｇ、０．５８ｍｍｏｌ）を量り取り、エタノール（２ｍＬ）及びＤＩＰＥＡ（０．１０ｍＬ、０．５８ｍｍｏｌ）を加え、マイクロウェーブ反応装置を用い１４０℃で３時間撹拌した。反応混合物を濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（クロロホルムのみ〜クロロホルム／メタノール＝９８／２）及びプレパラティブＴＬＣで精製し、ｔｅｒｔ−ブチル １０−ブロモ−４，５−ジヒドロ−１Ｈ−ピリド［１’，２’：１，２］イミダゾ［４，５−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（以下、中間体１２）（６．２ｍｇ、１７μｍｏｌ）を無色油状物として得た（収率２．９％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.47 (1H, d, J = 8.3 Hz), 6.97-6.89 (2H, m), 3.89-3.79 (2H, m), 3.75-3.68 (4H, m), 3.19-3.16 (2H, m), 1.47 (9H, m).
MS (ESI): m/z 366 ([M+H]⁺). Example 10 Synthesis of 10-bromo-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride:

In a 10 mL microwave reaction vessel, 2-amino-6-bromopyridine (0.10 mg, 0.58 mmol) and tert-butyl 4-bromo-5-oxoazepan-1-carboxylate (0.17 g, 0.58 mmol). Weighed out, added ethanol (2 mL) and DIPEA (0.10 mL, 0.58 mmol), and stirred at 140 ° C. for 3 hours using a microwave reactor. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (chloroform only to chloroform / methanol = 98/2) and preparative TLC, and tert-butyl 10-bromo-4,5-dihydro 1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine-3 (2H) -carboxylate (hereinafter, intermediate 12) (6.2 mg, 17 μmol) was obtained as a colorless oil (Yield 2.9%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.47 (1H, d, J = 8.3 Hz), 6.97-6.89 (2H, m), 3.89-3.79 (2H, m), 3.75-3.68 (4H, m ), 3.19-3.16 (2H, m), 1.47 (9H, m).
MS (ESI): m / z 366 ([M + H] ⁺ ).

The obtained intermediate 12 (6.2 mg, 17 μmol) was dissolved in 1,4-dioxane (0.2 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. did. The crude product obtained by concentrating the reaction mixture was purified by preparative TLC (ammonia saturated chloroform / methanol = 10/1), and then the obtained solid was dissolved in 1,4-dioxane (0.2 mL). 4M Hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated and subsequently recrystallized with methanol-diethyl ether and 10-bromo-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5 -D] Azepine dihydrochloride (hereinafter, the compound of Example 10) (3.2 mg, 9.4 μmol) was obtained as a white solid (yield 55%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.86-7.80 (1H, m), 7.72-7.67 (2H, m), 4.12 (2H, t, J = 5.6 Hz), 3.72-3.65 (4H, m), 3.40 (2H, t, J = 5.6 Hz).
mp: 223-237 ° C.

１０ｍＬマイクロウェーブ反応容器に、２−アミノ−６−（トリフルオロメチル）ピリジン（８０ｍｇ、０．４９ｍｍｏｌ）及びｔｅｒｔ−ブチル ４−ブロモ−５−オキソアゼパン−１−カルボキシラート（０．１３ｇ、０．４９ｍｍｏｌ）を量り取り、エタノール（２ｍＬ）及びＤＩＰＥＡ（８６μＬ、０．４９ｍｍｏｌ）を加え、マイクロウェーブ反応装置を用い１４０℃で２時間撹拌した。反応混合物を濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝９０／１０〜５０／５０）で精製し、ｔｅｒｔ−ブチル １０−（トリフルオロメチル）−４，５−ジヒドロ−１Ｈ−ピリド［１’，２’：１，２］イミダゾ［４，５−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（以下、中間体１３）（５．５ｍｇ、１５μｍｏｌ）を無色油状物として得た（収率３．２％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.76 (1H, d, J = 9.3 Hz), 7.36 (1H, d, J = 7.1 Hz), 7.15 (1H, t, J = 8.0 Hz), 3.90-3.79 (2H, m), 3.77-3.68 (2H, m), 3.28-3.14 (4H, m), 1.48 (9H, s).
MS (ESI): m/z 356 ([M+H]⁺). Example 11 10- (Trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride Synthesis of:

In a 10 mL microwave reaction vessel, 2-amino-6- (trifluoromethyl) pyridine (80 mg, 0.49 mmol) and tert-butyl 4-bromo-5-oxoazepan-1-carboxylate (0.13 g, 0.49 mmol). ), Ethanol (2 mL) and DIPEA (86 μL, 0.49 mmol) were added, and the mixture was stirred at 140 ° C. for 2 hours using a microwave reactor. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (n-hexane / ethyl acetate = 90 / 10-50 / 50), and tert-butyl 10- (trifluoromethyl) -4. , 5-Dihydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine-3 (2H) -carboxylate (hereinafter intermediate 13) (5.5 mg, 15 μmol) Was obtained as a colorless oil (yield 3.2%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.76 (1H, d, J = 9.3 Hz), 7.36 (1H, d, J = 7.1 Hz), 7.15 (1H, t, J = 8.0 Hz), 3.90 -3.79 (2H, m), 3.77-3.68 (2H, m), 3.28-3.14 (4H, m), 1.48 (9H, s).
MS (ESI): m / z 356 ([M + H] ⁺ ).

The obtained intermediate 13 (5.5 mg, 15 μmol) was dissolved in 1,4-dioxane (0.2 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. did. After the crude product obtained by concentrating the reaction mixture was purified by preparative TLC (ammonia saturated chloroform / = 10/1), the obtained solid was dissolved in 1,4-dioxane (0.2 mL), 4M Hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture is concentrated and subsequently recrystallized from methanol-diethyl ether, and 10- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride (hereinafter, the compound of Example 11) (2.0 mg, 7.8 μmol) was obtained as a white solid (yield 52%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.11 (1H, d, J = 8.5 Hz), 8.01 (1H, d, J = 7.3 Hz), 7.89 (1H, t, J = 8.0 Hz), 3.72-3.69 (2H, m), 3.68-3.65 (2H, m), 3.58-3.52 (2H, m), 3.47-3.42 (2H, m).
MS (ESI): m / z 256 ([M + H] ⁺ ).
mp: 223-232 ° C.

１０ｍＬフラスコに、ＴＨＦ（０．２ｍＬ）を加え、０℃に冷却した後、ｎ−プロピルマグネシウムクロリド（２Ｍ ＴＨＦ溶液、９２μＬ、０．１８ｍｍｏｌ）及びジクロロ亜鉛（１．９Ｍ ２−メチルＴＨＦ溶液、６５μＬ、０．１２ｍｍｏｌ）を加え、室温で３０分撹拌した。ここにＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２（３．３ｍｇ、４．１μｍｏｌ）及びＴＨＦ（０．３ｍＬ）に溶解した中間体９（１５ｍｇ、４１μｍｏｌ）を加え、５５℃で１時間撹拌した。反応混合物を室温まで冷却した後、濃縮して得られた粗生成物をプレパラティブＴＬＣ（クロロホルム／メタノール ＝１０／１）で精製し、ｔｅｒｔ−ブチル ７−プロピル−４，５−ジヒドロ−１Ｈ−ピリド［１’，２’：１，２］イミダゾ［４，５−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（以下、中間体１４）（７．５ｍｇ、２３μｍｏｌ）を黄色油状物として得た（収率５６％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.70 (1H, d, J = 6.6 Hz), 6.93 (1H, d, J = 6.3 Hz), 6.74 (1H, t, J = 7.0 Hz), 3.79 (2H, dt, J = 15.4, 5.5 Hz), 3.70 (2H, dt, J = 12.7, 5.5 Hz), 3.20 (2H, dt, J = 13.7, 5.5 Hz), 3.02-2.95 (4H, m), 1.82 (2H, tq, J = 7.6, 7.6 Hz), 1.48 (9H, s), 1.02 (3H, t, J = 7.3 Hz).
MS (ESI): m/z 330 ([M+H]⁺). Example 12 Synthesis of 7-propyl-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride:

After adding THF (0.2 mL) to a 10 mL flask and cooling to 0 ° C., n-propylmagnesium chloride (2 M THF solution, 92 μL, 0.18 mmol) and dichlorozinc (1.9 M 2-methyl THF solution, 65 μL). 0.12 mmol) and stirred at room temperature for 30 minutes. PdCl ₂ (dppf) · CH ₂ Cl ₂ (3.3 mg, 4.1 μmol) and Intermediate 9 (15 mg, 41 μmol) dissolved in THF (0.3 mL) were added thereto, and the mixture was stirred at 55 ° C. for 1 hour. After cooling the reaction mixture to room temperature, the crude product obtained by concentration was purified by preparative TLC (chloroform / methanol = 10/1), and tert-butyl 7-propyl-4,5-dihydro-1H- Pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine-3 (2H) -carboxylate (hereinafter intermediate 14) (7.5 mg, 23 μmol) was obtained as a yellow oil. (Yield 56%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.70 (1H, d, J = 6.6 Hz), 6.93 (1H, d, J = 6.3 Hz), 6.74 (1H, t, J = 7.0 Hz), 3.79 (2H, dt, J = 15.4, 5.5 Hz), 3.70 (2H, dt, J = 12.7, 5.5 Hz), 3.20 (2H, dt, J = 13.7, 5.5 Hz), 3.02-2.95 (4H, m), 1.82 (2H, tq, J = 7.6, 7.6 Hz), 1.48 (9H, s), 1.02 (3H, t, J = 7.3 Hz).
MS (ESI): m / z 330 ([M + H] ⁺ ).

The obtained intermediate 14 (7.5 mg, 23 μmol) was dissolved in 1,4-dioxane (0.2 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hours. did. After the crude product obtained by concentrating the reaction mixture was purified by preparative TLC (ammonia saturated chloroform / = 10/1), the obtained solid was dissolved in 1,4-dioxane (0.2 mL), 4M hydrogen chloride-1,4-oxane (0.1 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated and 7-propyl-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride (hereinafter, The compound of Example 12 (3.13 mg, 10 μmol) was obtained as a white solid (yield 45%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.54 (1H, d, J = 6.3 Hz), 7.78 (1H, d, J = 6.2 Hz), 7.46 (1H, t, J = 6.6 Hz), 3.69-3.64 (4H, m), 3.49 (2H, t, J = 5.4 Hz), 3.43 (2H, t, J = 5.4 Hz), 2.97 (2H, t, J = 7.7 Hz), 1.81 (2H, tq , J = 7.4, 7.4 Hz), 1.06 (3H, t, J = 7.2 Hz).
MS (ESI): m / z 230 ([M + H] ⁺ ).
mp: 121-135 ° C.

１０ｍＬフラスコに、ＴＨＦ（０．３ｍＬ）を加え、０℃に冷却した後、ｎ−プロピルマグネシウムクロリド（２Ｍ ＴＨＦ溶液、０．１２ｍＬ、０．２５ｍｍｏｌ）及びジクロロ亜鉛（１．９Ｍ ２−メチルＴＨＦ溶液、８６μＬ、０．１６ｍｍｏｌ）を加え、室温で３０分撹拌した。ここににＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２（４．５ｍｇ、５．５μｍｏｌ）及びＴＨＦ（０．３ｍＬ）に溶解した中間体１０（２０ｍｇ、５５μｍｏｌ）を加え、５５℃で１時間撹拌した。反応混合物を室温まで冷却した後、濃縮して得られた粗生成物をプレパラティブＴＬＣ（ｎ−ヘキサン／酢酸エチル＝５０／５０）で精製し、ｔｅｒｔ−ブチル ８−プロピル−４，５−ジヒドロ−１Ｈ−ピリド［１’，２’：１，２］イミダゾ［４，５−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（以下、中間体１５）（１１ｍｇ、３４μｍｏｌ）を無色油状物として得た（収率６２％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.73 (1H, d, J = 6.8 Hz), 7.28 (1H, s), 6.66 (1H, dd, J = 7.0, 1.6 Hz), 3.81-3.73 (2H, m), 3.72-3.66 (2H, m), 3.14 (2H, dt, J = 14.6, 5.4 Hz), 2.97 (2H, dt, J = 19.1, 5.4 Hz), 2.62 (2H, t, J = 7.6 Hz), 1.67 (2H, tq, J = 7.4, 7.4 Hz), 1.48 (9H, s), 0.95 (3H, t, J = 7.3 Hz).
MS (ESI): m/z 330 ([M+H]⁺). Example 13 Synthesis of 8-propyl-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride:

After adding THF (0.3 mL) to a 10 mL flask and cooling to 0 ° C., n-propylmagnesium chloride (2 M THF solution, 0.12 mL, 0.25 mmol) and dichlorozinc (1.9 M 2-methyl THF solution) were added. , 86 μL, 0.16 mmol), and stirred at room temperature for 30 minutes. To this was added PdCl ₂ (dppf) · CH ₂ Cl ₂ (4.5 mg, 5.5 μmol) and Intermediate 10 (20 mg, 55 μmol) dissolved in THF (0.3 mL), and the mixture was stirred at 55 ° C. for 1 hour. . After cooling the reaction mixture to room temperature, the crude product obtained by concentration was purified by preparative TLC (n-hexane / ethyl acetate = 50/50) and tert-butyl 8-propyl-4,5-dihydro −1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine-3 (2H) -carboxylate (hereinafter intermediate 15) (11 mg, 34 μmol) was obtained as a colorless oil. (Yield 62%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.73 (1H, d, J = 6.8 Hz), 7.28 (1H, s), 6.66 (1H, dd, J = 7.0, 1.6 Hz), 3.81-3.73 ( 2H, m), 3.72-3.66 (2H, m), 3.14 (2H, dt, J = 14.6, 5.4 Hz), 2.97 (2H, dt, J = 19.1, 5.4 Hz), 2.62 (2H, t, J = 7.6 Hz), 1.67 (2H, tq, J = 7.4, 7.4 Hz), 1.48 (9H, s), 0.95 (3H, t, J = 7.3 Hz).
MS (ESI): m / z 330 ([M + H] ⁺ ).

The obtained intermediate 15 (11 mg, 34 μmol) was dissolved in 1,4-dioxane (0.2 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hr. After the crude product obtained by concentrating the reaction mixture was purified by preparative TLC (ammonia saturated chloroform / = 10/1), the obtained solid was dissolved in 1,4-dioxane (0.2 mL), 4M Hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated and 8-propyl-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride (hereinafter, The compound of Example 13) (7.6 mg, 25 μmol) was obtained as a white solid (yield 75%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.60 (1H, d, J = 6.8 Hz), 7.68 (1H, s), 7.44 (1H, d, J = 6.6 Hz), 3.68-3.63 (4H , m), 3.50 (2H, brs), 3.41 (2H, brs), 2.87 (2H, t, J = 7.6 Hz), 1.78 (2H, tq, J = 7.5, 7.5 Hz), 1.02 (3H, t, J = 7.3 Hz).
MS (ESI): m / z 230 ([M + H] ⁺ ).
mp: 135-143 ° C.

１０ｍＬフラスコに、ＴＨＦ（０．２ｍＬ）を加え、０℃に冷却した後、ｎ−プロピルマグネシウムクロリド（２Ｍ ＴＨＦ溶液、０．１２ｍＬ、０．２５ｍｍｏｌ）及びジクロロ亜鉛（１．９Ｍ ２−メチルＴＨＦ溶液、８６μＬ、０．１６ｍｍｏｌ）を加え、室温で３０分撹拌した。ここにＰｄＣｌ_２（ｄｐｐｆ）・ＣＨ_２Ｃｌ_２（４．５ｍｇ、５．５μｍｏｌ）及びＴＨＦ（０．３ｍＬ）に溶解した中間体１１（２０ｍｇ、５５μｍｏｌ）を加え、５５℃で１時間撹拌した。反応混合物を室温まで冷却した後、濃縮して得られた粗生成物をプレパラティブＴＬＣ（ｎ−ヘキサン／酢酸エチル＝５０／５０）で精製し、ｔｅｒｔ−ブチル ９−プロピル−４，５−ジヒドロ−１Ｈ−ピリド［１’，２’：１，２］イミダゾ［４，５−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（以下、中間体１６）（１０ｍｇ、３０μｍｏｌ）を無色油状物として得た（収率５５％）。
1H-NMR (400 MHz, CDCl₃) δ: 7.60 (1H, s), 7.44 (1H, d, J = 9.0 Hz), 7.00 (1H, dd, J = 9.1, 1.3 Hz), 3.78 (2H, dt, J = 14.8, 5.7 Hz), 3.69 (2H, dt, J = 12.2, 5.7 Hz), 3.15 (2H, dt, J = 15.8, 5.6 Hz), 2.98 (2H, dt, J = 11.0, 5.6 Hz), 2.58 (2H, t, J = 7.6 Hz), 1.67 (2H, tq, J = 7.5, 7.5 Hz), 1.48 (9H, s), 0.96 (3H, t, J = 7.4 Hz).
MS (ESI): m/z 330 ([M+H]⁺). Example 14 Synthesis of 9-propyl-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride:

After adding THF (0.2 mL) to a 10 mL flask and cooling to 0 ° C., n-propylmagnesium chloride (2 M THF solution, 0.12 mL, 0.25 mmol) and dichlorozinc (1.9 M 2-methyl THF solution) were added. , 86 μL, 0.16 mmol), and stirred at room temperature for 30 minutes. To this was added PdCl ₂ (dppf) · CH ₂ Cl ₂ (4.5 mg, 5.5 μmol) and Intermediate 11 (20 mg, 55 μmol) dissolved in THF (0.3 mL), and the mixture was stirred at 55 ° C. for 1 hour. After cooling the reaction mixture to room temperature, the crude product obtained by concentration was purified by preparative TLC (n-hexane / ethyl acetate = 50/50) and tert-butyl 9-propyl-4,5-dihydro −1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine-3 (2H) -carboxylate (hereinafter intermediate 16) (10 mg, 30 μmol) was obtained as a colorless oil. (Yield 55%).
1H-NMR (400 MHz, CDCl ₃ ) δ: 7.60 (1H, s), 7.44 (1H, d, J = 9.0 Hz), 7.00 (1H, dd, J = 9.1, 1.3 Hz), 3.78 (2H, dt , J = 14.8, 5.7 Hz), 3.69 (2H, dt, J = 12.2, 5.7 Hz), 3.15 (2H, dt, J = 15.8, 5.6 Hz), 2.98 (2H, dt, J = 11.0, 5.6 Hz) , 2.58 (2H, t, J = 7.6 Hz), 1.67 (2H, tq, J = 7.5, 7.5 Hz), 1.48 (9H, s), 0.96 (3H, t, J = 7.4 Hz).
MS (ESI): m / z 330 ([M + H] ⁺ ).

The obtained intermediate 16 (10 mg, 30 μmol) was dissolved in 1,4-dioxane (0.2 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hr. After the crude product obtained by concentrating the reaction mixture was purified by preparative TLC (ammonia saturated chloroform / = 10/1), the obtained solid was dissolved in 1,4-dioxane (0.2 mL), 4M Hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated and 9-propyl-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride (hereinafter, The compound of Example 14) (5.5 mg, 18 μmol) was obtained as a white solid (61% yield).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 7.96 (1H, s), 7.36 (1H, dd, J = 9.1, 0.6 Hz), 7.14 (1H, dd, J = 9.1, 1.6 Hz), 3.16 -3.13 (2H, m), 3.10-3.07 (2H, m), 3.03-3.01 (4H, m), 2.63 (2H, t, J = 7.6 Hz), 1.69 (2H, tq, J = 7.5, 7.5 Hz ), 0.97 (3H, t, J = 7.3 Hz).
MS (ESI): m / z 230 ([M + H] ⁺ ).
mp: 152-161 ° C.

２０ｍＬフラスコに、中間体９（２３ｍｇ、６３μｍｏｌ）、シクロプロピルボロン酸（１４ｍｇ、０．１６ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（２．１ｍｇ、９．４μｍｏｌ）、トリシクロヘキシルホスフィン（５．３ｍｇ、１９μｍｏｌ）及びリン酸カリウム（１３ｍｇ、６３μｍｏｌ）を量り取り、トルエン（１．２ｍＬ）及び水（０．１２ｍＬ）を加え、８０℃で２０時間撹拌した。反応混合物を室温まで冷却した後、濃縮して得られた粗生成物をフラッシュシリカゲルカラムクロマトグラフィー（アミンシリカ、ｎ−ヘキサン／酢酸エチル＝６０／４０〜５０／５０）で精製し、ｔｅｒｔ−ブチル ７−プロピル−４，５−ジヒドロ−１Ｈ−ピリド［１’２’：１，２］イミダゾ［４，５−ｄ］アゼピン−３（２Ｈ）−カルボキシラート（以下、中間体１７）（１３ｍｇ、３９μｍｏｌ）を無色油状物として得た（収率６２％）。
¹H-NMR (400 MHz, CDCl₃) δ: 7.66 (1H, d, J = 6.3 Hz), 6.72 (1H, t, J = 7.0 Hz), 6.60 (1H, d, J = 6.8 Hz), 3.82-3.68 (4H, m), 3.25-3.19 (2H, m), 2.98 (2H, dt, J = 19.0, 5.3 Hz), 2.61-2.56 (1H, m), 1.48 (9H, s), 1.14-1.09 (2H, m), 0.85-0.81 (2H, m).
MS (ESI): m/z 328 ([M+H]⁺). Example 15 Synthesis of 7-cyclopropyl-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4,5-d] azepine dihydrochloride:

In a 20 mL flask, intermediate 9 (23 mg, 63 μmol), cyclopropylboronic acid (14 mg, 0.16 mmol), Pd (OAc) ₂ (2.1 mg, 9.4 μmol), tricyclohexylphosphine (5.3 mg, 19 μmol). And potassium phosphate (13 mg, 63 μmol) were weighed, toluene (1.2 mL) and water (0.12 mL) were added, and the mixture was stirred at 80 ° C. for 20 hours. After cooling the reaction mixture to room temperature, the crude product obtained by concentration was purified by flash silica gel column chromatography (amine silica, n-hexane / ethyl acetate = 60 / 40-50 / 50), and tert-butyl 7 -Propyl-4,5-dihydro-1H-pyrido [1′2 ′: 1,2] imidazo [4,5-d] azepine-3 (2H) -carboxylate (hereinafter intermediate 17) (13 mg, 39 μmol) ) Was obtained as a colorless oil (yield 62%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.66 (1H, d, J = 6.3 Hz), 6.72 (1H, t, J = 7.0 Hz), 6.60 (1H, d, J = 6.8 Hz), 3.82 -3.68 (4H, m), 3.25-3.19 (2H, m), 2.98 (2H, dt, J = 19.0, 5.3 Hz), 2.61-2.56 (1H, m), 1.48 (9H, s), 1.14-1.09 (2H, m), 0.85-0.81 (2H, m).
MS (ESI): m / z 328 ([M + H] ⁺ ).

The obtained intermediate 17 (13 mg, 39 μmol) was dissolved in 1,4-dioxane (0.2 mL), 4M hydrogen chloride-1,4-dioxane (0.1 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated and subsequently recrystallized from methanol-diethyl ether to give 7-cyclopropyl-2,3,4,5-tetrahydro-1H-pyrido [1 ′, 2 ′: 1,2] imidazo [4 5-d] azepine dihydrochloride (hereinafter, the compound of Example 15) (9.6 mg, 32 μmol) was obtained as a white solid (yield 82%).
¹ H-NMR (400 MHz, CD ₃ OD) δ: 8.54 (1H, d, J = 6.8 Hz), 7.60 (1H, d, J = 7.6 Hz), 7.44 (1H, t, J = 7.1 Hz), 3.70-3.66 (4H, m), 3.53-3.47 (4H, m), 2.29-2.22 (1H, m), 1.27-1.22 (2H, m), 0.97-0.93 (2H, m).
MS (ESI): m / z 228 ([M + H] ⁺ ).
mp: 248-253 ° C.

Example 16 Human 5-HT2C Receptor Agonism:
Using cells stably expressing human 5-HT2C receptor (hereinafter, cells expressing human 5-HT2C receptor), the imidazopyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid thereof The addition salt was evaluated for human 5-HT2C receptor agonism.

  PCI-neo-HTR2C prepared by cloning the human 5-HT2C receptor gene into the expression vector pCI-neo (manufactured by Promega) was introduced into HEK-293 cells (American Type Culture Collection) and introduced cells A single clone was obtained by the limiting dilution method, and human 5-HT2C receptor-expressing cells were prepared.

Human 5-HT2C receptor expressing cells are 10% fetal bovine serum (dialyzed), 1% MEM non-essential amino acids, 100 U / mL penicillin, 100 μg / mL streptomycin and 500 μg / mL Geneticin Dulbecco's Modified Eagle The culture medium was maintained in a 5% CO ₂ incubator at 37 ° C. using 's Medium as a culture solution.

Human 5-HT2C receptor-expressing cells are suspended in the above-mentioned culture solution (but not Geneticin) and seeded at 8 × 10 ^{4 in} each well of a 96-well black plate (Corning) at 37 ° C., The cells were cultured overnight at 5% CO ₂ and used for the following evaluation.

  Evaluation of human 5-HT2C receptor operability was performed by measuring an increase in intracellular calcium concentration due to activation of human 5-HT2C receptor.

  For the measurement of intracellular calcium concentration, FLIPR (registered trademark) Calcium 5 Assay Kit (manufactured by Molecular Devices) was used. As an assay buffer, a solution obtained by adding 2.5 mmol / L probenecid (manufactured by SIGMA) to Hank's balanced salt solution containing 20 mmol / L HEPES (pH 7.3) was used.

The medium of the plate seeded with human 5-HT2C receptor-expressing cells was removed, and FLIPR (registered trademark) Calcium5 Assay Reagent (included in the Kit) 150 μL / well dissolved in the assay buffer according to the instructions attached to the Kit In addition, the cells were incubated at 37 ° C. and 5% CO ₂ for 60 minutes under light shielding, and further allowed to stand at room temperature for 15 minutes under light shielding. Using FLIPR (registered trademark) TETRA (manufactured by Molecular Devices), 50 μL / well of a test compound was automatically added, and the fluorescence intensity was measured at an excitation wavelength of 470-495 nm and a fluorescence wavelength of 515-575 nm for 5 minutes.

Evaluation of each test compound was carried out by triplicate at each concentration at a common ratio of 3. The fluorescence intensity when no test compound is added is 0% response value, and the maximum fluorescence intensity when serotonin (manufactured by Nacalai Tesque), which is a human 5-HT2C receptor agonist, is added instead of the test compound is 100% response. As a value, the reaction rate (%) at each concentration of each test compound was determined. The EC ₅₀ value of each test compound (concentration showing 50% response to 100% response value of serotonin) was determined by linear regression using the reaction rate (%) at each concentration of each test compound. Each test compound and serotonin were dissolved in DMSO and then diluted with an assay buffer.

The EC ₅₀ values for each test compound are shown in Table 2. As is clear from the results in Table 2, it is shown that the imidazopyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has 5-HT2C receptor agonist activity. It was done.

Since the imidazopyridine derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has 5-HT2C receptor agonistic activity, it is preferable to use a drug containing them as an active ingredient, particularly 5-HT2C. It can be used as a therapeutic agent and a prophylactic agent for diseases related to receptors.

Claims (5)

An imidazopyridine derivative represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof.

[Wherein m represents 1 or 2,
When m represents 1, R ¹ and R ² each independently represent a hydrogen atom, a propyl group, a butyl group or a cyclopropyl group, R ³ and R ⁴ represent a hydrogen atom,
When m represents 2, R ¹ represents a hydrogen atom, bromine atom, propyl group or cyclopropyl group, R ² and R ³ each independently represent a hydrogen atom, bromine atom or propyl group, R ⁴ represents a hydrogen atom, a bromine atom or a trifluoromethyl group,
Any ^{one of} R ^{1 to} R ⁴ represents other than a hydrogen atom. ] when m represents 1, R ² is a hydrogen atom or a propyl group;
If m represents 2, R ¹ is a hydrogen atom, a bromine atom or a propyl group, imidazopyridine derivative or a pharmacologically acceptable acid addition salt according to claim 1, wherein. when m represents 1, R ¹ is a cyclopropyl group, R ² is a hydrogen atom,
When m represents 2, R ¹ is a hydrogen atom or a propyl group, R ² is a hydrogen atom, R ³ is a hydrogen atom or a propyl group, and R ⁴ is a hydrogen atom or a bromine atom. The imidazopyridine derivative according to claim 1, or a pharmacologically acceptable acid addition salt thereof.   The pharmaceutical which contains the imidazopyridine derivative or its pharmacologically acceptable acid addition salt as described in any one of Claims 1-3 as an active ingredient. A 5-HT2C receptor agonist comprising the imidazopyridine derivative according to any one of claims 1 to 3 or a pharmacologically acceptable acid addition salt thereof as an active ingredient.