JPWO2013081094A1 - Imidazo [1,2-a] pyridine derivative and its pharmaceutical use - Google Patents

Abstract

【選択図】なしAn object of the present invention is to provide a compound that selectively acts on mGluR5 and inhibits signal transduction of mGluR5. The present invention provides imidazo [1,2-a] pyridine derivatives represented by the following compounds or pharmacologically acceptable acid addition salts thereof.

[Selection figure] None

Description

  The present invention relates to imidazo [1,2-a] pyridine derivatives and pharmaceutical uses thereof.

  Metabotropic glutamate receptors are receptors for glutamate, which is an important excitatory transmitter in the central nervous system, and 8 subtypes have been identified so far. One of these subtypes, metabotropic glutamate receptor 5 (hereinafter referred to as mGluR5) is deeply involved in various biological functions, and when mGluR5 signal transduction is excessive, it is associated with various diseases. It is known to cause.

  Diseases caused by excessive signal transduction of mGluR5 include, for example, L-DOPA-induced dyskinesia in Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis or fragile X syndrome, Various types of gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), gastrointestinal disorders such as functional gastrointestinal disorders and postoperative ileus, migraine, visceral pain, postoperative pain, inflammatory pain and neuropathic pain Pain, panic disorder, social anxiety disorder, specific phobia, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), generalized anxiety disorder (GAD), mood disorders such as depression and bipolar disorder Disorders, dysuria such as overactive bladder and urge incontinence, drug dependence, etc. have been reported (Non-Patent Documents 1 to 7).

  Therefore, drugs that inhibit excessive signal transduction of mGluR5 are considered to be useful as therapeutic agents for the above-mentioned diseases. L-DOPA-induced dyskinesia, fragile X syndrome and gastroesophageal reflux disease (GERD) in Parkinson's disease ) Has actually been confirmed to be effective in humans (Non-Patent Documents 8 to 10).

On the other hand, as a compound having an imidazo [1,2-a] pyridine structure, Patent Document 1 discloses a compound represented by the following general formula (A).

JP-T-2004-525192

Gregory et al., Neuropharmacology, 2011, 60, p. 66-81 Bruno et al., Journal Of Cerebral Blood Flow & Metabolism, 2001, Vol. 21, p. 1013-1033 Jensen et al., European Journal of Pharmacology, 2005, 519, p. 154-157 Zhu et al., European Journal of Pharmacology, 2004, 506, p. 107-118 Lindstom et al., Pain, 2008, 137, p. 295-305 Guarneri et al., British Journal of Urology International, 2008, 102, p. 890-898 Olive, Current Drug Abuse Reviews, 2009, Volume 2, p. 83-98 Berg et al., Movement Disorders, 2011, 26, p. 1243-1250 Berry-Kravis et al., Journal of MEDICAL GENETICS, 2009, 46, p. 266-271 Keywood et al., Gut, 2009, 58, p. 1192-1199

  However, the compound disclosed in Patent Document 1 is an unsubstituted imidazo [1,2-a] pyridine derivative at the 3-position, and a compound having a substituent at the 3-position is not disclosed. In addition, there has been no suggestion or disclosure about the possibility that an imidazo [1,2-a] pyridine derivative substituted with pyridine has an inhibitory effect on mGluR5 signaling.

  Therefore, an object of the present invention is to provide a compound that selectively acts on mGluR5 and inhibits signal transduction of mGluR5.

［式中、Ｒ^１〜Ｒ^３は、それぞれ独立して、水素、炭素数１〜６のアルキル又はハロゲンを表し、Ｒ^４及びＲ^７は、それぞれ独立して、水素又は炭素数１〜６のアルキルを表し、Ｒ^５は、炭素数１〜６のアルキルを表し、Ｒ^６は、水素又はハロゲンを表す。］
で示されるイミダゾ［１，２−ａ］ピリジン誘導体又はその薬理学的に許容される酸付加塩を提供する。As a result of intensive studies to achieve the above object, a novel imidazo [1,2-a] pyridine derivative that strongly inhibits signal transduction of mGluR5 has been found and the present invention has been completed. That is, the present invention relates to the general formula (I)

[Wherein R ^{1 to} R ³ each independently represent hydrogen, alkyl or halogen having 1 to 6 carbon atoms, and R ⁴ and R ⁷ each independently represent hydrogen or 1 to 6 carbon atoms. Represents alkyl, R ⁵ represents alkyl having 1 to 6 carbon atoms, and R ⁶ represents hydrogen or halogen. ]
Or a pharmacologically acceptable acid addition salt thereof.

In the above imidazo [1,2-a] pyridine derivative or a pharmacologically acceptable acid addition salt thereof, R ⁶ is preferably hydrogen, fluoro or chloro, and R ⁷ is preferably hydrogen or methyl. More preferably, R ^{1 to} R ³ are each independently hydrogen, methyl or fluoro, R ⁴ is hydrogen or methyl, and R ⁵ is methyl, ethyl or propyl.

  These compounds significantly inhibit mGluR5 signaling by selectively acting on mGluR5, and are useful as inhibitors of mGluR5.

Further, R ¹ and R ³ are each independently hydrogen or fluoro, R ² is more preferably hydrogen, methyl or fluoro, R ² is hydrogen or fluoro, and R ⁵ is propyl. R ⁶ is particularly preferably fluoro or chloro and R ⁷ is methyl.

  These compounds inhibit mGluR5 signaling more significantly by selectively acting on mGluR5, and are particularly useful as inhibitors of mGluR5.

  The present invention also provides a medicament comprising an imidazo [1,2-a] pyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

  Furthermore, the present invention provides an inhibitor of mGluR5 containing an imidazo [1,2-a] pyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient. .

  The imidazo [1,2-a] pyridine derivative of the present invention and a pharmacologically acceptable acid addition salt thereof have an activity of inhibiting mGluR5 signal transduction, which is caused by excessive signal transduction of mGluR5. It can be used as a therapeutic agent for a disease.

［式中、Ｒ^１〜Ｒ^３は、それぞれ独立して、水素、炭素数１〜６のアルキル又はハロゲンを表し、Ｒ^４及びＲ^７は、それぞれ独立して、水素又は炭素数１〜６のアルキルを表し、Ｒ^５は、炭素数１〜６のアルキルを表し、Ｒ^６は、水素又はハロゲンを表す。］The imidazo [1,2-a] pyridine derivative of the present invention is characterized by being represented by the following general formula (I).

[Wherein R ^{1 to} R ³ each independently represent hydrogen, alkyl or halogen having 1 to 6 carbon atoms, and R ⁴ and R ⁷ each independently represent hydrogen or 1 to 6 carbon atoms. Represents alkyl, R ⁵ represents alkyl having 1 to 6 carbon atoms, and R ⁶ represents hydrogen or halogen. ]

  “C1-C6 alkyl” means a monovalent linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms composed of carbon and hydrogen, such as methyl, ethyl , Propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl. “Halogen” means fluoro, chloro, bromo or iodo.

Preferred specific examples of R ^{1 to} R ⁷ in the general formula (I) are shown below.

R ^{1 to} R ³ are each independently preferably hydrogen, methyl, ethyl, propyl, fluoro or chloro, more preferably hydrogen, methyl or fluoro, and even more preferably hydrogen or fluoro. R ⁴ is preferably hydrogen, methyl, ethyl or propyl, more preferably hydrogen or methyl. R ⁵ is preferably methyl, ethyl, propyl, isopropyl or butyl, more preferably methyl, ethyl or propyl, and even more preferably propyl. R ⁶ is preferably hydrogen, fluoro, chloro or bromo, more preferably hydrogen, fluoro or chloro, and still more preferably fluoro or chloro. R ⁷ is preferably hydrogen, methyl, ethyl, propyl or isopropyl, more preferably hydrogen or methyl, and even more preferably methyl.

  Examples of the pharmacologically acceptable acid addition salt of the imidazo [1,2-a] pyridine derivative represented by the above general formula (I) include hydrochloride, sulfate, nitrate, hydrobromide, Inorganic acid salts such as hydroiodide or phosphate, acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleic acid Organic carboxylates such as salts, benzoates or phthalates, or organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate or camphorsulfonate However, hydrochloride, hydrobromide, phosphate, tartrate or methanesulfonate is preferred, and hydrochloride, tartrate or methanesulfonate is more preferred.

Of the imidazo [1,2-a] pyridine derivatives represented by the above general formula (I), preferred specific examples are shown in Tables 1 and 2.

  The imidazo [1,2-a] pyridine derivative represented by the above general formula (I) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the type of substituent. The starting materials and reagents used in this production are generally available and can be synthesized by known methods.

［式中、Ｒ^１〜Ｒ^７は、上記定義に同じであり、Ｘは、クロロ、ブロモ又はヨードを表す。］(Production method 1)
The imidazo [1,2-a] pyridine derivative represented by the above general formula (I) includes, for example, a halopyridine derivative represented by the general formula (II) and a general formula (III) as shown in the following scheme 1. It can be produced by a coupling reaction with the aminopyridine derivative shown.

[Wherein, R ^{1 to} R ⁷ are the same as defined above, and X represents chloro, bromo or iodo. ]

  The coupling reaction between the halopyridine derivative represented by the above general formula (II) and the aminopyridine derivative represented by the above general formula (III) is generally a method using a ligand and a base together with a palladium catalyst. For example, the method of Tsuji (Palladium Reagent and Catalysts, 2004, p. 373-391 (Wiley)) or the method of Wolfe et al. (The Journal of Organic Chemistry, 2000, Vol. 65, p. 1144-1157). It can be implemented similarly.

  In the coupling reaction, the equivalent amount of the aminopyridine derivative represented by the general formula (III) is preferably 0.5 to 20 equivalents relative to the halopyridine derivative represented by the general formula (II). 5 equivalents are more preferable, and 1-2 equivalents are more preferable.

  Examples of the palladium catalyst used in the coupling reaction include tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, or palladium acetate, and palladium acetate is preferable. The equivalent of the palladium catalyst is preferably 0.01 to 1 equivalent, more preferably 0.01 to 0.1 equivalent, relative to the halopyridine derivative represented by the above general formula (II).

  Examples of the ligand used in the coupling reaction include triphenylphosphine, tri (o-tolyl) phosphine, 1,2-bis (diphenylphosphino) ethane, 1,2-bis (diphenylphosphino) butane, , 1′-bis (diphenylphosphino) ferrocene or 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (hereinafter referred to as BINAP), preferably BINAP. 1-10 equivalent is preferable with respect to said palladium catalyst, and, as for the equivalent of this ligand, 1-3 equivalent is more preferable.

Examples of the base used for the coupling reaction include sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium, and tert-butoxy potassium, with cesium carbonate being preferred. 1-20 equivalent is preferable with respect to the halopyridine derivative shown by said general formula (II), and, as for the equivalent of this base, 1-3 equivalent is more preferable.
Examples of the solvent used in the coupling reaction include ether solvents such as diethyl ether, tetrahydrofuran (hereinafter referred to as THF), dimethoxyethane (hereinafter referred to as DME) or dioxane, and aromatic solvents such as benzene, toluene or xylene. However, an aromatic solvent is preferable and toluene is more preferable.

  The reaction temperature of the coupling reaction is preferably 0 to 150 ° C, more preferably 20 to 130 ° C, further preferably 80 to 110 ° C, and the reaction time of the coupling reaction varies depending on the substrate or reaction conditions, but 1 to 72 Time is preferable, and 10 to 24 hours is more preferable.

  The concentration at the start of the reaction of the halopyridine derivative represented by the above general formula (II) in the coupling reaction is preferably 0.1 mM to 1M, and more preferably 0.01 to 0.8M. The concentration of the aminopyridine derivative represented by the general formula (III) in the coupling reaction at the start of the reaction is preferably 0.1 mM to 1M, more preferably 0.01 to 0.8M, and 0.05 to 0.5M is more preferable. The aminopyridine derivative represented by the general formula (III) used for the coupling reaction may be a commercially available product or a compound synthesized from a commercially available product.

  By dissolving the imidazo [1,2-a] pyridine derivative represented by the general formula (I) obtained by the above production method 1 in an appropriate solvent and adding an acid thereto, the general formula (I) Acid addition salts of the indicated imidazo [1,2-a] pyridine derivatives can be obtained. Examples of the solvent used in the reaction include halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, alcohol solvents such as methanol, ethanol or propanol, ether solvents such as dioxane or diethyl ether, hexane or ethyl acetate. And hydrocarbon solvents such as these, and mixed solvents thereof are preferable, but chloroform, methanol, ethyl acetate, or mixed solvents thereof are preferable. The equivalent of the acid to be added is preferably 1 to 30 equivalents, more preferably 1 to 10 equivalents, and 1 to 5 equivalents with respect to the imidazo [1,2-a] pyridine derivative represented by the above general formula (I). Further preferred. 0-50 degreeC is preferable and, as for the reaction temperature of this reaction, 0-30 degreeC is more preferable. Although the reaction time of this reaction changes with substrates or reaction conditions, 5 minutes-5 hours are preferable and 5 minutes-1 hour are more preferable.

［式中、Ｒ^１〜Ｒ^６及びＸは、上記定義に同じである。］(Production method 2)
The halopyridine derivative represented by the above general formula (II), which is a starting material in the above production method 1, is a commercially available product or a general formula (IV) that can be synthesized by a known method, for example, as shown in Scheme 2. ) And an α-bromoketone derivative represented by the general formula (V) which can be synthesized by a commercially available product or a method described in, for example, International Publication No. 2005/040156. Can be manufactured.

[Wherein, R ^{1 to} R ⁶ and X are the same as defined above. ]

  The condensation cyclization reaction of the aminopyridine derivative represented by the above general formula (IV) and the α-bromoketone derivative represented by the above general formula (V) can be carried out, for example, by the method described in US Pat. No. 4,727,145. It can be implemented similarly.

  In the condensed cyclization reaction, the equivalent amount of the aminopyridine derivative represented by the above general formula (IV) is preferably 0.5 to 20 equivalents relative to the α-bromoketone derivative represented by the above general formula (V). ˜2 equivalents are more preferred.

  Examples of the solvent used for the condensation cyclization reaction include alcohol solvents such as methanol, ethanol or propanol, ether solvents such as diethyl ether, THF, DME or dioxane, or a mixed solvent thereof. Preferably, ethanol is more preferable.

  The reaction temperature of the condensation cyclization reaction is preferably 0 to 200 ° C, more preferably 25 to 180 ° C, further preferably 80 to 150 ° C, and the reaction time of the condensation cyclization reaction varies depending on the substrate or reaction conditions, but 0 .1 to 72 hours are preferable, and 0.3 to 24 hours are more preferable.

  The concentration at the start of the reaction of the aminopyridine derivative represented by the above general formula (IV) in the condensed cyclization reaction is preferably 0.1 mM to 5M, more preferably 0.01 to 3M, and further preferably 0.1 to 2M. preferable. Further, the concentration at the start of the reaction of the α-bromoketone derivative represented by the above general formula (V) in the reaction is preferably 0.1 mM to 1M, and more preferably 0.01 to 0.8M.

  In the condensed cyclization reaction, it may be preferable to add a base in order to promote the reaction. Examples of the base include sodium carbonate, sodium hydrogen carbonate, or potassium carbonate, and sodium hydrogen carbonate is preferable. . The equivalent of the base is preferably 1 to 20 equivalents and more preferably 1 to 3 equivalents with respect to the α-bromoketone derivative represented by the general formula (V). In addition, as the aminopyridine derivative represented by the general formula (IV) used in the condensed cyclization reaction, a commercially available product or a compound synthesized from a commercially available product may be used.

(Production method 3)
Among the halopyridine derivatives represented by the above general formula (II), which are the starting materials in the above production method 1, when R ⁵ is an alkyl group having 1 to 6 carbon atoms, for example, the method of Chernyak et al. (Angewandte Chemie International Edition, 2010, Vol. 49, p. 2743-2746).

  mGluR5 is a G protein-coupled receptor that is widely distributed in the central nervous system, and is activated by the binding of glutamic acid, causing signaling coupled to the G protein in the cell. The “inhibitor of mGluR5” means a compound that inhibits mGluR5 signal transduction or a composition containing the compound as an active ingredient.

  The imidazo [1,2-a] pyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has an activity of inhibiting mGluR5 signal transduction, for example, mGluR5 stable Inhibition of the production of inositol-1-phosphate produced in cells when mGluR5 is activated by treating glutamic acid on the expressed cells can be evaluated as an index. A method for measuring intracellular inositol-1-phosphate can be carried out by, for example, the method of Brandish et al. (Analytical Biochemistry, 2003, Vol. 313, p. 311-318), but commercially available inositol-1-phosphate The measurement kit can also be used.

  The imidazo [1,2-a] pyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has an activity of inhibiting mGluR5 signal transduction, and therefore is used as a medicine. In particular, it can be used as a therapeutic agent for diseases caused by excessive signal transduction of mGluR5.

  Examples of diseases caused by excessive signal transduction of mGluR5 include neurodegenerative disorders such as Parkinson's disease L-DOPA-induced dyskinesia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis or fragile X syndrome, gastroesophageal tract Various pains such as reflux disease (GERD), irritable bowel syndrome (IBS), gastrointestinal disorders such as functional gastrointestinal disorders or postoperative ileus, migraine, visceral pain, postoperative pain, inflammatory pain or neuropathic pain Panic disorder, social anxiety disorder, specific phobia, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD) or generalized anxiety disorder (GAD), mood disorders such as depression or bipolar disorder, Examples include dysuria such as overactive bladder or urge incontinence or drug addiction.

  A medicament containing the imidazo [1,2-a] pyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is not only effective for humans but also humans. It is also effective against other mammals such as mice, rats, hamsters, rabbits, cats, dogs, cows, sheep and monkeys.

  When the imidazo [1,2-a] pyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is used clinically as a medicine, the drug is a free base or The acid addition salt itself may be used, and for example, additives such as excipients, stabilizers, preservatives, buffers, solubilizers, emulsifiers, diluents or tonicity agents may be mixed as appropriate. . Examples of the dosage form include oral administration such as tablets, capsules, granules, powders or syrups, parenteral administration such as injections, suppositories or liquids, and local administration such as ointments, creams or patches. Can be mentioned.

  The above medicament contains 0.00001 to 90% by weight of an imidazo [1,2-a] pyridine derivative represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient. The content is preferably 0.0001 to 70% by weight. The dosage is appropriately selected according to the patient's symptoms, age and weight, and administration method, etc., but for adults, the amount of active ingredient is 0.1 μg to 1 g per day in the case of injections, orally. In the case of an agent, 1 μg to 10 g per day is preferable, and in the case of a patch, 1 μg to 10 g per day is preferable, and can be administered once or divided into a plurality of times.

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

Reference Example 1 Synthesis of 2- (5,6-dichloropyridin-3-yl) -5-methyl-3-((trimethylsilyl) methyl) imidazo [1,2-a] pyridine:
To a solution of 5,6-dichloropyridine-3-carboxaldehyde (140 mg, 0.80 mmol) and 2-amino-6-methylpyridine (95.0 mg, 0.88 mmol) in toluene (3.6 mL) was added trimethylsilylacetylene (0 .40 mL, 2.89 mmol), copper (I) chloride (7.9 mg, 0.08 mmol) and copper (II) trifluoromethanesulfonate (28.8 mg, 0.08 mmol) were added, and the mixture was stirred at 120 ° C. for 8 hours. . The reaction mixture was cooled to room temperature, added with triethylamine, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to give 2- (5,6-dichloropyridin-3-yl) -5--5 as a white solid. Methyl-3-((trimethylsilyl) methyl) imidazo [1,2-a] pyridine (hereinafter referred to as the compound of Reference Example 1) was obtained (148 mg, yield 51%).

Reference Example 2 Synthesis of 2- (5,6-dichloropyridin-3-yl) -3,5-dimethylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 1 (50.0 mg, 0.14 mmol) in THF (1.0 mL) was added tetrabutylammonium fluoride in THF (1.0 M, 0.41 mL, 0.41 mmol), and at room temperature. Stir for 10 minutes. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The crude product obtained by drying the organic layer over anhydrous sodium sulfate and concentrating the product was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to give 2- (5 , 6-Dichloropyridin-3-yl) -3,5-dimethylimidazo [1,2-a] pyridine (hereinafter referred to as the compound of Reference Example 2) was obtained (38.5 mg, yield 96%).

Example 1 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3,5-dimethylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 2 (38.5 mg, 0.13 mmol) in toluene (2.0 mL), 3-amino-6-methylpyridine (15.5 mg, 0.14 mmol), palladium acetate (2.9 mg, 0 0.01 mmol), BINAP (16.2 mg, 0.03 mmol) and cesium carbonate (85.0 mg, 0.26 mmol) were added, and the mixture was stirred at 100 ° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform: methanol = 98: 2) to give 2- (5-chloro-6- (6-methylpyridin-3-yl) amino as a white solid. Pyridin-3-yl) -3,5-dimethylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 1) was obtained (37.6 mg, yield 79%).

Example 2 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3,5-dimethylimidazo [1,2-a] pyridine hydrochloride :
To a solution of the compound of Example 1 (104 mg, 0.26 mmol) in ethyl acetate (3.0 mL) was added 10% hydrogen chloride methanol solution (0.26 mL). The precipitated solid was collected by filtration to give 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3,5-dimethylimidazo [1,2-a as a white solid. Pyridine hydrochloride (hereinafter, the compound of Example 2) was obtained (94.3 mg, yield 91%).

Reference Example 3 Synthesis of 5,6-dichloro-N-methoxy-N-methylnicotinic acid amide:
To a solution of 5,6-dichloronicotinic acid (5.00 g, 26 mmol) in 1,2-dichloroethane (20 mL), thionyl chloride (3.8 mL, 52 mmol) and N, N-dimethylformamide (hereinafter DMF) (30 μL) And stirred at 85 ° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated. A solution of the obtained crude product in dichloromethane (20 mL) was added dropwise at 0 ° C. to a solution of N, O-dimethylhydroxyamine hydrochloride (3.05 g, 31 mmol) and triethylamine (8.7 mL, 63 mmol) in dichloromethane (20 mL). And stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with chloroform, and then 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 recrystallized (n-hexane-ethyl acetate) to obtain the title compound (4.32 g, yield 71%) as a white solid. . Furthermore, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 7: 3) to give 5,6-dichloro-N- as a white solid. Methoxy-N-methylnicotinic acid amide (hereinafter referred to as the compound of Reference Example 3) was obtained (1.46 g, yield 24%).

Reference Example 4 Synthesis of 1- (5,6-dichloropyridin-3-yl) pentan-1-one:
To a THF (40 mL) solution of the compound of Reference Example 3 (3.00 g, 13 mmol), a THF solution (0.91 M, 28 mL, 26 mmol) of n-butylmagnesium chloride was added dropwise at −15 ° C. over 20 minutes, followed by And stirred for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with diethyl ether, and then the organic layer was washed with water. The crude product obtained by drying and concentrating the organic layer over anhydrous sodium sulfate was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 20: 1) to give 1- (5 , 6-Dichloropyridin-3-yl) pentan-1-one (hereinafter referred to as the compound of Reference Example 4) was obtained (1.83 g, yield 62%).

Reference Example 5 Synthesis of 2-bromo-1- (6-bromo-5-chloropyridin-3-yl) pentan-1-one:
To a 1,2-dichloroethane (50 mL) solution of the compound of Reference Example 4 (3.06 g, 13 mmol), pyridinium bromide perbromide (4.43 g, 14 mmol) was added and stirred at 50 ° C. for 4 hours. A 30% hydrobromic acetic acid solution (2.0 mL) was added to the reaction mixture, and the mixture was stirred at 50 ° C. for 14 hr. The reaction mixture was cooled to room temperature, 1N aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with n-hexane-diethyl ether mixed solution (n-hexane: diethyl ether = 1: 1). The organic layer was washed with water, saturated aqueous ammonium chloride solution and saturated brine. The crude product obtained by drying the organic layer over anhydrous sodium sulfate and concentrating was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 20: 1) to give 2-bromo as a colorless oil. -1- (6-Bromo-5-chloropyridin-3-yl) pentan-1-one (hereinafter referred to as the compound of Reference Example 5) was obtained (3.79 g, yield 81%).

Reference Example 6 Synthesis of 2- (6-bromo-5-chloropyridin-3-yl) -3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 5 (3.70 g, 10 mmol) in ethanol (20 mL) was added 2-aminopyridine (1.18 g, 13 mmol), and the mixture was stirred at 80 ° C. for 18 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. Subsequently, the organic layer was washed with water and saturated brine. The crude product obtained by drying and concentrating the organic layer with anhydrous sodium sulfate was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 7: 3) to give 2- (6-Bromo-5-chloropyridin-3-yl) -3-propylimidazo [1,2-a] pyridine (hereinafter referred to as the compound of Reference Example 6) was obtained (2.32 g, yield 64%).

Example 3 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 6 (1.50 g, 4.3 mmol) in toluene (15 mL), 5-amino-2-methylpyridine (0.51 g, 4.7 mmol), palladium acetate (38.0 mg, 0.17 mmol). ), BINAP (0.27 g, 0.43 mmol) and cesium carbonate (2.09 g, 6.4 mmol) were added and stirred at 100 ° C. for 18 hours. The reaction mixture was cooled to room temperature, chloroform was added and filtered, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform: methanol = 98: 2) to give 2- (5-chloro-6- (6-methylpyridin-3-yl) amino as a white solid. Pyridin-3-yl) -3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 3) was obtained (1.46 g, yield 90%).

Example 4 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine hydrochloride:
A 10% hydrogen chloride methanol solution (10 mL) was added to an ethyl acetate-methanol mixed solution (ethyl acetate: methanol = 4: 1) (30 mL) solution of the compound of Example 3 (1.33 g, 3.5 mmol) and then concentrated. did. The obtained crude product was recrystallized (ethanol-diethyl ether) to give 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3-yl as a pale yellow solid. Propylimidazo [1,2-a] pyridine hydrochloride (hereinafter, the compound of Example 4) was obtained (1.58 g, quantitative).

Reference Example 7 Synthesis of 6-bromo-N-methoxy-N-methylnicotinic acid amide:
To a solution of 6-bromonicotinic acid (2.00 g, 9.9 mmol) in dichloromethane (20 mL) was added N, O-dimethylhydroxyamine hydrochloride (1.06 g, 11 mmol), 1-ethyl-3- (3-dimethylamino). Propyl) carbodiimide hydrochloride (2.09 g, 11 mmol), 1-hydroxybenzotriazole monohydrate (1.67 g, 11 mmol) and triethylamine (1.8 mL, 13 mmol) were added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with a mixed solution of n-hexane-ethyl acetate (n-hexane: ethyl acetate = 1: 1), and then the organic layer was washed with saturated brine. The crude product obtained by drying the organic layer over anhydrous sodium sulfate and concentrating was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 7: 3) to give 6-bromo as a colorless oil. -N-methoxy-N-methylnicotinic acid amide (hereinafter referred to as the compound of Reference Example 7) was obtained (2.05 g, yield 84%).

Reference Example 8 Synthesis of 1- (6-bromopyridin-3-yl) pentan-1-one:
To a THF (40 mL) solution of the compound of Reference Example 7 (2.00 g, 8.2 mmol), a THF solution (0.91 M, 13.5 mL, 13 mmol) of n-butylmagnesium chloride was added at 0 ° C. over 20 minutes. Followed by stirring for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with diethyl ether, and then the organic layer was washed with water. The crude product obtained by drying and concentrating the organic layer over anhydrous sodium sulfate was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 20: 1) to give 1- (6 -Bromopyridin-3-yl) pentan-1-one (hereinafter referred to as the compound of Reference Example 8) was obtained (1.44 g, yield 73%).

Reference Example 9 Synthesis of 2-bromo-1- (6-bromopyridin-3-yl) pentan-1-one:
Pyridinium bromide perbromide (727 mg, 2.3 mmol) was added to a solution of the compound of Reference Example 8 (500 mg, 2.1 mmol) in 1,2-dichloroethane (10 mL), and the mixture was stirred at 50 ° C. for 16 hours. The reaction mixture was cooled to room temperature, 1N aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with n-hexane-diethyl ether mixed solution (n-hexane: diethyl ether = 1: 1). The organic layer was washed with water, saturated aqueous ammonium chloride solution and saturated brine. The crude product obtained by drying the organic layer over anhydrous sodium sulfate and concentrating was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 20: 1) to give 2-bromo as a colorless oil. -1- (6-Bromopyridin-3-yl) pentan-1-one (hereinafter, the compound of Reference Example 9) was obtained (647 mg, yield 97%).

Reference Example 10 Synthesis of 2- (6-bromopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 9 (640 mg, 2.0 mmol) in ethanol (8.0 mL) was added 2-aminopyridine (206 mg, 2.2 mmol), and the mixture was stirred at 150 ° C. for 25 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. Subsequently, the organic layer was washed with water and saturated brine. The crude product obtained by drying and concentrating the organic layer with anhydrous sodium sulfate was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 3) to give 2- (6 -Bromopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Reference Example 10) was obtained (375 mg, yield 60%).

(Example 5)
Synthesis of 2- (6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 10 (200 mg, 0.63 mmol) in toluene (3.0 mL), 5-amino-2-methylpyridine (96.0 mg, 0.89 mmol), palladium acetate (7.1 mg, 0.03 mmol). ), BINAP (51.2 mg, 0.08 mmol) and cesium carbonate (309 mg, 0.95 mmol) were added and stirred at 100 ° C. for 18 hours. The reaction mixture was cooled to room temperature, chloroform was added and filtered, and then the filtrate was concentrated. The obtained crude product was purified by silica gel chromatography (eluent; chloroform: methanol = 96: 4) to give 2- (6- (6-methylpyridin-3-yl) aminopyridin-3-yl as a white solid. ) -3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 5) was obtained (151 mg, yield 69%).

Example 6 Synthesis of 2- (6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine hydrochloride:
To a mixed solution of the compound of Example 5 (100 mg, 0.29 mmol) in ethyl acetate-methanol (ethyl acetate: methanol = 5: 2) (7.0 mL) was added 10% hydrogen chloride methanol solution (3.0 mL). After concentration. The obtained crude product was recrystallized (ethanol-diethyl ether) to give 2- (6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3-propylimidazo [1 as a pale yellow solid. , 2-a] pyridine hydrochloride (hereinafter, the compound of Example 6) was obtained (115 mg, yield 95%).

Reference Example 11 Synthesis of 6-chloro-5-fluoro-N-methoxy-N-methylnicotinamide:
To a solution of 6-chloro-5-fluoronicotinic acid (1.00 g, 5.7 mmol) in dichloromethane (20 mL) was added oxalyl dichloride (0.55 mL, 6.3 mmol) and DMF (0.01 mL) at room temperature. Stir for 1 hour. The reaction mixture was concentrated, and N, O-dimethylhydroxyamine hydrochloride (0.68 g, 6.8 mmol) and triethylamine (2.38 mL, 17 mmol) were added to a solution of the resulting crude product in dichloromethane (20 mL). Stir at room temperature for 17 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. Subsequently, the organic layer was washed with water and saturated brine. The crude product obtained by drying the organic layer over anhydrous sodium sulfate and concentrating was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 1) to give 6-chloro- as a white solid. 5-Fluoro-N-methoxy-N-methylnicotinamide (hereinafter referred to as the compound of Reference Example 11) was obtained (1.13 g, yield 91%).

Reference Example 12 Synthesis of 1- (6-chloro-5-fluoropyridin-3-yl) pentan-1-one:
To a THF (10 mL) solution of the compound of Reference Example 11 (0.50 g, 2.3 mmol) was added a THF solution (0.91 M, 5.0 mL, 4.6 mmol) of n-butylmagnesium chloride at 0 ° C. Stir for hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate, and then the organic layer was washed with saturated brine. The crude product obtained by drying the organic layer with anhydrous sodium sulfate and concentrating was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 9: 1) to give 1- ( 6-chloro-5-fluoropyridin-3-yl) pentan-1-one (hereinafter referred to as the compound of Reference Example 12) was obtained (0.34 g, 69%).

Reference Example 13 Synthesis of 2-bromo-1- (6-bromo-5-fluoropyridin-3-yl) pentan-1-one:
To a solution of the compound of Reference Example 12 (330 mg, 1.5 mmol) in 1,2-dichloroethane (5.0 mL), pyridinium bromide perbromide (587 mg, 1.8 mmol) and 30% hydrobromic acetic acid solution (0.90 mL, 4.6 mmol) was added and the mixture was stirred at 60 ° C. for 16 hours. The reaction mixture was cooled to room temperature, ice and 1N aqueous sodium hydroxide solution were added, and the mixture was extracted with dichloromethane. The organic layer was washed with 0.1N hydrochloric acid and saturated brine. The crude product obtained by drying the organic layer over anhydrous magnesium sulfate and concentrating was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 5: 1) to give 2-bromo as a yellow oil. -1- (6-Bromo-5-fluoropyridin-3-yl) pentan-1-one (hereinafter, the compound of Reference Example 13) was obtained (502 mg, 97%).

Reference Example 14 Synthesis of 2- (6-bromo-5-fluoropyridin-3-yl) -3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 13 (180 mg, 0.53 mmol) in ethanol (3.0 mL) was added 2-aminopyridine (100 mg, 1.1 mmol), and the mixture was stirred at 80 ° C. for 24 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated brine. The crude product obtained by drying and concentrating the organic layer over anhydrous sodium sulfate was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 3: 2) to give 2- ( 6-bromo-5-fluoropyridin-3-yl) -3-propylimidazo [1,2-a] pyridine (hereinafter referred to as the compound of Reference Example 14) was obtained (146 mg, 82%).

Example 7 Synthesis of 2- (5-fluoro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 14 (100 mg, 0.30 mmol) in toluene (3.0 mL), 5-amino-2-methylpyridine (49.0 mg, 0.45 mmol), palladium acetate (6.7 mg, 0.03 mmol). ), BINAP (37.0 mg, 0.06 mmol) and cesium carbonate (195 mg, 0.60 mmol) were added, and the mixture was stirred at 110 ° C. for 19 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added and then filtered, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 30: 1) to give 2- (5-fluoro-6- (6-methylpyridin-3-yl) as a slightly yellow solid. Aminopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 7) was obtained (121 mg, 93%).

Example 8 Synthesis of 2- (5-fluoro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine hydrochloride:
To a solution of the compound of Example 7 (120 mg, 0.28 mmol) in ethyl acetate-chloroform mixture (ethyl acetate: chloroform = 6: 1) (3.5 mL) was added 10% hydrogen chloride methanol solution (0.12 mL). . The precipitated solid was collected by filtration and 2- (5-fluoro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -3-propylimidazo [1,2-a] as a slightly yellow solid. Pyridine hydrochloride (hereinafter, the compound of Example 8) was obtained (60.0 mg, 48%).

Example 9 Synthesis of 2- (5-chloro-6- (3-pyridyl) aminopyridin-3-yl) -3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 6 (70.0 mg, 0.20 mmol) in toluene (1.0 mL), 3-aminopyridine (24.4 mg, 0.26 mmol), palladium acetate (3.1 mg, 0.01 mmol), BINAP (18.7 mg, 0.03 mmol) and cesium carbonate (98.0 mg, 0.30 mmol) were added, and the mixture was stirred at 100 ° C. for 18 hours. The reaction mixture was cooled to room temperature, chloroform was added and filtered, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform: methanol = 96: 4) to give 2- (5-chloro-6- (3-pyridyl) aminopyridin-3-yl as a white solid. ) -3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 9) was obtained (40.0 mg, 55% yield).

Reference Example 15 Synthesis of 2- (6-bromo-5-chloropyridin-3-yl) -8-methyl-3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 5 (121 mg, 0.43 mmol) in ethanol (4.0 mL) was added 2-amino-3-methylpyridine (93.0 mg, 0.86 mmol), and the mixture was stirred at 80 ° C. for 24 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. Subsequently, the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate: = 7: 3) to give 2- ( 6-Bromo-5-chloropyridin-3-yl) -8-methyl-3-propylimidazo [1,2-a] pyridine (hereinafter referred to as the compound of Reference Example 15) was obtained (93.7 mg, yield 60). %).

Example 10 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -8-methyl-3-propylimidazo [1,2-a] pyridine :
To a toluene (3.0 mL) solution of the compound of Reference Example 15 (93.7 mg, 0.26 mmol), 5-amino-2-methylpyridine (33.3 mg, 0.31 mmol), palladium acetate (2.9 mg, 0 0.01 mmol), BINAP (16.2 mg, 0.03 mmol) and cesium carbonate (126 mg, 0.39 mmol) were added, and the mixture was stirred at 100 ° C. for 5 hours. The reaction mixture was cooled to room temperature, chloroform was added and filtered, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 97: 3), and 2- (5-chloro-6- (6-methylpyridin-3-yl) amino was obtained as a yellow solid. Pyridin-3-yl) -8-methyl-3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 10) was obtained (100 mg, quantitative).

Example 11 2- (5-Chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -8-methyl-3-propylimidazo [1,2-a] pyridine hydrochloride Synthesis of:
To a solution of the compound of Example 10 (100 mg, 0.26 mmol) in ethyl acetate (10 mL) was added 10% hydrogen chloride methanol solution (2.0 mL). The precipitated solid was collected by filtration and 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -8-methyl-3-propylimidazo [1,2 as a yellow solid -A] Pyridine hydrochloride (hereinafter, the compound of Example 11) was obtained (106 mg, yield 89%).

Reference Example 16 Synthesis of 2- (6-bromo-5-chloropyridin-3-yl) -7-methyl-3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 5 (0.50 g, 1.4 mmol) in ethanol (25 mL) was added 2-amino-4-methylpyridine (0.30 g, 2.8 mmol), and the mixture was stirred at 80 ° C. for 19 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The crude product obtained by drying and concentrating the organic layer over anhydrous sodium sulfate was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate: = 3: 2) to give 2- ( 6-Bromo-5-chloropyridin-3-yl) -7-methyl-3-propylimidazo [1,2-a] pyridine (hereinafter referred to as the compound of Reference Example 16) was obtained (0.41 g, yield 80). %).

Example 12 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -7-methyl-3-propylimidazo [1,2-a] pyridine :
To a solution of the compound of Reference Example 16 (100 mg, 0.27 mmol) in toluene (3.0 mL), 5-amino-2-methylpyridine (44.0 mg, 0.41 mmol), palladium acetate (6.2 mg, 0.03 mmol). ), BINAP (34.0 mg, 0.06 mmol) and cesium carbonate (179 mg, 0.55 mmol) were added and stirred at 110 ° C. for 16 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added and then filtered, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate: = 1: 9) to give 2- (5-chloro-6- (6-methylpyridine-3) as a yellow solid. -Yl) aminopyridin-3-yl) -7-methyl-3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 12) was obtained (76.0 mg, 71% yield).

Example 13 2- (5-Chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -7-methyl-3-propylimidazo [1,2-a] pyridine hydrochloride Synthesis of:
To a solution of the compound of Example 12 (75.0 mg, 0.19 mmol) in ethyl acetate-chloroform (ethyl acetate: chloroform = 4: 1) (2.5 mL) was added 10% hydrogen chloride methanol solution (0.12 mL). added. The precipitated solid was collected by filtration to give 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -7-methyl-3-propylimidazo [1,2 as a white solid. -A] Pyridine hydrochloride (hereinafter, the compound of Example 13) was obtained (49.0 mg, yield 56%).

Reference Example 17 Synthesis of 2- (6-bromo-5-chloropyridin-3-yl) -6-fluoro-3-propylimidazo [1,2-a] pyridine:
5-Fluoro-2-aminopyridine (114 mg, 1.0 mmol) was added to a solution of the compound of Reference Example 5 (300 mg, 0.84 mmol) in ethanol (4.0 mL), and the mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was cooled to room temperature, added with triethylamine, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to give 2- (6-bromo-5-chloropyridin-3-yl)-as a white solid. 6-Fluoro-3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Reference Example 17) was obtained (112 mg, yield 36%).

Example 14 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -6-fluoro-3-propylimidazo [1,2-a] pyridine :
To a solution of the compound of Reference Example 17 (110 mg, 0.30 mmol) in toluene (3.0 mL), 5-amino-2-methylpyridine (38.7 mg, 0.36 mmol), palladium acetate (6.7 mg, 0 0.03 mmol), BINAP (37.2 mg, 0.06 mmol) and cesium carbonate (194 mg, 0.60 mmol) were added and stirred at 100 ° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 97: 3) to give 2- (5-chloro-6- (6-methylpyridin-3-yl) amino as a white solid. Pyridin-3-yl) -6-fluoro-3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 14) was obtained (104 mg, yield 88%).

Example 15 2- (5-Chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -6-fluoro-3-propylimidazo [1,2-a] pyridine hydrochloride Synthesis of:
To a solution of the compound of Example 14 (104 mg, 0.26 mmol) in ethyl acetate (3.0 mL) was added 10% hydrogen chloride methanol solution (0.26 mL). The precipitated solid was collected by filtration, and 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -6-fluoro-3-propylimidazo [1,2 was obtained as a white solid. -A] Pyridine hydrochloride (hereinafter, the compound of Example 15) was obtained (94.3 mg, yield 91%).

Reference Example 18 Synthesis of 2- (6-bromo-5-chloropyridin-3-yl) -7-fluoro-3-propylimidazo [1,2-a] pyridine:
4-Fluoro-2-aminopyridine (151 mg, 1.35 mmol) was added to an ethanol (3.0 mL) solution of the compound of Reference Example 5 (320 mg, 0.90 mmol), and the mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was cooled to room temperature, added with triethylamine, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to give 2- (6-bromo-5-chloropyridin-3-yl)-as a white solid. 7-fluoro-3-propylimidazo [1,2-a] pyridine (hereinafter referred to as the compound of Reference Example 18) was obtained (144 mg, 43% yield).

Example 16 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -7-fluoro-3-propylimidazo [1,2-a] pyridine :
To a toluene (3.0 mL) solution of the compound of Reference Example 18 (143 mg, 0.39 mmol), 5-amino-2-methylpyridine (50.3 mg, 0.47 mmol), palladium acetate (8.7 mg, 0.04 mmol). ), BINAP (48.3 mg, 0.08 mmol) and cesium carbonate (253 mg, 0.78 mmol) were added, and the mixture was stirred at 100 ° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 97: 3) to give 2- (5-chloro-6- (6-methylpyridin-3-yl) amino as a white solid. Pyridin-3-yl) -7-fluoro-3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 16) was obtained (117 mg, yield 76%).

Example 17 2- (5-Chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -7-fluoro-3-propylimidazo [1,2-a] pyridine hydrochloride Synthesis of:
To a solution of the compound of Example 16 (117 mg, 0.30 mmol) in ethyl acetate (6.0 mL) was added 10% hydrogen chloride methanol solution (0.29 mL). The precipitated solid was collected by filtration, and 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -7-fluoro-3-propylimidazo [1,2 was obtained as a white solid. -A] Pyridine hydrochloride (hereinafter, the compound of Example 17) was obtained (106 mg, yield 90%).

Reference Example 19 Synthesis of 2- (6-bromo-5-chloropyridin-3-yl) -8-fluoro-3-propylimidazo [1,2-a] pyridine:
3-Fluoro-2-aminopyridine (151 mg, 1.35 mmol) was added to a solution of the compound of Reference Example 5 (320 mg, 0.90 mmol) in ethanol (3.0 mL), and the mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was cooled to room temperature, added with triethylamine, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to give 2- (6-bromo-5-chloropyridin-3-yl)-as a white solid. 8-Fluoro-3-propylimidazo [1,2-a] pyridine (hereinafter referred to as the compound of Reference Example 19) was obtained (114 mg, yield 34%).

Example 18 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -8-fluoro-3-propylimidazo [1,2-a] pyridine :
To a solution of the compound of Reference Example 19 (113 mg, 0.31 mmol) in toluene (3.0 mL), 5-amino-2-methylpyridine (39.8 mg, 0.37 mmol), palladium acetate (6.9 mg, 0.03 mmol). ), BINAP (38.2 mg, 0.06 mmol) and cesium carbonate (200 mg, 0.61 mmol) were added and stirred at 100 ° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 97: 3) to give 2- (5-chloro-6- (6-methylpyridin-3-yl) amino as a white solid. Pyridin-3-yl) -8-fluoro-3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 18) was obtained (116 mg, yield 96%).

Example 19 2- (5-Chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -8-fluoro-3-propylimidazo [1,2-a] pyridine hydrochloride Synthesis of:
To a solution of the compound of Example 18 (116 mg, 0.29 mmol) in chloroform (4.0 mL) was added 10% hydrogen chloride methanol solution (0.29 mL). The precipitated solid was collected by filtration and 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -8-fluoro-3-propylimidazo [1,2 as a white solid. -A] Pyridine hydrochloride (hereinafter, the compound of Example 19) was obtained (111 mg, yield 96%).

Reference Example 20 Synthesis of 2- (6-bromo-5-chloropyridin-3-yl) -5-methyl-3-propylimidazo [1,2-a] pyridine:
To a solution of the compound of Reference Example 5 (1.05 g, 3.0 mmol) in ethanol (4.0 mL), 2-amino-6-methylpyridine (0.80 g, 7.4 mmol) was added, and under microwave irradiation, 150 Stir at 0 ° C. for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. Subsequently, the organic layer was washed with water and saturated brine. The crude product obtained by drying and concentrating the organic layer over anhydrous sodium sulfate was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 7: 3) to give 2- (6 -Bromo-5-chloropyridin-3-yl) -5-methyl-3-propylimidazo [1,2-a] pyridine (hereinafter referred to as the compound of Reference Example 20) was obtained (0.16 g, 15% yield). ).

Example 20 Synthesis of 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -5-methyl-3-propylimidazo [1,2-a] pyridine :
To a toluene (3.0 mL) solution of the compound of Reference Example 20 (228 mg, 0.63 mmol), 5-amino-2-methylpyridine (101 mg, 0.94 mmol), palladium acetate (9.8 mg, 0.04 mmol), BINAP (78.0 mg, 0.13 mmol) and cesium carbonate (305 mg, 0.94 mmol) were added and stirred at 100 ° C. for 16 hours. The reaction mixture was cooled to room temperature, chloroform was added and filtered, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 98: 2) to give 2- (5-chloro-6- (6-methylpyridin-3-yl) amino as a yellow solid. Pyridin-3-yl) -5-methyl-3-propylimidazo [1,2-a] pyridine (hereinafter, the compound of Example 20) was obtained (184 mg, 75% yield).

Example 21 2- (5-Chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -5-methyl-3-propylimidazo [1,2-a] pyridine hydrochloride Synthesis of:
To a solution of the compound of Example 20 (184 mg, 0.47 mmol) in ethyl acetate-methanol (ethyl acetate: methanol = 4: 1) (10 mL) was added 10% hydrogen chloride methanol solution (4.0 mL). The precipitated solid was collected by filtration, and 2- (5-chloro-6- (6-methylpyridin-3-yl) aminopyridin-3-yl) -5-methyl-3-propylimidazo [1,2 -A] Pyridine hydrochloride (hereinafter, the compound of Example 21) was obtained (212 mg, 97% yield).

Comparative Example 1 2- (6- (6-Methylpyridin-3-yl) aminopyridin-3-yl) -3-propyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine Synthesis of:
To a solution of the compound of Example 3 (40.0 mg, 0.11 mmol) in methanol (2.0 mL) was added 10% palladium-carbon (22.5 mg), and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. The reaction mixture was filtered followed by concentration of the filtrate. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 19: 1) to give 2- (6- (6-methylpyridin-3-yl) aminopyridine-3- as a yellow solid. Yl) -3-propyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine (hereinafter, compound of Comparative Example 1) was obtained (20.0 mg, yield 55%).

Comparative Example 2 Synthesis of 2- (3-bromophenyl) imidazo [1,2-a] pyridine:
2-Bromo-1- (3-bromophenyl) ethanone (292 mg, 1.1 mmol) was added to a solution of 2-aminopyridine (94.1 mg, 1.0 mmol) in ethanol (2.0 mL), and the mixture was stirred at 80 ° C. for 22 hours. Stir for hours. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate was added. The precipitated solid was filtered off and the filtrate was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 2- (3-bromophenyl) imidazo [1,2-a] pyridine (hereinafter, compound of Comparative Example 2) as a yellow solid (181 mg, 66%).

  The spectral data and melting points of the compounds of Examples, Reference Examples and Comparative Examples are shown in Tables 3 to 7 below.

(Example 22) Evaluation of mGluR5 signaling inhibition activity in human mGluR5 stably expressing cells:
This method uses mGluR5 of a test compound as an index with the inhibition of the production of inositol-1-phosphate (hereinafter referred to as IP1) produced in cells when mGluR5 is activated by treating glutamate to mGluR5 stably expressing cells. Signaling inhibitory activity was evaluated. Specifically, it implemented as follows.

Human mGluR5 stably expressing cells used for evaluation of mGluR5 signal transduction inhibitory activity were expressed using an expression vector (pcDNA4 / TO; Invitrogen) incorporating a gene encoding human mGluR5 (NCBI Reference Sequence Number: NM_000842), T-REx-293. It was established by introduction into cells (Invitrogen). The established human mGluR5 stably expressing cells are Dulbecco's modified Eagle's medium (hereinafter, DMEM) containing 10% fetal bovine serum (hereinafter FBS), blasticidin (5 μg / mL), Zeocin (200 μg / mL) and Penicillin / Streptomycin. Was cultured in an incubator at 37 ° C. and 5% CO ₂ and maintained for subculture.

On the day before evaluation of mGluR5 signaling inhibition activity, human mGluR5 stably expressing cells were detached from the culture flask and then suspended in DMEM containing 10% Dialyzed FBS (Invitrogen) and GlutaMAX-1 (Invitrogen). Thereafter, human mGluR5 stably expressing cells were seeded in a 96-well poly-L-lysine plate at 60,000 cells / 100 μL / well and cultured overnight (12 hours or longer) in an incubator at 37 ° C. and 5% CO ₂ .

For the measurement of intracellular IP1 production, IP-One Tb Kit (Cisbio) was used. After removing the culture solution of human mGluR5 stable expression cells cultured in a 96-well poly-L-lysine plate, 40 μL of Stimulation buffer (attached to the above kit) containing 2.5 μM glutamic acid, 1% dimethyl sulfoxide and a test compound was added to the well Then, it was incubated for 60 minutes in an incubator at 37 ° C. and 5% CO ₂ . As a control, 40 μL of Stimulation buffer containing 2.5 μM glutamic acid and 1% dimethyl sulfoxide, not containing the test compound, was added to the well, and similarly incubated at 37 ° C. in a 5% CO ₂ incubator for 60 minutes. Thereafter, 16.5 μL of Lysis buffer (attached to the above kit) was added to each well to lyse the cells to obtain a cell lysate.

  As a standard for an IP1 calibration curve, a stock solution of IP1 calibrator (attached to the above kit) is serially diluted with a mixture of Stimulation buffer / Lysis buffer (40: 16.5), and the final concentration of IP1 is 11,000, 2 , 750, 688, 172, 43 and 11 nM.

  7 μL of each of the above cell lysate and IP1 standard for calibration curve was added to each well of a 384 well black plate. IP1-d2 conjugate (attached to the kit) and Anti-IP1 Cryptate Tb conjugate (attached to the kit), each diluted 10-fold with a stimulation buffer, were mixed in equal amounts, and the mixture was mixed with the 384-well black solution described above. 5 μL was added to each well of the plate and allowed to react for 60 minutes or more at room temperature. Thereafter, the fluorescence intensity (excitation wavelength 340 nm, fluorescence wavelengths 615 and 665 nm) of each well of the 384 well black plate was measured using a multi-label counter (Arvo; PerkinElmer).

The reaction between the human mGluR5 stably expressing cells and the test compound in the 96-well poly-L-lysine plate was performed in 2 cases. Moreover, the measurement of the fluorescence intensity in said 384 well black plate was implemented by the number 2 of examples. From the measurement result of fluorescence intensity, Ratio was calculated using the following formula.
Ratio = (A665nm / B615nm) × 10,000
A665 nm: measured value at 665 nm B615 nm: measured value at 615 nm

A calibration curve was created using the standard ratio for IP1 calibration curve, and the amount of IP1 produced in each cell lysate was determined. The mGluR5 signal transduction inhibitory activity of the test compound is the rate of inhibition of the rate of decrease in IP1 production due to the addition of the test compound compared to the amount of intracellular IP1 production when 2.5 μM glutamic acid is added (no test compound added) as a control. Calculated as (%). The concentration of the test compound corresponding to the inflection point of the sigmoid curve obtained by creating a graph with the calculated inhibition rate (%) on the vertical axis and the logarithmic value of the test compound concentration on the horizontal axis was taken as IC ₅₀ value. In addition, Prism 4.0 or 5.0 (GraphPad software) was used for the calculation.

  The results are shown in Table 8. Any of the imidazo [1,2-a] pyridine derivatives represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has an activity of inhibiting the signal transduction of human mGluR5. Furthermore, it was shown that the inhibitory activity is significantly stronger than the inhibitory activities of the compounds of Comparative Example 1 and Comparative Example 2.

Since the imidazo [1,2-a] pyridine derivative of the present invention or a pharmacologically acceptable acid addition salt thereof has an activity of strongly inhibiting the signal transduction of mGluR5, a pharmaceutical comprising them as an active ingredient, In particular, it can be used as a therapeutic agent for diseases caused by excessive signal transduction of mGluR5.

Claims (7)

Formula (I)

[Wherein R ^{1 to} R ³ each independently represent hydrogen, alkyl or halogen having 1 to 6 carbon atoms, and R ⁴ and R ⁷ each independently represent hydrogen or 1 to 6 carbon atoms. Represents alkyl, R ⁵ represents alkyl having 1 to 6 carbon atoms, and R ⁶ represents hydrogen or halogen. ]
An imidazo [1,2-a] pyridine derivative represented by the formula or a pharmacologically acceptable acid addition salt thereof. The imidazo [1,2-a] pyridine derivative or a pharmacologically acceptable acid addition salt thereof according to claim 1, wherein R ⁶ is hydrogen, fluoro or chloro, and R ⁷ is hydrogen or methyl. ^3. The imidazo according to claim 1, wherein R ^{1 to} R ³ are each independently hydrogen, methyl or fluoro, R ⁴ is hydrogen or methyl, and R ⁵ is methyl, ethyl or propyl. [1,2-a] pyridine derivative or a pharmacologically acceptable acid addition salt thereof. 4. The imidazo [1,2-a] according to claim 1, wherein R ¹ and R ³ are each independently hydrogen or fluoro, and R ² is hydrogen, methyl or fluoro. A pyridine derivative or a pharmacologically acceptable acid addition salt thereof. The imidazo according to any one of claims 1 to 4, wherein R ² is hydrogen or fluoro, R ⁵ is propyl, R ⁶ is fluoro or chloro, and R ⁷ is methyl. 1,2-a] pyridine derivative or a pharmacologically acceptable acid addition salt thereof. A pharmaceutical comprising the imidazo [1,2-a] pyridine derivative according to any one of claims 1 to 5 or a pharmacologically acceptable acid addition salt thereof as an active ingredient. An inhibitor of metabotropic glutamate receptor 5, comprising the imidazo [1,2-a] pyridine derivative according to any one of claims 1 to 5 or a pharmacologically acceptable acid addition salt thereof as an active ingredient. .