JP2016011257A - Tetrahydroxazoropyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for neurological disorders and neurodegenerative diseases related to mGluR5, having effects as a metabolism type glutamic acid receptor subtype 5 (mGluR5) negative modulator, having an oral absorption property excellent in pharmacokinetics, high biological availability and excellent safety.SOLUTION: There is provided a compound of the formula (I) and a pharmaceutically acceptable salt. Formula (I), where Rrepresents a halogen, methyl or cyano, Rand Rrepresent each independently a hydrogen atom, halogen, Calkyl, Calkoxy or cyano.

Description

  The present invention relates to a novel tetrahydrooxazolopyridine derivative useful as a medicament having an action as a metabotropic glutamate receptor subtype 5 (mGluR5) negative modulator. More specifically, mGluR5 receptors such as schizophrenia, anxiety disorder, mood disorder, drug dependence, neurodegenerative disease, levodopa-induced dyskinesia, Parkinson's disease, fragile X syndrome, autism, depression, Huntington's disease are involved. The present invention relates to a novel compound useful as a therapeutic agent for psychiatric or neurodegenerative diseases.

  L-glutamate is a major excitatory neurotransmitter in the central nervous system, binds to nerve cells, and activates cell surface receptors. L-glutamate acts through two heterogeneous receptor families: ion channel and metabotropic glutamate receptors (mGluR). mGluR is a G-protein coupled receptor and activates a second messenger in the cell when bound to glutamic acid. Eight mGluR subtypes have been cloned and classified into three groups based on sequence similarity and pharmacological properties. mGluR1 and mGluR5 belong to group I and initiate cellular responses by G-protein coupled mechanisms, activate phospholipase C, cause inositol phospholipid hydrolysis and intracellular calcium mobilization (Schoepp, DD, et al ., Neuropharmacology 1999, 38, 1431).

  mGluR5 is expressed both in the central nervous system and in the periphery (Chizh, B.A., et al., Amino Acids 2002, 23, 169). Thus, modulation of mGluR5 activity is useful for the treatment of disorders in both the peripheral and CNS. With respect to peripheral disorders, mGluR5 negative modulators have been shown to be effective in the treatment of gastrointestinal (GI) tract disorders such as gastroesophageal reflux disease (GERD).

  In CNS, excessive activation of mGluR5 may be involved in many diseases (various painful conditions, mental disorders such as anxiety and depression, other neurological disorders such as drug dependence and drug withdrawal symptoms) It is shown. For example, mGluR5 negative modulators are effective in various animal models of anxiety such as stress hyperthermia and fear-enhancing startle.

  Other peripheral and CNS disorders associated with mGluR5 regulation include schizophrenia, anxiety disorders, mood disorders, drug addiction, neurodegenerative diseases, levodopa-induced dyskinesia, Parkinson's disease, fragile X syndrome, autism, depression And Huntington's disease. Therefore, the usefulness of an mGluR5 modulator that is effective as a method for treating various disorders such as neuropathy is very high.

  As a compound having an action as an mGluR5 negative modulator, a compound having a bicyclic skeleton condensed with a 5-membered heterocycle shown below has been reported (Patent Document 1). Specifically, the formula (A):

[Where:
R ¹ is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted;
R ² is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted;
R ³ and R ⁴ are each independently a hydrogen atom, halogen, or lower alkyl;
When R ³ and R ⁴ are attached to the same carbon atom, CR ³ R ⁴ is C═O or R ³ and R ⁴ together with the carbon atom to which they are attached are 3 to 7 membered spiro May form a cycloalkyl; or, when R ³ and R ⁴ are attached to different carbon atoms, R ³ and R ⁴ together with the carbon atom to which they are attached are 3 to 7 membered bridged or fused May form a cycloalkyl;
L ¹ is a bond, —S—, —SO—, —SO ₂ —, —O—, —NR ⁹ —, —CR ⁵ R ⁶ —, —CR ⁵ R ⁶ —CR ⁷ R ⁸ —, optionally substituted. Optionally substituted cycloalkyl, optionally substituted heterocyclyl; optionally substituted aryl, or optionally substituted heteroaryl;
L ² is a ^{bond, -O -, - NR 9 -} , - CR 5 R 6 - or ^{-CR 5 R 6 -CR 7 R 8} - and is;
X is C or N;
Y is O, S, N, NR ¹⁰ , or CR ¹⁰ ;
Z is O, S, N, NR ¹⁰ , or CR ¹⁰ ; where Y and Z are not both O or both S;
R ⁵ and R ⁶ are each independently a hydrogen atom, halogen, or lower alkyl, or CR ⁵ R ⁶ is C═O; or R ⁵ and R ⁶ together with the carbon atom to which they are attached May form a 3 to 7 membered cycloalkyl;
R ⁷ and R ⁸ are each independently a hydrogen atom, halogen, or lower alkyl, or CR ⁷ R ⁸ is C═O; or R ⁷ and R ⁸ together with the carbon atom to which they are attached May form a 3 to 7 membered cycloalkyl;
R ⁹ and R ¹⁰ are each independently a hydrogen atom or lower alkyl;
G is N, CH, CR ′, COR ′, or CNR′R ″;
R ′ is lower alkyl;
R ″ is lower alkyl;
L ² and R ′ or L ² and R ″ together may form a 3 to 10 membered ring;
o is 0, 1, or 2;
p is 1 or 2]
It has disclosed that the compound represented by these has an effect | action as a mGluR5 negative modulator.

International Publication No. 10/114971

  The formation of glutathione (GSH) adducts suggests the possibility of chemical reactivity that causes the formation of adducts with proteins in vivo, ie in the human body. Because protein adducts are thought to cause or at least be associated with severe specific toxicity, compounds that produce reactive metabolites that are prone to form such adducts are safe. (For example, Uetrecht J.P., Chem Res Toxicol. 1999 12 (5): 387-395. Yamada Hisayo, Yamaguchi Junichi, Iida Izumi, Okuyama Shigeru. Idiosyncratic drug toxicity. Japan Pharmacology Journal 2006 127 (6): 473-480 etc.).

  The problem to be solved by the present invention is to provide a novel compound having an action as an mGluR5 negative modulator. Since such an mGluR5 negative modulator is expected to be useful as a therapeutic agent for mental disorders or neurodegenerative diseases in which mGluR5 is involved, it is possible to provide a drug with excellent therapeutic effect and higher safety. It is a subject of the invention. Specific problems include the action as a strong mGluR5 negative modulator, pharmacokinetically excellent oral absorption, high bioavailability, and excellent safety, such as GSH adducts. For example, providing a drug that does not produce or is unlikely to occur.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have been substituted at the 2-position of the 4,5,6,7-tetrahydrooxolo [4,5-c] pyridine skeleton as a chemical structural feature. A tetrahydrooxazolopyridine derivative having a 2-pyridyl group and a benzoyl group optionally substituted at the 5-position nitrogen atom or a pharmaceutically acceptable salt thereof is a strong mGluR5 negative modulator In addition, the present inventors have found that the GSH adduct is not produced or hardly produced, and has excellent pharmacokinetic oral absorption. Based on these findings, the present invention has been completed. The present invention relates to the following tetrahydrooxazolopyridine derivative represented by the following formula (I) having an action as an mGluR5 negative modulator or a pharmaceutically acceptable salt thereof.

[Item 1] Formula (I):

[Wherein R ¹ represents halogen, methyl or cyano;
R ² and R ³ each independently represents a hydrogen atom, halogen, C _1-3 alkyl, C _1-3 alkoxy or cyano.
Or a pharmaceutically acceptable salt thereof.

[Item 2] R ¹ is fluorine or chlorine.
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[Claim 3] R ¹ is fluorine,
Item 3. The compound according to Item 1 or Item 2, or a pharmaceutically acceptable salt thereof.

[Claim 4] R ² and R ³ are each independently a hydrogen atom, fluorine, chlorine, methyl, methoxy or cyano.
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Item 5] R ² and R ³ are each independently a hydrogen atom, fluorine, chlorine, or methyl.
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.

[Item 6] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
[2- (5-Fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone (Example 1) ,
(3-Chloro-5-fluorophenyl) [2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl ] Methanone (Example 2),
(2-Fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone ( Example 7),
(3-Fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone ( Example 8),
(4-Fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone ( Example 9), and (3-chlorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H) -Il] methanone (Example 10).

[Item 7] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
[2- (5-Fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone (Example 1) ,
(3-Chloro-5-fluorophenyl) [2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl ] Methanone (Example 2),
(2-Fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone ( Example 7),
(3-Fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone ( Example 8), and (4-fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H ) -Yl] methanone (Example 9).

[Item 8] A pharmaceutical composition comprising the compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[Item 9] A psychiatric disorder or neurodegenerative disease involving metabotropic glutamate receptor subtype 5 comprising the compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient Therapeutic agent.

[Item 10] Mental or neurodegenerative diseases involving metabotropic glutamate receptor subtype 5 are schizophrenia, anxiety disorder, mood disorder, drug dependence, neurodegenerative disease, levodopa-induced dyskinesia, Parkinson's disease, fragile X syndrome, autism, depression or Huntington's disease
Item 10. The therapeutic agent according to Item 9.

[Item 11] Use of the compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for a disease involving metabotropic glutamate receptor subtype 5.

[Item 12] The compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof, schizophrenia, anxiety disorder, mood disorder, drug dependence, neurodegenerative disease, levodopa-induced A pharmaceutical comprising a combination of at least one drug selected from therapeutic agents for dyskinesia, Parkinson's disease, fragile X syndrome, autism, depression or Huntington's disease.

[Item 13] Anxiety / obsessive-compulsive disorder involving metabotropic glutamate receptor subtype 5 comprising the compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient Anxiety disorders such as depression, mood disorders such as depression and bipolar disorder, cognitive disorders such as Alzheimer's disease, psychosis such as schizophrenia, Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, amyotrophic lateral sclerosis, etc. Neurodegenerative disease; autism; developmental disorder of fragile X syndrome or attention deficit hyperactivity disorder; intellectual disorder such as Down syndrome; inflammatory pain; neuropathic pain; postoperative pain; acute thermal hyperalgesia; Pain such as visceral pain and chronic pain; epilepsy; epilepsy seizure; aggressiveness; post-traumatic stress disorder; tactile hypersensitivity; sensory excitability; oxygen deficiency disorder such as stroke and head trauma; .

  According to the present invention, mGluR5 receptors such as schizophrenia, anxiety disorder, mood disorder, drug dependence, neurodegenerative disease, levodopa-induced dyskinesia, Parkinson's disease, fragile X syndrome, autism, depression, Huntington's disease are involved. It is possible to provide a tetrahydrooxazolopyridine derivative or a pharmaceutically acceptable salt thereof that is useful as a therapeutic agent for psychiatric or neurodegenerative diseases, and it can also be useful as a prophylactic agent for the above diseases. In detail, according to the present invention, a tetrahydrooxazolopyridine derivative having an action as a strong mGluR5 negative modulator and having no or hardly generated GSH adduct and having excellent pharmacokinetic oral absorption or a derivative thereof. It is possible to provide a pharmaceutically acceptable salt.

  Since the compounds provided by the present invention or pharmaceutically acceptable salts thereof may exist in the form of hydrates and / or solvates, these hydrates and / or solvates may also be present. Also included in the compounds of the present invention.

  The compounds of formula (I) are included in the scope of the present invention in the case where optical isomers, stereoisomers, positional isomers, and rotational isomers can exist, both of individual single compounds and mixtures thereof. The For example, it may have one or more asymmetric carbon atoms, and may cause geometric isomerism and axial chirality, so it may exist as several stereoisomers. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention. Further, a deuterium converter obtained by converting any one or two or more 1H of the compound represented by the general formula (I) into 2H (D) is also included in the compound represented by the general formula (I). . A crystal polymorph may exist in the compound represented by the general formula (I) obtained as a crystal or a pharmaceutically acceptable salt thereof, and the crystal polymorph is also included in the present invention.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications and patents cited herein are incorporated by reference in their entirety.

In the present specification, for example, C _1-3 represents 1 to 3 carbon atoms, and C ₃ represents 3 carbon atoms. The same applies to other numbers.

“C _1-3 alkyl” means a straight or branched saturated aliphatic hydrocarbon having 1 to 3 carbon atoms, and specific examples thereof include methyl, ethyl, 1-propyl, 2-propyl. Etc., preferably methyl.

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

“C _1-3 alkoxy” means an oxy group substituted with the above “C _1-3 alkyl”, and specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy, etc., preferably methoxy is Can be mentioned.

  In the compound of the present invention represented by the formula (I), suitable substituents are as follows.

R ¹ is halogen, methyl or cyano, preferably fluorine or chlorine, more preferably fluorine.

R ² and R ³ are each independently a hydrogen atom, halogen, C _1-3 alkyl, C _1-3 alkoxy or cyano, preferably a hydrogen atom, fluorine, chlorine, methyl, methoxy or cyano. More preferably, a hydrogen atom, fluorine, and chlorine are mentioned.

  As used herein, unless otherwise indicated, the term “pharmaceutically acceptable salt” is prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Meaning salt. For example, but not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furonic acid, gluconic acid, glutamic acid, glucorenic acid, Galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid , Salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like.

  As used herein, unless otherwise indicated, the term “solvate” refers to a compound of the present invention or salt thereof further comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Means. When the solvent is water, the solvate is a hydrate.

  As used herein, unless otherwise indicated, the term “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition or medium, such as a liquid or solid extender, Mean diluent, solvent or encapsulating material. In one embodiment, each ingredient is “pharmaceutically acceptable” in the sense that it is compatible with the other ingredients of the pharmaceutical formulation, and excessive toxicity, irritation, allergic reaction, antigenicity, or other problems Or suitable for use in contact with human or animal tissues or organs commensurate with a reasonable benefit / risk ratio without causing complications. For example, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

  The production method of compound (I) in the present invention will be described.

  The tetrahydrooxazolopyridine compound of the present invention can be produced from known compounds by appropriately combining synthetic methods well known to those skilled in the art by the following production method or a method according to the following production method. The raw material compound may be a known compound, or may be produced by appropriately combining synthetic methods well known to those skilled in the art according to the method described in Examples below or the method according to Examples below. The compound used in the following production method may form a salt as long as it does not interfere with the reaction. Also, the reaction may be scaled up or down depending on the amount of substance to be produced.

  In the following production methods, when performing an amidation reaction, a coupling reaction, an oxidation reaction, a reduction reaction, a cyclization reaction, a hydrolysis reaction, etc., these reactions are performed according to various methods known to those skilled in the art. It can be carried out. Examples of such a method include a method described in Comprehensive Organic Transformations, 1999, VCH Publishers, Inc.

  In each of the following production methods, a method for introducing a protecting group and a method for removing a protecting group are known to those skilled in the art [Protective Groups in Organic Synthesis, 3rd edition, John Willy and Sons (John) Wiley & Sons, INC.) Etc.]. In addition, the protecting groups used in this case may be those described in Protective Groups in Organic Synthesis 3rd edition, John Wiley & Sons, Inc. it can.

  This reaction is advantageously performed using a solvent inert to the reaction (inert solvent). Examples of the “inert solvent” include aromatic solvents such as benzene, toluene, xylene and pyridine; hydrocarbon solvents such as hexane, pentane and cyclohexane; tetrahydrofuran (THF), diethyl ether, 1,2-dimethoxyethane, Ether solvents such as 1,4-dioxane; ester solvents such as ethyl acetate and ethyl formate; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone Amide solvents such as N, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylacetamide; sulfoxide solvents such as dimethyl sulfoxide; nitrile solvents such as acetonitrile and propionitrile; Chloroform, a halogen-based solvent and water, such as dichloromethane, as well as their homogeneous or heterogeneous mixed solvents and the like. These inert solvents are appropriately selected according to various reaction conditions known to those skilled in the art.

  In the production method described in detail below, the “base” is, for example, an alkali metal or alkaline earth metal hydride such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, Alkali metal or alkaline earth metal amides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; sodium methoxide, sodium ethoxide, potassium tert -Lower alkoxides of alkali metals or alkaline earth metals such as butoxide; alkyllithiums such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, hydroxide Alkali metal or alkaline earth metal hydroxides such as lithium, lithium hydroxide and barium hydroxide; Alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; Sodium hydrogen carbonate, hydrogen carbonate Alkali metal or alkaline earth metal hydrogen carbonates such as potassium; triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), With amines such as 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and N, N-dimethylaniline; basic heterocyclic compounds such as pyridine, imidazole and 2,6-lutidine is there. These bases are appropriately selected according to various reaction conditions known to those skilled in the art.

  Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.

[Production Method 1]
The compound represented by the formula (I) can be produced, for example, by the following method.

[Wherein Hal represents a halogen atom, and other symbols are as defined above. ]

Step 1 : Compound (I) can be obtained by forming amide bond between compound (A-1) or a salt thereof and carboxylic acid (A-2) by various amidation reactions known to those skilled in the art. . Alternatively, compound (A-1) and carboxylic acid halide (A-3) can be obtained by an amidation reaction in an inert solvent in the presence or absence of a base.
Here, the amidation reaction using compound (A-1) or a salt thereof and carboxylic acid (A-2) is, for example, O- (7-azabenzotriazole in an inert solvent in the presence or absence of a base. -1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphoric acid (HATU), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetra Methyluronium hexafluorophosphoric acid (HBTU), N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl), diphenylphosphoryl azide (DPPA) Or amidation reaction using a condensing agent such as 1,1'-carbonyldiimidazole (CDI), ethyl chlorocarbonate, isobutyl chlorocarbonate or trimethyla Chirukurorido the like amidation reaction via a mixed acid anhydride using, for example. Here, in the amidation reaction using a condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary.

[Production Method 2]
The compound represented by compound (A-1) or a salt thereof can be produced, for example, by the following method.

[Wherein, PG represents an amino-protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl, and other symbols are as defined above.] ]

Step 2 : Compound (A-7) is compound (A-4) or a salt thereof, which can be produced by the method described in WO20111029046, in an inert solvent in the presence or absence of a base, various substituted picolinic acids ( It can be obtained by subjecting it to an amidation reaction with A-5) or various substituted picolinic acid halides (A-6). In the amidation reaction using the compound (A-4) and the carboxylic acid (A-5), the condensing agent and additive described in Step 1 can be used.

Step 3 : Compound (A-8) can be obtained by subjecting Compound (A-7) to an appropriate oxidation reaction in an inert solvent. As an appropriate oxidation reaction, an oxidation reaction that can oxidize alcohol to convert it into a ketone, such as DMSO oxidation using Swan oxidation or sulfur trioxide / pyridine complex, hypervalent iodine such as Dess-Martin reagent, etc. Examples thereof include an oxidation reaction using a reagent and a chromium (VI) reagent such as PCC and PDC.

Step 4 : Compound (A-9) can be obtained by reacting Compound (A-8) with an appropriate dehydrating agent in an inert solvent. Examples of suitable dehydrating cyclizing agents include thionyl chloride, phosphorus oxychloride, diphosphorus pentoxide, Burgess reagent, and the like.

Step 5 : Compound (A-1) can be obtained by subjecting compound (A-9) to a deprotection reaction by a method known in the literature relating to the protecting group shown above.

[Production Method 3]
The compound represented by the compound (A-8) can also be produced, for example, by the following production method.

[The symbols in the formula are as defined above. ]

Step 6 : Compound (A-8) is a commercially available compound (A-10) or a salt thereof that can be produced according to the method described in CN10185565, etc., in the presence or absence of a base in an inert solvent. It can be obtained by subjecting it to an amidation reaction with a substituted picolinic acid halide (A-6).

[Production Method 4]
The compound represented by the compound (A-8) is a series of steps 7-1, 7-2 and 7-3 described below from a compound (A-11) which is commercially available or can be produced by a method according to the description of CN10187565. It can also be manufactured by conversion.

[Wherein LG represents a leaving group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group or an o-nitrobenzenesulfonyloxy group; ^Ra represents a lower alkyl group such as ^a methyl group or an ethyl group; Is as defined above. ]

Steps 7-1 and 7-2 : The reaction intermediate represented by the compound (A-12) is a commercially available compound (A-11) that can be produced by a method similar to that described in CN10187565 in an inert solvent. A rearrangement reaction (Step 7-1) by reacting with a suitable base, followed by an amidation reaction (Step 7-2) with various substituted picolinic acid halides (A-6) in the presence or absence of a base. It can obtain by providing. Here, examples of the suitable base used in Step 7-1 include lower alkoxides of alkali metals such as sodium methoxide and sodium ethoxide.

Step 7-3 : The compound (A-8) can be obtained by subjecting the reaction intermediate represented by the compound (A-12) to a ring-opening reaction with an acidic aqueous solution in an inert solvent.

[Production Method 5]
Among the compounds represented by the compound (A-9), the compound (A-9-b) in which R ¹ is cyano can also be produced, for example, by the following method.

Step 8 : Among the compounds represented by the compound (A-9), the compound (A-9-b) in which R ¹ is cyano is present in an inert solvent in the presence of a palladium catalyst, a ligand, and a base. Alternatively, in the absence of the compound represented by the compound (A-9), the compound (A-9-a) produced by the method described in Production Method 2 wherein R ¹ is a bromo group and the metal cyanide It can obtain also by cyanation reaction. Here, the palladium catalyst is a palladium compound such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, bis (benzonitrile) palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium chloride or palladium acetate. It is. Ligand is dimethylphenylphosphine, diphenylphosphinoferrocene (DPPF), trimethylphosphine, triethylphosphine, tritert-butylphosphine, tricyclohexylphosphine, trimethoxyphosphine, triethoxyphosphine, tritert-butoxyphosphine, triphenyl. Phosphine (PPh ₃ ), 1,2-bis (diphenylphosphino) ethane (DPPE), 1,3-bis (diphenylphosphino) propane (DPPP), triphenoxyphosphine, tri-o-tolylphosphine, tri-m -Tolylphosphine, tri-p-tolylphosphine and the like. Examples of the metal cyanide include sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide, potassium hexacyanide iron (II) and potassium hexacyanide iron (III).

  The raw materials and reagents used in the above production method are commercially available compounds, or can be produced from known compounds using known methods, unless otherwise specified. Further, in the compound of the above formula (I), another compound of the formula (I) may be obtained by appropriately converting a functional group. The conversion of the functional group is carried out by a commonly used general method [for example, Comprehensive Organic Transformations, Earl. Sea. By R. C. Larock (1989), etc.].

  In the production method, if any functional group other than the reactive site changes under the described reaction conditions or is inappropriate for carrying out the described method, the functional group is described in advance in the above-mentioned document or the like. The target compound can be obtained by carrying out the reaction after protecting with an appropriate protecting group and then deprotecting. Specifically, examples of the protecting group for amine include ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzoyl, benzyl and the like, and examples of the hydroxyl protecting group include trialkylsilyl, acetyl, benzoyl, benzyl and the like. be able to. Examples of the protecting group for ketone include dimethyl acetal, 1,3-dioxane, 1,3-dioxolane, S, S'-dimethyldithioacetal, 1,3-dithiane, oxime and the like.

  In the said manufacturing method, this invention compound (I) and an intermediate body are isolated and purified by a well-known means (For example, solvent extraction, neutralization, filtration, washing | cleaning, drying, concentration, distillation, recrystallization, chromatography etc.). Can do. In addition, the compound used in each production method can be isolated and purified by the same known means as described above. Isolation and purification may be performed after each reaction or after completion of several reactions.

  In order to obtain a pharmaceutically acceptable salt of the compound represented by the formula (I), the compound (I) may be purified as it is when obtained in the form of a pharmaceutically acceptable salt, When it is obtained in a free form, it may be dissolved or suspended in a suitable organic solvent, and the acid mentioned above may be added to form a salt by a conventional method. For example, a salt can be obtained by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, acetone or the like.

Next, the present invention will be described in more detail with reference to production methods, examples and test examples, but the technical scope of the present invention is not limited to these examples. Moreover, you may change in the range which does not deviate from the range of this invention. In addition, the compound name shown in the following Examples is named by ACD / Name (ACD / Labs 10.01, Advanced Chemistry Development Inc.) and does not necessarily follow the IUPAC nomenclature.
The following abbreviations may be used in the examples.

Me: methyl Et: ethyl Ph: phenyl n-: normal tert-: tertiary Boc: tert-butoxycarbonyl THF: tetrahydrofuran DMF: N, N-dimethylformamide DMP: Dess-Martin periodinane EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide HOBt: 1-hydroxybenzotriazole CDI: 1,1′-carbonyldiimidazole ObsMS [M + 1]: observed protonated molecule Rt: retention time

Proton nuclear magnetic resonance absorption spectrum ( ¹ H-NMR spectrum) and mass spectrum (LC-MS) were used for identification of the compound. In the LC-MS analysis, the mass spectrum of the protonated molecule was observed by the electrospray ion method (ESI).

  In the following production examples and examples, “room temperature” means a temperature of 0 to 30 ° C., and “%” means weight percent unless otherwise specified. “Silica gel” and “NH silica gel” when purified using column chromatography were silica gel and NH silica gel commercially available from Yamazen Co., Ltd. Each device data described in the production examples and examples was measured by the following measuring devices.

High-performance liquid chromatograph / mass spectrometer; LCMS measurement conditions are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by MH +, and the retention time is represented by Rt (min).
MS spectrum:
LCMS: Shimadzu LCMS-2020
LC Column:
Phenomenex Kinetex 1.7 μm C18 (50 mm × 2.10 mm)
Solvent:
Liquid A: 0.05% TFA / H2O, Liquid B: MeOH
Gradient Condition:
0.0 min; A / B = 70: 30
0.0-1.90 min; A / B = 1: 99
1.91-3.00 min; A / B = 70: 30
Flow rate:
0.5 mL / min
UV:
220, 254 nm
Column temperature:
40 ° C

NMR: NMR measurement conditions are as follows, and in order to simplify the description, the following abbreviations may be used in the examples and tables in the examples. The symbols used in NMR are as follows: s is a single line, d is a double line, dd is a double double line, t is a triple line, td is a triple double line, q is a quadruple line, m is Multiple lines, br means broad, brs means wide single line, brd means wide double line, and brt means wide triple line.
NMR spectrum: 400 MHz (JEOL AL400, JEOL) or 300 MHz (JEOL LA300, JEOL)

Example 1:
[2- (5-Fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone

2- (5-Fluoropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine (Preparation Examples 1-3, 10.0 g) and triethylamine A solution of benzoyl chloride (6.94 g) in dichloromethane (30 mL) was added dropwise to a solution of (6.73 g) in dichloromethane (230 mL) under ice cooling, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was recrystallized from ethanol (420 mL) to give the title compound (14.2 g) as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 (m, 1H), 8.20-7.95 (brm, 1H), 7.58-7.51 (brm, 1H), 7.45 (brs) , 5H), 4.90-4.48 (brm, 2H), 4.25-3.67 (brm, 2H), 3.10-2.83 (brm, 2H)
ObsMS [M + 1]: 324
Rt (min): 1.54

  2- (5-Fluoropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine used in the production of Example 1 (Preparation Example 1 3) was prepared by the following method using benzyl 3-amino-4-oxopiperidine-1-carboxylate hydrochloride and 5-fluoropicolinic acid.

Production Example 1-1:
Benzyl 3-{[(5-fluoropyridin-2-yl) carbonyl] amino} -4-oxopiperidine-1-carboxylate

Thionyl chloride (44.1 g) was added to a suspension of 5-fluoropicolinic acid (34.9 g) in 1,4-dioxane (350 mL), and the mixture was heated to reflux for 2 hours. After the solvent was distilled off, the obtained residue was dissolved in THF (70 mL), and a suspension of benzyl 3-amino-4-oxopiperidine-1-carboxylate hydrochloride (57.6 g) in THF (600 mL) was obtained. Added to. Under ice cooling, triethylamine (71.6 g) was added dropwise and stirred for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was recrystallized from ethanol / hexane to give the title compound (60.4 g) as a solid.
¹ H NMR (300 MHz, CDCl ₃ ): δ 8.62 (br, 1H), 8.44 (d, J = 2.8 Hz, 1H), 8.22 (dd, J = 8.6, 4.5 Hz, 1H), 7.54 (ddd, J = 8.6, 8.2, 2.8 Hz, 1H), 7.45-7.32 (m, 5H), 5.30-5.18 (m, 2H) ), 5.08-5.00 (m, 1H), 4.78-4.71 (m, 1H), 4.63-4.40 (m, 1H), 3.18-3.11 (m) , 1H), 2.93-2.84 (m, 1H), 2.76-2.57 (m, 1H)
ObsMS [M + 1]: 372
Rt (min): 1.72

Production Example 1-2:
Benzyl 2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H) -carboxylate

Burgess reagent (104.5 g) was added to a THF (1.1 L) solution of Production Example 1-1 (100 g), and the mixture was stirred at 40 ° C. for 3.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound (74.3 g) as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.54 (d, J = 2.8 Hz, 1H), 8.08 (br, 1H), 7.51 (ddd, J = 8.6, 8.6) 2.8 Hz, 1H), 7.38-7.32 (m, 5H), 5.16 (s, 2H), 4.56 (br, 2H), 3.87 (br, 2H), 2.86 (Br, 2H)
ObsMS [M + 1]: 354
Rt (min): 1.86

Production Example 1-3:
2- (5-Fluoropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine

A solution of Production Example 1-2 (10.0 g) in AcOH (40 mL) was added dropwise to 30% HBr / AcOH (28 mL) at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was added to 1 mol / L aqueous HCl (200 mL) under ice cooling. The aqueous layer was washed twice with ethyl acetate / hexane (1/4), adjusted to pH 9-10 with aqueous sodium hydroxide (7.5 mol / L), and extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from acetonitrile to give the title compound (5.34 g) as a solid.
¹ H NMR (300 MHz, CDCl ₃ ): 8.55 (d, J = 2.7 Hz, 1H), 8.11 (dd, J = 8.8, 4.4 Hz, 1H), 7.52 (ddd, J = 8.8, 8.5, 2.7 Hz, 1H), 3.91 (t, J = 2.0 Hz, 2H), 3.22 (t, J = 5.7 Hz, 2H), 2.84 -2.80 (m, 2H)
ObsMS [M + 1]: 220
Rt (min): 0.27
Example 2:
(3-Chloro-5-fluorophenyl) [2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl ] Methanone

To a solution of Preparation Example 1-3 (0.88 g) in DMF (20 mL), 3-chloro-5-fluorobenzoic acid (0.72 g), EDC hydrochloride (1.15 g) and HOBt monohydrate (0 .81 g) was added and stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, hexane / ethyl acetate = 3 / 1-1 / 2) to obtain the title compound (1.20 g) as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 (d, J = 2.7 Hz, 1H), 8.18-8.00 (brs, 1H), 7.58-7.48 (m, 1H) 7.26-7.24 (m, 1H), 7.20 (ddd, J = 8.3, 2.0, 2.0 Hz, 1H), 7.08 (ddd, J = 8.0, 2 .2, 1.5 Hz, 1H), 4.88-4.36 (brm, 2H), 4.22-3.97 (brm, 1H), 3.88-3.63 (brm, 1H), 3 .08-2.85 (brm, 2H)
ObsMS [M + 1]: 376, 378
Rt (min): 1.76

Example 3:
[2- (5-Methylpyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone

In the same manner as described in Example 1, 2- (5-methylpyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo instead of Preparation Example 1-3 The title compound was prepared using [4,5-c] pyridine (Preparation Example 3-4).
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.53 (s, 1H), 8.09-7.82 (brm, 1H), 7.61 (m, 1H), 7.45 (brs, 5H), 4.89-4.43 (brm, 2H), 4.24-3.63 (brm, 2H), 3.08-2.81 (brm, 2H), 2.40 (s, 3H)
ObsMS [M + 1]: 320
Rt (min): 1.54

  2- (5-Methylpyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine used in the production of Example 3 (Preparation Example 3- 4) was prepared by the following method using benzyl trans-3-amino-4-hydroxypiperidine-1-carboxylate hydrochloride and 5-methylpicolinic acid.

Production Example 3-1:
Benzyl trans-4-hydroxy-3-{[(5-methylpyridin-2-yl) carbonyl] amino} piperidine-1-carboxylate

To a suspension of benzyl trans-3-amino-4-hydroxypiperidine-1-carboxylate hydrochloride (2.87 g) and 5-methylpicolinic acid (1.37 g) in DMF (50 mL) was added EDC hydrochloride (2. 87 g), HOBt monohydrate (2.30 g) and triethylamine (2.09 mL) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, chloroform / methanol = 99 / 1-95 / 5) to obtain the title compound (12.35 g) as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.34 (d, J = 1.5 Hz, 1H), 8.13 (d, J = 6.6 Hz, 1H), 8.06 (d, J = 7. 6 Hz, 1H), 7.64 (dd, J = 7.6, 1.5 Hz, 1H), 7.42-7.25 (m, 5H), 5.21-5.09 (m, 2H), 4.29-4.17 (m, 1H), 4.03-3.90 (m, 2H), 3.85-3.79 (m, 1H), 3.22-3.06 (m, 2H) ), 2.41 (s, 3H), 2.09-2.01 (m, 1H), 1.70-1.60 (m, 1H)
ObsMS [M + 1]: 370
Rt (min): 1.63

Production Example 3-2:
Benzyl 3-{[(5-methylpyridin-2-yl) carbonyl] amino} -4-oxopiperidine-1-carboxylate

To a solution of oxalyl chloride (1.09 mL) in dichloromethane (40 mL) was added DMSO (1.36 mL) dropwise at −78 ° C., and the mixture was stirred for 10 minutes. While maintaining the temperature at −78 ° C., a solution of Production Example 3-1 (2.35 g) in dichloromethane (30 mL) was added dropwise and stirred for 1 hour. Triethylamine (4.43 mL) was added dropwise, and the mixture was further stirred for 1 hour while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, hexane / ethyl acetate = 2 / 1-1 / 2) to give the title compound (2.23 g) as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.73 (brs, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7 .64 (dd, J = 8.0, 1.5 Hz, 1H), 7.43-7.30 (m, 5H), 5.32-5.18 (m, 2H), 5.03 (ddd, J = 12.9, 6.8, 2.9 Hz, 1H), 4.78-4.67 (m, 1H), 4.65-4.48 (m, 1H), 3.22-3.10. (M, 1H), 2.90 (dd, J = 12.9, 1.7 Hz, 1H), 2.75-2.55 (m, 2H), 2.41 (s, 3H)
ObsMS [M + 1]: 368
Rt (min): 1.77

Production Example 3-3:
Benzyl 2- (5-methylpyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H) -carboxylate

The title compound was produced in the same manner as described in Production Example 1-2 using Production Example 3-2 instead of Production Example 1-1.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.53 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.0, 1.7 Hz, 1H), 7.42-7.30 (m, 5H), 5.19 (s, 2H), 4.59 (s, 2H), 3.89 (brs, 2H), 2.89 (brs, 2H) ), 2.40 (s, 3H)
ObsMS [M + 1]: 350
Rt (min): 1.91

Production Example 3-4:
2- (5-Methylpyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine

Palladium hydroxide (55% wet, 1.00 g) was added to a methanol (150 mL) solution of Production Example 3-3 (1.55 g), and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. Insoluble material was removed by Celite filtration, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, chloroform / methanol = 99/1) to obtain the title compound (0.95 g) as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.52 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.59 (ddd, J = 8.0, 2.2, 0.7 Hz, 1H), 3.91 (t, J = 2.0 Hz, 2H), 3.21 (t, J = 5.6 Hz, 2H), 2.82 (m, 2H), 2.40 ( s, 3H)
ObsMS [M + 1]: 216
Rt (min): 0.27

Example 4:
[2- (5-Chloropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone

In the same manner as described in Example 1, 2- (5-chloropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo instead of Preparation Example 1-3 The title compound was prepared using [4,5-c] pyridine (Preparation Example 4-4).
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.65 (d, J = 2.2 Hz, 1H), 8.12-7.91 (brm, 1H), 7.79 (m, 1H), 7.45 (Brs, 5H), 4.89-4.43 (brm, 2H), 4.24-3.68 (brm, 2H), 3.08-2.84 (brm, 2H)
ObsMS [M + 1]: 340, 342
Rt (min): 1.68

  2- (5-Chloropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine used in the production of Example 4 (Preparation Example 4- 4) was prepared by the following method using trans-benzyl 4-hydroxy-3-aminopiperidine-1-carboxylate hydrochloride and 5-chloropicolinic acid.

Production Example 4-1
Benzyl trans-3-{[(5-chloropyridin-2-yl) carbonyl] amino} -4-hydroxy-piperidine-1-carboxylate

The title compound was synthesized by a method similar to the method described in Production Example 3-1 using 5-chloropicolinic acid instead of 5-methylpicolinic acid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.47 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.02-8.00 (m, 1H), 7.83 (dd, J = 8.3, 2.4 Hz, 1H), 7.39-7.28 (m, 5H), 5.20-5.11 (m, 2H), 4. 26-4.14 (m, 1H), 4.00-3.89 (m, 2H), 3.87-3.79 (m, 1H), 3.26-3.09 (m, 2H), 2.08-2.00 (m, 1H), 1.69-1.60 (m, 1H)
ObsMS [M + 1]: 390, 392
Rt (min): 1.75

Production Example 4-2:
Benzyl 3-{[(5-chloropyridin-2-yl) carbonyl] amino} -4-oxopiperidine-1-carboxylate

To a dichloromethane (40 mL) solution of Production Example 4-1 (3.24 g), DMP (4.57 g) was added at 0 ° C., and the mixture was stirred at room temperature for 16 hours. A 0.5 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was stirred for 30 minutes, and insoluble material was removed by filtration through Celite. Chloroform and water were added for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (silica gel, hexane / ethyl acetate = 2 / 1-1-1 / 1) to obtain the title compound (2.44 g) as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.65 (brs, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7 .83 (dd, J = 8.3, 2.4 Hz, 1H), 7.48-7.30 (m, 5H), 5.31-5.18 (m, 2H), 5.04 (ddd, J = 12.7, 6.8, 2.7 Hz, 1H), 4.77-4.66 (m, 1H), 4.65-4.48 (m, 1H), 3.22-3.10. (M, 1H), 2.88 (dd, J = 12.7, 1.2 Hz, 1H), 2.74-2.58 (m, 2H)
ObsMS [M + 1]: 388,390
Rt (min): 1.84

Production Example 4-3:
Benzyl 2- (5-chloropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H) -carboxylate

The title compound was produced in the same manner as described in Production Example 1-2, using Production Example 4-2 instead of Production Example 1-1.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.65 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 8. 5, 2.4 Hz, 1H), 7.38-7.29 (m, 5H), 5.19 (s, 2H), 4.59 (s, 2H), 3.89 (brs, 2H), 2 .89 (brs, 2H)
ObsMS [M + 1]: 370, 372
Rt (min): 2.01

Production Example 4-4:
2- (5-Chloropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine

To a solution of Production Example 4-3 (0.94 g) in dichloromethane (20 mL) was added dropwise iodotrimethylsilane (1.27 g) under ice-cooling and nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and extracted with 0.2 mol / L aqueous hydrochloric acid. A saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer to adjust the pH to 8-9, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, chloroform / methanol = 99 / 1-99 / 5) to obtain the title compound (0.54 g) as a solid.
¹ H NMR (300 MHz, CDCl ₃ ): δ 8.65 (dd, J = 2.4, 0.5 Hz, 1H), 8.03 (dd, J = 8.5, 0.7 Hz, 1H), 7. 78 (dd, J = 8.5, 2.4 Hz, 1H), 3.91 (t, J = 2.0 Hz, 2H), 3.22 (t, J = 5.9 Hz, 2H), 2.82 (M, 2H)
ObsMS [M + 1]: 236, 238
Rt (min): 0.48

Example 5:
[2- (5-Bromopyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone

In a manner similar to that described in Example 1, 2- (5-bromopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo instead of Preparation Example 1-3 The title compound was prepared using [4,5-c] pyridine (Preparation Example 5-3).
¹ H NMR (300 MHz, CDCl ₃ ): δ 8.76-8.74 (m, 1H), 8.02-7.89 (m, 2H), 7.51-7.40 (m, 5H), 4 .87-4.45 (m, 2H), 4.23-4.04 (m, 1H), 3.87-3.71 (m, 1H), 3.07-2.85 (m, 2H)
ObsMS [M + 1]: 384, 386
Rt (min): 1.73

  2- (5-Bromopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine used in the production of Example 5 (Preparation Example 5- 3) was prepared by the following method using benzyl 4-{[(methylsulfonyl) oxy] imino} piperidine-1-carboxylate and 5-bromopicolinic acid.

Production Example 5-1
Benzyl 3-{[(5-bromopyridin-2-yl) carbonyl] amino} -4-oxopiperidine-1-carboxylate

Thionyl chloride (1.25 mL) was added to a suspension of 5-bromopicolinic acid (2.32 g) in 1,4-dioxane (12 mL), and the mixture was stirred at 110 ° C. for 2 hours. The solvent was distilled off under reduced pressure to obtain 5-bromopicolinoyl chloride hydrochloride (2.46 g) as a solid. Used in the next reaction without purification.
Magnesium sulfate (2.41 g) was added to a dichloromethane-methanol solution (1/1, 20 mL) of benzyl 4-{[(methylsulfonyl) oxy] imino} piperidine-1-carboxylate (3.26 g), and ice-cooled. Sodium methoxide / methanol solution (5 mol / L, 3.4 mL) was added dropwise over 5 minutes. After stirring at room temperature for 1 hour, insoluble matters were removed by filtration through Celite, and the solvent was distilled off under reduced pressure until the total weight reached 10 g. Chloroform was added to the residue, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, chloroform was added to the residue, and the solvent was distilled off under reduced pressure.
Chloroform (25 mL) and triethylamine (3.04 g) were added to the residue, and then a solution of 5-bromopicolinoyl chloride hydrochloride (2.46 g) in 1,4-dioxane (20 mL) was added over 5 minutes under ice cooling. Added dropwise. After stirring at room temperature for 3 hours, chloroform was added to the reaction solution, and the mixture was washed successively with water, 1 mol / L hydrochloric acid aqueous solution and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 1,4-dioxane (10 mL), 4 mol / L hydrochloric acid / 1,4-dioxane solution (4 mL) and water (2 mL) were added, and the mixture was stirred at 60 ° C. for 2 hr and cooled to room temperature. A 1 mol / L aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol / hexane (6/1, 100 mL) to give the title compound (2.45 g) as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.65 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.99 (dd, J = 8. 3, 2.2 Hz, 1H), 7.43-7.33 (m, 5H), 5.25-5.19 (m, 2H), 5.03 (ddd, 12.9, 6.8, 2 .7 Hz, 1H), 4.75-4.67 (m, 1H), 3.22-3.12 (m, 1H), 2.88 (dd, J = 12.9, 11.2 Hz, 1H) , 2.73-2.56 (m, 2H)
ObsMS [M + 1]: 432, 434
Rt (min): 1.90

Production Example 5-2:
Benzyl 2- (5-bromopyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H) -carboxylate

The title compound was produced in the same manner as described in Production Example 1-2 using Production Example 5-1 instead of Production Example 1-1.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.76 (s, 1H), 7.95 (d, J = 1.92 Hz, 2H), 7.38-7.33 (m, 5H), 5.19 (S, 2H), 4.59 (s, 2H), 3.91 (brs, 2H), 2.90 (brs, 2H)
ObsMS [M + 1]: 414, 416
Rt (min): 2.05

Production Example 5-3:
2- (5-Bromopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine

The title compound was produced in the same manner as described in Production Example 4-4 using Production Example 5-2 instead of Production Example 4-3.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.76-8.75 (m, 1H), 7.98-7.92 (m, 2H), 3.91 (s, 2H), 3.22 (t , J = 5.6 Hz, 2H), 2.82 (t, J = 5.6 Hz, 2H)
ObsMS [M + 1]: 280,282
Rt (min): 0.43

Example 6:
6- [5- (phenylcarbonyl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl] pyridine-3-carbonitrile

In a manner similar to that described in Example 1, 2- (5-cyanopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo instead of Preparation Example 1-3 The title compound (42 mg) was prepared using [4,5-c] pyridine (Preparation Example 6-2).
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.96 (s, 1H), 8.29-8.11 (m, 1H), 8.11-8.02 (m, 1H), 7.46 (brs) , 5H), 4.82 (brs, 1H), 4.55 (brs, 1H), 4.16 (brs, 1H), 3.80 (brs, 1H), 3.09-2.92 (m, 2H)
ObsMS [M + 1]: 331
Rt (min): 1.40

  2- (5-Cyanopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine (Preparation Example 6-) used in the manufacture of Example 6 2) was produced by the following method using Production Example 5-2.

Production Example 6-1:
Benzyl 2- (5-cyanopyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H) -carboxylate

Preparation Example 5-2 (1.24 g), zinc cyanide (60%, 352 mg), zinc (47 mg), tris (dibenzylideneacetone) dipalladium (0) (110 mg) and 1,1′-bis (diphenyl) A solution of phosphino) ferrocene (133 mg) in DMA (30 mL) was stirred at 120 ° C. for 10 hours. The reaction solution was returned to room temperature and filtered through celite. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1-1 / 1) to give the title compound (1.03 g) as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.96 (s, 1H), 8.24-8.15 (m, 2H), 8.07 (d, J = 8.32 Hz, 2H), 7.42 -7.30 (m, 5H), 5.19 (s, 2H), 4.61 (brs, 2H), 3.91 (brs, 2H), 2.94 (brs, 2H)
ObsMS [M + 1]: 361
Rt (min): 1.54

Production Example 6-2:
2- (5-Cyanopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine

The title compound was produced in the same manner as described in Production Example 4-4 using Production Example 6-1 instead of Production Example 4-3.
¹ H NMR (400 MHz, CDCl ₃ ): δ 9.14 (s, 1H), 8.48 (d, J = 8.32 Hz, 2H), 8.21 (d, J = 8.32 Hz, 2H), 4 .24 (s, 2H), 3.50 (t, J = 5.88 Hz, 2H), 3.08 (t, J = 5.88 Hz, 2H)
ObsMS [M + 1]: 227
Rt (min): 0.26

Examples 7-19:
The compounds of Examples 7 to 19 were produced in the same manner as described in Examples 1 to 6 using the corresponding starting materials and reagents.

Example 7:
(2-Fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone

¹ H NMR (400 MHz, DMSO-d6): δ 8.69 (m, 1H), 8.16 (dd, J = 8.8, 4.6 Hz, 2 / 3H), 8.06 (dd, J = 8 .8, 4.6 Hz, 1 / 3H), 7.91 (m, 1H), 7.57-7.28 (m, 4H), 4.70 (brs, 4 / 3H), 4.30 (brs) , 2 / 3H), 4.07 (brs, 2 / 3H), 3.62 (brm, 4 / 3H), 2.95 (brs, 2 / 3H), 2.84 (brs, 4 / 3H)
ObsMS [M + 1]: 342
Rt (min): 1.50

Example 8:
(3-Fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 (d, J = 2.7 Hz, 1H), 8.08 (brs, 1H), 7.67-7.10 (m, 5H), 4.99 -4.34 (brm, 2H), 4.32-3.51 (brm, 2H), 3.18-2.67 (brm, 2H)
ObsMS [M + 1]: 342
Rt (min): 1.54

Example 9:
(4-Fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 (d, J = 2.7 Hz, 1H), 8.09 (brs, 1H), 7.56-7.44 (m, 3H), 7.13 (T, J = 8.5 Hz, 2H), 4.86-4.42 (brm, 2H), 4.20-3.66 (brm, 2H), 3.08-2.85 (brm, 2H)
ObsMS [M + 1]: 342
Rt (min): 1.54

Example 10:
(3-Chlorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56 (s, 1H), 8.08 (brs, 1H), 7.67-7.10 (m, 5H), 4.99-4.34 (brm) , 2H), 4.32-3.51 (brm, 2H), 3.18-2.67 (brm, 2H)
ObsMS [M + 1]: 358, 360
Rt (min): 1.71

Example 11:
(3-Fluoro-5-methylphenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H)- Il] methanone

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.54 (d, J = 2.4 Hz, 1H), 8.20-7.95 (brm, 1H), 7.51 (m, 1H), 7.02 (D, J = 0.7 Hz, 1H), 6.98-6.92 (m, 2H), 4.75 (brs, 1 / 2H), 4.48 (brs, 1 / 2H), 4.11 (Brs, 1 / 2H), 3.73 (brs, 1 / 2H), 2.98 (brs, 1 / 2H), 2.88 (brs, 1 / 2H), 2.37 (s, 3H)
ObsMS [M + 1]: 356
Rt (min): 1.73

Example 12:
(2-Fluoro-3-methylphenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H)- Il] methanone

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.55 (m, 1H), 8.13 (m, 1 / 2H), 8.02 (m, 1 / 2H), 7.55-7.49 (m , 1H), 7.26-7.04 (m, 3H), 4.83 (brs, 1 / 2H), 4.40 (brs, 1H), 3.68 (brs, 1 / 2H), 3. 00 (brs, 1 / 2H), 2.87 (brs, 1 / 2H), 2.30 (d, J = 2.0 Hz, 3 / 2H), 2.28 (d, J = 2.0 Hz, 3 / 2H)
ObsMS [M + 1]: 356
Rt (min): 1.67

Example 13:
(3-Chloro-5-methylphenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H)- Il] methanone

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.56 (d, J = 2.4 Hz, 1H), 8.19-7.99 (brs, 1H), 7.53 (m, 1H), 7.23 (Brs, 1H), 7.14 (brs, 1H), 4.86-4.41 (brm, 2H), 4.20-3.66 (brm, 2H), 3.07-2.83 (brm) , 2H), 2.37 (s, 3H)
ObsMS [M + 1]: 372, 374
Rt (min): 1.86

Example 14:
(5-Chloro-2-methylphenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H)- Il] methanone

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.56 (m, 1H), 8.15 (dd, J = 8.8, 4.4 Hz, 1 / 2H), 8.05 (dd, J = 8. 8, 4.4 Hz, 1 / 2H), 7.54 (m, 1H), 7.33-7.24 (brm, 1H), 7.22-7.11 (brm, 2H), 5.07- 4.92 (brm, 1 / 2H), 4.79-4.65 (brm, 1 / 2H), 4.48-4.21 (brm, 3 / 2H), 4.06-3.88 (brm , 1 / 2H), 3.71-3.55 (brm, 1H), 3.09-2.95 (brm, 1H), 2.91-2.74 (brm, 1H), 2.30 (s) , 3 / 2H), 2.19 (s, 3 / 2H)
ObsMS [M + 1]: 372, 374
Rt (min): 1.77

Example 15:
[2- (5-Fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (3-methoxyphenyl) methanone

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.56 (d, J = 2.2 Hz, 1H), 8.20-7.98 (brm, 1H), 7.61-7.45 (brm, 1H) 7.41-7.29 (brm, 1H), 7.08-6.91 (brm, 3H), 4.89-4.40 (brm, 2H), 4.25-3.98 (brm, 1H), 3.95-3.67 (brm, 4H), 3.09-2.81 (brm, 2H)
ObsMS [M + 1]: 354
Rt (min): 1.57

Example 16:
(3-Chloro-5-methoxyphenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H)- Il] methanone

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.56 (d, J = 2.8 Hz, 1H), 8.21-7.92 (brm, 1H), 7.60-7.47 (brm, 1H) , 7.00 (m, 1H), 6.87 (m, 1H), 4.87-4.39 (brm, 2H), 4.21-4.00 (brm, 1H), 3.85-3 .68 (brm, 4H), 3.08-2.85 (brm, 2H)
ObsMS [M + 1]: 388,390
Rt (min): 1.82

Example 17:
3-Fluoro-5-{[2-5-fluoropyridin] -2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] carbonyl} Benzonitrile

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.56 (d, J = 2.8 Hz, 1H), 8.21-7.92 (brm, 1H), 7.60-7.47 (brm, 1H) , 7.00 (m, 1H), 6.87 (m, 1H), 4.87-4.39 (brm, 2H), 4.21-4.00 (brm, 1H), 3.85-3 .68 (brm, 4H), 3.08-2.85 (brm, 2H)
ObsMS [M + 1]: 367
Rt (min): 1.41

Example 18:
[2- (5-Chloropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (2-fluorophenyl) methanone

¹ H NMR (400 MHz, CDCl 3): δ 8.66 (dd, J = 6.3, 1.7 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1 / 2H), 7.96 (d , J = 8.5 Hz, 1 / 2H), 7.79 (m, 1H), 7.48-7.37 (brm, 2H), 7.26-7.07 (brm, 2H), 4.85. (Brs, 1H), 4.63-3.74 (brm, 1H), 4.44 (brs, 1H), 3.71 (brs, 1H), 3.02 (brs, 1H), 2.91 ( brs, 1H)
ObsMS [M + 1]: 358, 360
Rt (min): 1.69

Example 19:
[2- (5-Chloropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (3-fluorophenyl) methanone

¹ H NMR (300 MHz, CDCl 3): δ 8.66 (s, 1H), 8.14-7.91 (brs, 1H), 7.81-7.72 (brm, 1H), 7.50-7. 36 (brm, 1H), 7.26-7.10 (brm, 3H), 4.89-4.41 (brm, 2H), 4.25-3.64 (brm, 2H), 3.13- 2.83 (brm, 2H)
ObsMS [M + 1]: 358, 360
Rt (min): 1.72

Test Examples The results of pharmacological tests and pharmacokinetic tests of representative compounds of the present invention are shown below, but the present invention is not limited to these test examples.

mGluR5 in vitro functional assay Functional assays were performed using an inducible cell line expressing the human recombinant mGluR5 receptor under the control of a tetracycline-inducible promoter. Specifically, the human mGluR5 gene was inserted into pcDNA4 / TO (invitrogen) and introduced into TR-expressing human kidney-derived HEK cells (ATCC). Thereafter, selection with Geneticin (invitrogen) was performed to obtain human mGluR5 stably expressing cells.

The mGluR5 cells grown in antibiotic (blastosidin, G418) medium were detached by gently flushing with 10-fold diluted TRYPLE EXPRESS (life technologies), and the assay buffer (HBSS, 20 mM HEPES, 0.1% BSA) was detached. It suspended so that it might become 3x10 < ⁴ > cells / ml. Apoaequorin was transiently introduced under tetracycline (final concentration 100 ng / mL), and 50 μL was dispensed into a 384-well plate, followed by overnight culture in a CO ₂ incubator. Cells were incubated with coelenterazine h (Promega, final concentration 5 nM) at room temperature for at least 4 hours. 10 μL of test compound diluted with assay buffer is added to the cells, and after incubation, 10 μL of glutamic acid solution is added to a final concentration of 2 μM, and the resulting luminescence is recorded using a Hamamatsu Functional Drug System 7000 (FDSS 7000). did. The percent inhibition was calculated based on activation by glutamic acid (final concentration 2 μmol / L). Stat Preclinica (Takumi Information Technology Co., Ltd.) software calculates inhibitory activity (IC ₅₀ ) against metabotropic glutamate receptor subtype 5 (mGluR5) by analysis using nonlinear regression applied to a sigmoidal dose response model did.

  The tetrahydrooxazolopyridine derivatives of the present invention obtained in the examples were subjected to the above test, and the results are shown in Table 1.

  From the above test results, it was revealed that the tetrahydrooxazolopyridine derivative or pharmaceutically acceptable salt of the present invention has an action as an mGluR5 negative modulator. Especially Example 2, Example 4, Example 10, and Example 13 showed the effect | action as a strong mGluR5 negative modulator.

Dansylated glutathione (dGSH) trapping assay As a method for detecting reactive metabolites, metabolites generated from test substances by metabolism in liver microsomes were detected and quantified by reacting with dansylated glutathione (dGSH). The metabolic reaction was measured using a screening robot (Tecan), and the metabolite-dGSH conjugate concentration was measured using a fluorescence detection UPLC system (Waters).

(Solution preparation)
A test substance was dissolved in DMSO to prepare a 10 mmol / L test substance solution. A microsome solution was prepared by adding 7.6 mL of potassium phosphate buffer (500 mmol / L, pH 7.4), 1.9 mL of human liver microsomes (Xenotech, 20 mg protein / mL) and 1.27 mL of pure water. Add 0.67 mL of pure water to 3.78 mL of the microsome solution, add 1.14 mL of dGSH solution (20 mmol / L) to 6.48 mL of the microsome solution, and add microsome (dGSH (+)) A solution was prepared. 80.9 mg of NADPH was dissolved in 30 mL of pure water to prepare a cofactor solution, and 33 mg of Tris (2-carboxyethyl) phosphine (TECP) was dissolved in 115 mL of methanol to prepare a reaction stop solution.

(reaction)
12 μL of the test substance solution was mixed with 388 μL of pure water, and 50 μL each was dispensed into 6 wells in a 96-well plate. The 6 wells were divided into 3 groups of 2 wells, which were designated as “reaction group”, “unreacted group” and “dGSH non-added group”, respectively. The microsome (dGSH (+)) solution was added to the “reaction group” and “unreacted group”, and 50 μL of the microsome (dGSH (−)) was added to the “dGSH non-added group”. Cofactor solution was added to the “reaction group” and “dGSH non-added group”, and 50 μL of pure water was added to the “non-reacted group”. After incubation at 37 ° C. for 60 minutes, 450 μL of reaction stop solution was added to stop the reaction. Purified water was added to the “reaction group” and “dGSH non-added group”, and 50 μL of cofactor solution was added to the “unreacted group”. The plate was cooled at −20 ° C. for 1 hour, and then centrifuged (4000 rpm, 10 minutes). went. The supernatant was collected on a separate plate and subjected to analysis.

(analysis)
Using a fluorescence detection UPLC system (manufactured by Waters), the metabolite-dGSH conjugate concentration was measured under the following conditions.
Column: Waters ACQUITY UPLC BEHC18 1.7 μm 2.1 × 10 mm
Elution solvent: A, 0.2% formic acid / 40% methanol; B, 0.2% formic acid / methanol gradient: B, 0% (0 min) → 83.3% (9.33 min) → 83.3% (10.63 min) → 0% (10.64 min) → 0% (13 min)
Since the fluorescence intensity varies depending on the organic solvent composition, correction was performed with the organic solvent composition during elution.

  The tetrahydrooxazolopyridine derivatives of the present invention obtained in the examples were subjected to the above test, and the results are shown in Table 2.

  The dGSH adduct production in Example 2 is a detected concentration that is considered to have a very low risk in terms of safety, and no adduct production is observed in other examples. Therefore, from the above test results, the tetrahydrooxazolopyridine derivative or the pharmaceutically acceptable salt of the present invention does not produce a dGSH adduct or hardly produces a reactive metabolite, or It was confirmed that the compound was difficult to produce and had excellent safety.

Pharmacokinetic test using rats For 7-week-old rats, the compound of the present invention was intravenously administered with a physiological saline solution or orally with a methylcellulose solution, and blood was collected at the following times.
Intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration Oral administration: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours after administration And the plasma obtained by centrifuging the collected blood by centrifugation at 3000 rpm for 10 minutes using a refrigerated centrifuge set at 4 ° C. was measured by HPLC, and the pharmacokinetic parameters were calculated based on the obtained time curve did.

  Table 1 shows the results of the above test for the preferred compounds of Example 1, Example 2, Example 7, Example 8, Example 9, Example 10, Example 11, Example 12 and Example 14. 3 shows.

  From the above test results, it was confirmed that the compound of the present invention was excellent in pharmacokinetics and useful in vivo. In particular, Example 1, Example 2, Example 7, Example 8, and Example 9 had good oral absorption and showed a bioavailability close to 100%. (Values exceeding 100% are due to experimental errors and may be considered to be almost 100%.)

  As explained above, it has been found that the compound of the present invention exhibits an action as a strong mGluR5 negative modulator and is excellent in safety and pharmacokinetics. Therefore, the compounds of the present invention are mGluR5 such as schizophrenia, anxiety disorder, mood disorder, drug dependence, neurodegenerative disease, levodopa-induced dyskinesia, Parkinson's disease, fragile X syndrome, autism, depression, Huntington's disease and the like. It is useful as a therapeutic agent for mental disorders or neurodegenerative diseases involving receptors.

Claims (13)

Formula (I):
[Where:
R ¹ is halogen, methyl, or cyano;
R ² and R ³ are each independently a hydrogen atom, halogen, C _1-3 alkyl, C _1-3 alkoxy or cyano;
Or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is fluorine or chlorine. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ is fluorine. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ² and R ³ are each independently a hydrogen atom, fluorine, chlorine, methyl, methoxy or cyano. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ² and R ³ are each independently a hydrogen atom, fluorine, chlorine or methyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
[2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone,
(3-Chloro-5-fluorophenyl) [2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl ] Methanone,
(2-fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone,
(3-fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone,
(4-fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone, And (3-chlorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
[2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone,
(3-Chloro-5-fluorophenyl) [2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl ] Methanone,
(2-fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone,
(3-fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone, And (4-fluorophenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] methanone . A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The therapeutic agent of the mental disease or neurodegenerative disease in which the metabotropic glutamate receptor subtype 5 which uses the compound as described in any one of Claims 1-7, or its pharmaceutically acceptable salt as an active ingredient. Mental or neurodegenerative diseases involving metabotropic glutamate receptor subtype 5 include schizophrenia, anxiety disorders, mood disorders, drug addiction, neurodegenerative diseases, levodopa-induced dyskinesia, Parkinson's disease, fragile X syndrome, self Autism, depression or Huntington's disease,
The therapeutic agent of Claim 9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for a disease involving metabotropic glutamate receptor subtype 5. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and schizophrenia, anxiety disorder, mood disorder, drug dependence, neurodegenerative disease, levodopa-induced dyskinesia, Parkinson A pharmaceutical comprising a combination of at least one drug selected from therapeutic agents for diseases, fragile X syndrome, autism, depression, or Huntington's disease. Anxiety such as anxiety and obsessive-compulsive disorder involving metabotropic glutamate receptor subtype 5 comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient Disorders; mood disorders such as depression and bipolar disorder; cognitive disorders such as Alzheimer's disease; psychosis such as schizophrenia; Parkinson's disease; levodopa-induced dyskinesia; neurodegenerative diseases such as Huntington's disease and amyotrophic lateral sclerosis Autism; developmental disorder of fragile X syndrome or attention deficit hyperactivity disorder; intellectual disorder such as Down syndrome; inflammatory pain; neuropathic pain; postoperative pain; acute thermal hyperalgesia; mechanical allodynia; -Pain such as chronic pain; epilepsy; epilepsy seizure; aggressiveness; post-traumatic stress disorder; tactile hypersensitivity; sensory excitability; oxygen deficiency disorder such as stroke / head trauma;