JPWO2015098991A1 - N-alkylamide derivatives and pharmaceutical use thereof - Google Patents

Abstract

An object of the present invention is to provide a new compound that strongly inhibits signal transduction of metabotropic glutamate receptor 5. The present invention provides an N-alkylamide derivative represented by the following or a pharmaceutically acceptable acid addition salt thereof.

Description

  The present invention relates to N-alkylamide 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 addiction, pruritus, etc. have been reported (Patent Document 1 and 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 been confirmed to be effective in humans (Non-Patent Documents 8 to 10).

On the other hand, Patent Document 2 discloses a compound represented by the following general formula (A) as a compound that inhibits mGluR5 signal transduction.

Non-Patent Document 11 describes the following compounds as compounds that inhibit mGluR5 signal transduction.

JP 2012-131829 A International Publication No. 2013/081094

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 Weiss et al., Bioorganic & Medicinal Chemistry Letters, 2011, Vol. 21, p. 4891-4899

  However, Patent Documents 1 and 2 and Non-Patent Document 11 do not disclose a compound having an optically active chain N-alkylamide structure, and even a compound that inhibits mGluR5 signaling is used as a pharmaceutical. There is no example that was confirmed to be effective.

  Therefore, an object of the present invention is to provide a new compound that strongly inhibits signal transduction of mGluR5.

［式中、Ｒ^１は、炭素数２〜６のアルキル、炭素数３〜６のシクロアルキル又は炭素数２〜６のアルケニルを表し、Ｒ^２は、炭素数１〜６のアルキル、炭素数１〜６のアルキルオキシ又はハロゲン原子を表し、Ａｒは、ピリジン−２−イル、オキサゾール−４−イル、オキサゾール−２−イル若しくはチアゾール−４−イル、又は、４位の水素原子がＲ^３で置換されていてもよいチアゾール−２−イルを表し、Ｒ^３は、炭素数１〜６のアルキルを表す。］As a result of intensive studies to achieve the above object, a novel N-alkylamide derivative having an optically active chain amine structure that strongly inhibits signal transduction of mGluR5 has been found and the present invention has been completed. It came. That is, the present invention provides an N-alkylamide derivative represented by the general formula (I) or a pharmaceutically acceptable acid addition salt thereof.

[Wherein, R ¹ represents alkyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, or alkenyl having 2 to 6 carbon atoms, and R ² represents alkyl having 1 to 6 carbon atoms or 1 carbon atom. -6 represents an alkyloxy or halogen atom, Ar is pyridin-2-yl, oxazol-4-yl, oxazol-2-yl or thiazol-4-yl, or a hydrogen atom at the 4-position is substituted by R ³ Represents optionally thiazol-2-yl, and R ³ represents alkyl having 1 to 6 carbon atoms. ]

In the above N-alkylamide derivative or a pharmaceutically acceptable acid addition salt thereof, R ¹ is ethyl, normal propyl, 2-propyl, normal butyl, 2-methylpropan-2-yl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, 2-propen-1-yl or 3-buten-1-yl, R ² is preferably a methyl, methoxy or fluorine atom, and R ³ is preferably methyl or 2-propyl. Further, R ¹ is ethyl, normal propyl, 2-propyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-propen-1-yl or 3-buten-1-yl, and R ² is a methyl, methoxy or fluorine atom There, Ar is pyridin-2-yl or oxazol-4-yl, or 4-position of the hydrogen atoms in ^{R 3} A conversion which may thiazol-2-yl also be, R ³ is more preferably a methyl.

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

Further, R ¹ is normal propyl, 2-propyl, cyclopropyl, cyclobutyl, 2-propen-1-yl or 3-buten-1-yl, R ² is methyl, Ar is thiazole-2- It is particularly preferable that

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

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

  The present invention also provides a therapeutic or prophylactic agent for anxiety disorders, which contains the N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

  The present invention also provides a therapeutic or prophylactic agent for pruritus comprising an N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

  The present invention also provides an inhibitor of mGluR5 containing the N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

  Since the N-alkylamide derivative of the present invention and a pharmaceutically acceptable acid addition salt thereof have an activity of strongly inhibiting mGluR5 signal transduction, it is particularly useful for drugs against diseases caused by excessive signal transduction of mGluR5. It can be used as a therapeutic or prophylactic agent for anxiety disorder or pruritus.

［式中、Ｒ^１は、炭素数２〜６のアルキル、炭素数３〜６のシクロアルキル又は炭素数２〜６のアルケニルを表し、Ｒ^２は、炭素数１〜６のアルキル、炭素数１〜６のアルキルオキシ又はハロゲン原子を表し、Ａｒは、ピリジン−２−イル、オキサゾール−４−イル、オキサゾール−２−イル若しくはチアゾール−４−イル、又は、４位の水素原子がＲ^３で置換されていてもよいチアゾール−２−イルを表し、Ｒ^３は、炭素数１〜６のアルキルを表す。］The N-alkylamide derivative of the present invention is characterized by being represented by the following general formula (I).

[Wherein, R ¹ represents alkyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, or alkenyl having 2 to 6 carbon atoms, and R ² represents alkyl having 1 to 6 carbon atoms or 1 carbon atom. -6 represents an alkyloxy or halogen atom, Ar is pyridin-2-yl, oxazol-4-yl, oxazol-2-yl or thiazol-4-yl, or a hydrogen atom at the 4-position is substituted by R ³ Represents optionally thiazol-2-yl, and R ³ represents alkyl having 1 to 6 carbon atoms. ]

  “C2-C6 alkyl” means a monovalent linear or branched saturated hydrocarbon group having 2 to 6 carbon atoms, consisting of carbon and hydrogen, such as ethyl, normal Examples include propyl, 2-propyl, normal butyl, 2-methylpropan-2-yl, normal pentyl or normal hexyl.

  “C3-C6 cycloalkyl” means a monovalent cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, consisting of carbon and hydrogen, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Is mentioned.

  “C2-C6 alkenyl” means a monovalent linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms, consisting of carbon and hydrogen, such as ethene- Examples include 1-yl, 2-propen-1-yl or 3-buten-1-yl.

  “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 , Normal propyl, 2-propyl, normal butyl, 2-methylpropan-2-yl, normal pentyl or normal hexyl.

  “C 1-6 alkyloxy” means a group in which the above C 1-6 alkyl is bonded to an oxygen atom, such as methoxy, ethoxy, normal propyloxy, 2-propyloxy, normal butyl. Examples include oxy, 2-methylpropan-2-yloxy, normal pentyloxy, or normal hexyloxy.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Preferred specific examples of R ¹ , R ² and Ar in the above general formula (I) are shown below.

R ¹ is ethyl, normal propyl, 2-propyl, normal butyl, 2-methylpropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-propen-1-yl or 3-buten-1-yl. Are preferred, ethyl, normal propyl, 2-propyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-propen-1-yl or 3-buten-1-yl are more preferred, normal propyl, 2-propyl, cyclopropyl, cyclobutyl, 2-propen-1-yl or 3-buten-1-yl is more preferred. R ² is preferably methyl, methoxy or a fluorine atom, more preferably methyl. Ar is preferably pyridin-2-yl or oxazol-4-yl, or thiazol-2-yl in which the hydrogen atom at the 4-position may be substituted with R ³ , and more preferably thiazol-2-yl. R ³ is preferably methyl or 2-propyl, more preferably methyl.

  Examples of the pharmaceutically acceptable acid addition salt of the N-alkylamide derivative represented by the above general formula (I) include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, Inorganic acid salts such as phosphate, acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate or Organic sulfonates such as phthalates or organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate or camphorsulfonate, Hydrobromide, phosphate, tartrate or methanesulfonate is preferred, and hydrochloride, tartrate or methanesulfonate is more preferred.

Of the N-alkylamide derivatives represented by the above general formula (I), preferred specific examples of combinations of Ar, R ¹ and R ² are shown in Tables 1 to 6. However, these do not limit the present invention. In addition, the dotted line part in a table | surface represents having substituted at the position.

  The N-alkylamide derivative represented by the above general formula (I) can be produced by an appropriate method based on 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、Ａｒ、Ｒ^１及びＲ^２は、上記定義に同じであり、Ｘは、塩素原子、臭素原子又はヨウ素原子を表す。］(Production method 1-1)
The N-alkylamide derivative represented by the above general formula (I) includes, for example, a halopyridine derivative represented by the general formula (II) and an aminopyridine derivative represented by the general formula (III) as shown in the following scheme 1. It can manufacture by a coupling reaction.

[Wherein, Ar, R ¹ and R ² are the same as defined above, and X represents a chlorine atom, a bromine atom or an iodine atom. ]

  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 from 0.01 to 1 equivalent, more preferably from 0.01 to 0.2 equivalent, based on 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 for the coupling reaction include ether solvents such as diethyl ether, tetrahydrofuran (hereinafter referred to as THF), dimethoxyethane (hereinafter referred to as DME) or 1,4-dioxane, or aromatic solvents such as benzene, toluene or xylene. Although a solvent is mentioned, 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 4 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.

［式中、Ａｒ、Ｒ^１及びＲ^２は、上記定義に同じである。］(Production method 1-2)
Further, the N-alkylamide derivative represented by the above general formula (I) is represented by the carboxylic acid derivative represented by the general formula (IV) and the general formula (V) as shown in the following scheme 2, for example. It can also be produced by a condensation reaction with an N-alkylamine derivative.

[Wherein, Ar, R ¹ and R ² are the same as defined above. ]

  In the condensation reaction of the carboxylic acid derivative represented by the general formula (IV) and the N-alkylamine derivative represented by the general formula (V), a method using a base together with a condensing agent is common.

  In the condensation reaction, the equivalent amount of the carboxylic acid derivative represented by the general formula (IV) is preferably 0.5 to 20 equivalents relative to the N-alkylamine derivative represented by the general formula (V). 5-5 equivalent is more preferable and 1-2 equivalent is still more preferable.

  Examples of the condensing agent used in the condensation reaction include dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride, O- (7-azabenzotriazol-1-yl) -1 , 1,3,3-tetramethyluronium hexafluorophosphate (hereinafter referred to as HATU), 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, O -(Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate, benzo Triazol-1-yl-oxytripiro Gino phosphonium hexafluorophosphate or bromo - tris - (pyrrolidino) - Although phosphonium hexafluorophosphate and the like, HATU are preferred. 1-20 equivalent is preferable with respect to the N-alkylamine derivative shown by said general formula (V), and, as for the equivalent of this condensing agent, 1-3 equivalent is more preferable.

  Examples of the base used in the condensation reaction include sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, triethylamine or N, N-diisopropylethylamine, but triethylamine or N , N-diisopropylethylamine is preferred. 1-20 equivalent is preferable with respect to the N-alkylamine derivative shown by said general formula (V), and, as for the equivalent of this base, 1-5 equivalent is more preferable.

  Examples of the solvent used in the condensation reaction include halogen solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, ether solvents such as diethyl ether, THF, DME, and 1,4-dioxane, benzene, toluene, and xylene. An aromatic solvent, N, N-dimethylformamide or a mixed solvent thereof can be mentioned, but dichloromethane, DMF or a mixed solvent thereof is preferable.

  The reaction temperature of the condensation reaction is preferably −50 ° C. to 150 ° C., more preferably 0 to 50 ° C., and the reaction time of the condensation reaction varies depending on the substrate or reaction conditions, but preferably 10 minutes to 72 hours, 30 minutes to More preferred is 24 hours.

  The concentration at the start of the reaction of the N-alkylamine derivative represented by the general formula (V) in the condensation reaction is preferably 0.1 mM to 1M, and more preferably 0.01 to 0.8M. In addition, the carboxylic acid derivative represented by the general formula (IV) used in the condensation reaction may be a commercially available product or a compound synthesized from a commercially available product.

［式中、Ａｒ、Ｒ^１及びＲ^２は、上記定義に同じであり、Ｙは、塩素原子、臭素原子又はヨウ素原子を表す。］(Production method 1-3)
Furthermore, the N-alkylamide derivative represented by the above general formula (I) is represented by, for example, an acid halide derivative represented by the general formula (VI) and a general formula (V) as shown in the following scheme 3. It can also be produced by an acylation reaction with an N-alkylamine derivative.

[Wherein, Ar, R ¹ and R ² are the same as defined above, and Y represents a chlorine atom, a bromine atom or an iodine atom. ]

  In the acylation reaction between the acid halide derivative represented by the general formula (VI) and the N-alkylamine derivative represented by the general formula (V), a base may be used.

  In the acylation reaction, the equivalent amount of the acid halide derivative represented by the general formula (VI) is preferably 0.5 to 20 equivalents relative to the N-alkylamine derivative represented by the general formula (V). 0.5-5 equivalent is more preferable, and 1-2 equivalent is still more preferable.

  Examples of the base used in the acylation reaction include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, triethylamine or N, N-diisopropylethylamine, but triethylamine or N, N-diisopropylethylamine is preferred. 0-20 equivalent is preferable with respect to the acid halide derivative shown by said general formula (VI), and, as for the equivalent of this base, 0-5 equivalent is more preferable.

  Examples of the solvent used in the acylation reaction include halogen solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, ether solvents such as diethyl ether, THF, DME, and 1,4-dioxane, benzene, toluene, and xylene. Aromatic solvent, DMF or a mixed solvent thereof is preferred, but dichloromethane, DMF or a mixed solvent thereof is preferred.

  The reaction temperature of the acylation reaction is preferably −50 ° C. to 100 ° C., more preferably 0 ° C. to 50 ° C., and the reaction time of the coupling reaction varies depending on the substrate or reaction conditions, but is preferably 10 minutes to 72 hours, 30 More preferably, min to 24 hours.

  The concentration at the start of the reaction of the N-alkylamine derivative represented by the general formula (V) in the acylation reaction is preferably 0.1 mM to 1M, and more preferably 0.01 to 0.8M. The acid halide derivative represented by the general formula (VI) used in the condensation reaction may be a commercially available product or a compound synthesized from a commercially available product.

  The N-alkylamide derivative represented by the general formula (I) obtained by the above production method 1-1, production method 1-2 or production method 1-3 is dissolved in a suitable solvent, and an acid is added thereto. Thus, an acid addition salt of the N-alkylamide derivative represented by the general formula (I) can be obtained. Examples of the solvent used in the reaction include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, alcohol solvents such as methanol, ethanol and propanol, ether solvents such as 1,4-dioxane and diethyl ether, A hydrocarbon solvent such as hexane or ethyl acetate or a mixed solvent thereof may be mentioned, but chloroform, methanol, ethyl acetate, hexane or a mixed solvent thereof is preferable. 0.5-30 equivalent is preferable with respect to the N-alkylamide derivative shown by said general formula (I), and, as for the equivalent of the acid to add, 0.9-15 equivalent is more preferable. 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. The concentration at the start of the reaction of the N-alkylamide derivative represented by the above general formula (I) in the reaction is preferably 0.1 mM to 1M, and more preferably 0.01 to 0.8M.

［式中、Ａｒ、Ｒ^１、Ｒ^２、Ｘ及びＹは、上記定義に同じである。］(Production method 2-1)
The halopyridine derivative represented by the above general formula (II), which is a starting material in the above production method 1-1, is, for example, an N-alkylsulfine represented by the general formula (VII) as shown in the following scheme 4. An amide derivative as a starting material, a solvolysis reaction of the derivative, followed by an N-alkylamine halopyridine derivative represented by the general formula (VIII) obtained by the solvolysis reaction, and the above general formula (IV) It can be produced by a condensation reaction with the indicated carboxylic acid derivative or an acylation reaction with the acid halide derivative represented by the above general formula (VI).

[Wherein, Ar, R ¹ , R ² , X and Y are the same as defined above. ]

  In the solvolysis reaction of the N-alkylsulfinamide derivative represented by the general formula (VII), a method using an acid is common.

  Examples of the acid used for the solvolysis reaction include hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, and trifluoroacetic acid, and hydrogen chloride is preferable. The acid may be a solution of water, methanol, ethanol, propanol, ethyl acetate, THF, 1,4-dioxane, cyclopentyl methyl ether or the like, and a solution of 1,4-dioxane is preferred. The equivalent of the acid is preferably 1 to 50 equivalents relative to the N-alkylsulfinamide derivative represented by the general formula (VII).

  Examples of the solvent used in the solvolysis reaction include alcohol solvents such as methanol, ethanol, and propanol, water, and mixed solvents thereof, and methanol or ethanol is preferable. These solvents include ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, ester solvents such as ethyl acetate, methyl acetate or butyl acetate, hydrocarbon solvents such as hexane or heptane, benzene An aromatic solvent such as toluene or xylene, a halogen solvent such as dichloromethane, 1,2-dichloroethane or chloroform or a mixed solvent thereof may be added. Examples of the solvent to be added include 1,4-dioxane, acetic acid Ethyl, hexane or a mixed solvent thereof is preferred.

  The reaction temperature of the solvolysis reaction is preferably 0 to 140 ° C., more preferably 0 to 50 ° C., and the reaction time of the solvolysis reaction varies depending on the substrate or reaction conditions, but preferably 10 minutes to 72 hours, 30 More preferably, min to 24 hours.

  The concentration at the start of the reaction of the N-alkylsulfinamide derivative represented by the above general formula (VII) in the solvolysis reaction is preferably 0.1 mM to 5M, more preferably 0.01 to 3M, ~ 2M is more preferred.

  Condensation reaction of the N-alkylamine halopyridine derivative represented by the above general formula (VIII) with the carboxylic acid derivative represented by the above general formula (IV) or the acid halide represented by the above general formula (VI) The acylation reaction with the derivative can be carried out in the same manner as in the above production method 1-2 and production method 1-3, respectively.

［式中、Ｒ^１、Ｒ^２及びＸは、上記定義に同じである。］(Production method 2-2)
The N-alkylamine derivative represented by the above general formula (V), which is the starting material in the above production method 1-2 or production method 1-3, has, for example, a general formula ( VII) and an aminopyridine derivative represented by the above general formula (III), followed by a coupling reaction represented by the above general formula (IX) obtained by the coupling reaction It can be produced by a solvolysis reaction of an N-alkylsulfinamidopyridylaminopyridine derivative.

[Wherein R ¹ , R ² and X are the same as defined above. ]

  The coupling reaction of the N-alkylsulfinamide derivative represented by the above general formula (VII) and the aminopyridine derivative represented by the above general formula (III) can be carried out in the same manner as in the above production method 1-1. is there.

  The solvolysis reaction of the N-alkylsulfinamidopyridylaminopyridine derivative represented by the above general formula (IX) can be carried out in the same manner as the solvolysis reaction in the production method 2-1.

［式中、Ｒ^１及びＸは、上記定義に同じである。］(Production method 3)
The N-alkylsulfinamide derivative represented by the above general formula (VII), which is a starting material in the above production method 2-1 and production method 2-2, is commercially available, for example, as shown in Scheme 5 below. Alternatively, a sulfinyl imination reaction of the derivative with (R) -2-methyl-2-propanesulfinamide, which can be synthesized from a commercially available product by a known method, using the aldehyde derivative represented by the general formula (X) as a starting material, followed , And can be produced by a nucleophilic addition reaction between a sulfinylimine derivative represented by the general formula (XI) obtained by the sulfinylimination reaction and a nucleophile.

[Wherein, R ¹ and X are the same as defined above. ]

  The sulfinyl imination reaction between the aldehyde derivative represented by the above general formula (X) and (R) -2-methyl-2-propanesulfinamide is generally a method using an additive that promotes dehydration condensation. For example, according to the method of Liu et al. (Journal of the American Chemical Society, 1997, Vol. 119, p. 9913-9914) or the method of Higashibayashi et al. (Synlett, 2003, Vol. 3, p. 457-460). Can be implemented.

  In the sulfinyl imination reaction, the equivalent amount of (R) -2-methyl-2-propanesulfinamide is preferably 0.5 to 20 equivalents relative to the aldehyde derivative represented by the general formula (X), -5 equivalents are more preferable, and 1-2 equivalents are more preferable.

  Examples of the additive used for the sulfinyl iminization reaction include magnesium sulfate, copper sulfate, titanium ethoxide, cesium fluoride, molecular sieve, or cesium carbonate, and cesium carbonate is preferable. 0.5-20 equivalent is preferable with respect to the aldehyde derivative shown by said general formula (X), and, as for the equivalent of this additive, 0.5-5 equivalent is more preferable.

  Examples of the solvent used for the sulfinylimination reaction include halogen solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, ether solvents such as diethyl ether, THF, DME, and 1,4-dioxane, benzene, toluene, and xylene. An aromatic solvent such as DMF or a mixed solvent thereof is exemplified, but dichloromethane is preferable.

  The reaction temperature of the sulfinyl imination reaction is preferably 0 to 40 ° C., more preferably 20 to 40 ° C., and the reaction time of the sulfinyl imination reaction varies depending on the substrate or reaction conditions, but preferably 30 minutes to 72 hours. -24 hours is more preferred.

  The concentration at the start of the reaction of the aldehyde derivative represented by the general formula (X) in the sulfinyl imination reaction is preferably 0.1 mM to 5M, more preferably 0.01 to 3M, and further preferably 0.05 to 2M. preferable.

  The nucleophilic addition reaction between the sulfinylimine derivative represented by the above general formula (XI) and a nucleophile is described in a review by Ellman et al. (Accounts of Chemical Research, 2002, Vol. 35, p. 984-995). As described above, a method using an organometallic compound is generally used, and can be performed, for example, according to the method of Liu et al. (Journal of the American Chemical Society, 1997, Vol. 119, p. 9913-9914). It is.

  Examples of the organometallic compound used for the nucleophilic addition reaction include an organolithium compound, a Grignard reagent, an organoaluminum compound, an organozinc compound, and an organoboron compound, with a Grignard reagent being preferred. The equivalent amount of the organometallic reagent is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents with respect to the sulfinylimine derivative represented by the above general formula (XI).

  For example, when a Grignard reagent is used for the nucleophilic addition reaction, the diastereomer represented by the above general formula (XII) is obtained as a by-product. In such a case, an additive may be used to suppress the by-production of the diastereomer represented by the general formula (XII). The additive is preferably, for example, an organic zinc compound such as dimethylzinc or diethylzinc or a zinc halogen compound such as zinc chloride, and the equivalent of the additive is preferably 0.1 to 10 equivalents relative to the Grignard reagent, 0.2-2 equivalent is more preferable.

  Examples of the solvent used for the nucleophilic addition reaction include halogen solvents such as dichloromethane or 1,2-dichloroethane, ether solvents such as diethyl ether, THF, DME or 1,4-dioxane, benzene, toluene or xylene. An aromatic solvent or a mixed solvent thereof may be mentioned, and THF is preferable.

  The reaction temperature of the nucleophilic addition reaction is preferably −100 ° C. to 100 ° C., more preferably −80 ° C. to 30 ° C., and the reaction time of the nucleophilic addition reaction varies depending on the substrate or reaction conditions, but is 10 minutes to 72 hours. Is preferable, and 10 minutes to 12 hours is more preferable.

  The concentration at the start of the reaction of the sulfinylimine derivative represented by the above general formula (XI) in the nucleophilic addition reaction is preferably 0.1 mM to 5M, more preferably 0.01 to 3M, and 0.05 to 2M. Further preferred.

  The medicament of the present invention, the therapeutic and preventive agent for anxiety disorder or pruritus, and the inhibitor of mGluR5 are the N-alkylamide derivatives represented by the above general formula (I) or pharmaceutically acceptable acid addition salts thereof Is contained as an active ingredient.

  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 N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has an activity to inhibit mGluR5 signaling (mGluR5 signaling inhibition activity), for example, mGluR5 Suppression of production of inositol-1-phosphate produced in cells when mGluR5 is activated by treating glutamic acid in stably expressing 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 N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has an activity of strongly inhibiting the signal transduction of mGluR5, and therefore is caused by excessive signal transduction of mGluR5. It can be used as a medicine for a disease to become, particularly as a therapeutic or prophylactic agent for anxiety disorder or pruritus.

  An anxiety disorder is a state in which anxiety is strong, or anxiety lasts for a long time or anxiety frequently occurs, causing problems in daily life. Examples of the anxiety disorder include panic disorder, social anxiety disorder, specific phobia, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD). However, these do not limit the present invention.

  Pruritus is defined as a skin-specific sensation with a desire to scratch. For example, atopic dermatitis, neural dermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum deficiency, senile skin pruritus, insect bite, photosensitivity, Urticaria, prurigo, shingles, impetigo, eczema, ringworm, lichen, psoriasis, pruritus, pruritus caused by skin diseases such as acne vulgaris, malignant tumor, diabetes, liver disease, chronic kidney disease, kidney Examples include pruritus caused by failure, blood disease, hemodialysis, peritoneal dialysis or multiple sclerosis, or pruritus caused by drug or psychosis. In addition, pruritus is roughly classified into pruritus mediated by histamine and pruritus not mediated by histamine (refractory pruritus). N-alkylamide derivatives represented by the above general formula (I) or pharmacologically thereof Acceptable acid addition salts are particularly effective against histamine-mediated pruritus (refractory pruritus). Examples of pruritus without histamine (refractory pruritus) include atopic dermatitis, contact dermatitis, sebum deficiency, senile pruritus, urticaria, psoriasis, malignant tumor, liver disease, chronic kidney disease, renal failure And pruritus with primary diseases such as blood diseases, hemodialysis, peritoneal dialysis, or multiple sclerosis, and are resistant to antihistamines. However, these do not limit the present invention.

  The N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has an anxiolytic action, for example, body temperature caused when a mouse feels anxiety or stress. The increase suppression can be evaluated using the index.

  That the N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has an antipruritic action is evaluated using, for example, scratching behavior using an itching model animal as an index. be able to. As a method for producing a pruritus model animal, it is well known that various types of raising substances represented by histamine, chloroquine or substance P are administered into the skin of a mouse. For example, Togashi et al. (European Journal of Pharmacology, 2002, Vol. 435, p. 259) and Andoh et al. (European Journal of Pharmacology, 2002, Vol. 436, p. 35). The scratching behavior of a pruritus model animal produced by intradermal administration of substance P to mice can be used as one of the intractable pruritus models with low therapeutic effects of antihistamines.

  As other pruritus model animals, NC / Nga mice described in Takano et al. (European Journal of Pharmacology, 2003, Vol. 471, p. 223) are known. The scratching behavior observed in this animal model of pruritus is a spontaneous scratching behavior associated with spontaneous dermatitis and can be used as one of the intractable pruritus models with low therapeutic effects of antihistamines.

  A medicament containing the N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof is not only effective for humans but also mammals other than humans, for example, It is also effective against mice, rats, hamsters, rabbits, cats, dogs, cows, sheep and monkeys.

  When the N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof is used clinically as a medicine, the drug may be a free base or the acid addition salt itself. 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 medicament preferably contains 0.00001 to 90% by weight of the N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. More preferably, the content is 0.0001 to 70% by weight. The dosage is appropriately selected according to the patient's symptoms, age and body weight, 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, oral preparations In the case of 1 μg to 10 g per day, and in the case of a patch, 1 μg to 10 g per day is preferable, and each can be administered once or divided into several times.

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

Reference Example 1 Synthesis of (R, E) -N-((5,6-dichloropyridin-3-yl) methylene) -2-methylpropane-2-sulfinamide:
To a solution of 5,6-dichloronicotinaldehyde (0.54 g, 3.1 mmol) and (R) -2-methylpropane-2-sulfinamide (0.37 g, 3.1 mmol) in dichloromethane (10 mL) was added cesium carbonate ( 2.0 g, 6.2 mmol) was added, and the mixture was stirred at 40 ° C. for 14 hours. The reaction mixture was cooled to room temperature and then filtered, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 5: 1) to give (R, E) -N-((5,6-dichloropyridine-3 as a white solid). -Yl) methylene) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 1) was obtained (0.86 g, yield 99%).

Reference Examples 2 and 3 (R) -N-((R) -1- (5,6-dichloropyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide and (R) -N Synthesis of-((S) -1- (5,6-dichloropyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide:
To a solution of the compound of Reference Example 1 (0.86 g, 3.1 mmol) in THF (15 mL) was added a solution of normal propylmagnesium chloride in diethyl ether (2.0 M, 2.3 mL, 4.6 mmol) at −78 ° C., Stir at -78 ° C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 5: 1) to give (R) -N as a white solid. -((R) -1- (5,6-dichloropyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 2) was obtained (0.58 g, yield). Rate 58%). In addition, (R) -N-((S) -1- (5,6-dichloropyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 3) as a white solid ) As a by-product (0.38 g, 38% yield).

Reference Example 4 (R) -N-((R) -1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -2-methyl Synthesis of propane-2-sulfinamide:
To a solution of the compound of Reference Example 2 (0.58 g, 1.8 mmol) in toluene (6.0 mL), 2-methyl-5-aminopyridine (0.23 g, 2.1 mmol), palladium acetate (40 mg, 0.18 mmol). ), BINAP (0.22 g, 0.36 mmol) and cesium carbonate (1.2 g, 3.6 mmol) were added and stirred at 100 ° C. for 12 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 = 98: 2) and (R) -N-((R) -1- (5-chloro-) as a slightly yellow oily substance. 6-((6-Methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 4) was obtained (0.61 g, Yield 86%).

Reference Example 5 Synthesis of (R) -5- (1-aminobutyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a methanol (7.7 mL) solution of the compound of Reference Example 4 (0.61 g, 1.5 mmol), a 4N hydrogen chloride 1,4-dioxane solution (7.7 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. did. The reaction mixture was concentrated, and the resulting crude product was slurry washed with a normal hexane-ethyl acetate mixed (15 mL) solvent to give (R) -5- (1-aminobutyl) -3-chloro-N- as a white solid. (6-Methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 5) was obtained (0.59 g, yield 100%).

Example 1 Synthesis of (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide:
To a solution of the compound of Reference Example 5 (0.17 g, 0.47 mmol) in dichloromethane (2.0 mL) was added thiazole-2-carbonyl chloride (0.10 g, 0.70 mmol) and triethylamine (0.26 mL, 1.8 mmol). And stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate = 7: 3) to give (R) -N- (1- (5-chloro-6- 6) as a pale yellow oil. ((6-Methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide (hereinafter, the compound of Example 1) was obtained (0.14 g, yield 82%).

Example 2 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide hydrochloride Synthesis:
A 10% hydrogen chloride methanol solution (0.15 mL) was added to a chloroform (3.0 mL) solution of the compound of Example 1 (0.14 g, 0.35 mmol), and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 2) was obtained (0.14 g, yield 84%).

Reference Example 6 Synthesis of (R) -N-((R) -1- (5,6-dichloropyridin-3-yl) -2-methylpropyl) -2-methylpropane-2-sulfinamide:
A solution of the compound of Reference Example 1 (0.27 g, 0.97 mmol) in toluene (5.5 mL) at 2-78 ° C. in 2-propylmagnesium chloride in diethyl ether (2.0 M, 0.68 mL, 1.4 mmol). And stirred at -78 ° C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 1) to give (R)- N-((R) -1- (5,6-dichloropyridin-3-yl) -2-methylpropyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 6) was obtained ( 0.16 g, yield 50%).

Reference Example 7 (R) -N-((R) -1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -2-methylpropyl) Synthesis of 2-methylpropane-2-sulfinamide:
To a toluene (4.0 mL) solution of the compound of Reference Example 6 (0.19 g, 0.60 mmol), 2-methyl-5-aminopyridine (78 mg, 0.72 mmol), palladium acetate (13 mg, 0.06 mmol), BINAP (75 mg, 0.12 mmol) and cesium carbonate (0.39 g, 1.20 mmol) were added, and the mixture was stirred at 100 ° C. for 12 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 = 98: 2) and (R) -N-((R) -1- (5-chloro-) as a slightly yellow oily substance. 6-((6-Methylpyridin-3-yl) amino) pyridin-3-yl) -2-methylpropyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 7) was obtained ( 0.13 g, yield 56%).

Reference Example 8 Synthesis of (R) -5- (1-amino-2-methylpropyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a solution of the compound of Reference Example 7 (0.13 g, 0.34 mmol) in methanol (2.0 mL) was added 4N hydrogen chloride 1,4-dioxane solution (1.6 mL) at 0 ° C., then 1 at room temperature. Stir for hours. The reaction mixture was concentrated and (R) -5- (1-amino-2-methylpropyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride ( The compound of Reference Example 8) was obtained (0.12 g, yield 100%).

Example 3 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -2-methylpropyl) thiazole-2- Synthesis of carboxamide:
To a solution of the compound of Reference Example 8 (0.12 g, 0.34 mmol) in dichloromethane (2.0 mL) was added thiazole-2-carbonyl chloride (56 mg, 0.44 mmol) and triethylamine (0.23 mL, 1.7 mmol). And stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 7: 3) to give (R) -N- (1- (5-chloro-6- ( (6-Methylpyridin-3-yl) amino) pyridin-3-yl) -2-methylpropyl) thiazole-2-carboxamide (hereinafter, the compound of Example 3) was obtained (0.11 g, yield 81%). ).

Example 4 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -2-methylpropyl) thiazole-2- Synthesis of carboxamide hydrochloride:
To a solution of the compound of Example 3 (0.11 g, 0.27 mmol) in chloroform (3.0 mL) was added a 10% hydrogen chloride methanol solution (0.11 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) -2-methylpropyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 4) was obtained (89 mg, 75% yield).

Reference Example 9 Synthesis of (R) -N-((R) -1- (5,6-dichloropyridin-3-yl) propyl) -2-methylpropane-2-sulfinamide:
To a THF (18 mL) solution of the compound of Reference Example 1 (1.0 g, 3.6 mmol) was added a THF solution of ethylmagnesium bromide (1.0 M, 4.3 mL, 4.3 mmol) at −78 ° C., and − Stir at 78 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 1) to give (R) -N as a white solid. -((R) -1- (5,6-dichloropyridin-3-yl) propyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 9) was obtained (0.80 g, yield). 72%).

Reference Example 10 (R) -N-((R) -1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) propyl) -2-methyl Synthesis of propane-2-sulfinamide:
To a toluene (9.0 mL) solution of the compound of Reference Example 9 (0.79 g, 2.6 mmol), 2-methyl-5-aminopyridine (0.33 mg, 3.1 mmol), palladium acetate (58 mg, 0.26 mmol). ), BINAP (0.32 g, 0.51 mmol) and cesium carbonate (1.7 g, 5.1 mmol) were added and stirred at 100 ° C. for 12 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 = 98: 2) to give (R) -N-((R) -1- (5-chloro-) as a slightly orange oil. 6-((6-Methylpyridin-3-yl) amino) pyridin-3-yl) propyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 10) was obtained (0.37 g, Yield 38%).

Reference Example 11 Synthesis of (R) -5- (1-aminopropyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a methanol (5.0 mL) solution of the compound of Reference Example 10 (0.37 g, 0.97 mmol), a 4N hydrogen chloride 1,4-dioxane solution (5.0 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. did. The reaction mixture was concentrated, and the resulting crude product was slurry washed with a normal hexane-ethyl acetate mixed (15 mL) solvent to give (R) -5- (1-aminopropyl) -3-chloro-N- as a white solid. (6-Methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 11) was obtained (0.35 g, yield 100%).

Example 5 Synthesis of (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) propyl) thiazole-2-carboxamide:
To a solution of the compound of Reference Example 11 (0.20 g, 0.57 mmol) in dichloromethane (2.0 mL) was added thiazole-2-carbonyl chloride (0.11 g, 0.74 mmol) and triethylamine (0.32 mL, 2.3 mmol). And stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 9) to give (R) -N- (1- (5-chloro-6- ( (6-Methylpyridin-3-yl) amino) pyridin-3-yl) propyl) thiazole-2-carboxamide (hereinafter, the compound of Example 5) was obtained (0.18 g, yield 79%).

Example 6 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) propyl) thiazole-2-carboxamide hydrochloride Synthesis:
To a solution of the compound of Example 5 (0.18 g, 0.45 mmol) in chloroform (4.0 mL) was added a 10% hydrogen chloride methanol solution (0.22 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) propyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 6) was obtained (0.17 g, yield 89%).

Reference Example 12 Synthesis of (R) -N-((R) -cyclobutyl (5,6-dichloropyridin-3-yl) methyl) -2-methylpropane-2-sulfinamide:
Iodine (50 mg) was added to a THF (7.0 mL) mixture of magnesium (0.30 g, 12 mmol), and the mixture was stirred at 45 ° C. for 30 minutes. To this mixture was added cyclobutyl bromide (0.57 mL, 6.1 mmol), and the mixture was stirred at 45 ° C. for 1.5 hours, and then cooled to room temperature. This reaction solution was added to a solution of the compound of Reference Example 1 (1.0 g, 3.6 mmol) in THF (18 mL) at −78 ° C., and the mixture was stirred at −78 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 1) to give (R) -N as a white solid. -((R) -cyclobutyl (5,6-dichloropyridin-3-yl) methyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 12) was obtained (0.45 g, yield). 38%).

Reference Example 13 (R) -N-((R)-(5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclobutyl) methyl) -2- Synthesis of methylpropane-2-sulfinamide:
To a toluene (5.0 mL) solution of the compound of Reference Example 12 (0.45 g, 1.3 mmol), 2-methyl-5-aminopyridine (0.17 g, 1.6 mmol), palladium acetate (30 mg, 0.13 mmol). ), BINAP (0.17 g, 0.27 mmol) and cesium carbonate (0.88 g, 2.7 mmol) were added, and the mixture was stirred at 100 ° C. for 13 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 = 98: 2) to give (R) -N-((R)-(5-chloro-6- ( (6-Methylpyridin-3-yl) amino) pyridin-3-yl) (cyclobutyl) methyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 13) was obtained (0.43 g, Yield 80%).

Reference Example 14 Synthesis of (R) -5- (amino (cyclobutyl) methyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a methanol (5.3 mL) solution of the compound of Reference Example 13 (0.43 g, 1.1 mmol), a 4N hydrogen chloride 1,4-dioxane solution (5.3 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. did. The reaction mixture was concentrated, and the resulting crude product was mixed with normal hexane-ethyl acetate (15 mL) and washed with slurry to give (R) -5- (amino (cyclobutyl) methyl) -3-chloro as a white solid. -N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 14) was obtained (0.40 g, yield 100%).

Example 7 Synthesis of (R) -N-((5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclobutyl) methyl) thiazole-2-carboxamide :
To a solution of the compound of Reference Example 14 (0.20 g, 0.53 mmol) in dichloromethane (2.0 mL) was added thiazole-2-carbonyl chloride (0.10 g, 0.69 mmol) and triethylamine (0.30 mL, 2.1 mmol). And stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate = 1: 9), and (R) -N-((5-chloro-6-((6 -Methylpyridin-3-yl) amino) pyridin-3-yl) (cyclobutyl) methyl) thiazole-2-carboxamide (hereinafter, the compound of Example 7) was obtained (0.19 g, yield 88%).

Example 8 (R) -N-((5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclobutyl) methyl) thiazole-2-carboxamide hydrochloride Synthesis of:
A 10% hydrogen chloride methanol solution (0.23 mL) was added to a chloroform (3.0 mL) solution of the compound of Example 7 (0.19 g, 0.47 mmol) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N-((5-chloro-6-((6-methylpyridin-3-yl) amino) as a white solid. Pyridin-3-yl) (cyclobutyl) methyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 8) was obtained (0.16 g, yield 76%).

Reference Example 15 Synthesis of (R) -N-((R) -cyclopropyl (5,6-dichloropyridin-3-yl) methyl) -2-methylpropane-2-sulfinamide:
To a solution of the compound of Reference Example 1 (1.0 g, 3.6 mmol) in THF (18 mL) at −78 ° C. was added cyclopropylmagnesium bromide in THF (0.5 M, 8.6 mL, 4.3 mmol), The mixture was stirred at -78 ° C for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 1) to give (R) -N as a white solid. -((R) -cyclopropyl (5,6-dichloropyridin-3-yl) methyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 15) was obtained (0.40 g, yield). Rate 35%).

Reference Example 16 (R) -N-((R)-(5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopropyl) methyl) -2 -Synthesis of methylpropane-2-sulfinamide:
To a toluene (5.0 mL) solution of the compound of Reference Example 15 (0.40 g, 1.2 mmol), 2-methyl-5-aminopyridine (0.16 g, 1.5 mmol), palladium acetate (28 mg, 0.12 mmol). ), BINAP (0.16 g, 0.25 mmol) and cesium carbonate (0.81 g, 2.5 mmol) were added and stirred at 100 ° C. for 12 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 = 98: 2) to give (R) -N-((R)-(5-chloro-6- ( (6-Methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopropyl) methyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 16) was obtained (0.39 g). 79% yield).

Reference Example 17 Synthesis of (R) -5- (amino (cyclopropyl) methyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a methanol (5.0 mL) solution of the compound of Reference Example 16 (0.39 g, 0.98 mmol), a 4N hydrogen chloride 1,4-dioxane solution (5.0 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. did. The reaction mixture was concentrated and the resulting crude product was recrystallized (normal hexane-ethyl acetate) to give (R) -5- (amino (cyclopropyl) methyl) -3-chloro-N- (6 -Methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 17) was obtained (0.35 g, yield 100%).

Example 9 (R) -N-((5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopropyl) methyl) thiazole-2-carboxamide Synthesis:
To a solution of the compound of Reference Example 17 (0.20 g, 0.55 mmol) in dichloromethane (2.0 mL) was added thiazole-2-carbonyl chloride (0.12 g, 0.83 mmol) and triethylamine (0.39 mL, 2.8 mmol). And stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate = 1: 9), and (R) -N-((5-chloro-6-((6 -Methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopropyl) methyl) thiazole-2-carboxamide (hereinafter, the compound of Example 9) was obtained (0.20 g, yield 90%).

Example 10 (R) -N-((5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopropyl) methyl) thiazole-2-carboxamide hydrochloride Salt synthesis:
To a solution of the compound of Example 9 (0.20 g, 0.50 mmol) in chloroform (5.0 mL) was added a 10% hydrogen chloride methanol solution (0.24 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N-((5-chloro-6-((6-methylpyridin-3-yl) amino) as a white solid. Pyridin-3-yl) (cyclopropyl) methyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 10) was obtained (0.20 g, yield 89%).

Reference Example 18 Synthesis of (R) -N-((R) -1- (5.6-dichloropyridin-3-yl) -2,2-dimethylpropyl) -2-methylpropane-2-sulfinamide :
To a solution of the compound of Reference Example 1 (1.0 g, 3.6 mmol) in THF (18 mL) at −78 ° C. was added 2-methylpropan-2-ylmagnesium chloride in THF (1.0 M, 4.3 mL, 4. 3 mmol) was added, and the mixture was stirred at −78 ° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 3: 2) to give (R) -N as a white solid. -((R) -1- (5.6-dichloropyridin-3-yl) -2,2-dimethylpropyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 18) was obtained. (78 mg, 6.5% yield).

Reference Example 19 (R) -N-((R) -1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -2,2-dimethyl Synthesis of propyl) -2-methylpropane-2-sulfinamide:
To a toluene (2.0 mL) solution of the compound of Reference Example 18 (78 mg, 0.23 mmol), 2-methyl-5-aminopyridine (30 mg, 0.28 mmol), palladium acetate (5.2 mg, 0.023 mmol), BINAP (29 mg, 0.047 mmol) and cesium carbonate (0.15 g, 0.46 mmol) were added, and the mixture was stirred at 100 ° C. for 12 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 = 98: 2) to give (R) -N-((R) -1- (5-chloro-6) as a colorless oil. -((6-Methylpyridin-3-yl) amino) pyridin-3-yl) -2,2-dimethylpropyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 19) was obtained. (72 mg, 76% yield).

Reference Example 20 Synthesis of (R) -5- (1-amino-2,2-dimethylpropyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a methanol (1.0 mL) solution of the compound of Reference Example 19 (72 mg, 0.18 mmol) was added 4N hydrogen chloride 1,4-dioxane solution (1.0 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting crude product was recrystallized (normal hexane-ethyl acetate) to give (R) -5- (1-amino-2,2-dimethylpropyl) -3-chloro- as a white solid. N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 20) was obtained (67 mg, 100% yield).

Example 11 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -2,2-dimethylpropyl) thiazole- Synthesis of 2-carboxamide:
To a solution of the compound of Reference Example 20 (67 mg, 0.18 mmol) in dichloromethane (1.0 mL) was added thiazole-2-carbonyl chloride (39 mg, 0.26 mmol) and triethylamine (0.12 mL, 0.88 mmol) at room temperature. For 1 hour. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 3: 7), and (R) -N- (1- (5-chloro-6- ( (6-Methylpyridin-3-yl) amino) pyridin-3-yl) -2,2-dimethylpropyl) thiazole-2-carboxamide (hereinafter, the compound of Example 11) was obtained (51 mg, yield 70%). ).

Example 12 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -2,2-dimethylpropyl) thiazole- Synthesis of 2-carboxamide hydrochloride:
A 10% hydrogen chloride methanol solution (0.060 mL) was added to a chloroform (1.0 mL) solution of the compound of Example 11 (51 mg, 0.12 mmol) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) -2,2-dimethylpropyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 12) was obtained (45 mg, 82% yield).

Reference Example 21 Synthesis of (R) -N-((R) -cyclopentyl (5,6-dichloropyridin-3-yl) methyl) -2-methylpropane-2-sulfinamide:
A solution of cyclopentylmagnesium bromide in diethyl ether (2.0 M, 1.4 mL, 2.7 mmol) in THF (1.5 mL) at 0 ° C. with a normal hexane solution of dimethylzinc (1.0 M, 2.7 mL, 2 mL 0.7 mmol) was added, and the mixture was stirred at 0 ° C. for 30 minutes. To this solution was added a THF (1.5 mL) solution of the compound of Reference Example 1 (0.50 g, 1.8 mmol), and the mixture was stirred at 0 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 1) to give (R) -N as a white solid. -((R) -cyclopentyl (5,6-dichloropyridin-3-yl) methyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 21) was obtained (0.36 g, yield). 58%).

Reference Example 22 (R) -N-((R)-(5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopentyl) methyl) -2- Synthesis of methylpropane-2-sulfinamide:
To a solution of the compound of Reference Example 21 (0.36 g, 1.0 mmol) in toluene (7.0 mL), 2-methyl-5-aminopyridine (0.13 g, 1.2 mmol), palladium acetate (23 mg, 0.10 mmol). ), BINAP (0.13 g, 0.21 mmol) and cesium carbonate (0.67 g, 2.1 mmol) were added and stirred at 100 ° C. for 10 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 = 98: 2) to give (R) -N-((R)-(5-chloro-6- ( (6-Methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopentyl) methyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 22) was obtained (0.34 g, Yield 78%).

Reference Example 23 Synthesis of (R) -5- (amino (cyclopentyl) methyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a methanol (4.0 mL) solution of the compound of Reference Example 22 (0.34 g, 0.80 mmol), a 4N hydrogen chloride 1,4-dioxane solution (4.0 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. did. The reaction mixture was concentrated and the resulting crude product was recrystallized (normal hexane-ethyl acetate) to give (R) -5- (amino (cyclopentyl) methyl) -3-chloro-N- (6- Methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 23) was obtained (0.31 g, yield 100%).

Example 13 Synthesis of (R) -N-((5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopentyl) methyl) thiazole-2-carboxamide :
To a solution of the compound of Reference Example 23 (0.31 g, 0.80 mmol) in dichloromethane (3.0 mL) was added thiazole-2-carbonyl chloride (0.18 g, 1.2 mmol) and triethylamine (0.56 mL, 4.0 mmol). And stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate = 1: 9), and (R) -N-((5-chloro-6-(( 6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopentyl) methyl) thiazole-2-carboxamide (hereinafter the compound of Example 13) was obtained (0.29 g, 83%).

Example 14 (R) -N-((5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclopentyl) methyl) thiazole-2-carboxamide hydrochloride Synthesis of:
To a solution of the compound of Example 13 (0.29 g, 0.67 mmol) in chloroform (5.0 mL) was added a 10% hydrogen chloride methanol solution (0.33 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N-((5-chloro-6-((6-methylpyridin-3-yl) amino) as a white solid. Pyridin-3-yl) (cyclopentyl) methyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 14) was obtained (0.22 g, 70%).

Reference Example 24 Synthesis of (R) -N-((R) -cyclohexyl (5,6-dichloropyridin-3-yl) methyl) -2-methylpropane-2-sulfinamide:
A THF solution (1.0 M, 5.4 mL, 5.4 mmol) of cyclohexylmagnesium bromide was added to a THF (36 mL) solution of the compound of Reference Example 1 (1.0 g, 3.6 mmol) at −78 ° C., and − Stir at 78 ° C. for 1 hour. 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 organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 3: 2) to give (R) -N as a white powder. -((R) -cyclohexyl (5,6-dichloropyridin-3-yl) methyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 24) was obtained (0.37 g, yield). 29%).

Reference Example 25 (R) -N-((R)-(5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclohexyl) methyl) -2- Synthesis of methylpropane-2-sulfinamide:
To a solution of the compound of Reference Example 24 (0.37 g, 1.0 mmol) in toluene (4.0 mL), 2-methyl-5-aminopyridine (0.13 g, 1.2 mmol), palladium acetate (23 mg, 0.10 mmol). ), BINAP (0.13 g, 0.21 mmol) and cesium carbonate (0.67 g, 2.1 mmol) were added and stirred at 100 ° C. for 14 hours. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted 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 purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 9) to give (R) as a tan oil. -N-((R)-(5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclohexyl) methyl) -2-methylpropane-2-sulfinamide ( The compound of Reference Example 25) was obtained (0.16 g, yield 35%).

Reference Example 26 Synthesis of (R) -5- (amino (cyclohexyl) methyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a methanol (4.0 mL) solution of the compound of Reference Example 25 (0.16 g, 0.36 mmol), a 4N hydrogen chloride 1,4-dioxane solution (4.0 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. did. The reaction mixture was concentrated, and the resulting crude product was recrystallized (methanol-normal hexane-ethyl acetate) to give (R) -5- (amino (cyclopentyl) methyl) -3-chloro-N- ( 6-methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 26) was obtained (0.11 g, yield 79%).

Example 15 Synthesis of (R) -N-((5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclohexyl) methyl) thiazole-2-carboxamide :
To a solution of the compound of Reference Example 26 (0.11 g, 0.27 mmol) in dichloromethane (3.0 mL) was added thiazole-2-carbonyl chloride (60 mg, 0.41 mmol) and triethylamine (0.13 mL, 0.90 mmol). And stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Subsequently, 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 silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 9) to give (R) -N as a white powder. -((5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclohexyl) methyl) thiazole-2-carboxamide (hereinafter, the compound of Example 15) was obtained. (0.12 g, 100% yield).

Example 16 (R) -N-((5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) (cyclohexyl) methyl) thiazole-2-carboxamide hydrochloride Synthesis of:
To a solution of the compound of Example 15 (0.12 g, 0.27 mmol) in methanol (3.0 mL) was added a 10% hydrogen chloride methanol solution (0.50 mL) and then concentrated. The resulting crude product was recrystallized (methanol-ethyl acetate-normal hexane) and (R) -N-((5-chloro-6-((6-methylpyridin-3-yl) amino) as a white solid. Pyridin-3-yl) (cyclohexyl) methyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 16) was obtained (0.11 g, 83%).

Reference Example 27 Synthesis of (R) -N-((R) -1- (5,6-dichloropyridin-3-yl) pentyl) -2-methylpropane-2-sulfinamide:
To a THF (10 mL) solution of the compound of Reference Example 1 (0.50 g, 1.8 mmol), a THF solution of normal butyl magnesium chloride (0.9 M, 4.0 mL, 3.6 mmol) was added at −78 ° C., − The mixture was stirred at 78 ° C. for 2 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 organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 9) to give (R) -N as a white solid. -((R) -1- (5,6-dichloropyridin-3-yl) pentyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 27) was obtained (0.42 g, yield). 70%).

Reference Example 28 (R) -N-((R) -1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) pentyl) -2-methyl Synthesis of propane-2-sulfinamide:
To a solution of the compound of Reference Example 27 (0.42 g, 1.2 mmol) in toluene (6.0 mL), 2-methyl-5-aminopyridine (0.16 g, 1.5 mmol), palladium acetate (28 mg, 0.13 mmol). ), BINAP (0.16 g, 0.25 mmol) and cesium carbonate (0.81 g, 2.5 mmol) were added and stirred at 100 ° 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: chloroform: methanol = 98: 2) and (R) -N-((R) -1- (5-chloro-) as a slightly yellow oily substance. 6-((6-Methylpyridin-3-yl) amino) pyridin-3-yl) pentyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 28) was obtained (0.47 g, Yield 96%).

Reference Example 29 Synthesis of (R) -5- (1-aminopentyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a methanol (6.0 mL) solution of the compound of Reference Example 28 (0.47 g, 1.1 mmol), a 4N hydrogen chloride 1,4-dioxane solution (4.0 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. did. The reaction mixture was concentrated, and the resulting crude product was recrystallized (normal hexane-ethyl acetate) to give (R) -5- (1-aminopentyl) -3-chloro-N- (6- Methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 29) was obtained (0.41 g, yield 96%).

Example 17 Synthesis of (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) pentyl) thiazole-2-carboxamide:
To a solution of the compound of Reference Example 29 (0.41 g, 1.1 mmol) in dichloromethane (10 mL) was added thiazole-2-carbonyl chloride (0.24 g, 1.6 mmol) and triethylamine (0.76 mL, 5.5 mmol). And stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. Subsequently, 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 silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 9) to give (R) as a pale yellow oil. -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) pentyl) thiazole-2-carboxamide (hereinafter referred to as the compound of Example 17) was obtained. (0.23 g, yield 51%).

Example 18 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) pentyl) thiazole-2-carboxamide hydrochloride Synthesis:
To a solution of the compound of Example 17 (0.23 g, 0.56 mmol) in methanol (1.5 mL) was added a 10% hydrogen chloride methanol solution (0.20 mL) and then concentrated. The obtained crude product was recrystallized (diethyl ether) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridine-3 as a white solid. -Yl) pentyl) thiazole-2-carboxamide hydrochloride (hereinafter referred to as the compound of Example 18) was obtained (0.11 g, yield 46%).

Reference Example 30 (R) -N-((R) -1- (5,6-dichloropyridin-3-yl) -4-penten-1-yl) -2-methylpropane-2-sulfinamide Synthesis:
Cyclopropylmethyl bromide (0.34 mL, 3.6 mmol) was added to a mixture of magnesium (0.17 g, 7.2 mmol) in THF (4.0 mL), and the mixture was stirred at room temperature for 1 hour. This reaction solution was added to a solution of the compound of Reference Example 1 (0.50 g, 1.8 mmol) in THF (5.0 mL) at −78 ° C. and stirred at −78 ° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 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; normal hexane: ethyl acetate = 4: 1) to give (R) -N as a white solid. -((R) -1- (5,6-dichloropyridin-3-yl) -4-penten-1-yl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 30) was obtained. (0.31 g, 52% yield).

Reference Example 31 (R) -N-((R) -1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -4-pentene-1 Synthesis of -yl) -2-methylpropane-2-sulfinamide:
To a solution of the compound of Reference Example 30 (0.31 g, 0.93 mmol) in toluene (5.0 mL), 2-methyl-5-aminopyridine (0.12 g, 1.1 mmol), palladium acetate (21 mg, 0.094 mmol). ), BINAP (0.12 g, 0.19 mmol) and cesium carbonate (0.60 g, 1.8 mmol) were added and stirred at 100 ° C. for 12 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 = 98: 2) and (R) -N-((R) -1- (5-chloro-) as a slightly yellow oily substance. 6-((6-Methylpyridin-3-yl) amino) pyridin-3-yl) -4-penten-1-yl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 31). Obtained (0.36 g, yield 95%).

Reference Example 32 Synthesis of (R) -5- (1-amino-4-penten-1-yl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride :
To a methanol (4.5 mL) solution of the compound of Reference Example 31 (0.35 g, 0.86 mmol), a 4N hydrogen chloride 1,4-dioxane solution (4.3 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. did. The reaction mixture was concentrated, and the resulting crude product was slurry washed with a normal hexane-ethyl acetate mixed (15 mL) solvent to give (R) -5- (1-amino-4-penten-1-yl) as a white solid -3-Chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 32) was obtained (0.26 g, yield 82%).

Example 19 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -4-penten-1-yl) thiazole Synthesis of 2-carboxamide:
To a solution of the compound of Reference Example 32 (0.26 g, 0.72 mmol) in dichloromethane (7.0 mL) was added thiazole-2-carbonyl chloride (0.14 g, 0.94 mmol) and triethylamine (0.50 mL, 3.6 mmol). And stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate = 7: 3) to give (R) -N- (1- (5-chloro-6- 6) as a pale yellow oil. ((6-Methylpyridin-3-yl) amino) pyridin-3-yl) -4-penten-1-yl) thiazole-2-carboxamide (hereinafter the compound of Example 19) was obtained (0.26 g, Yield 90%).

Example 20 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -4-penten-1-yl) thiazole Synthesis of 2-carboxamide hydrochloride:
To a solution of the compound of Example 19 (0.26 g, 0.63 mmol) in methanol (3.0 mL) was added a 10% hydrogen chloride methanol solution (0.50 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) -4-penten-1-yl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 20) was obtained (0.25 g, yield 91%).

Example 21 Synthesis of (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-4-carboxamide:
To a solution of the compound of Reference Example 5 (0.23 g, 0.63 mmol) and thiazole-4-carboxylic acid (90 mg, 0.70 mmol) in dichloromethane (5.0 mL) was added HATU (0.29 g, 0.76 mmol) and triethylamine. (0.26 mL, 1.9 mmol) was added and stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The crude product obtained by drying the organic layer over anhydrous magnesium sulfate and concentrating was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 9) to give (R)-as a slightly yellow oil. N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-4-carboxamide (hereinafter, the compound of Example 21) was obtained. (0.25 g, yield 100%).

Example 22 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-4-carboxamide hydrochloride Synthesis:
To a solution of the compound of Example 21 (0.25 g, 0.63 mmol) in methanol (5.0 mL) was added a 10% hydrogen chloride methanol solution (0.50 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) thiazole-4-carboxamide hydrochloride (hereinafter, the compound of Example 22) was obtained (0.20 g, yield 72%).

Reference Example 33 Synthesis of (R) -N- (1- (5,6-dichloropyridin-3-yl) butyl) thiazole-2-carboxamide:
To a solution of the compound of Reference Example 2 (0.94 g, 2.9 mmol) in ethanol (7.0 mL) was added 4N hydrogen chloride 1,4-dioxane solution (15 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting crude product was slurry washed with a normal hexane-ethyl acetate mixed (30 mL) solvent to obtain a white solid. To a solution of this white solid in dichloromethane (10 mL) were added thiazole-2-carbonyl chloride (0.61 g, 4.1 mmol) and triethylamine (1.9 mL, 14 mmol), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 2: 1) to give (R) -N- (1- (5,6-dichloropyridine as a slightly yellow oil). -3-yl) butyl) thiazole-2-carboxamide (hereinafter referred to as the compound of Reference Example 33) was obtained (0.88 g, yield 98%).

Example 23 Synthesis of (R) -N- (1- (5-chloro-6-((6-fluoropyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide:
To a toluene (2.0 mL) solution of the compound of Reference Example 33 (50 mg, 0.15 mmol), 2-fluoro-5-aminopyridine (20 mg, 0.18 mmol), palladium acetate (3.4 mg, 0.015 mmol), BINAP (18 mg, 0.029 mmol) and cesium carbonate (99 mg, 0.30 mmol) were added and stirred at 100 ° 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: chloroform: methanol = 98: 2) to give (R) -N- (1- (5-chloro-6-(( 6-fluoropyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide (hereinafter, the compound of Example 23) was obtained (51 mg, yield 82%).

Example 24 (R) -N- (1- (5-Chloro-6-((6-fluoropyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide hydrochloride Synthesis:
To a solution of the compound of Example 23 (51 mg, 0.13 mmol) in methanol (2.0 mL) was added a 10% hydrogen chloride methanol solution (0.50 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-fluoropyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 24) was obtained (32 mg, 63% yield).

Example 25 Synthesis of (R) -N- (1- (5-chloro-6-((6-methoxypyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide:
To a toluene (2.0 mL) solution of the compound of Reference Example 33 (50 mg, 0.15 mmol), 2-methoxy-5-aminopyridine (22 mg, 0.18 mmol), palladium acetate (3.4 mg, 0.019 mmol), BINAP (18 mg, 0.029 mmol) and cesium carbonate (99 mg, 0.30 mmol) were added and stirred at 100 ° 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: chloroform: methanol = 98: 2) to give (R) -N- (1- (5-chloro-6-(( 6-methoxypyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide (hereinafter, the compound of Example 25) was obtained (42 mg, 67% yield).

Example 26 (R) -N- (1- (5-Chloro-6-((6-methoxypyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide hydrochloride Synthesis:
To a solution of the compound of Example 25 (42 mg, 0.10 mmol) in methanol (2.0 mL) was added a 10% hydrogen chloride methanol solution (0.50 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methoxypyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 26) was obtained (20 mg, yield 44%).

Example 27 Synthesis of (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) picolinamide:
To a solution of the compound of Reference Example 5 (0.23 g, 0.63 mmol) and picolinic acid (86 mg, 0.70 mmol) in dichloromethane (2.0 mL) was added HATU (0.29 g, 0.76 mmol) and triethylamine (0.44 mL). 3.2 mmol) and stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The crude product obtained by drying the organic layer over anhydrous magnesium sulfate and concentrating was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 9) to give (R)-as a slightly yellow oil. N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) picolinamide (hereinafter referred to as the compound of Example 27) was obtained (0. 23 g, yield 92%).

Example 28 Synthesis of (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) picolinamide hydrochloride:
To a solution of the compound of Example 27 (0.23 g, 0.58 mmol) in methanol (3.0 mL) was added a 10% hydrogen chloride methanol solution (0.80 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) picolinamide hydrochloride (hereinafter, the compound of Example 28) was obtained (0.25 g, yield 100%).

Example 29 Synthesis of (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) oxazole-4-carboxamide:
To a solution of the compound of Reference Example 5 (0.23 g, 0.63 mmol) and oxazole-4-carboxylic acid (79 mg, 0.70 mmol) in dichloromethane (2.0 mL) was added HATU (0.29 g, 0.76 mmol) and triethylamine. (0.44 mL, 3.2 mmol) was added and stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The crude product obtained by drying the organic layer over anhydrous magnesium sulfate and concentrating was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 1: 9) to give (R)-as a slightly yellow oil. N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) oxazole-4-carboxamide (hereinafter, the compound of Example 29) was obtained. (0.22 g, 90% yield).

Example 30 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) oxazole-4-carboxamide hydrochloride Synthesis:
To a solution of the compound of Example 29 (0.22 g, 0.57 mmol) in methanol (3.0 mL) was added a 10% hydrogen chloride methanol solution (0.80 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) oxazole-4-carboxamide hydrochloride (hereinafter, the compound of Example 30) was obtained (0.19 g, yield 77%).

Example 31 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -4-methylthiazole-2- Synthesis of carboxamide:
To a solution of the compound of Reference Example 5 (0.18 g, 0.50 mmol) and 4-methylthiazole-2-carboxylic acid (85 mg, 0.59 mmol) in dichloromethane (2.5 mL) was added HATU (0.23 g, 0.59 mmol). ) And triethylamine (0.35 mL, 2.5 mmol) were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 92: 8) to give (R) -N as a pale yellow oil. -(1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -4-methylthiazole-2-carboxamide (hereinafter the compound of Example 31) (0.15 g, 75% yield) was obtained.

Example 32 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -4-methylthiazole-2- Synthesis of carboxamide hydrochloride:
To a solution of the compound of Example 31 (0.15 g, 0.37 mmol) in methanol (2.0 mL) was added a 10% hydrogen chloride methanol solution (0.30 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) -4-methylthiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 32) was obtained (0.11 g, yield 64%).

Reference Example 34 (R) -N-((R) -1- (5,6-dichloropyridin-3-yl) -3-buten-1-yl) -2-methylpropane-2-sulfinamide Synthesis:
To a solution of zinc chloride (0.37 g, 2.7 mmol) in diethyl ether-THF (16 mL) was added an allylmagnesium bromide diethyl ether solution (0.7 M, 11 mL, 8.1 mmol) at 0 ° C. For 30 minutes. To this solution was added a THF (3.6 mL) solution of the compound of Reference Example 1 (0.50 g, 1.8 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel chromatography (eluent; normal hexane: ethyl acetate = 3: 2) to give (R) -N— as a white solid. ((R) -1- (5,6-dichloropyridin-3-yl) -3-buten-1-yl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 34) was obtained. (0.31 g, 54% yield).

Reference Example 35 (R) -N-((R) -1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -3-butene-1 Synthesis of -yl) -2-methylpropane-2-sulfinamide:
To a solution of the compound of Reference Example 34 (0.30 g, 0.93 mmol) in toluene (6.0 mL), 2-methyl-5-aminopyridine (0.12 g, 1.1 mmol), palladium acetate (21 mg, 0.094 mmol). ), BINAP (0.12 g, 0.19 mmol) and cesium carbonate (0.61 g, 1.9 mmol) were added, and the mixture was stirred at 100 ° C. for 12 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 = 98: 2) to give (R) -N-((R) -1- (5-chloro-6- 6) as a white solid. ((6-Methylpyridin-3-yl) amino) pyridin-3-yl) -3-buten-1-yl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 35) was obtained. (0.30 g, 81% yield).

Reference Example 36 Synthesis of (R) -5- (1-amino-3-buten-1-yl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride :
To a solution of the compound of Reference Example 35 (0.30 g, 0.75 mmol) in ethanol (2.0 mL) was added 4N hydrogen chloride 1,4-dioxane solution (3.8 mL) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. did. The reaction mixture is concentrated and (R) -5- (1-amino-3-buten-1-yl) -3-chloro-N- (6-methylpyridin-3-yl) pyridine is obtained as a white solid crude product. 2-Amine hydrochloride (hereinafter referred to as the compound of Reference Example 36) was obtained (0.30 g, yield 100%).

Example 33 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -3-buten-1-yl) thiazole Synthesis of 2-carboxamide:
To a solution of the compound of Reference Example 36 (0.30 g, 0.75 mmol) in dichloromethane (5.0 mL) was added thiazole-2-carbonyl chloride (0.17 g, 1.1 mmol) and triethylamine (0.53 mL, 3.8 mmol). And stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 2: 3) to give (R) -N- (1- (5-chloro-6- ( (6-Methylpyridin-3-yl) amino) pyridin-3-yl) -3-buten-1-yl) thiazole-2-carboxamide (hereinafter the compound of Example 33) was obtained (0.28 g, yield). 92%).

Example 34 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) -3-buten-1-yl) thiazole Synthesis of 2-carboxamide hydrochloride:
To a solution of the compound of Example 33 (0.28 g, 0.69 mmol) in chloroform (3.0 mL) was added 10% hydrogen chloride methanol solution (0.40 mL), and the mixture was concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) -3-buten-1-yl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 34) was obtained (0.20 g, yield 66%).

Example 35 Synthesis of (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) oxazole-2-carboxamide:
To a solution of the compound of Reference Example 5 (0.23 g, 0.63 mmol) and oxazole-2-carboxylic acid (72 mg, 0.63 mmol) in dichloromethane (5.0 mL) was added HATU (0.29 g, 0.76 mmol) and triethylamine. (0.26 mL, 1.9 mmol) was added and stirred at room temperature for 6 hours. The crude product obtained by concentrating the reaction mixture was purified by silica gel column chromatography (eluent; chloroform: methanol = 97: 3) to give (R) -N- (1- (5-chloro) as a colorless oil. -6-((6-Methylpyridin-3-yl) amino) pyridin-3-yl) butyl) oxazole-2-carboxamide (hereinafter the compound of Example 35) was obtained (0.22 g, yield 92%). ).

Example 36 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) oxazole-2-carboxamide hydrochloride Synthesis:
To a solution of the compound of Example 35 (0.22 g, 0.58 mmol) in methanol (2.0 mL) was added 10% hydrogen chloride methanol solution (0.50 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) oxazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 36) was obtained (0.22 g, yield 88%).

Example 37 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -4- (2-propyl) Synthesis of thiazole-2-carboxamide:
To a solution of the compound of Reference Example 5 (0.25 g, 0.69 mmol) and 4- (2-propyl) thiazole-2-carboxylic acid (0.14 g, 0.83 mmol) in DMF (3.0 mL) was added HATU (0 .31 g, 0.83 mmol) and triethylamine (0.48 mL, 3.4 mmol) were added and stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 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; normal hexane: ethyl acetate = 3: 2) to give (R)-as a colorless oil. N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -4- (2-propyl) thiazole-2-carboxamide (hereinafter referred to as implementation) Example 37) was obtained (0.24 g, 78% yield).

Example 38 (R) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -4- (2-propyl) Synthesis of thiazole-2-carboxamide hydrochloride:
To a solution of the compound of Example 37 (0.24 g, 0.54 mmol) in chloroform (4.0 mL) was added a 10% hydrogen chloride methanol solution (0.26 mL) and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (R) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) -4- (2-propyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Example 38) was obtained (0.20 g, yield 79%).

  The synthesis of the enantiomer (Comparative Example 1) and the racemate (Comparative Example 2) corresponding to the compound of Example 2 used for comparison with the present compound is subsequently shown.

Reference Example 37 (R) -N-((S) -1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -2-methyl Synthesis of propane-2-sulfinamide:
To a toluene (4.0 mL) solution of the compound of Reference Example 3 (0.38 g, 1.2 mmol), 2-methyl-5-aminopyridine (0.15 g, 1.4 mmol), palladium acetate (26 mg, 0.12 mmol). ), BINAP (0.15 g, 0.23 mmol) and cesium carbonate (0.76 g, 2.3 mmol) were added, and the mixture was stirred at 100 ° C. for 12 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 = 98: 2) to give (R) -N-((S) -1- (5-chloro- 6-((6-Methylpyridin-3-yl) amino) pyridin-3-yl) butyl) -2-methylpropane-2-sulfinamide (hereinafter referred to as the compound of Reference Example 37) was obtained (0.31 g, Yield 66%).

Reference Example 38 Synthesis of (S) -5- (1-aminobutyl) -3-chloro-N- (6-methylpyridin-3-yl) pyridin-2-amine hydrochloride:
To a solution of the compound of Reference Example 37 (0.31 g, 0.77 mmol) in methanol (4.4 mL) was added 4N hydrogen chloride 1,4-dioxane solution (4.4 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. did. The reaction mixture was concentrated and the resulting crude product was slurry washed with a normal hexane-ethyl acetate mixed (15 mL) solvent to give (S) -5- (1-aminobutyl) -3-chloro-N- as a white solid. (6-Methylpyridin-3-yl) pyridin-2-amine hydrochloride (hereinafter referred to as the compound of Reference Example 38) was obtained (0.30 g, yield 100%).

Reference Example 39 Synthesis of (S) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide:
To a solution of the compound of Reference Example 38 (0.17 g, 0.47 mmol) in dichloromethane (2.0 mL) was added thiazole-2-carbonyl chloride (0.10 g, 0.70 mmol) and triethylamine (0.26 mL, 1.8 mmol). And stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, followed by filtration, and then the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: normal hexane: ethyl acetate = 7: 3) to give (S) -N- (1- (5-chloro-6- 6) as a pale yellow oil. ((6-Methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide (hereinafter referred to as the compound of Reference Example 39) was obtained (0.16 g, yield 83%).

(Comparative Example 1) (S) -N- (1- (5-Chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide hydrochloride Synthesis:
To a chloroform (3.0 mL) solution of the compound of Reference Example 39 (0.16 g, 0.39 mmol) was added a 10% hydrogen chloride methanol solution (0.15 mL), and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give (S) -N- (1- (5-chloro-6-((6-methylpyridin-3-yl)) as a white solid. Amino) pyridin-3-yl) butyl) thiazole-2-carboxamide hydrochloride (hereinafter, compound of Comparative Example 1) was obtained (0.15 g, yield 86%).

As shown in Scheme 6 below, the racemate of the compound of Example 2 was obtained by using commercially available (5,6-dichloropyridin-3-yl) methanol as a starting material, a mesylation reaction, an azidation reaction, a reduction reaction, It was synthesized by condensation reaction, C-alkylation reaction and coupling reaction.

Reference Example 40 Synthesis of methanesulfonic acid (5,6-dichloropyridin-3-yl) methyl:
To a solution of (5,6-dichloropyridin-3-yl) methanol (2.0 g, 11 mmol) and triethylamine (3.1 mL, 22 mmol) in dichloromethane (22 mL) at 0 ° C., methanesulfonyl chloride (1.1 mL, 15 mmol). And stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 3: 2) to give methanesulfonic acid ( 5,6-dichloropyridin-3-yl) methyl (hereinafter, the compound of Reference Example 40) was obtained (1.5 g, yield 54%).

Reference Example 41 Synthesis of 5- (azidomethyl) -2,3-dichloropyridine:
To a DMF (20 mL) solution of the compound of Reference Example 40 (1.5 g, 6.0 mmol), sodium azide (0.59 g, 9.0 mmol) was added at room temperature, and the mixture was stirred at 90 ° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 7: 3) to give 5- (azidomethyl) as a colorless oil. ) -2,3-dichloropyridine (hereinafter, the compound of Reference Example 41) was obtained (1.2 g, yield 100%).

Reference Example 42 Synthesis of (5,6-dichloropyridin-3-yl) methanamine hydrochloride:
Triphenylphosphine (1.7 g, 6.6 mmol) was added to a solution of compound 41 (1.2 g, 6.0 mmol) in THF (30 mL) at 0 ° C., and the mixture was added at room temperature for 1 hour and further at 60 ° C. for 2 hours. Stir. The reaction mixture was cooled to room temperature and water was added followed by stirring at 70 ° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated. To a solution of the crude product obtained by concentration in ethyl acetate (20 mL) was added 4N hydrogen chloride ethyl acetate solution (1.8 mL) at room temperature. The resulting solid was collected by filtration and washed with ethyl acetate to obtain (5,6-dichloropyridin-3-yl) methanamine hydrochloride (hereinafter referred to as the compound of Reference Example 42) as a white solid (1.1 g, yield). 87%).

Reference Example 43 Synthesis of N-((5,6-dichloropyridin-3-yl) methyl) thiazole-2-carboxamide:
To a solution of the compound of Reference Example 42 (0.55 g, 2.6 mmol) and thiazole-2-carboxylic acid (0.40 g, 3.1 mmol) in dichloromethane-DMF (4.5 mL), HATU (1.3 g, 3 mmol, .3 mmol) and triethylamine (1.5 mL, 11 mmol) were added and stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution 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 magnesium sulfate and concentrating was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 7: 3) to give N-((5 , 6-Dichloropyridin-3-yl) methyl) thiazole-2-carboxamide (hereinafter referred to as compound of Reference Example 43) was obtained (0.52 g, yield 70%).

Reference Example 44 Synthesis of N- (1- (5,6-dichloropyridin-3-yl) butyl) thiazole-2-carboxamide:
To a solution of the compound of Reference Example 43 (0.10 g, 0.35 mmol) and N, N, N ′, N′-tetramethylethylenediamine (0.16 mL, 1.0 mmol) in THF (2.0 mL) at −78 ° C. Then, a solution of lithium diisopropylamide in diethyl ether (1.0 M, 1.0 mL, 1.0 mmol) was added and stirred at −78 ° C. for 2 hours. 1-iodopropane (0.10 mL, 1.0 mmol) was added to the reaction solution at −78 ° C., and the mixture was stirred at −78 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; normal hexane: ethyl acetate = 3: 2) to give N- ( 1- (5,6-dichloropyridin-3-yl) butyl) thiazole-2-carboxamide (hereinafter referred to as the compound of Reference Example 44) was obtained (26 mg, yield 22%).

Reference Example 45 Synthesis of N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide:
To a toluene (1.5 mL) solution of the compound of Reference Example 44 (25 mg, 0.076 mmol), 2-methyl-5-aminopyridine (9.8 mg, 0.091 mmol), palladium acetate (1.7 mg, 0.0076 mmol). ), BINAP (9.4 mg, 0.015 mmol) and cesium carbonate (49 mg, 0.15 mmol) were added and stirred at 100 ° C. for 7 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 = 98: 2), and N- (1- (5-chloro-6-((6-methylpyridine- 3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide (hereinafter referred to as the compound of Reference Example 45) was obtained (30 mg, 100% yield).

Comparative Example 2 Synthesis of N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridin-3-yl) butyl) thiazole-2-carboxamide hydrochloride:
To a chloroform (1.0 mL) solution of the compound of Reference Example 45 (30 mg, 0.076 mmol) was added a 10% hydrogen chloride methanol solution (0.040 mL), and then concentrated. The obtained crude product was recrystallized (chloroform-ethyl acetate-normal hexane) to give N- (1- (5-chloro-6-((6-methylpyridin-3-yl) amino) pyridine-) as a white solid. 3-yl) butyl) thiazole-2-carboxamide hydrochloride (hereinafter, the compound of Comparative Example 2) was obtained (28 mg, 85% yield).

The compound in which the optically active chain amine structure of the compound of Example 2 was racemized and converted to a cyclic amine structure was obtained by using commercially available 5,6-dichloronicotinaldehyde as the starting material as shown in Scheme 7 below. Synthesis was performed by a hydration reaction, an azidation reaction, a cyclization reaction, a condensation reaction, and a coupling reaction.

Reference Example 46 Synthesis of 3- (1-azido-3-buten-1-yl) 5,6-dichloropyridine:
To a solution of 5,6-dichloronicotinaldehyde (0.50 g, 2.8 mmol) in ethanol (7.0 mL) was added 30% aqueous ammonia (3.5 mL, 57 mmol), and the mixture was stirred at room temperature for 30 minutes. Allyl-4,4,5,5-tetramethyl 1,3,2-dioxaborolane (0.64 mL, 3.4 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid was added to the reaction mixture for liquid separation, and the aqueous layer was washed with diethyl ether, 1N aqueous sodium hydroxide solution was added until pH = 9, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. To a solution of the obtained crude product in methanol (10 mL), potassium carbonate (0.79 g, 5.7 mmol), copper sulfate pentahydrate (7.1 mg, 0.028 mmol), imidazole-1-sulfonyl azide hydrochloride (0.77 g, 3.7 mmol) was added and stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, followed by filtration. Subsequently, the filtrate 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; normal hexane: ethyl acetate = 9: 1) to give 3- (1 -Azido-3-buten-1-yl) 5,6-dichloropyridine (hereinafter, compound of Reference Example 46) was obtained (0.35 mg, yield 51%).

Reference Example 47 Synthesis of 3- (pyrrolidin-2-yl) 5,6-dichloropyridine:
To a solution of cyclohexene (0.45 g, 5.4 mmol) in THF (2.0 mL) was added borane dimethyl sulfide complex (0.27 mL, 2.8 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours. A THF (2.0 mL) solution of the compound of Reference Example 46 (0.22 g, 0.91 mmol) was added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 16 hours. Methanol, 1N hydrochloric acid, and diethyl ether were added to the reaction mixture for liquid separation, and the organic layer was extracted with 1N hydrochloric acid. After combining the aqueous layers, a 1N aqueous sodium hydroxide solution was added until pH = 9, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 3- (pyrrolidin-2-yl) 5,6-dichloropyridine (hereinafter referred to as the compound of Reference Example 47) as a pale yellow oil (0.20 g, yield). Rate 100%).

Reference Example 48 Synthesis of (2- (5,6-dichloropyridin-3-yl) pyrrolidin-1-yl) (thiazol-2-yl) methanone:
The compound of Reference Example 47 (75 mg, 0.35 mmol), thiazole-2-carboxylic acid (58 mg, 0.45 mmol), 1-hydroxybenzotriazole (69 mg, 0.45 mmol) and N-ethyl-N ′-(3- N, N-diisopropylethylamine (0.48 mL, 3.4 mmol) was added to a solution of (dimethylaminopropyl) carbodiimide hydrochloride (99 mg, 0.52 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 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; normal hexane: ethyl acetate = 4: 1) to give (2- ( 5,6-dichloropyridin-3-yl) pyrrolidin-1-yl) (thiazol-2-yl) methanone (hereinafter, the compound of Reference Example 48) was obtained (65 mg, 57% yield).

Reference Example 49 Synthesis of (2- (5-chloro-6- (6-methylpyridin-3-ylamino) pyridin-3-yl) pyrrolidin-1-yl) (thiazol-2-yl) methanone:
To a toluene (1.0 mL) solution of the compound of Reference Example 48 (60 mg, 0.18 mmol), 2-methyl-5-aminopyridine (30 mg, 0.27 mmol), palladium acetate (4.1 mg, 0.018 mmol), BINAP (29 mg, 0.046 mmol) and cesium carbonate (150 mg, 0.46 mmol) were added and stirred at 100 ° C. for 18 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 = 96: 4) to give (2- (5-chloro-6- (6-methylpyridin-3-ylamino) as a colorless oil. ) Pyridin-3-yl) pyrrolidin-1-yl) (thiazol-2-yl) methanone (hereinafter referred to as the compound of Reference Example 49) was obtained (70 mg, yield 96%).

Comparative Example 3 Synthesis of (2- (5-chloro-6- (6-methylpyridin-3-ylamino) pyridin-3-yl) pyrrolidin-1-yl) (thiazol-2-yl) methanone hydrochloride:
To a solution of the compound of Reference Example 49 (70 mg, 0.18 mmol) in ethyl acetate (1.0 mL) was added 10% hydrogen chloride methanol solution (0.50 mL), and the mixture was concentrated. The obtained crude product was recrystallized (ethanol-diethyl ether) to give (2- (5-chloro-6- (6-methylpyridin-3-ylamino) pyridin-3-yl) pyrrolidin-1- as a white solid. Yl) (thiazol-2-yl) methanone hydrochloride (hereinafter, compound of Comparative Example 3) was obtained (62 mg, yield 81%).

  The spectral data and melting points of the compounds of Examples, Reference Examples and Comparative Examples are shown in Tables 7 to 16 below.

Example 39 Evaluation of mGluR5 Signaling Inhibitory Activity in Human mGluR5 Stable Expression Cells:
Inhibition of mGluR5 signaling of test compounds using as an index suppression of production of inositol-1-phosphate (hereinafter referred to as IP1) produced when mGluR5 is activated by treating glutamic acid in human mGluR5 stably expressing cells 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). Established human mGluR5 stably expressing cells are Dulbecco's modified Eagle 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 the IC50 value. In addition, Prism 4.0 or 5.0 (GraphPad software) was used for the calculation.

  The results are shown in Table 17. All of the evaluated example compounds were shown to have potent human mGluR5 signaling inhibitory activity.

  On the other hand, the compounds of Comparative Example 1 and Comparative Example 2 correspond to the enantiomers and racemates of the compound of Example 2 having an optically active chain amine structure, respectively. The compound of Comparative Example 3 is a racemate having a cyclic amine structure. The compound of Comparative Example 2 having a chain amine structure has a stronger mGluR5 signal transduction inhibitory activity than the compound of Comparative Example 3 having a cyclic amine structure. It was shown to be important for transmission inhibitory activity. In addition, the compound of Example 2 has potent mGluR5 signal transduction inhibitory activity compared to the compound of Comparative Example 1 corresponding to the enantiomer and the compound of Comparative Example 2 corresponding to the racemate, so that optical resolution is performed. Was also shown to be important for mGluR5 signaling inhibition activity.

  From this result, the N-alkylamide derivative represented by the above general formula (I) having an optically active chain amine structure or a pharmaceutically acceptable acid addition salt thereof has potent human mGluR5 signaling inhibitory activity. It was shown to have

(Example 40) Anti-anxiety action evaluation using mouse stress-induced body temperature increase as an index:
Evaluation of the anxiolytic action of the test compound is based on the method described in the publicly known literature (Satow et al., The Journal of Pharmacology And Experimental Therapeutics, 2008, Vol. 326, p. 577). Inhibition of body temperature rise caused by the above was performed as an index. Specifically, it was carried out as follows.

  Four to six week old male ddY mice (Japan SLC, Inc.) were carried into the laboratory by the day before the evaluation of drug efficacy. On the medicinal evaluation day, each individual is accommodated in each compartment of a cage (1 compartment is 10 cm long, 14 cm wide, 30 cm high) divided into 4 compartments so that the mice cannot see each other. Accustomed to time. Acclimatized mice were orally administered with a solvent (0.5% w / v methylcellulose) or a test compound (suspended or dissolved in 0.5% w / v methylcellulose) in a volume of 0.1 mL / 10 g body weight. Returned inside. In addition, the group which administered the solvent to the mouse was made into the solvent administration group, and the group which administered the test compound was made into the test compound administration group.

  The rectal temperature (hereinafter, T1) of the mouse 60 to 70 minutes after oral administration was measured, and the rectal temperature (hereinafter, T2) 10 to 20 minutes after the T1 measurement was measured. The rectal temperature was measured by inserting a life chip (Dainippon Sumitomo Pharma Co., Ltd.) into the rectum of a mouse and using a life chip reader (Dainippon Sumitomo Pharma Co., Ltd.) or connected to Terumo Finer CTM-303 (Terumo Co., Ltd.). The measurement was carried out by inserting a body temperature measurement probe into the rectum of a mouse. In addition, when measuring rectal temperature using a life chip and a life chip reader, the rectal temperature is measured several times until the measured value becomes stable, and the value obtained when all three consecutive measured values match is adopted. did. In the case of measuring rectal temperature using the Termofiner CTM-303, the value displayed at 30 seconds after the probe insertion was adopted. Usually, since it is stress for mice to measure rectal temperature itself, rectal temperature (T2) measured again 10 to 20 minutes after initial rectal temperature (T1) measurement is increased compared to T1. Seen. Here, the increase in rectal temperature (Δ (T2−T1)) obtained by subtracting the value of T1 from the value of T2 is defined as the stress-induced increase in body temperature, and the suppression of the stress-induced increase in body temperature is used as an index. Anxiety effects were evaluated.

  As the statistical treatment, Williams test or Shirley-Williams test was performed on Δ (T2-T1) as a test of the test compound administration group with respect to the solvent administration group. The significance level was 2.5% (lower side).

  Tables 18 and 19 show the effect of each test compound on Δ (T2-T1). In addition, * mark or # mark in the table indicates that it is statistically significant in comparison with the solvent administration group (* p <0.025: Williams test (lower side), #p <0.025 : Shirley-Williams test (lower side)). In addition, the compound dose of 0 mg / kg in Table 18 and Table 19 is the solvent administration group.

  From these results, it was shown that any of the evaluated compounds of the examples suppressed the stress-induced increase in body temperature of mice upon oral administration. Therefore, it was shown that the N-alkylamide derivative represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has an excellent anxiolytic action.

(Example 41) Antipruritic evaluation using mouse substance P-induced scratching behavior as an index:
Substance P-induced scratching behavior of mice was induced based on the method described in publicly known literature (Togashi et al., European Journal of Pharmacology, 2002, Vol. 435, p. 259, etc.). In addition, the evaluation of the scratching behavior was automatically detected using MicroAct (Neuroscience) based on the method described in a known document (Hashimoto et al., Allergy International, 2004, Vol. 53, p.349). Specifically, it was carried out as follows.

  6 days before drug efficacy evaluation, a neodymium magnet (diameter: 1 mm, length: 3 mm) coated with parafilm on the back of both hind limbs of male ICR mice (Japan SLC), 5 weeks old, under isoflurane anesthesia. Inserted. On the day before the drug efficacy evaluation day, the neck of the mouse was shaved with a clipper under isoflurane anesthesia. On the day of drug efficacy evaluation, one mouse (6 weeks old) was housed one by one in a measurement chamber (diameter 11 cm, height 18 cm), and then a solvent (0.5% w / v methylcellulose) or a test compound (0.5 (Suspended in% w / v methylcellulose) was orally administered in a volume of 0.1 mL / 10 g body weight, and returned to the measurement chamber. Sixty minutes after oral administration, substance P (5 mmol / L) or phosphate buffered saline as its solvent was intradermally administered to the back of the neck (0.05 mL / site), and measurement of the number of scratching behaviors was started immediately after. . In the round coil around the measurement chamber, the current induced by the movement of the magnet inserted into the hind limb was amplified and recorded, and the number of scratching behaviors was calculated. The measurement was performed in an unattended environment, and the efficacy evaluation was performed using the number of scratching behaviors for 15 minutes after the start of the measurement as an index.

  A group (test compound: 0 mg / kg, substance P: 0 nmol / site) administered with only the solvent was a “non-induced control group”, and a group administered with substance P but not administered a test compound (test compound: 0 mg / kg, Substance P: 250 nmol / site) was designated as “induction control group”, and a group administered with substance P and test compound was designated as “test compound administration group”. In addition, the compound dose in Table 20 represents the dose of the test compound.

The inhibition rate (%) of scratching behavior by the test compound was calculated from the following formula.
Inhibition rate (%) = [1- (A−C) / (B−C)] × 100
Here, A, B, and C represent the average values of the number of scratching actions of the test compound administration group, the induced control group, and the non-induced control group, respectively.

  As a statistical treatment, Williams test was performed as a test of the test compound administration group with respect to the induction control group. The significance level was 2.5% (lower side).

  Table 20 shows the effect of the compound of Example 2 on the number of scratching behaviors. * Mark in a table | surface shows that it is statistically significant compared with an induction | guidance | derivation control group (* p <0.025: Williams test (lower side)).

  From these results, it was shown that the evaluated compound of Example 2 suppresses substance P-induced scratching behavior known as an intractable pruritus model and has an excellent antipruritic effect in oral administration.

  The N-alkylamide derivative of the present invention or a pharmaceutically acceptable acid addition salt thereof strongly inhibits signal transduction of mGluR5. Therefore, a drug containing them as an active ingredient, particularly mGluR5 such as anxiety disorder and pruritus, etc. It can be used as a therapeutic or prophylactic agent for diseases caused by excessive signal transduction.

Claims (8)

N-alkylamide derivatives represented by the following general formula (I) or pharmaceutically acceptable acid addition salts thereof.

[Wherein R ¹ represents alkyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, or alkenyl having 2 to 6 carbon atoms,
R ² represents an alkyl having 1 to 6 carbon atoms, an alkyloxy having 1 to 6 carbon atoms, or a halogen atom,
Ar represents pyridin-2-yl, oxazol-4-yl, oxazol-2-yl or thiazol-4-yl, or thiazol-2-yl in which the hydrogen atom at the 4-position may be substituted with R ^3. Represent,
R ³ represents an alkyl having 1 to 6 carbon atoms. ] R ¹ is ethyl, normal propyl, 2-propyl, normal butyl, 2-methylpropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-propen-1-yl or 3-buten-1-yl Yes,
R ² is a methyl, methoxy or fluorine atom,
R ³ is methyl or 2-propyl, according to claim 1 N- alkylamide derivative or a pharmaceutically acceptable acid addition salts. R ¹ is ethyl, normal propyl, 2-propyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-propen-1-yl or 3-buten-1-yl;
R ² is a methyl, methoxy or fluorine atom,
Ar is pyridin-2-yl or oxazol-4-yl, or thiazol-2-yl in which the hydrogen atom at the 4-position may be substituted with R ³ ;
R ³ is methyl, according to claim 1 N- alkylamide derivative or a pharmaceutically acceptable acid addition salts. R ¹ is normal propyl, 2-propyl, cyclopropyl, cyclobutyl, 2-propen-1-yl or 3-buten-1-yl;
R ² is methyl;
The N-alkylamide derivative or pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein Ar is thiazol-2-yl.   The pharmaceutical which contains the N-alkylamide derivative as described in any one of Claims 1-4, or its pharmaceutically acceptable acid addition salt as an active ingredient.   A therapeutic or prophylactic agent for anxiety disorders comprising the N-alkylamide derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.   A therapeutic or prophylactic agent for pruritus comprising the N-alkylamide derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. An inhibitor of metabotropic glutamate receptor 5, comprising the N-alkylamide derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.