WO2015163472A1 - Heteroaryl compound substituted by triazolyl - Google Patents

Heteroaryl compound substituted by triazolyl Download PDF

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WO2015163472A1
WO2015163472A1 PCT/JP2015/062612 JP2015062612W WO2015163472A1 WO 2015163472 A1 WO2015163472 A1 WO 2015163472A1 JP 2015062612 W JP2015062612 W JP 2015062612W WO 2015163472 A1 WO2015163472 A1 WO 2015163472A1
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alkyl
substituted
alkoxy
group
compound
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PCT/JP2015/062612
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French (fr)
Japanese (ja)
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洋一郎 須賀
由紀 清水
憲一 川部
綾子 坊野
まこと 濱田
正人 高橋
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大正製薬株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to a compound that inhibits prolyl hydroxylase (hereinafter also referred to as “PHD”), and particularly to a compound that inhibits prolyl hydroxylase 2 (hereinafter also referred to as “PHD2”).
  • PLD prolyl hydroxylase
  • PPD2 a compound that inhibits prolyl hydroxylase 2
  • Red blood cells in the blood are responsible for oxygen transport throughout the body and play an important role in maintaining a constant in vivo oxygen concentration. If the number of red blood cells or hemoglobin in the blood decreases due to bleeding from certain diseases, accidents, or surgery, the symptoms of anemia such as malaise, dizziness, shortness of breath, etc. may occur. When anemia develops, the whole body is exposed to oxygen deficiency. Under such hypoxic conditions, the living body is compensated by the hematopoietic factor erythropoietin (hereinafter referred to as “EPO”) that promotes the formation of red blood cells mainly from the kidney. ) And increase the amount of red blood cells and hemoglobin in the blood to promote anemia.
  • EPO hematopoietic factor erythropoietin
  • Non-Patent Documents 1 and 2 See Non-Patent Documents 1 and 2.
  • ESA erythropoiesis stimulating factor preparations
  • erythropoietin also has an effect of protecting tissues such as the heart and brain placed in a hypoxic state accompanying ischemia. Therefore, orally administrable ESA may be widely applicable not only to anemia caused by various causes including renal anemia but also to various ischemic diseases (see Non-Patent Document 3).
  • HIF hypoxia-inducible factors
  • Patent Document 1 4-hydroxyisoquinoline derivatives (see Patent Document 1), 4-hydroxy-2-oxo-1,2-dihydroquinoline derivatives (see Patent Document 2), 3-hydroxypyridine derivatives (Patent Document) 3), 2-oxo-2,3-dihydroindole derivatives (see Patent Document 4) and the like have been reported, but compounds having a heteroaryl structure substituted with triazolyl are not disclosed.
  • Patent Documents 5 to 10 dihydropyrazolone derivatives
  • Patent Documents 11 to 19 which may be substituted with hydroxy or the like have been reported. Compounds having a substituted heteroaryl structure are not disclosed.
  • An object of the present invention is to provide a novel compound that inhibits PHD2.
  • the present inventors have found that a compound represented by the following formula (I) has a PHD2 inhibitory action.
  • the present invention will be described in detail.
  • the embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
  • R 1 represents a hydrogen atom or C 1-3 alkyl (the C 1-3 alkyl may be substituted with hydroxy);
  • X represents the formula CR 2 or a nitrogen atom;
  • R 2 represents a hydrogen atom, a halogen atom, C 1-3 alkyl, or C 1-3 alkoxy,
  • R 3 represents a hydrogen atom, a halogen atom, C 1-3 alkyl, or C 1-3 alkoxy,
  • Y represents a formula —CONR 41 —W 1 —, a formula —CONR 42 —W 2 —CO—, a structure represented by the following formula ( ⁇ ), a formula —CH 2 NHCO—, a formula —CH 2 OCH 2 —, or The formula —NHCOCH 2 —
  • R 41 represents a hydrogen atom or C 1-3 alkyl
  • W 1 represents a single bond, C 1-3 alkanediyl, or the formula —CH 2 CH 2 O—
  • the C 1-3 alkanediyl may be substituted with 1 to 2 substituents selected from the same or different from the substituent group ⁇ 1.
  • Substituent group ⁇ 1 is hydroxy, carbamoyl, C 1-3 alkyl (the C 1-3 alkyl may be substituted with one hydroxy or C 1-3 alkoxy), C 3-6 cycloalkyl, Aryl, heteroaryl (the heteroaryl may be substituted with one C 1-3 alkyl), C 1-3 alkoxycarbonyl, diC 1-3 alkylaminocarbonyl, and 4 containing a nitrogen atom
  • one of the carbon atoms of the C 1-3 alkanediyl may be replaced with C 3-6 cycloalkanediyl or a divalent 4- to 6-membered cyclic ether
  • R 42 represents a hydrogen atom or a C 1-3 alkyl
  • W 2 represents a single bond or C 1-3 alkanediyl
  • Ring B in the above formula ( ⁇ ) represents a 4- to 8-membered saturated
  • Ring A is C 3-8 cycloalkyl (the C 3-8 cycloalkyl may be substituted with one group selected from the substituent group ⁇ 2); Phenyl (the phenyl may be substituted with 1 to 2 groups selected from the same or different from the substituent group ⁇ 3); Dihydroindenyl, Azetidinyl [wherein the azetidinyl is arylsulfonyl, which may be substituted with one C 1-6 alkyl or haloC 1-6 alkyl]], Piperidinyl [wherein the piperidinyl is aryl C 1-3 alkyl, arylcarbonyl (the arylcarbonyl may be substituted with one C 1-6 alkoxy), arylsulfonyl (the arylsulfonyl is one C Optionally substituted with 1-6 alkyl or haloC 1-6 alkyl), and one group selected from the group
  • Pyrimidinyl The pyrimidinyl may be substituted with one group selected from the group consisting of a halogen atom and aryl (the aryl may be substituted with one C 1-6 alkoxy). ], Pyrazolyl (which may be substituted with one group selected from the group consisting of C 1-6 alkyl and phenyl), Thiazolyl (which may be substituted with one C 1-6 alkyl), Dihydropyridinyl [wherein the dihydropyridinyl is C 1-6 alkyl, C 3-8 cycloalkyl, aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1- 3 alkyl may be substituted with one halogen atom.), and may be substituted with one group selected identical to or different from the group consisting of oxo.
  • Benzofuranyl Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom, C 1-6 alkyl, the same or different), Chromanil, Dihydropyranopyridinyl, Dihydrofuropyridinyl, Tetrahydroquinolyl, Tetrahydroisoquinolyl, Dihydrobenzodioxinyl, It is to provide a compound or a pharmaceutically acceptable salt thereof according to (1), which is tetrahydrotriazoloazepinyl.
  • X is the formula CR 2 R 2 is a hydrogen atom or methoxy
  • Y is of the formula -CONR 41 -W 1-
  • R 41 is a hydrogen atom
  • W 1 is C 1-3 alkanediyl
  • Ring A is Phenyl (the phenyl may be substituted with 1 to 2 groups selected from the same or different from the substituent group ⁇ 3)
  • Dihydroindenyl, Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy).
  • heterocyclyl saturated C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (said aryloxy may be substituted with one halogen atom or C 1-6 alkyl ), Heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy may be substituted with 1 C 1-6 alkyl.), And 1 to 2 groups selected identically or differently from the group consisting of saturated heterocyclyl C 1-3 alkoxy May be substituted.
  • Dihydropyridinyl [wherein the dihydropyridinyl is C 1-6 alkyl, C 3-8 cycloalkyl, aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1- 3 alkyl may be substituted with one halogen atom), and may be substituted with one group selected identically or differently from the group consisting of oxo.
  • Benzofuranyl Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom, C 1-6 alkyl, the same or different), Chromanil, Dihydropyranopyridinyl, Dihydrofuropyridinyl, Tetrahydroquinolyl, Tetrahydroisoquinolyl, It is to provide a compound or a pharmaceutically acceptable salt thereof according to (1) or (2) which is dihydrobenzodioxinyl.
  • An object of the present invention is to provide an EPO production promoter containing the compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • (1) It is intended to provide a prophylactic or therapeutic agent for anemia containing the compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of the present invention has a PHD2 inhibitory action.
  • the present invention provides a compound represented by the above formula (I) having a PHD2 inhibitory action or a pharmaceutically acceptable salt thereof.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-3 alkyl refers to a linear or branched alkyl having 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, and isopropyl.
  • C 1-6 alkyl refers to a linear or branched alkyl having 1 to 6 carbon atoms.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like can be mentioned.
  • Halo C 1-6 alkyl refers to a linear or branched alkyl having 1 to 6 carbon atoms, substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 5, and a preferred halogen atom is a fluorine atom.
  • C 3-6 cycloalkyl refers to a cyclic alkyl having 3 to 6 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 3-8 cycloalkyl refers to cyclic alkyl having 3 to 8 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • C 3-8 cycloalkenyl refers to cyclic alkenyl having 3 to 8 carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Aryl refers to a monocyclic aromatic hydrocarbon group or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. For example, phenyl, naphthyl, anthryl and the like can be mentioned.
  • aryl a group partially saturated in aryl is also included in “aryl”.
  • the “partially saturated group in aryl” means a partially saturated condensed polycyclic group in a monocyclic aromatic hydrocarbon group or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms.
  • a cyclic heterocyclic group is shown. For example, dihydroindenyl and the like can be mentioned.
  • “Saturated heterocyclyl” is a 3 to 8 membered monocyclic group composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 7 carbon atoms.
  • a saturated heterocyclic group is shown. Examples include azetidinyl, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, piperazinyl, pyrazolidinyl, quinuclidinyl, morpholinyl, oxetanyl, oxolanyl, oxanyl and the like.
  • the 4- to 7-membered saturated heterocyclyl containing nitrogen atom refers to a 4- to 7-membered monocyclic saturated heterocyclic group containing one nitrogen atom in the ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and the like.
  • the 4- to 8-membered saturated heterocycle containing a nitrogen atom refers to a 4- to 8-membered monocyclic saturated heterocyclic group containing one nitrogen atom in the ring.
  • azetidine, pyrrolidine, piperidine and the like can be mentioned.
  • “4- to 8-membered saturated heterocyclyl containing nitrogen atom” refers to a 4- to 8-membered monocyclic saturated heterocyclic group containing one nitrogen atom in the ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, azocanyl, morpholinyl and the like.
  • Heteroaryl is a 5- to 7-membered monocyclic fragrance composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 6 carbon atoms.
  • a polycyclic aromatic heterocyclic group is shown.
  • a group partially saturated in heteroaryl is also included in “heteroaryl”.
  • the “partially saturated group in heteroaryl” refers to one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or 1 to 6 carbon atoms.
  • C 3-8 cycloalkyl C 1-3 alkyl refers to the above “C 1-3 alkyl” having one “C 3-8 cycloalkyl” as a substituent. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, and the like.
  • Aryl C 1-3 alkyl refers to the above “C 1-3 alkyl” having one “aryl” as a substituent.
  • aryl for example, benzyl, naphthylmethyl, phenethyl, 3-phenylpropyl and the like can be mentioned.
  • Heterocyclyl C 1-3 alkyl, saturated refers to “C 1-3 alkyl” above having one as a substituent “heterocyclyl saturation” of the. Examples include pyrrolidinylmethyl, piperidinylmethyl, tetrahydropyranylmethoxy, morpholinylmethyl, 2-pyrrolidinylethyl, 3-pyrrolidinylpropyl, and the like.
  • C 1-3 alkoxy refers to linear or branched alkoxy having 1 to 3 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy.
  • C 1-6 alkoxy represents linear or branched alkoxy having 1 to 6 carbon atoms.
  • Halo C 1-6 alkoxy refers to a straight or branched alkoxy having 1 to 6 carbon atoms, which is substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 5, and a preferred halogen atom is a fluorine atom.
  • C 3-8 cycloalkoxy refers to cyclic alkoxy having 3 to 8 carbon atoms. Examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
  • Aryloxy refers to a group in which the above “aryl” is bonded to an oxygen atom.
  • aryl For example, phenoxy, naphthyloxy, anthryloxy and the like can be mentioned.
  • Heteroaryloxy refers to a group in which the above “heteroaryl” is bonded to an oxygen atom. Examples thereof include pyridyloxy, pyrimidinyloxy, pyrazinyloxy, pyridazinyloxy, indolyloxy, benzopyrazolyloxy, benzotriazolyloxy, benzofuranyloxy, benzothiophenyloxy, quinolyloxy, isoquinolyloxy and the like.
  • C 3-8 cycloalkyl C 1-3 alkoxy refers to the above “C 1-3 alkoxy” having one “C 3-8 cycloalkyl” as a substituent. Examples include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclopropylethoxy, 3-cyclopropylpropoxy and the like.
  • saturated heterocyclyl C 1-3 alkoxy refers to the above “C 1-3 alkoxy” having one “saturated heterocyclyl” as a substituent.
  • saturated heterocyclyl examples include pyrrolidinylmethoxy, piperidinylmethoxy, tetrahydropyranylmethoxy, morpholinylmethoxy, 2-pyrrolidinylethoxy, 3-pyrrolidinylpropoxy and the like.
  • Arylcarbonyl refers to a group in which the above “aryl” and carbonyl are bonded. Examples include benzoyl and naphthylcarbonyl.
  • C 1-3 alkoxycarbonyl refers to a group in which the above “C 1-3 alkoxy” is bonded to carbonyl. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and isopropoxycarbonyl.
  • “Di-C 1-3 alkylaminocarbonyl” refers to a group in which amino and carbonyl having the same “C 1-3 alkyl” as the substituent are the same or different. Examples include dimethylaminocarbonyl, diethylaminocarbonyl, di (n-propyl) aminocarbonyl, di (isopropyl) aminocarbonyl, ethylmethylaminocarbonyl, methyl (n-propyl) aminocarbonyl and the like.
  • the 4 to 7-membered saturated heterocyclylcarbonyl containing nitrogen atom refers to a group in which the above “4 to 7-membered saturated heterocyclyl containing nitrogen atom” and carbonyl are bonded. Examples include azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and the like.
  • the “4- to 8-membered saturated heterocyclylcarbonyl containing nitrogen atom” refers to a group in which the above-mentioned “4- to 8-membered saturated heterocyclyl containing nitrogen atom” and carbonyl are bonded. Examples thereof include azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, azocanylcarbonyl, morpholinylcarbonyl and the like.
  • Arylsulfonyl refers to a group in which the above “aryl” and sulfonyl are bonded. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Oxo refers to a substituent ( ⁇ O) in which an oxygen atom is substituted via a double bond. Therefore, when oxo is substituted with a carbon atom, it forms a carbonyl together with the carbon atom, and when one oxo is substituted with one sulfur atom, it forms a sulfinyl together with the sulfur atom, When two oxos are substituted with one sulfur atom, they are combined with the sulfur atom to form a sulfonyl.
  • saturated heterocyclyl substituted with oxo when oxo is substituted with saturated heterocyclyl include 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, 3 -Oxopiperazinyl, 1,1-dioxidetetrahydrothiophenyl, 1-oxidetetrahydro-2H-thiopyranyl, 1,1-dioxidetetrahydro-2H-thiopyranyl, 1,1-dioxideisothiazolidinyl, 2- Examples thereof include oxo-1,3-oxazolidinyl, 6-oxo-1,1-dihydropyridazinyl and the like.
  • C 1-3 alkanediyl refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 1 to 3 carbon atoms.
  • methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl, propane-2,2- Examples include diyl.
  • C 3-6 cycloalkane-diyl refers to a divalent cyclic hydrocarbon group formed by removing one hydrogen atom from a cycloalkyl group having 3 to 6 carbon atoms. Examples include cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, and cyclohexane-1,1-diyl.
  • “Divalent 4- to 6-membered cyclic ether” refers to a divalent formed by removing one hydrogen atom from a 4- to 6-membered monocyclic saturated heterocyclic group containing one oxygen atom in the ring. A monocyclic saturated heterocyclic group is shown. And tetrahydropyran-4,4-diyl.
  • Preferred embodiments of the compound of the present invention are as follows.
  • R 1 is a hydrogen atom or C 1-3 alkyl, More preferred R 1 is a hydrogen atom or methyl, and further preferred R 1 is a hydrogen atom.
  • Preferred X is formula CR 2 or a nitrogen atom
  • preferred R 2 is a hydrogen atom, C 1-3 alkyl, or C 1-3 alkoxy
  • More preferred X is the formula CR 2
  • preferred R 2 is a hydrogen atom, methyl or methoxy
  • More preferred R 2 is a hydrogen atom or methoxy
  • Further preferred R 2 is a hydrogen atom
  • Preferred R 3 is a hydrogen atom or a halogen atom
  • More preferred R 3 is a hydrogen atom or a fluorine atom
  • More desirable R 3 is a hydrogen atom.
  • Preferred Y is a formula —CONR 41 —W 1 —, a formula —CONR 42 —W 2 —CO—, a structure represented by the following formula ( ⁇ ), or a formula —NHCOCH 2 —.
  • preferable R 41 is a hydrogen atom
  • preferable W 1 is a single bond or C 1-3 alkanediyl
  • preferable R 42 is a hydrogen atom
  • preferable W 2 is C 1-3 alkanediyl
  • a preferable ring B in the formula ( ⁇ ) is pyrrolidine-1,2-diyl
  • preferable W 3 is a single bond
  • More preferred Y is the formula -CONR 41 -W 1 - a and,
  • preferable R 41 is a hydrogen atom
  • preferable W 1 is C 1-3 alkanediyl
  • More preferred W 1 is methanediyl, ethane-1,1-diyl, or ethane-1,2-diyl, propane-2,2-diyl
  • More preferred W 1 is methanediyl.
  • Preferred embodiments of ring A are the following (1) to (6).
  • Preferred ring A is C 3-8 cycloalkyl (the C 3-8 cycloalkyl may be substituted with one group selected from the substituent group ⁇ 2); Aryl (the aryl may be substituted with 1 to 2 groups selected from the same or different from substituent group ⁇ 3); Saturated heterocyclyl (the saturated heterocyclyl may be substituted with one group selected from substituent group ⁇ 4), or heteroaryl (the heteroaryl is the same or different from substituent group ⁇ 5) And may be substituted with 1 to 2 groups).
  • a preferable group in the substituent group ⁇ 2 is C 1-6 alkyl, aryl, or a 4- to 8-membered saturated heterocyclylcarbonyl containing a nitrogen atom
  • a preferable group in the substituent group ⁇ 3 is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy or C 1-6 alkoxy), halo.
  • a preferable group in the substituent group ⁇ 4 are aryl C 1-3 alkyl, arylcarbonyl (the arylcarbonyl may be substituted with one C 1-6 alkoxy), arylsulfonyl (the aryl Sulfonyl may be substituted with one C 1-6 alkyl or haloC 1-6 alkyl), or oxo;
  • a preferable group in the substituent group ⁇ 5 is a halogen atom, C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 Cycloalkoxy, aryloxy, heteroaryloxy (the aryloxy and heteroaryloxy may be substituted with one C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, or a nitrogen atom 4 to 8 membered saturated heterocyclylcarbonyl,
  • preferable groups in the substituent group ⁇ 4 are aryl C
  • heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy, with one C 1-6 alkyl It may be conversion.) Saturated heterocyclyl C 1-3 alkoxy, or oxo.
  • More preferable ring A is C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted with one group selected from the group consisting of C 1-6 alkyl, aryl, and a 4- to 8-membered saturated heterocyclylcarbonyl containing nitrogen atom) May be)
  • Phenyl the phenyl is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy or C 1-6 alkoxy), halo C 1-6 alkyl, aryl , C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy, hetero
  • Aryloxy the aryloxy and heteroaryloxy may be substituted with 1 C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, and a 4 to 8 membered saturated nitrogen atom It may be
  • Pyrimidinyl The pyrimidinyl may be substituted with one group selected from the group consisting of a halogen atom and aryl (the aryl may be substituted with one C 1-6 alkoxy). ], Pyrazolyl (which may be substituted with one group selected from the group consisting of C 1-6 alkyl and phenyl), Thiazolyl (which may be substituted with one C 1-6 alkyl), Dihydropyridinyl [the dihydropyridinyl is aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1-3 alkyl is substituted with one halogen atom And may be substituted with one group selected from the group consisting of oxo and the same or different.
  • Benzofuranyl Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups identically selected from the group consisting of a halogen atom and C 1-6 alkyl), Chromanil, Dihydropyranopyridinyl, Dihydrofuropyridinyl, Tetrahydroquinolyl, Tetrahydroisoquinolyl, Dihydrobenzodioxinyl, Tetrahydrotriazoloazepinyl.
  • ring A is Phenyl [the phenyl is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy or C 1-6 alkoxy), halo C 1-6 alkyl, aryl , C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy, hetero Aryloxy (the aryloxy and heteroaryloxy may be substituted with 1 C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, and a 4 to 8 membered saturated nitrogen atom It may be substituted with 1 to 2 groups selected from the group consisting of heterocyclylcarbonyl, the same or different.
  • Dihydroindenyl Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy).
  • Dihydropyridinyl [wherein dihydropyridinyl is aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (wherein aryl C 1-3 alkyl is substituted with one halogen atom) And may be substituted with one group selected from the group consisting of oxo and the same or different.
  • Benzofuranyl Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups identically selected from the group consisting of a halogen atom and C 1-6 alkyl), Chromanil, Dihydropyranopyridinyl, Dihydrofuropyridinyl, Tetrahydroquinolyl, Tetrahydroisoquinolyl, Dihydrobenzodioxinyl.
  • Phenyl is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy or C 1-6 alkoxy), halo C 1-6 alkyl, aryl , C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy, hetero Aryloxy (the aryloxy and heteroaryloxy may be substituted with 1 C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, and a 4 to 8 membered saturated nitrogen atom It may be substituted with 1 to 2 groups selected from the group consisting of heterocyclylcarbonyl, the same or different. ] It is.
  • Another particularly preferred ring A is Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy).
  • Dihydropyridinyl [wherein dihydropyridinyl is aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (wherein aryl C 1-3 alkyl is substituted with one halogen atom) And may be substituted with one group selected from the group consisting of oxo and the same or different. ] It is.
  • Another particularly preferred ring A is Dihydroindenyl, Benzofuranyl, Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups identically selected from the group consisting of a halogen atom and C 1-6 alkyl), Chromanil, Dihydrobenzodioxinyl, Dihydropyranopyridinyl or dihydrofuropyridinyl.
  • One preferred embodiment of the compound of the present invention is a compound represented by the following formula (Ia) or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , W 1 , and ring A are: As described above.
  • R 1 is a hydrogen atom or methyl
  • R 2 is a hydrogen atom or methoxy
  • W 1 is methanediyl, ethane-1,1-diyl, or propane-2,2-diyl
  • Ring A is phenyl [the phenyl is the same or different from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl (the methyl may be substituted with one methoxy), and methoxy. May be substituted with 1 to 2 groups.
  • R 1 is a hydrogen atom or methyl
  • R 2 is a hydrogen atom or methoxy
  • W 1 is methanediyl, ethane-1,1-diyl, or propane-2,2-diyl
  • Ring A is phenyl (the phenyl may be substituted with one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, and methoxy)
  • pyridyl the pyridyl is trifluoro Selected from the group consisting of methyl, isopropoxy, cyclopropoxy (the cyclopropoxy may be substituted with one methyl), and phenyl (the phenyl may be substituted with one methoxy). May be substituted with one group. Or dihydrobenzofuranyl.
  • R 1 is hydrogen atom
  • R 2 is a hydrogen atom
  • W 1 is methanediyl or ethane-1,1-diyl
  • ring A is phenyl (the phenyl may be substituted with one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, and methoxy) or dihydrobenzofuranyl. is there.
  • R 1 is hydrogen atom, R 2 is methoxy; W 1 is ethane-1,1-diyl or propane-2,2-diyl; Ring A is phenyl (the phenyl may be substituted with one fluorine atom) or pyridyl [the pyridyl is one phenyl (the phenyl may be substituted with one methoxy. ) May be substituted. ] This is the case.
  • Another preferred embodiment of the compound of the present invention is a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof.
  • R 1 , W 1 , and ring A are: As described above.
  • R 1 is a hydrogen atom or methyl
  • W 1 is methanediyl, ethane-1,1-diyl, or propane-2,2-diyl
  • Ring A is phenyl (the phenyl may be substituted with one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, and methoxy), pyridyl [the pyridyl is trifluoro Selected from the group consisting of methyl, isopropoxy, cyclopropoxy (the cyclopropoxy may be substituted with one methyl), and phenyl (the phenyl may be substituted with one methoxy). May be substituted with one group. Or dihydrobenzofuranyl.
  • R 1 is a hydrogen atom
  • W 1 is ethane-1,1-diyl
  • Ring A is phenyl (the phenyl may be substituted with 1 methoxy) This is the case.
  • the compound of the present invention is a compound having a heteroaryl substituted with triazolyl, and the compound of the present invention may be a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compound of the present invention” as appropriate).
  • the compounds of the present invention include tautomers.
  • tautomers compounds represented by the above formula (I) and tautomers (I ′) and (I ′′) thereof are shown below.
  • Examples of pharmaceutically acceptable salts include hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, nitrates, mineral salts such as methanesulfonate, ethanesulfone, and the like.
  • Acid salt such as trifluoromethane sulfonate, oxalate, tartrate, citrate, maleate, succinate, acetate, tri Acid addition salts such as organic acid salts such as fluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, malate, glycine salt, lysine salt, arginine salt, ornithine salt, Amino acid salts such as glutamate and aspartate, or inorganic or ammonium salts such as lithium, sodium, potassium, calcium and magnesium salts; Triethylamine salts, diisopropylamine salts, salts with organic bases such as cyclohexylamine salts.
  • the salt includes a hydrated salt.
  • the compound of the present invention may have an asymmetric center, in which case various optical isomers exist.
  • the compounds of the present invention may exist as separate optically active forms of (R) and (S) and as racemates or (RS) mixtures.
  • diastereomers by respective optical isomerism also exist.
  • the compounds of the present invention also include mixtures containing all these types in any proportion.
  • diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can.
  • the compound of the present invention may have geometric isomers such as cis isomer and trans isomer.
  • the compound of the present invention has tautomerism, and various tautomers exist.
  • the compounds of the present invention include those isomers and mixtures containing these isomers in any proportion.
  • PHD2 prolyl hydroxylase domain-2
  • PHD2 is a protein belonging to the prolyl hydroxylase family.
  • PHD2 is an enzyme having hypoxia-inducible factor (HIF) prolyl hydroxylase activity, and in particular under normal oxygen conditions, HIF-1 ⁇ , HIF-2 ⁇ , HIF-3 ⁇ molecules (hereinafter collectively referred to as HIF- ⁇ molecules).
  • HIF- ⁇ molecules Hypoxia-inducible factor
  • HIF- ⁇ factor is a transcription factor for erythropoietin, a hematopoietic factor.
  • PHD2 promotes decomposition by hydroxylating HIF and suppresses excessive erythropoietin production.
  • the compound of the present invention has an excellent PHD2 inhibitory action as described above. Therefore, inhibition of PHD2 prevents hydroxylation of specific proline residues in the HIF- ⁇ molecule, contributing to stabilization of the HIF- ⁇ molecule. Thereby, production of EPO in the body can be promoted, and anemia or anemia-related disease can be prevented or treated.
  • the compound of the present invention can be used as an active ingredient of a PHD2 inhibitor, an EPO production promoter, or an anemia or an anemia-related disease prevention or treatment agent.
  • anemia includes “renal anemia” that develops due to a decrease in EPO production ability due to decreased kidney function, “iron deficiency anemia” due to iron metabolism failure, and other types caused by specific causes. Anemia is included.
  • Diseases related to anemia include chronic kidney disease, heart failure and the like.
  • the compound of the present invention can be expected to improve ischemic disease and inflammatory disease by inhibiting PHD2 and promoting stabilization of HIF- ⁇ .
  • organ protective action by the expressed EPO can be expected.
  • the organs mentioned here include the kidney, pancreas, brain and the like.
  • the compound of the present invention can be administered alone or with a pharmaceutically or pharmaceutically acceptable additive.
  • the medicament of the present invention can be produced by blending the compound of the present invention with a pharmaceutically acceptable additive.
  • a pharmaceutically acceptable additive Specifically, conventional excipients or diluents, and commonly used binders, disintegrating agents, lubricants, coating agents, dragees, pH adjusting agents, solubilizers, or aqueous or non-aqueous It can be prepared into tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, etc. by adding conventional solvents and the like.
  • the additive examples include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, Methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil cocoa butter, ethylene glycol, low viscosity hydroxypropylcellulose (HPC-L) , Microcrystalline cellulose, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), etc. It is what can be mentioned.
  • the compound of the present invention can be formulated by forming an inclusion compound with ⁇ , ⁇ , ⁇ -cyclodextrin, methylated cyclodextrin or the like.
  • Formulation Example 1 A granule containing the following ingredients is produced.
  • Component A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, lactose, corn starch, HPC-L.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and lactose are passed through a sieve. Pass cornstarch through sieve. These are mixed with a mixer. An HPC-L aqueous solution is added to the mixed powder, kneaded, granulated (extruded granulation), and dried. The obtained dried granules are sieved with a vibration sieve to obtain granules.
  • Formulation Example 2 A powder for capsule filling containing the following components is produced.
  • Component Compound represented by formula (I) or a pharmaceutically acceptable salt thereof, lactose, corn starch, magnesium stearate.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and lactose are passed through a sieve. Pass cornstarch through sieve. These and magnesium stearate are mixed in a mixer to obtain a powder. The resulting powder can be filled into capsules.
  • Formulation Example 3 A capsule filling granule containing the following ingredients is produced.
  • Component A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, lactose, corn starch, HPC-L.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and lactose are passed through a sieve. Pass cornstarch through sieve. These are mixed with a mixer. An HPC-L aqueous solution is added to the mixed powder, kneaded, granulated, and dried. The obtained dried granule is sieved with a vibration sieve and sized to obtain a granule. The resulting granules can be filled into capsules.
  • Formulation Example 4 A tablet containing the following ingredients is produced.
  • Component Compound represented by formula (I) or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, magnesium stearate, CMC-Na.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, and CMC-Na are passed through a sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a tablet.
  • the compound of the present invention When the compound of the present invention is used as a PHD2 inhibitor or the like, the compound of the present invention may be administered orally or parenterally as it is. Moreover, you may administer orally or parenterally as an agent which contains this invention compound as an active ingredient. Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like.
  • the dose is preferably 1 mg to 200 mg, and it is desirable to administer this amount once to three times a day or once every two to three days.
  • the present compound was confirmed to have a PHD2 inhibitory action.
  • the administration of the preferred embodiments of the compounds represented by the formulas (Ia) and (Ib) increased erythropoietin production in normal mice and rats.
  • the method for confirming the increase in production of erythropoietin can be performed according to a known method.
  • Blood, 1989, 74, 645-651 discloses a method for measuring the concentration of erythropoietin in blood.
  • the compounds of the present invention there are compounds having desirable properties as pharmaceuticals.
  • excessive production of erythropoietin adversely affects the body, such as secondary polycythemia, but has the property of avoiding excessive production of erythropoietin.
  • the PHD2 inhibitory action of the compound of the present invention can be evaluated according to a known method such as the method described in Test Examples of the present specification.
  • the production method of the compound according to the present invention will be described in detail, but it is not particularly limited to those exemplified.
  • the solvent used for the reaction is not particularly limited as long as it does not inhibit each reaction.
  • Compound (I) can be produced by a method known per se, for example, the production methods 1 to 4 shown below or a method analogous thereto.
  • the raw material compound may be used as a salt, and examples of the salt include the above-mentioned “pharmaceutically acceptable salts”.
  • the target compound can also be obtained as a salt, and examples of the salt include the above-mentioned “pharmaceutically acceptable salts”.
  • the obtained target compound can be used in the next step without purification.
  • the compound (I-10) belonging to the compound (I) of the present invention can be produced, for example, by the following production method 1 or a method analogous thereto.
  • R 1 , R 2 , R 3 , X, Y is represented by the formula -CONR 41 -W 1- , the formula -CONR 42 -W 2 -CO-, the formula ( ⁇ ) Wherein R 41 , W 1 , R 42 , W 2 and ⁇ are as defined above), ring A, ring B and W 3 are as defined above, and R 1 ′ is a hydrogen atom or C 1-3 alkyl (wherein the C 1-3 alkyl may be substituted with hydroxy. In some cases, the hydroxy may be a common protecting group for alcohol, such as Protective Groups in Organic Synthesis (3rd edition, 1999, G. M. W uts, T . W.
  • Greene ed like group as described in, specifically, benzyl, may be protected by 4-methoxybenzyl and the like.
  • P 1 is carboxy General protecting groups of, for example, Pro ective Groups i n Organic Synthesis (third edition, 1999, G. M. W u t s, T. W. Greene ed) represents a group described in such, in particular C 1-6 alkyl, benzyl, 4- Methoxybenzyl, 2- (trimethylsilyl) ethyl and the like are shown.
  • P 2 represents a protecting group for triazole, such as tetrahydropyranyl, triphenylmethyl and the like.
  • Step 1-1 In this step, compound (I-1) is reacted with an alkoxide, then compound (I-2) is added to construct a 1,2,4-triazole ring, and compound (I-3) is produced.
  • alkoxide usually include sodium methoxide, sodium ethoxide and the like.
  • Solvents used in the reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, and aromatic hydrocarbon solvents such as toluene and xylene. Is mentioned.
  • the compound (I-3) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 1-2 This step is by protecting the 1,2,4-triazole ring of compound (I-3) with a suitable protecting group P 2, which is a method for producing a compound (I-4).
  • protecting group P 2 is tetrahydropyranyl, triphenylmethyl, and the like.
  • the protecting group P 2 when the protecting group P 2 is tetrahydropyranyl, it can be obtained by reacting compound (I-3) with 3,4-dihydro-2H-pyran in the presence of an acid catalyst.
  • the acid used in the reaction include p-toluenesulfonic acid monohydrate and methanesulfonic acid.
  • Solvents used in the reaction are ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, ethyl acetate, N, N-dimethylformamide.
  • aprotic polar solvents such as When the protecting group P 2 is triphenylmethyl, it can be obtained by reacting compound (I-3) with triphenylmethyl chloride or the like in the presence of a base.
  • the base used in the reaction include triethylamine, N, N-diisopropylethylamine, sodium hydride and the like.
  • Solvents used in the reaction include ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, N, N-dimethylformamide, N, Examples include aprotic polar solvents such as N-dimethylacetamide.
  • the compound (I-4) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound of the present invention includes tautomers, and the compound (I-4) protected with the protecting group P 2 may contain isomers.
  • isomers compound (I-4) and isomers (I-4 ′) and (I-4 ′′) are shown below.
  • Step 1-3 This step is a method for producing compound (I-5) by deprotecting the carboxy-protecting group P 1 of compound (I-4).
  • This reaction can be performed by, for example, the method described in Protective Groups in Organic Synthesis (3rd edition, 1999, edited by GM Wuts, edited by TW Greene), or the like.
  • protecting group P 1 is tert-butyl, 4-methoxybenzyl or trimethylsilyl, ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, toluene, xylene and the like
  • Compound (I-5) can be produced using a mineral acid such as hydrochloric acid or an organic acid such as acetic acid or trifluoroacetic acid in the above aromatic hydrocarbon solvent.
  • the protecting group P 1 is benzyl or 4-methoxybenzyl
  • alcohol solvents such as methanol and ethanol
  • ether solvents such as tetrahydrofuran and dioxane
  • halogenated hydrocarbon solvents such as methylene chloride and chloroform, toluene, xylene and the like
  • Compound (I-5) can also be produced by hydrogenolysis in the presence of a catalyst such as palladium-carbon in the above aromatic hydrocarbon solvent.
  • protecting group P 1 is 2- (trimethylsilyl) ethyl, trimethylsilyl, tert-butyldimethylsilyl, compound (I-5) can also be produced by treatment with potassium fluoride, tetrabutylammonium fluoride or the like. .
  • the compound (I-5) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (I-9) is produced by a condensation reaction of compound (I-5) with compound (I-6), compound (I-7), or compound (I-8) using a condensing agent. It is a method to do.
  • Solvents used in the reaction are ether solvents such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, Examples include aprotic polar solvents such as ethyl acetate, acetonitrile, and N, N-dimethylformamide.
  • a base can be used as an additive.
  • the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine and the like.
  • the condensing agent used in the reaction is O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-1- Ile-N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide ( DCC), 1,1′-carbonylbis (1H-imidazole) (CDI), (1H-benzotriazol-1-yloxy) (tripyrrolidin-1-yl) phosphonium hexafluorophosphate (PyBOP), 4- ( 4,6-Dimethyl-1,3,5-soriadin-2-yl) -4-methylmorpholinium chloride (DMT-MM), etc.
  • the compound (I-9) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 1-5 In this step, by deprotecting the protective group P 2 of the triazole compound (I-9), a method for producing a compound (I-10).
  • a method for producing a compound (I-10) for example, when the protecting group P 2 is tetrahydropyranyl, an alcohol solvent such as methanol or ethanol, a mixed solvent of any ratio of these with water, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, toluene Compound (I-10) can be produced by using a mineral acid such as hydrochloric acid or an organic acid such as acetic acid or trifluoroacetic acid in an aromatic hydrocarbon solvent such as xylene.
  • the protecting group P 2 is triphenylmethyl
  • the compound (I-10) can also be produced by a method analogous to the above.
  • the compound (I-10) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Compound (II-7) belonging to compound (I) of the present invention can be produced, for example, by the following production method 2 or a method analogous thereto.
  • R 1 , R 2 , R 3 , X, P 2 and ring A are as defined above.
  • P 3 represents C 1-6 alkyl, benzyl, 4-methoxybenzyl.
  • Z represents a chlorine atom, a bromine atom, or hydroxy.
  • Step 2-1 This step is a method for producing a compound (II-3) by reacting an isocyanate produced by the Curtius rearrangement of the compound (II-1) with the compound (II-2).
  • Examples of the azidating agent used in the Curtius rearrangement include diphenyl phosphate azide and bis (p-nitrophenyl) phosphate azide.
  • Examples of the solvent used in the reaction include aromatic hydrocarbon solvents such as toluene and xylene, and halogenated hydrocarbon solvents such as 1,2-dichloroethane and chloroform.
  • a base can be used as an additive.
  • the base include triethylamine, N, N-diisopropylethylamine and the like.
  • the compound (II-3) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 2-2 This step is a method for producing compound (II-4) from compound (II-3) which is carbamate.
  • P 3 is benzyl or 4-methoxybenzyl
  • alcohol solvents such as methanol and ethanol
  • ether solvents such as tetrahydrofuran and dioxane
  • halogenated hydrocarbon solvents such as methylene chloride and chloroform, toluene, xylene and the like
  • Compound (II-4) can be produced by hydrogenolysis in the presence of a catalyst such as palladium-carbon in the above aromatic hydrocarbon solvent.
  • ether solvents such as tetrahydrofuran and dioxane
  • aprotic polar solvents such as ethyl acetate
  • halogenated hydrocarbon solvents such as methylene chloride and chloroform
  • aromatics such as toluene and xylene
  • the compound (II-4) can also be produced using a mineral acid such as hydrochloric acid or hydrobromic acid or an organic acid such as acetic acid or trifluoroacetic acid in an aromatic hydrocarbon solvent.
  • the compound (II-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 2-3 This step is a method for producing compound (II-6) by a condensation reaction of compound (II-4) and compound (II-5).
  • Z is a chlorine atom or a bromine atom
  • ether solvents such as tetrahydrofuran and dioxane
  • aprotic polar solvents such as ethyl acetate
  • halogenated hydrocarbon solvents such as methylene chloride and chloroform
  • aromatics such as toluene and xylene
  • Compound (II-6) can be produced using a base such as triethylamine or pyridine in an aromatic hydrocarbon solvent. These reactions can usually be performed at 0 ° C. to room temperature.
  • Z is hydroxy
  • compound (II-6) can be produced according to the method described in Step 1-4 of Production Method 1.
  • the compound (II-6) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 2-4 In this step, by deprotecting the protective group P 2 of the triazole compound (II-6), a method for producing a compound (II-7).
  • This reaction can be carried out according to the method described in Process 1-5, Step 1-5.
  • the compound (II-7) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (III-5) belonging to the compound (I) of the present invention can be produced, for example, by the following production method 3 or a method analogous thereto.
  • LG means a leaving group, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom.
  • Step 3-1 This step is a method for producing compound (III-2) by a reduction reaction of compound (III-1) with a metal hydride.
  • the reducing agent used in the reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, diborane and the like.
  • the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and aromatic hydrocarbon solvents such as toluene and xylene.
  • the compound (III-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 3-2 This step is a method for producing compound (III-4) by reacting compound (III-2) with compound (III-3) in the presence of a base.
  • the base used in the reaction include alkali metal hydrides such as sodium hydride.
  • Solvents used in the reaction are ether solvents such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as toluene and xylene, aprotic such as acetonitrile and N, N-dimethylformamide. Examples include polar solvents.
  • the compound (III-4) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 3-3 In this step, by deprotecting the compound (III-4) protecting group P 2 of the triazole, which is a method for producing a compound (III-5).
  • This reaction can be carried out according to the method described in Process 1-5, Step 1-5.
  • the compound (III-5) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (IV-5) belonging to the compound (I) of the present invention can be produced, for example, by the following production method 4 or a method analogous thereto.
  • Step 4-1 This step is a method for producing compound (IV-1) by reacting compound (III-2) obtained in step 3-1 of production method 3 with an azidating agent.
  • the azidating agent used in the reaction include diphenyl phosphate azide, bis (p-nitrophenyl) phosphate azide, and the like.
  • a base can be used as an additive.
  • An example of a base is 1,8-diazabicyclo [5.4.0] undec-7-ene.
  • diethyl azodicarboxylate, triphenylphosphine, or the like is used as an additive.
  • Solvents used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as toluene and xylene, aprotic polarities such as N, N-dimethylformamide and N, N-dimethylacetamide. A solvent etc. are mentioned.
  • the compound (IV-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 4-2 This step is a method for producing compound (IV-2) by carrying out a reduction reaction using compound (IV-1).
  • the reducing agent used in the reaction include phosphorus compounds such as trimethylphosphine, tributylphosphine, and triphenylphosphine, and metal hydrides such as lithium aluminum hydride and sodium borohydride.
  • the solvent used in the reaction include a mixed solvent of an ether solvent such as diethyl ether, tetrahydrofuran and dioxane and water in an arbitrary ratio when a phosphorus compound is used as the reducing agent.
  • ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as toluene and xylene, and the like can be given.
  • the compound (IV-2) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 4-3 This step is a method for producing compound (IV-4) by a condensation reaction between compound (IV-2) and compound (IV-3).
  • This reaction can be carried out according to the method described in Step 2-3 of Production Method 2.
  • the compound (IV-4) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 4-4 In this step, by deprotecting the protective group P 2 of the triazole compound (IV-4), a method for producing a compound (IV-5).
  • This reaction can be carried out according to the method described in Process 1-5, Step 1-5.
  • the compound (IV-5) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • MS mass spectrum was measured with the following apparatus.
  • PlatformMLC Waters
  • LCMS-2010EV Shiadzu
  • LCMS-IT-TOF Shiadzu
  • GCT Micromass
  • Agilent 6130 Alignment
  • Agilent 6150 Alignment
  • LCQ Deca XP ThermoFisher Scientific
  • an ESI (Electrospray Ionization) method, an EI (Electron Ionization) method, or an ESI and APCI (Atmospheric Pressure Chemical Ionization) method and a dual method using an atmospheric pressure chemical ionization method are used. It was. The data described the actual value (found). Usually, a molecular ion peak is observed, but in the case of a compound having hydroxy (—OH), a peak from which H 2 O is eliminated may be observed as a fragment peak. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
  • the microwave reactor used was Biotage Initiator.
  • the compound name was named by ACD / Name (ACD / Labs 2012, Advanced Chemistry Development Inc.).
  • the crude crystals were recrystallized from ethyl acetate (500 mL), combined with the fraction recovered from the filtrate, and suspended in diethyl ether. The obtained crystals were collected by filtration, dried under reduced pressure, and methyl 6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3. The carboxylate was obtained as a light brown solid (83.3 g).
  • Reference Examples 8-2 to 8-16 below show the corresponding commercially available halogenated pyridinecarbonitrile, hydroxypyridinecarbonitrile, or hydroxybenzonitrile and the corresponding commercially available alcohol, alkyl halide, aryl halide or hydroxypyridine. And synthesized according to the method described in Reference Example 8-1 (1) to (2) or a method analogous thereto. Their structures, NMR data, and MS data are shown in Table 1-1 to Table 1-2.
  • the precipitated gummy solid was filtered off and neutralized by adding 28% aqueous ammonia solution to the filtrate. Ethanol, methanol, and ethyl acetate were added to the precipitate and stirred at 60 ° C. for a while. The reaction mixture was returned to room temperature and collected by filtration to obtain amino (4-chlorophenyl) acetic acid as a crude product (pale yellow solid, 1.55 g), which was used in the next reaction as the crude product.
  • Sodium hydride (60% mineral oil dispersion, 53.0 mg) was added to a tetrahydrofuran solution (40.0 mL) of the compound (300 mg) obtained in Reference Example 14 (1) under ice cooling. After stirring at the same temperature for 10 minutes, methyl iodide (82.0 ⁇ L) was added. After stirring at the same temperature for 1 hour and at room temperature for 4 hours, water and ethyl acetate were added. Dilute hydrochloric acid was added to the resulting emulsion to separate the organic layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were passed through a phase separator and concentrated under reduced pressure.
  • Benzyl bromide (107 ⁇ L) was added to an acetonitrile suspension (7.50 mL) of the compound (200 mg) obtained above (2) and potassium carbonate (370 mg), and the mixture was stirred at room temperature for 3 days. Chloroform was added to the reaction solution to dissolve the precipitate. Anhydrous magnesium sulfate was added to the resulting solution and stirred, and the insoluble material was filtered off.
  • Reference Examples 16-2 to 16-3 were prepared by using Reference Example 16-1 (3) using the compound obtained in Reference Example 16-1 (2) and the corresponding commercially available aralkyl halide or alkyl halide. ) To (4) or a method analogous thereto. Their structures, NMR data, and MS data are shown in Reference Example Table 3-1.
  • Triethylamine (2.24 mL) was added to a chloroform suspension (32.0 mL) of the compound (690 mg) obtained in (3) above, and then trifluoroacetic anhydride (1.34 mL) was added dropwise under ice cooling. did. After stirring at room temperature for 2 hours, water (32.0 mL) was added under ice cooling. After stirring for a while at room temperature, the two layers were separated. The aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure.
  • 1,4-Dibromo-2-fluorobenzene (8.00 g) was charged with ethylene glycol (40.8 mL), N-methyl-2-pyrrolidone (4.08 mL), and potassium tert-butoxide (12.4 g). In addition, the mixture was stirred at 100 ° C. for 10 hours. After cooling to room temperature, water (16.0 mL) was added to the reaction solution and stirred for 1 hour. Insoluble matters were filtered off, water (140 mL) was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes and under ice-cooling for 30 minutes. The precipitate was collected by filtration and washed with water.
  • Phosphorus tribromide (1.14 mL) was added to a toluene solution (53.0 mL) of the compound (7.88 g) obtained in (1) above, and the mixture was stirred at 90 ° C. for 2 hours. After cooling to room temperature, water (26.0 mL) was added in small portions. After stirring at 90 ° C. for 3 hours, the mixture was cooled to room temperature, 1 mol / L aqueous sodium hydroxide solution (47.0 mL) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. The two layers were separated and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure.
  • Trichloroacetic anhydride (1.90 mL) was added to a chloroform solution (10.0 mL) of the compound (500 mg) obtained in (1) above under ice-cooling. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (10.0 mL), sodium methoxide (about 25%, methanol solution, 200 mg) was added, and the mixture was stirred at room temperature for 1 hr.
  • Reference Examples 29-2 to 29-4 were synthesized by the method described in Reference Example 29-1 (1) to (2) using the compound obtained in Reference Example 28 and a commercially available corresponding amine. Their structures, NMR data, and MS data are shown in Table 4-1.
  • Reference Examples 29-1 to 29-4 have the following human PHD2 inhibitory activity in Test Example 1 or 2 described later.
  • Reference Example 29-1 Test Example 1 inhibition rate, 97% (at 1 ⁇ M) Reference Example 29-2 Test Example 1, inhibition rate, 85% (at 1 ⁇ M) Reference Example 29-3 Test Example 1, inhibition rate, 96% (at 1 ⁇ M) Reference Example 29-4 Test Example 1, inhibition rate, 105% (at 1 ⁇ M) Test example 2, inhibition rate, 89% (at 1 ⁇ M)
  • Test Example 2 was carried out with a 50 ng / well human PHD2 enzyme solution.
  • the title compound was prepared in the same manner as in Reference Examples 1 (1) to (3) using methyl 6-cyanopyridine-3-carboxylate (3.25 g) and acetohydrazide (1.63 g) instead of formohydrazide. Obtained as a crude product (2.91 g of colorless solid). The title compound was used in the next reaction as a crude product.
  • Lithium aluminum hydride (2.36 g) was added to a tetrahydrofuran suspension (12.0 mL) of the compound (1.17 g) obtained in Reference Example 1 (2) under ice cooling, and the mixture was stirred at the same temperature for 2 hours. . Under ice cooling, sodium sulfate decahydrate (6.50 g) was added little by little to the reaction solution, and the mixture was stirred for 15 minutes. After warming to room temperature and stirring for 1.5 hours, the insoluble material was filtered off by Celai® (registered trademark) filtration.
  • Reference Examples 37-2 to 37-3 below show 1- (2,4-dimethoxyphenyl) methanamine and a commercially available corresponding aldehyde
  • Reference Examples 37-4 to 37-5 show 1- (2,4-
  • the compound was synthesized by the method described in Reference Example 37-1 using dimethoxyphenyl) methanamine and the corresponding aldehyde synthesized by a known method (see WO 2014/021281, Reference Example 13-3 and Reference Example 13-15). Their structures, NMR data, and MS data are shown in Table 5-1.
  • Dess-Martin periodinane (864 mg) was added to a chloroform solution (10.0 mL) of the compound (399 mg) obtained in (3) above under ice cooling, and the mixture was warmed to room temperature and stirred for 1.5 hours. did.
  • An aqueous sodium thiosulfate solution was added to the reaction solution and stirred for 30 minutes, and then the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure.
  • 1-Benzyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde was obtained as a crude product (444 mg of brown oil).
  • Reference Examples 39-2 to 39-3 below were prepared using Reference Examples 39 (1) to 39-3 using commercially available corresponding 2-bromo-1,3-difluorobenzene and 1-bromo-2,3-difluorobenzene. It was synthesized by the method described in (3) or a method analogous thereto. Their structures, NMR data, and MS data are shown in Table 6-1.
  • Example 1-4 uses the compound obtained in Reference Example 1 and the corresponding amine synthesized by a known method (see WO2011 / 002624, Example 1, 1-D).
  • Examples 1 (1) to (2) It was synthesized by the method described in 1.
  • Examples 1-51 and 1-52 were synthesized by the method described in Example 1 (1) using the compound obtained in Reference Example 2 and a commercially available corresponding amine. Their structures, NMR data, and MS data are shown in Tables 7-1 to 7-25.
  • Example 2-2 the compound obtained in Reference Example 23 and the corresponding amine synthesized by a known method (see WO2011 / 002624, Example 1, 1-D) are used as raw materials, and Examples 2-3 and 2 -10 was synthesized by the method described in Example 2-1 or a method analogous thereto, using the compound obtained in Reference Example 23 and a commercially available corresponding amine as raw materials.
  • Their structures, NMR data, and MS data are shown in Table 8-1.
  • Example 1-1 (1) to (2) Using the compound (200 mg) obtained in Reference Example 26 and (2,3-dihydrobenzofuran-5-yl) methanamine (170 mg), the same procedure as in Example 1-1 (1) to (2) was used. The title compound was obtained as a colorless solid (119 mg).
  • Example 1-1 (1) to (2) Using the compound (254 mg) obtained in Reference Example 27 and (2,3-dihydrobenzofuran-5-yl) methanamine (218 mg), the same procedure as in Example 1-1 (1) to (2) was used. The title compound was obtained as a colorless solid (42.0 mg).
  • Example 1-1 (1) to (2) Using the compound obtained in Reference Example 27 and [6- (propan-2-yloxy) pyridin-3-yl] methanamine (273 mg), the same procedure as in Example 1-1 (1) to (2) was performed. To give the title compound as a colorless solid (87.0 mg).
  • Example 8-1 N-[(1S) -1- (4-methoxyphenyl) ethyl] -6- (3-methyl-1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
  • Examples 8-2 to 8-4 were synthesized by the method described in Example 1-1 (1) to (2) using the compound obtained in Reference Example 31 and a commercially available corresponding amine. Their structures, NMR data, and MS data are shown in Table 9-1.
  • Example 9-1 4-Methoxy-N-[(1S) -1- (4-methoxyphenyl) ethyl] -6- (3-methyl-1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
  • Examples 9-2 to 9-3 were synthesized by the method according to Example 2-1 using the compound obtained in Reference Example 32 and a commercially available corresponding amine. Their structures, NMR data, and MS data are shown in Table 10-1.
  • Example 13-1 4-Fluoro-N- ⁇ [6- (1H-1,2,4-triazol-5-yl) pyridin-3-yl] methyl ⁇ benzamide
  • Examples 13-2 to 13-3 were synthesized by the method according to Example 11 using the compound obtained in Reference Example 36 and a commercially available corresponding carboxylic acid. Their structures, NMR data, and MS data are shown in Table 11-1.
  • Examples 14-2 to 14-11 were prepared using the compound obtained in Reference Example 1 and the compounds obtained in Reference Examples 37-2 to 5, 38, 39-1 to 3, and 40-1 to 2 as raw materials. This was synthesized by the method described in Example 14-1. Their structures, NMR data, and MS data are shown in Tables 12-1 to 12-2.
  • a 1 mol / L aqueous sodium hydroxide solution (3.00 mL) was added to a methanol solution (18.0 mL) of the compound (700 mg) obtained in (1) above and refluxed for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (10.0 mL), and 1,2,3,4-tetrahydroisoquinoline (800 mg), 1-hydroxybenzotriazole monohydrate (460 mg), and 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (576 mg) was added and stirred at room temperature for 2 hours.
  • Test example 1 Expression and preparation of human PHD2 Human PHD2 was expressed in insect cells (HighFive cells).
  • the human PHD2 registration sequence (NM — 022051) was introduced into the pFastBac1 vector (Invitrogen), and the sequence was confirmed.
  • the vector was introduced into Sf9 insect cells (Invitrogen) to obtain human PHD2 baculovirus.
  • HighFive insect cells (Invitrogen) were infected with this recombinant virus, and after culturing at 27 ° C. for 72 hours, a cell lysis solution containing various protease inhibitors was added and suspended.
  • the disrupted suspension was centrifuged at 100,000 ⁇ g for 30 minutes at 4 ° C., and the supernatant was recovered to obtain a cell lysate.
  • Western Plot analysis confirmed the expression of human PHD2 protein only in PHD2 baculovirus-infected cell lysates.
  • Human PHD2 enzyme activity was measured using a 19-residue partial peptide based on the sequence of HIF-1 ⁇ as a substrate. Specifically, a conversion reaction from 2-oxoglutarate to succinic acid that occurs simultaneously with the PHD2 enzyme hydroxylating a proline residue contained in a peptide was used. That is, [ 14 C] -2-oxoglutarate is added to the reaction system to start the enzymatic reaction, and the remaining [ 14 C] -2-oxoglutarate is combined with 2,4-dinitrophenylhydrate (DNPH) to precipitate The product was removed by a filter. Thereafter, the radiation count of the produced [ 14 C] -succinic acid was measured.
  • DNPH 2,4-dinitrophenylhydrate
  • the enzyme and substrate were diluted with 20 mM Tris-HCl buffer (pH 7.5) containing 6.67 mM KCl, 2 mM MgCl 2 , 13.3 ⁇ M iron sulfate, 2.67 mM ascorbic acid, 1.33 mM DTT, and the test compound was Diluted with dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • test compound HIF-1 ⁇ peptide and [ 14 C] -2-oxoglutarate were previously added to a 96-well plate, and the reaction was started by adding human PHD2 enzyme solution (4 ⁇ g / well). After incubation at 37 ° C. for 15 minutes, a stop solution containing DNPH was added and allowed to stand at room temperature for 30 minutes. Thereafter, an excessive amount of non-radiolabeled 2-oxoglutarate was added and allowed to stand at room temperature for 60 minutes. The produced precipitate was removed by a filter, and the radioactivity count of [ 14 C] -succinic acid was quantified (in microbeta). The radiocount of each well was measured, and the human PHD2 inhibitory activity of the test compound was calculated based on the values of the group without the substrate and the group without the test substance.
  • Test example 2 (1) Expression and preparation of human PHD2 Human PHD2 was expressed in human cells (293FT cells).
  • the human PHD2 registration sequence (NM — 022051) was introduced into pcDNA3.1 / Hygro (+) vector (Invitrogen), and the sequence was confirmed.
  • the vector was introduced into 293FT cells (Invitrogen), cultured at 37 ° C. in the presence of 5% carbon dioxide gas for 48 hours, and then added with a cell lysis solution containing various protease inhibitors and suspended. The disrupted suspension was centrifuged at 4 ° C. and 100,000 ⁇ g for 30 minutes, and the supernatant was recovered to obtain a cell lysate.
  • the expression of human PHD2 protein was confirmed in the cell lysate by Western blot analysis.
  • the human PHD2 enzyme activity is determined by using FP (Fluorescence Polarization) for hydroxylation of proline residues contained in peptides using a 19-residue partial peptide based on the sequence of HIF-1 ⁇ as a substrate. ) Method.
  • the enzyme and substrate were diluted with 50 mM Tris-HCl buffer (pH 7.5) containing 12.5 mM KCl, 3.75 mM MgCl 2 , 25 ⁇ M iron sulfate, 5 mM ascorbic acid, 2.5 mM DTT, and the test compound was dimethyl sulfoxide (DMSO ).
  • test compound and the substrate solution were previously added to the 384-well plate, and the reaction was started by adding human PHD2 enzyme solution (40 ng / well or 50 ng / well). After incubation at 30 ° C. for 20 minutes, a stop solution containing EDTA was added, a HIF-OH antibody solution was added and bound, and the amount of hydroxylated proline residues was quantified by fluorescence polarization measurement.
  • the fluorescence polarization of each well was measured, and the human PHD2 inhibitory activity of the test compound was calculated based on the value of the test substance-free group.
  • Examples carried out with a 50 ng / well human PHD2 enzyme solution are shown in Examples 1-5, 1-6, 1-8, 1-9, 1-12 to 1-14, 1-18. ⁇ 1-36, 1-43, 1-44, 1-46 to 1-50, 1-129 to 1-142, 2-8 to 2-10, 3, 4-1, 4-2, 5-1 5-2, 6-1, 6-2, 8-1 to 8-4, 9-1 to 9-3, 10-1, 10-2, 11, 14-7 to 14-11.
  • the compound of the present invention has an excellent PHD2 inhibitory action, and according to the present invention, it is possible to provide a drug effective for the prevention or treatment of diseases caused by anemia, thereby reducing the burden on patients and contributing to the development of the pharmaceutical industry. Is expected to do.

Abstract

　The present invention provides a compound represented by formula (I) having a PHD-2-inhibiting action or a pharmacologically acceptable salt thereof. (I) (In formula (I), R1 shows a hydrogen atom or optionally substituted C1-3 alkyl; X shows the formula CR2 or a nitrogen atom; R3 shows a hydrogen atom, halogen atom, C1-3 alkyl, or C1-3 alkoxy; Y shows the formula -CONR41-W1-, the formula -CONR42-W2-CO-, a structure represented by formula (β), the formula -CH2NHCO-, formula -CH2OCH2-, or the formula -NHCOCH2-; and ring A shows an optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted aryl, optionally substituted saturated heterocyclyl, or optionally substituted heteroaryl.)

Description

トリアゾリルで置換されたヘテロアリール化合物Heteroaryl compounds substituted with triazolyl
　本発明は、プロリルヒドロキシラーゼ（ｐｒｏｌｙｌ　ｈｙｄｒｏｘｙｌａｓｅ、以下、「ＰＨＤ」ともいう）を阻害する化合物、特にプロリルヒドロキシラーゼ２（以下、「ＰＨＤ２」ともいう）を阻害する化合物に関する。 The present invention relates to a compound that inhibits prolyl hydroxylase (hereinafter also referred to as “PHD”), and particularly to a compound that inhibits prolyl hydroxylase 2 (hereinafter also referred to as “PHD2”).
　血液中の赤血球細胞は全身への酸素運搬を担い、恒常的な生体内の酸素濃度の維持に重要な働きをしている。ある種の疾病や事故・手術などによる出血により、血液中の赤血球数やヘモグロビン量が低下すると、倦怠感やめまい、息切れ等の貧血症状を呈する。貧血になると全身が酸素不足にさらされることになるが、この様な低酸素条件下では、生体は代償反応として、主に腎臓から赤血球の形成を促進する造血因子エリスロポエチン（以下、「ＥＰＯ」ともいう。）を産生し、血液中の赤血球やヘモグロビン量を増加させて貧血の改善を促す。しかしながら、ある種の疾病においては、このエリスロポエチンによる赤血球新生作用が障害を受け、慢性的な貧血が持続する。例えば腎臓に障害を持つような腎不全患者では、この低酸素条件下でのエリスロポエチン産生機構が上手く機能せず、赤血球数やヘモグロビン量が低下した貧血（腎性貧血）を呈することが知られている（非特許文献１、２参照）。 Red blood cells in the blood are responsible for oxygen transport throughout the body and play an important role in maintaining a constant in vivo oxygen concentration. If the number of red blood cells or hemoglobin in the blood decreases due to bleeding from certain diseases, accidents, or surgery, the symptoms of anemia such as malaise, dizziness, shortness of breath, etc. may occur. When anemia develops, the whole body is exposed to oxygen deficiency. Under such hypoxic conditions, the living body is compensated by the hematopoietic factor erythropoietin (hereinafter referred to as “EPO”) that promotes the formation of red blood cells mainly from the kidney. ) And increase the amount of red blood cells and hemoglobin in the blood to promote anemia. However, in certain diseases, the erythropoietin-induced erythropoiesis action is impaired and chronic anemia persists. For example, in patients with renal failure who have impaired kidneys, the erythropoietin production mechanism under this hypoxic condition does not function well, and anemia with reduced red blood cell count and hemoglobin (renal anemia) is known. (See Non-Patent Documents 1 and 2).
　腎性貧血及び癌の化学療法やＨＩＶ感染患者の薬剤療法に伴う貧血の治療は、現在遺伝子組み換えヒトエリスロポエチン製剤等の赤血球造血刺激因子製剤（ＥＳＡ）により行われている。ＥＳＡは赤血球数、ヘモグロビン量を増加させ貧血に伴う症状を改善することで、患者の生活の質の向上に大きく貢献している。しかしながら一方で現在のＥＳＡはいずれも生物製剤であり高価な注射薬であることから、経口投与可能な貧血治療医薬品が望まれている。 Treatment of anemia associated with renal anemia and cancer chemotherapy and drug therapy for HIV-infected patients is currently carried out with erythropoiesis stimulating factor preparations (ESA) such as recombinant human erythropoietin preparations. ESA greatly contributes to improving the quality of life of patients by increasing the number of red blood cells and the amount of hemoglobin to improve symptoms associated with anemia. However, since all current ESAs are biopharmaceuticals and expensive injections, an orally administrable pharmaceutical for anemia is desired.
　また最近の研究では、エリスロポエチンには、虚血に伴う低酸素状態に置かれた心臓や脳等の組織を保護する作用もあることが報告されている。したがって経口投与可能なＥＳＡは、腎性貧血を含む種々の原因で起こる貧血のみならず、さまざまな虚血性疾患にも幅広く適応できる可能性がある（非特許文献３参照）。 In recent research, it has been reported that erythropoietin also has an effect of protecting tissues such as the heart and brain placed in a hypoxic state accompanying ischemia. Therefore, orally administrable ESA may be widely applicable not only to anemia caused by various causes including renal anemia but also to various ischemic diseases (see Non-Patent Document 3).
　エリスロポエチンの産生を増加させる因子として低酸素誘導因子（Ｈｙｐｏｘｉａ　ｉｎｄｕｃｉｂｌｅ　ｆａｃｔｏｒ、以下、「ＨＩＦ」ともいう）が挙げられる。ＨＩＦは、酸素濃度の変化により分解が調節されるαサブユニットと、恒常的に発現しているβサブユニットからなる転写因子である。ＨＩＦのαサブユニット（ＨＩＦ－α）の分解を調節する因子としてプロリルヒドロキシラーゼ（ＰＨＤ－１, ２, ３）が知られている。正常の酸素圧条件下では、これらプロリルヒドロキシラーゼによりＨＩＦ－αのプロリン残基が水酸化され、速やかにＨＩＦ－αはプロテアソームにより分解される。一方、低酸素条件下では、プロリルヒドロキシラーゼの活性が低下するため、ＨＩＦ－αの分解が抑制され、その結果エリスロポエチンを含むＨＩＦ応答性遺伝子の転写が促進される。従ってプロリルヒドロキシラーゼを阻害することで、ＨＩＦ－αの安定化を促し、エリスロポエチンの産生を増加させることが可能となる（非特許文献１、２、４参照）。 Examples of factors that increase the production of erythropoietin include hypoxia-inducible factors (hereinafter referred to as “HIF”). HIF is a transcription factor composed of an α subunit whose degradation is regulated by a change in oxygen concentration and a β subunit that is constantly expressed. Prolyl hydroxylase (PHD-1, 2, 3) is known as a factor that regulates the degradation of HIF α subunit (HIF-α). Under normal oxygen tension conditions, these prolyl hydroxylases hydroxylate the proline residues of HIF-α, and HIF-α is rapidly degraded by the proteasome. On the other hand, under hypoxic conditions, the activity of prolyl hydroxylase decreases, so that degradation of HIF-α is suppressed, and as a result, transcription of HIF-responsive genes including erythropoietin is promoted. Therefore, by inhibiting prolyl hydroxylase, it is possible to promote the stabilization of HIF-α and increase the production of erythropoietin (see Non-Patent Documents 1, 2, and 4).
　これらプロリルヒドロキシラーゼの活性を阻害する化合物は、エリスロポエチン量を増加させ、それにより貧血を治療する手段を提供することができる。また貧血のみならずさまざまな虚血性疾患（脳卒中、心筋梗塞、虚血性腎障害など）や糖尿病性合併症（腎症、網膜症、神経症）等に対しても、治療や予防あるいは症状の改善や緩和が期待できる（非特許文献５参照）。 These compounds that inhibit the activity of prolyl hydroxylase can increase the amount of erythropoietin, thereby providing a means of treating anemia. In addition to anemia, various ischemic diseases (stroke, myocardial infarction, ischemic nephropathy, etc.) and diabetic complications (nephropathy, retinopathy, neurosis) are treated, prevented, or improved in symptoms. And relaxation can be expected (see Non-Patent Document 5).
　ＰＨＤを阻害する化合物としては、４－ヒドロキシイソキノリン誘導体（特許文献１参照）、４－ヒドロキシ－２－オキソ－１，２－ジヒドロキノリン誘導体（特許文献２参照）、３－ヒドロキシピリジン誘導体（特許文献３参照）、２－オキソ－２，３－ジヒドロインドール誘導体（特許文献４参照）等が報告されているが、トリアゾリルで置換されたヘテロアリール構造を有する化合物は開示されていない。また、他のＰＨＤを阻害する化合物として、ジヒドロピラゾロン誘導体（特許文献５～１０）やヒドロキシ等で置換されてもよいピリミジン誘導体（特許文献１１～１９）が報告されているが、これらもトリアゾリルで置換されたヘテロアリール構造を有する化合物は開示されていない。 As compounds that inhibit PHD, 4-hydroxyisoquinoline derivatives (see Patent Document 1), 4-hydroxy-2-oxo-1,2-dihydroquinoline derivatives (see Patent Document 2), 3-hydroxypyridine derivatives (Patent Document) 3), 2-oxo-2,3-dihydroindole derivatives (see Patent Document 4) and the like have been reported, but compounds having a heteroaryl structure substituted with triazolyl are not disclosed. Further, as other PHD-inhibiting compounds, dihydropyrazolone derivatives (Patent Documents 5 to 10) and pyrimidine derivatives (Patent Documents 11 to 19) which may be substituted with hydroxy or the like have been reported. Compounds having a substituted heteroaryl structure are not disclosed.
ＷＯ２００４／１０８６８１号WO2004 / 108681 ＷＯ２００７／０３８５７１号WO2007 / 038571 ＵＳ２００７／０２９９０８６号US2007 / 0299086 ＷＯ２００８／１４４２６６号WO2008 / 144266 ＷＯ２００６／１１４２１３号WO2006 / 114213 ＷＯ２００８／０４９５３８号WO2008 / 049538 ＷＯ２００８／０６７８７１号WO2008 / 067871 ＷＯ２００８／０６７８７４号WO2008 / 067874 ＷＯ２００９／１２９９４５号WO2009 / 129945 ＷＯ２０１２／０６５９６７号WO2012 / 065967 ＷＯ２００９／１１７２６９号WO2009 / 117269 ＷＯ２０１１／００２６２３号WO2011 / 002623 ＷＯ２０１１／００２６２４号WO2011 / 002624 ＷＯ２０１１／１３０９０８号WO2011 / 130908 ＷＯ２０１１／１３３４４４号WO2011 / 133444 ＷＯ２０１３／０４０７８９号WO2013 / 040789 ＷＯ２０１３／０４０７９０号WO2013 / 040790 ＷＯ２０１３／０４３６２１号WO2013 / 043621 ＷＯ２０１３／０４３６２４号WO2013 / 043624
　本発明の目的は、ＰＨＤ２を阻害する新規化合物を提供することである。 An object of the present invention is to provide a novel compound that inhibits PHD2.
　本発明者らは、上記課題を達成すべく鋭意検討を重ねた結果、下記式（Ｉ）で表される化合物が、ＰＨＤ２阻害作用を有することを見出した。　以下、本発明を詳細に説明する。本発明の態様（以下、「本発明化合物」という）は以下に示すものである。 As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that a compound represented by the following formula (I) has a PHD2 inhibitory action. Hereinafter, the present invention will be described in detail. The embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
　すなわち、本発明は、
（１）下記式（Ｉ） That is, the present invention
(1) The following formula (I)
Figure JPOXMLDOC01-appb-C000003
      
　　　　　　　　　　（Ｉ）
［式（Ｉ）中、
　Ｒ1は、水素原子又はＣ1-3アルキル（該Ｃ1-3アルキルは、ヒドロキシで置換されてもよい。）を示し、
　Ｘは、式ＣＲ2又は窒素原子を示し、
　Ｒ2は、水素原子、ハロゲン原子、Ｃ1-3アルキル、又はＣ1-3アルコキシを示し、
　Ｒ3は、水素原子、ハロゲン原子、Ｃ1-3アルキル、又はＣ1-3アルコキシを示し、
　Ｙは、式-ＣＯＮＲ41-Ｗ1-、式-ＣＯＮＲ42-Ｗ2-ＣＯ-、下記式（β）で表される構造、式-ＣＨ2ＮＨＣＯ-、式-ＣＨ2ＯＣＨ2-、又は式-ＮＨＣＯＣＨ2-を示し、
Figure JPOXMLDOC01-appb-C000003
(I)
[In the formula (I),
R 1 represents a hydrogen atom or C 1-3 alkyl (the C 1-3 alkyl may be substituted with hydroxy);
X represents the formula CR 2 or a nitrogen atom;
R 2 represents a hydrogen atom, a halogen atom, C 1-3 alkyl, or C 1-3 alkoxy,
R 3 represents a hydrogen atom, a halogen atom, C 1-3 alkyl, or C 1-3 alkoxy,
Y represents a formula —CONR 41 —W 1 —, a formula —CONR 42 —W 2 —CO—, a structure represented by the following formula (β), a formula —CH 2 NHCO—, a formula —CH 2 OCH 2 —, or The formula —NHCOCH 2 —
Figure JPOXMLDOC01-appb-C000004
 　　　　　　　（β）
Figure JPOXMLDOC01-appb-C000004
 (Β)
　Ｒ41は、水素原子又はＣ1-3アルキルを示し、
　Ｗ1は、単結合、Ｃ1-3アルカンジイル、又は式-ＣＨ2ＣＨ2Ｏ-を示し、
　このとき、Ｃ1-3アルカンジイルは、置換基群α１から同一に又は異なって選ばれる１～２個の置換基で置換されてもよく、
　置換基群α１は、ヒドロキシ、カルバモイル、Ｃ1-3アルキル（該Ｃ1-3アルキルは、１個のヒドロキシ又はＣ1-3アルコキシで置換されてもよい。）、Ｃ3-6シクロアルキル、アリール、ヘテロアリール（該ヘテロアリールは、１個のＣ1-3アルキルで置換されてもよい。）、Ｃ1-3アルコキシカルボニル、ジＣ1-3アルキルアミノカルボニル、及び窒素原子を含む４から７員の飽和のヘテロシクリルカルボニルからなる群を示し、
また、Ｃ1-3アルカンジイルの炭素原子の１つは、Ｃ3-6シクロアルカンジイル又は二価の４から６員の環状エーテルと置き換わってもよく、
　Ｒ42は、水素原子又はＣ1-3アルキルを示し、
　Ｗ2は、単結合又はＣ1-3アルカンジイルを示し、
　上記式（β）中の環Ｂは、窒素原子を含む４から８員の飽和のヘテロ環を示し、
　Ｗ3は、単結合又はＣ1-3アルカンジイルを示し、
　環Ａは、
　Ｃ3-8シクロアルキル、Ｃ3-8シクロアルケニル（該Ｃ3-8シクロアルキル及びＣ3-8シクロアルケニルは、置換基群α２から選ばれる１個の基で置換されてもよい。）、
　アリール（該アリールは、置換基群α３から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
　飽和のヘテロシクリル（該飽和のヘテロシクリルは、置換基群α４から選ばれる１個の基で置換されてもよい。）、又は
　ヘテロアリール（該ヘテロアリールは、置換基群α５から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）を示し、
　置換基群α２は、Ｃ1-6アルキル、アリール、及び窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルからなる群を示し、
　置換基群α３は、ハロゲン原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは、１個のヒドロキシ又はＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルキル、アリール、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、１個のＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ、ヘテロアリールオキシ（該アリールオキシ及びヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、飽和のヘテロシクリルＣ1-3アルキル、及び窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルからなる群を示し、
　置換基群α４は、アリールＣ1-3アルキル、アリールカルボニル（該アリールカルボニルは、１個のＣ1-6アルコキシで置換されてもよい。）、アリールスルホニル（該アリールスルホニルは、１個のＣ1-6アルキル又はハロＣ1-6アルキルで置換されてよい。）、及びオキソからなる群を示し、
　置換基群α５は、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、飽和のヘテロシクリルＣ1-3アルコキシ、及びオキソからなる群を示す。］
で表される化合物又はその製薬学的に許容される塩を提供することである。 R 41 represents a hydrogen atom or C 1-3 alkyl,
W 1 represents a single bond, C 1-3 alkanediyl, or the formula —CH 2 CH 2 O—,
At this time, the C 1-3 alkanediyl may be substituted with 1 to 2 substituents selected from the same or different from the substituent group α1.
Substituent group α1 is hydroxy, carbamoyl, C 1-3 alkyl (the C 1-3 alkyl may be substituted with one hydroxy or C 1-3 alkoxy), C 3-6 cycloalkyl, Aryl, heteroaryl (the heteroaryl may be substituted with one C 1-3 alkyl), C 1-3 alkoxycarbonyl, diC 1-3 alkylaminocarbonyl, and 4 containing a nitrogen atom Represents a group consisting of 7-membered saturated heterocyclylcarbonyl;
Also, one of the carbon atoms of the C 1-3 alkanediyl may be replaced with C 3-6 cycloalkanediyl or a divalent 4- to 6-membered cyclic ether,
R 42 represents a hydrogen atom or a C 1-3 alkyl,
W 2 represents a single bond or C 1-3 alkanediyl,
Ring B in the above formula (β) represents a 4- to 8-membered saturated heterocycle containing a nitrogen atom,
W 3 represents a single bond or C 1-3 alkanediyl,
Ring A is
C 3-8 cycloalkyl, C 3-8 cycloalkenyl (the C 3-8 cycloalkyl and C 3-8 cycloalkenyl may be substituted with one group selected from the substituent group α2),
Aryl (the aryl may be substituted with 1 to 2 groups selected from the same or different from substituent group α3);
Saturated heterocyclyl (the saturated heterocyclyl may be substituted with one group selected from substituent group α4), or heteroaryl (the heteroaryl is the same or different from substituent group α5) And may be substituted with 1 to 2 groups
Substituent group α2 represents a group consisting of C 1-6 alkyl, aryl, and a 4- to 8-membered saturated heterocyclylcarbonyl containing a nitrogen atom,
Substituent group α3 is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with 1 hydroxy or C 1-6 alkoxy), halo C 1-6 alkyl, aryl , C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy, hetero Aryloxy (the aryloxy and heteroaryloxy may be substituted with 1 C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, and a 4 to 8 membered saturated nitrogen atom Represents a group consisting of heterocyclylcarbonyl,
Substituent group α4 is aryl C 1-3 alkyl, arylcarbonyl (the arylcarbonyl may be substituted with one C 1-6 alkoxy), arylsulfonyl (the arylsulfonyl is one C And optionally substituted with 1-6 alkyl or haloC 1-6 alkyl), and oxo
Substituent Group α5 represents a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (said aryl may be substituted with one C 1-6 alkoxy. ), Saturated heterocyclyl, C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1-3 alkyl may be substituted with one halogen atom), C 1 -6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (the aryloxy may be substituted with one halogen atom or C 1-6 alkyl), heteroaryloxy ( The heteroaryloxy may be substituted with one C 1-6 alkyl.), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy is 1 may be substituted with pieces of C 1-6 alkyl.), saturated Heterocyclyl C 1-3 alkoxy, and shows the group consisting of oxo. ]
Or a pharmaceutically acceptable salt thereof.
（２）本発明の他の態様としては、
　前記式（Ｉ）において、
　環Ａが、
　Ｃ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、前記置換基群α２から選ばれる１個の基で置換されてもよい。）、
　フェニル（該フェニルは、前記置換基群α３から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
　ジヒドロインデニル、
　アゼチジニル［該アゼチジニルは、アリールスルホニル（該アリールスルホニルは、１個のＣ1-6アルキル又はハロＣ1-6アルキルで置換されてよい。）］、
　ピペリジニル［該ピペリジニルは、アリールＣ1-3アルキル、アリールカルボニル（該アリールカルボニルは、１個のＣ1-6アルコキシで置換されてもよい。）、アリールスルホニル（該アリールスルホニルは、１個のＣ1-6アルキル又はハロＣ1-6アルキルで置換されてよい。）、及びオキソからなる群から選ばれる１個の基で置換されてもよい。］、
　ピリジル［該ピリジルは、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、及び飽和のヘテロシクリルＣ1-3アルコキシからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］、
　ピリミジニル［該ピリミジニルは、ハロゲン原子及びアリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）からなる群から選ばれる１個の基で置換されてもよい。］、
　ピラゾリル（該ピラゾリルは、Ｃ1-6アルキル及びフェニルからなる群から選ばれる１個の基で置換されてもよい。）、
　チアゾリル（該チアゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、
　ジヒドロピリジニル［該ジヒドロピリジニルは、Ｃ1-6アルキル、Ｃ3-8シクロアルキル、アリールＣ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、及びオキソからなる群から同一に又は異なって選ばれる１個の基で置換されてもよい。］、
　ベンゾフラニル、
　ジヒドロベンゾフラニル（該ジヒドロベンゾフラニルは、ハロゲン原子、Ｃ1-6アルキルからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
　クロマニル、
　ジヒドロピラノピリジニル、
　ジヒドロフロピリジニル、
　テトラヒドロキノリル、
　テトラヒドロイソキノリル、
　ジヒドロベンゾジオキシニル、
　テトラヒドロトリアゾロアゼピニル
である（１）に記載の化合物又はその製薬学的に許容される塩を提供することである。 (2) As another aspect of the present invention,
In the formula (I),
Ring A is
C 3-8 cycloalkyl (the C 3-8 cycloalkyl may be substituted with one group selected from the substituent group α2);
Phenyl (the phenyl may be substituted with 1 to 2 groups selected from the same or different from the substituent group α3);
Dihydroindenyl,
Azetidinyl [wherein the azetidinyl is arylsulfonyl, which may be substituted with one C 1-6 alkyl or haloC 1-6 alkyl]],
Piperidinyl [wherein the piperidinyl is aryl C 1-3 alkyl, arylcarbonyl (the arylcarbonyl may be substituted with one C 1-6 alkoxy), arylsulfonyl (the arylsulfonyl is one C Optionally substituted with 1-6 alkyl or haloC 1-6 alkyl), and one group selected from the group consisting of oxo. ],
Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy). ), Saturated heterocyclyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (the aryloxy may be substituted with one halogen atom or C 1-6 alkyl) ), Heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy may be substituted with 1 C 1-6 alkyl.), And 1 to 2 groups selected identically or differently from the group consisting of saturated heterocyclyl C 1-3 alkoxy May be substituted. ],
Pyrimidinyl [The pyrimidinyl may be substituted with one group selected from the group consisting of a halogen atom and aryl (the aryl may be substituted with one C 1-6 alkoxy). ],
Pyrazolyl (which may be substituted with one group selected from the group consisting of C 1-6 alkyl and phenyl),
Thiazolyl (which may be substituted with one C 1-6 alkyl),
Dihydropyridinyl [wherein the dihydropyridinyl is C 1-6 alkyl, C 3-8 cycloalkyl, aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1- 3 alkyl may be substituted with one halogen atom.), and may be substituted with one group selected identical to or different from the group consisting of oxo. ],
Benzofuranyl,
Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom, C 1-6 alkyl, the same or different),
Chromanil,
Dihydropyranopyridinyl,
Dihydrofuropyridinyl,
Tetrahydroquinolyl,
Tetrahydroisoquinolyl,
Dihydrobenzodioxinyl,
It is to provide a compound or a pharmaceutically acceptable salt thereof according to (1), which is tetrahydrotriazoloazepinyl.
（３）本発明の他の態様としては、
　前記式（Ｉ）において、
　Ｘが、式ＣＲ2であり、
　Ｒ2が、水素原子又はメトキシであり、
　Ｙが、式-ＣＯＮＲ41-Ｗ1-であり、
　Ｒ41が、水素原子であり、
　Ｗ1が、Ｃ1-3アルカンジイルであり、
　環Ａが、
　フェニル（該フェニルは、前記置換基群α３から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
　ジヒドロインデニル、
　ピリジル［該ピリジルは、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、及び飽和のヘテロシクリルＣ1-3アルコキシからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］、
　ジヒドロピリジニル［該ジヒドロピリジニルは、Ｃ1-6アルキル、Ｃ3-8シクロアルキル、アリールＣ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、及びオキソからなる群から同一に又は異なって選ばれる１個の基で置換されてもよい。］、
　ベンゾフラニル、
　ジヒドロベンゾフラニル（該ジヒドロベンゾフラニルは、ハロゲン原子、Ｃ1-6アルキルからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
　クロマニル、
　ジヒドロピラノピリジニル、
　ジヒドロフロピリジニル、
　テトラヒドロキノリル、
　テトラヒドロイソキノリル、
　ジヒドロベンゾジオキシニル
である（１）又は（２）に記載の化合物又はその製薬学的に許容される塩を提供することである。 (3) As another aspect of the present invention,
In the formula (I),
X is the formula CR 2
R 2 is a hydrogen atom or methoxy;
Y is of the formula -CONR 41 -W 1-
R 41 is a hydrogen atom,
W 1 is C 1-3 alkanediyl,
Ring A is
Phenyl (the phenyl may be substituted with 1 to 2 groups selected from the same or different from the substituent group α3);
Dihydroindenyl,
Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy). ), heterocyclyl saturated, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (said aryloxy may be substituted with one halogen atom or C 1-6 alkyl ), Heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy may be substituted with 1 C 1-6 alkyl.), And 1 to 2 groups selected identically or differently from the group consisting of saturated heterocyclyl C 1-3 alkoxy May be substituted. ],
Dihydropyridinyl [wherein the dihydropyridinyl is C 1-6 alkyl, C 3-8 cycloalkyl, aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1- 3 alkyl may be substituted with one halogen atom), and may be substituted with one group selected identically or differently from the group consisting of oxo. ],
Benzofuranyl,
Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom, C 1-6 alkyl, the same or different),
Chromanil,
Dihydropyranopyridinyl,
Dihydrofuropyridinyl,
Tetrahydroquinolyl,
Tetrahydroisoquinolyl,
It is to provide a compound or a pharmaceutically acceptable salt thereof according to (1) or (2) which is dihydrobenzodioxinyl.
（４）本発明の他の態様としては、
　（１）～（３）のいずれかに記載の化合物又はその製薬学的に許容される塩を有効成分として含有する医薬を提供することである。 (4) As another aspect of the present invention,
(1) To provide a medicament containing the compound according to any one of (3) or a pharmaceutically acceptable salt thereof as an active ingredient.
（５）本発明の他の態様としては、
　（１）～（３）のいずれかに記載の化合物又はその製薬学的に許容される塩を有効成分として含有するＰＨＤ２阻害剤を提供することである。 (5) As another aspect of the present invention,
(1) It is to provide a PHD2 inhibitor containing the compound according to any one of (3) or a pharmaceutically acceptable salt thereof as an active ingredient.
（６）本発明の他の態様としては、
　（１）～（３）のいずれかに記載の化合物又はその製薬学的に許容される塩を有効成分として含有するＥＰＯ産生促進剤を提供することである。 (6) As another aspect of the present invention,
An object of the present invention is to provide an EPO production promoter containing the compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.
（７）本発明の他の態様としては、
　（１）～（３）のいずれかに記載の化合物又はその製薬学的に許容される塩を有効成分として含有する貧血の予防薬又は治療薬を提供することである。 (7) As another aspect of the present invention,
(1) It is intended to provide a prophylactic or therapeutic agent for anemia containing the compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.
　本発明の化合物は、ＰＨＤ２阻害作用を有する。 The compound of the present invention has a PHD2 inhibitory action.
　本発明は、ＰＨＤ２阻害作用を有する前記式（Ｉ）で表される化合物又はその製薬学的に許容される塩を提供する。 The present invention provides a compound represented by the above formula (I) having a PHD2 inhibitory action or a pharmaceutically acceptable salt thereof.
　以下に、本発明の化合物についてさらに詳細に説明するが、本発明は、例示されたものに特に限定されない。 Hereinafter, the compound of the present invention will be described in more detail, but the present invention is not particularly limited to those exemplified.
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を示す。 “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
　「Ｃ1-3アルキル」とは、炭素原子を１～３個有する直鎖状又は分岐状のアルキルを示す。メチル、エチル、ｎ－プロピル、イソプロピルが挙げられる。 “C 1-3 alkyl” refers to a linear or branched alkyl having 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, and isopropyl.
　「Ｃ1-6アルキル」とは、炭素原子を１～６個有する直鎖状又は分岐状のアルキルを示す。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、２－メチルブチル、ｎ－ヘキシル、イソヘキシル等が挙げられる。 “C 1-6 alkyl” refers to a linear or branched alkyl having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like can be mentioned.
　「ハロＣ1-6アルキル」とは、ハロゲン原子で置換された、炭素原子を１～６個有する直鎖状又は分岐状のアルキルを示す。ハロゲン原子の好ましい置換数は１～５個であり、好ましいハロゲン原子はフッ素原子である。例えば、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、１－フルオロエチル、１，１－ジフルオロエチル、１，１，２，２，２－ペンタフルオロエチル、２－フルオロエチル、２－フルオロ－２－メチルプロピル、２，２－ジフルオロプロピル、１－フルオロ－２－メチルプロパン－２－イル、１，１－ジフルオロ－２－メチルプロパン－２－イル、１－フルオロペンチル、１－フルオロヘキシル等が挙げられる。 “Halo C 1-6 alkyl” refers to a linear or branched alkyl having 1 to 6 carbon atoms, substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 5, and a preferred halogen atom is a fluorine atom. For example, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2-fluoroethyl, 2-fluoro-2- Methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl, 1-fluoropentyl, 1-fluorohexyl, etc. It is done.
　「Ｃ3-6シクロアルキル」とは、炭素原子を３～６個有する環状のアルキルを示す。シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルが挙げられる。 “C 3-6 cycloalkyl” refers to a cyclic alkyl having 3 to 6 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
　「Ｃ3-8シクロアルキル」とは、炭素原子を３～８個有する環状のアルキルを示す。シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルが挙げられる。 “C 3-8 cycloalkyl” refers to cyclic alkyl having 3 to 8 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
　「Ｃ3-8シクロアルケニル」とは、炭素原子を３～８個有する環状のアルケニルを示す。例えば、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロオクテニルが挙げられる。 “C 3-8 cycloalkenyl” refers to cyclic alkenyl having 3 to 8 carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
　「アリール」とは、炭素原子を６～１４個有する単環式芳香族炭化水素基又は縮合多環式芳香族炭化水素基を示す。例えば、フェニル、ナフチル、アントリル等が挙げられる。 “Aryl” refers to a monocyclic aromatic hydrocarbon group or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. For example, phenyl, naphthyl, anthryl and the like can be mentioned.
　また、アリールにおいて部分的に飽和された基も「アリール」に含まれる。「アリールにおける部分的に飽和された基」とは、炭素原子を６～１４個有する単環式芳香族炭化水素基又は縮合多環式芳香族炭化水素基において、部分的に飽和された縮合多環式複素環基を示す。例えば、ジヒドロインデニル等が挙げられる。 Further, a group partially saturated in aryl is also included in “aryl”. The “partially saturated group in aryl” means a partially saturated condensed polycyclic group in a monocyclic aromatic hydrocarbon group or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. A cyclic heterocyclic group is shown. For example, dihydroindenyl and the like can be mentioned.
　「飽和のヘテロシクリル」とは、酸素原子、硫黄原子及び窒素原子からなる群より同一に又は異なって選ばれる１個以上の原子と１～７個の炭素原子からなる３～８員の単環式飽和複素環基を示す。例えば、アゼチジニル、ピロリジニル、ピペリジニル、ヘキサメチレンイミニル、ピペラジニル、ピラゾリジニル、キヌクリジニル、モルホリニル、オキセタニル、オキソラニル、オキサニル等が挙げられる。 “Saturated heterocyclyl” is a 3 to 8 membered monocyclic group composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 7 carbon atoms. A saturated heterocyclic group is shown. Examples include azetidinyl, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, piperazinyl, pyrazolidinyl, quinuclidinyl, morpholinyl, oxetanyl, oxolanyl, oxanyl and the like.
　「窒素原子を含む４から７員の飽和のヘテロシクリル」とは、１個の窒素原子を環内に含む４～７員の単環式飽和複素環基を示す。例えば、アゼチジニル、ピロリジニル、ピペリジニル、モルホリニル等が挙げられる。 “The 4- to 7-membered saturated heterocyclyl containing nitrogen atom” refers to a 4- to 7-membered monocyclic saturated heterocyclic group containing one nitrogen atom in the ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and the like.
　「窒素原子を含む４から８員の飽和のヘテロ環」とは、１個の窒素原子を環内に含む４～８員の単環式飽和複素環基を示す。例えば、アゼチジン、ピロリジン、ピペリジン等が挙げられる。 “The 4- to 8-membered saturated heterocycle containing a nitrogen atom” refers to a 4- to 8-membered monocyclic saturated heterocyclic group containing one nitrogen atom in the ring. For example, azetidine, pyrrolidine, piperidine and the like can be mentioned.
　「窒素原子を含む４から８員の飽和のヘテロシクリル」とは、１個の窒素原子を環内に含む４～８員の単環式飽和複素環基を示す。例えば、アゼチジニル、ピロリジニル、ピペリジニル、アゾカニル、モルホリニル等が挙げられる。 “4- to 8-membered saturated heterocyclyl containing nitrogen atom” refers to a 4- to 8-membered monocyclic saturated heterocyclic group containing one nitrogen atom in the ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, azocanyl, morpholinyl and the like.
　「ヘテロアリール」とは、酸素原子、硫黄原子及び窒素原子からなる群より同一に若しくは異なって選ばれる１個以上の原子と１～６個の炭素原子からなる５～７員の単環式芳香族複素環基又は酸素原子、硫黄原子及び窒素原子からなる群より同一に若しくは異なって選ばれる１個以上の原子と１～１３個の炭素原子からなる９～１４個の原子から構成される縮合多環式芳香族複素環基を示す。例えばイミダゾリル、ピラゾリル、チアゾリル、チアジアゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、ピロリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、トリアジニル、インドリル、ベンゾピラゾリル、ベンゾトリアゾリル、ベンゾフラニル、ベンゾチオフェニル、キノリル、イソキノリル等が挙げられる。 “Heteroaryl” is a 5- to 7-membered monocyclic fragrance composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 6 carbon atoms. A group consisting of one or more atoms selected from the group consisting of a heterocyclic group or an oxygen atom, a sulfur atom and a nitrogen atom, or 9 to 14 atoms consisting of 1 to 13 carbon atoms. A polycyclic aromatic heterocyclic group is shown. For example imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzopyrazolyl, benzotriazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl Etc.
　また、ヘテロアリールにおいて部分的に飽和された基も「ヘテロアリール」に含まれる。「ヘテロアリールにおける部分的に飽和された基」とは、酸素原子、硫黄原子及び窒素原子からなる群より同一に若しくは異なって選ばれる１個以上の原子と１～６個の炭素原子からなる５～７員の部分的に飽和された単環式複素環基又は酸素原子、硫黄原子及び窒素原子からなる群より同一に若しくは異なって選ばれる１個以上の原子と１～１３個の炭素原子からなる９～１４個の原子から構成される部分的に飽和された縮合多環式複素環基を示す。例えばオキサゾリジニル、チアゾリニル、ジヒドロピリジニル、ジヒドロベンゾフラニル、クロマニル、ジヒドロピラノピリジニル、ジヒドロフロピリジニル、テトラヒドロキノリル、テトラヒドロキノリル、ジヒドロベンゾジオキシニル、テトラヒドロトリアゾロアゼピニル等が挙げられる。 Further, a group partially saturated in heteroaryl is also included in “heteroaryl”. The “partially saturated group in heteroaryl” refers to one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or 1 to 6 carbon atoms. A 7-membered partially saturated monocyclic heterocyclic group or one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or 1 to 13 carbon atoms, the same or different And a partially saturated condensed polycyclic heterocyclic group composed of 9 to 14 atoms. For example, oxazolidinyl, thiazolinyl, dihydropyridinyl, dihydrobenzofuranyl, chromanyl, dihydropyranopyridinyl, dihydrofuropridinyl, tetrahydroquinolyl, tetrahydroquinolyl, dihydrobenzodioxinyl, tetrahydrotriazoloazepinyl, etc. Is mentioned.
　「Ｃ3-8シクロアルキルＣ1-3アルキル」とは、前記の「Ｃ3-8シクロアルキル」を置換基として１個有する前記の「Ｃ1-3アルキル」を示す。例えば、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、２－シクロプロピルエチル、３－シクロプロピルプロピル等が挙げられる。 “C 3-8 cycloalkyl C 1-3 alkyl” refers to the above “C 1-3 alkyl” having one “C 3-8 cycloalkyl” as a substituent. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, and the like.
　「アリールＣ1-3アルキル」とは、前記の「アリール」を置換基として１個有する前記の「Ｃ1-3アルキル」を示す。例えば、ベンジル、ナフチルメチル、フェネチル、３－フェニルプロピル等が挙げられる。 “Aryl C 1-3 alkyl” refers to the above “C 1-3 alkyl” having one “aryl” as a substituent. For example, benzyl, naphthylmethyl, phenethyl, 3-phenylpropyl and the like can be mentioned.
　「飽和のヘテロシクリルＣ1-3アルキル」とは、前記の「飽和のヘテロシクリル」を置換基として１個有する前記の「Ｃ1-3アルキル」を示す。例えば、ピロリジニルメチル、ピペリジニルメチル、テトラヒドロピラニルメトキシ、モルホリニルメチル、２－ピロリジニルエチル、３－ピロリジニルプロピル等が挙げられる。 "Heterocyclyl C 1-3 alkyl, saturated" refers to "C 1-3 alkyl" above having one as a substituent "heterocyclyl saturation" of the. Examples include pyrrolidinylmethyl, piperidinylmethyl, tetrahydropyranylmethoxy, morpholinylmethyl, 2-pyrrolidinylethyl, 3-pyrrolidinylpropyl, and the like.
　「Ｃ1-3アルコキシ」とは、炭素原子を１～３個有する直鎖状又は分岐状のアルコキシを示す。メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシが挙げられる。 “C 1-3 alkoxy” refers to linear or branched alkoxy having 1 to 3 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy.
　「Ｃ1-6アルコキシ」とは、炭素原子を１～６個有する直鎖状又は分岐状のアルコキシを示す。例えば、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ｎ－ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、２－メチルブトキシ、ｎ－ヘキシルオキシ、イソヘキシルオキシ等が挙げられる。 “C 1-6 alkoxy” represents linear or branched alkoxy having 1 to 6 carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, n-hexyloxy, And isohexyloxy.
　「ハロＣ1-6アルコキシ」とは、ハロゲン原子で置換された、炭素原子を１～６個有する直鎖状又は分岐状のアルコキシを示す。ハロゲン原子の好ましい置換数は１～５個であり、好ましいハロゲン原子はフッ素原子である。例えば、モノフルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシ、１－フルオロエトキシ、１，１－ジフルオロエトキシ、１，１，２，２－テトラフルオロエトキシ、２－フルオロエトキシ、２，２，２－トリフルオロエトキシ、３，３，３－トリフルオロプロポキシ、１，３－ジフルオロプロパン－２－イルオキシ、２－フルオロ－２－メチルプロポキシ、２，２－ジフルオロプロポキシ、１－フルオロ－２－メチルプロパン－２－イルオキシ、１，１－ジフルオロ－２－メチルプロパン－２－イルオキシ、４，４，４－トリフルオロブトキシ等が挙げられる。 “Halo C 1-6 alkoxy” refers to a straight or branched alkoxy having 1 to 6 carbon atoms, which is substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 5, and a preferred halogen atom is a fluorine atom. For example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2,2,2-trifluoro Ethoxy, 3,3,3-trifluoropropoxy, 1,3-difluoropropan-2-yloxy, 2-fluoro-2-methylpropoxy, 2,2-difluoropropoxy, 1-fluoro-2-methylpropane-2- Ilyloxy, 1,1-difluoro-2-methylpropan-2-yloxy, 4,4,4-trifluorobutoxy and the like can be mentioned.
　「Ｃ3-8シクロアルコキシ」とは、炭素原子を３～８個有する環状のアルコキシを示す。例えば、シクロプロポキシ、シクロブトキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロヘプチルオキシ、シクロオクチルオキシが挙げられる。 “C 3-8 cycloalkoxy” refers to cyclic alkoxy having 3 to 8 carbon atoms. Examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
　「アリールオキシ」とは、前記の「アリール」と酸素原子が結合した基を示す。例えば、フェノキシ、ナフチルオキシ、アントリルオキシ等が挙げられる。 “Aryloxy” refers to a group in which the above “aryl” is bonded to an oxygen atom. For example, phenoxy, naphthyloxy, anthryloxy and the like can be mentioned.
　「ヘテロアリールオキシ」とは、前記の「ヘテロアリール」と酸素原子が結合した基を示す。例えば、ピリジルオキシ、ピリミジニルオキシ、ピラジニルオキシ、ピリダジニルオキシ、インドリルオキシ、ベンゾピラゾリルオキシ、ベンゾトリアゾリルオキシ、ベンゾフラニルオキシ、ベンゾチオフェニルオキシ、キノリルオキシ、イソキノリルオキシ等が挙げられる。 “Heteroaryloxy” refers to a group in which the above “heteroaryl” is bonded to an oxygen atom. Examples thereof include pyridyloxy, pyrimidinyloxy, pyrazinyloxy, pyridazinyloxy, indolyloxy, benzopyrazolyloxy, benzotriazolyloxy, benzofuranyloxy, benzothiophenyloxy, quinolyloxy, isoquinolyloxy and the like.
　「Ｃ3-8シクロアルキルＣ1-3アルコキシ」とは、前記の「Ｃ3-8シクロアルキル」を置換基として１個有する前記の「Ｃ1-3アルコキシ」を示す。シクロプロピルメトキシ、シクロブチルメトキシ、シクロペンチルメトキシ、シクロヘキシルメトキシ、２－シクロプロピルエトキシ、３－シクロプロピルプロポキシ等が挙げられる。 “C 3-8 cycloalkyl C 1-3 alkoxy” refers to the above “C 1-3 alkoxy” having one “C 3-8 cycloalkyl” as a substituent. Examples include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclopropylethoxy, 3-cyclopropylpropoxy and the like.
　「飽和のヘテロシクリルＣ1-3アルコキシ」とは、前記の「飽和のヘテロシクリル」を置換基として１個有する前記の「Ｃ1-3アルコキシ」を示す。例えば、ピロリジニルメトキシ、ピペリジニルメトキシ、テトラヒドロピラニルメトキシ、モルホリニルメトキシ、２－ピロリジニルエトキシ、３－ピロリジニルプロポキシ等が挙げられる。 The “saturated heterocyclyl C 1-3 alkoxy” refers to the above “C 1-3 alkoxy” having one “saturated heterocyclyl” as a substituent. Examples include pyrrolidinylmethoxy, piperidinylmethoxy, tetrahydropyranylmethoxy, morpholinylmethoxy, 2-pyrrolidinylethoxy, 3-pyrrolidinylpropoxy and the like.
　「アリールカルボニル」とは、前記の「アリール」とカルボニルが結合した基を示す。例えば、ベンゾイル、ナフチルカルボニル等が挙げられる。 “Arylcarbonyl” refers to a group in which the above “aryl” and carbonyl are bonded. Examples include benzoyl and naphthylcarbonyl.
　「Ｃ1-3アルコキシカルボニル」とは、前記の「Ｃ1-3アルコキシ」とカルボニルが結合した基を示す。例えば、メトキシカルボニル、エトキシカルボニル、ｎ－プロポキシカルボニル、イソプロポキシカルボニルが挙げられる。 “C 1-3 alkoxycarbonyl” refers to a group in which the above “C 1-3 alkoxy” is bonded to carbonyl. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and isopropoxycarbonyl.
　「ジＣ1-3アルキルアミノカルボニル」とは、前記の「Ｃ1-3アルキル」を、置換基として同一に又は異なって２個有するアミノとカルボニルが結合した基を示す。例えば、ジメチルアミノカルボニル、ジエチルアミノカルボニル、ジ（ｎ－プロピル）アミノカルボニル、ジ（イソプロピル）アミノカルボニル、エチルメチルアミノカルボニル、メチル（ｎ－プロピル）アミノカルボニル等が挙げられる。 “Di-C 1-3 alkylaminocarbonyl” refers to a group in which amino and carbonyl having the same “C 1-3 alkyl” as the substituent are the same or different. Examples include dimethylaminocarbonyl, diethylaminocarbonyl, di (n-propyl) aminocarbonyl, di (isopropyl) aminocarbonyl, ethylmethylaminocarbonyl, methyl (n-propyl) aminocarbonyl and the like.
　「窒素原子を含む４から７員の飽和のヘテロシクリルカルボニル」とは、前記の「窒素原子を含む４から７員の飽和のヘテロシクリル」とカルボニルが結合した基を示す。例えば、アゼチジニルカルボニル、ピロリジニルカルボニル、ピペリジニルカルボニル、モルホリニルカルボニル等が挙げられる。 “The 4 to 7-membered saturated heterocyclylcarbonyl containing nitrogen atom” refers to a group in which the above “4 to 7-membered saturated heterocyclyl containing nitrogen atom” and carbonyl are bonded. Examples include azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and the like.
　「窒素原子を含む４から８員の飽和のヘテロシクリルカルボニル」とは、前記の「窒素原子を含む４から８員の飽和のヘテロシクリル」とカルボニルが結合した基を示す。例えば、アゼチジニルカルボニル、ピロリジニルカルボニル、ピペリジニルカルボニル、アゾカニルカルボニル、モルホリニルカルボニル等が挙げられる。 The “4- to 8-membered saturated heterocyclylcarbonyl containing nitrogen atom” refers to a group in which the above-mentioned “4- to 8-membered saturated heterocyclyl containing nitrogen atom” and carbonyl are bonded. Examples thereof include azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, azocanylcarbonyl, morpholinylcarbonyl and the like.
　「アリールスルホニル」とは、前記の「アリール」とスルホニルが結合した基を示す。例えば、フェニルスルホニル、ナフチルスルホニル等が挙げられる。 “Arylsulfonyl” refers to a group in which the above “aryl” and sulfonyl are bonded. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
　「オキソ」とは、酸素原子が二重結合を介して置換する置換基（＝Ｏ）を示す。従って、オキソが炭素原子に置換した場合は当該炭素原子と一緒となってカルボニルを形成し、１つのオキソが１つの硫黄原子に置換した場合は当該硫黄原子と一緒となってスルフィニルを形成し、２つのオキソが１つの硫黄原子に置換した場合は当該硫黄原子と一緒になってスルホニルを形成する。本発明においてオキソが飽和のヘテロシクリルに置換した場合のオキソが置換した飽和のヘテロシクリルの具体的な例としては、２－オキソピロリジニル、２－オキソピペリジニル、２－オキソピペラジニル、３－オキソピペラジニル、１，１－ジオキシドテトラヒドロチオフェニル、１－オキシドテトラヒドロ－２Ｈ－チオピラニル、１，１－ジオキシドテトラヒドロ－２Ｈ－チオピラニル、１，１－ジオキシドイソチアゾリジニル、２－オキソ－１，３－オキサゾリジニル、６－オキソ－１，１－ジヒドロピリダジニルなどが挙げられる。 “Oxo” refers to a substituent (═O) in which an oxygen atom is substituted via a double bond. Therefore, when oxo is substituted with a carbon atom, it forms a carbonyl together with the carbon atom, and when one oxo is substituted with one sulfur atom, it forms a sulfinyl together with the sulfur atom, When two oxos are substituted with one sulfur atom, they are combined with the sulfur atom to form a sulfonyl. In the present invention, specific examples of the saturated heterocyclyl substituted with oxo when oxo is substituted with saturated heterocyclyl include 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, 3 -Oxopiperazinyl, 1,1-dioxidetetrahydrothiophenyl, 1-oxidetetrahydro-2H-thiopyranyl, 1,1-dioxidetetrahydro-2H-thiopyranyl, 1,1-dioxideisothiazolidinyl, 2- Examples thereof include oxo-1,3-oxazolidinyl, 6-oxo-1,1-dihydropyridazinyl and the like.
　「Ｃ1-3アルカンジイル」とは、炭素原子を１～３個有するアルキル基から水素原子１個を除去してなる２価の炭化水素基を示す。例えば、メタンジイル、エタン－１，１－ジイル、エタン－１，２－ジイル、プロパン－１，１－ジイル、プロパン－１，２－ジイル、プロパン－１，３－ジイル、プロパン－２，２－ジイルが挙げられる。 “C 1-3 alkanediyl” refers to a divalent hydrocarbon group formed by removing one hydrogen atom from an alkyl group having 1 to 3 carbon atoms. For example, methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl, propane-2,2- Examples include diyl.
　「Ｃ3-6シクロアルカンジイル」とは、炭素原子を３～６個有するシクロアルキル基から水素原子１個を除去してなる２価の環状の炭化水素基を示す。シクロプロパン－１，１－ジイル、シクロブタン－１，１－ジイル、シクロペンタン－１，１－ジイル、シクロヘキサン－１，１－ジイルが挙げられる。 The "C 3-6 cycloalkane-diyl" refers to a divalent cyclic hydrocarbon group formed by removing one hydrogen atom from a cycloalkyl group having 3 to 6 carbon atoms. Examples include cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, and cyclohexane-1,1-diyl.
　「二価の４から６員の環状エーテル」とは、１個の酸素原子を環内に含む４～６員の単環式飽和複素環基から水素原子１個を除去してなる２価の単環式飽和複素環基を示す。テトラヒドロピラン－４，４－ジイル等が挙げられる。 “Divalent 4- to 6-membered cyclic ether” refers to a divalent formed by removing one hydrogen atom from a 4- to 6-membered monocyclic saturated heterocyclic group containing one oxygen atom in the ring. A monocyclic saturated heterocyclic group is shown. And tetrahydropyran-4,4-diyl.
　本発明化合物の好ましい態様は、以下の通りである。 Preferred embodiments of the compound of the present invention are as follows.
　好ましいＲ1は、水素原子又はＣ1-3アルキルであり、
より好ましいＲ1は、水素原子又はメチルであり、さらに好ましいＲ1は、水素原子である。 Preferred R 1 is a hydrogen atom or C 1-3 alkyl,
More preferred R 1 is a hydrogen atom or methyl, and further preferred R 1 is a hydrogen atom.
　好ましいＸは、式ＣＲ2又は窒素原子であり、
　　このとき、好ましいＲ2は、水素原子、Ｃ1-3アルキル、又はＣ1-3アルコキシであり、
　より好ましいＸは、式ＣＲ2であり、
　　このとき、好ましいＲ2は、水素原子、メチル、又はメトキシであり、
　　より好ましいＲ2は、水素原子、又はメトキシであり、
　　さらに好ましいＲ2は、水素原子であり、
　好ましいＲ3は、水素原子又はハロゲン原子であり、
　より好ましいＲ3は、水素原子又はフッ素原子であり、
　さらに好ましいＲ3は、水素原子である。 Preferred X is formula CR 2 or a nitrogen atom,
In this case, preferred R 2 is a hydrogen atom, C 1-3 alkyl, or C 1-3 alkoxy,
More preferred X is the formula CR 2,
In this case, preferred R 2 is a hydrogen atom, methyl or methoxy,
More preferred R 2 is a hydrogen atom or methoxy,
Further preferred R 2 is a hydrogen atom,
Preferred R 3 is a hydrogen atom or a halogen atom,
More preferred R 3 is a hydrogen atom or a fluorine atom,
More desirable R 3 is a hydrogen atom.
　好ましいＹは、式-ＣＯＮＲ41-Ｗ1-、式-ＣＯＮＲ42-Ｗ2-ＣＯ-、下記式（β）で表される構造、又は式-ＮＨＣＯＣＨ2-であり、 Preferred Y is a formula —CONR 41 —W 1 —, a formula —CONR 42 —W 2 —CO—, a structure represented by the following formula (β), or a formula —NHCOCH 2 —.
Figure JPOXMLDOC01-appb-C000005
 　　　　　　（β）
Figure JPOXMLDOC01-appb-C000005
 (Β)
　　このとき、好ましいＲ41は、水素原子であり、
　　このとき、好ましいＷ1は、単結合又はＣ1-3アルカンジイルであり、
　　このとき、好ましいＲ42は、水素原子であり、
　　このとき、好ましいＷ2は、Ｃ1-3アルカンジイルであり、
　　このとき、上記式（β）中の環Ｂで好ましいものは、ピロリジン－１，２－ジイルであり、
　　このとき、好ましいＷ3は、単結合であり、
　より好ましいＹは、式-ＣＯＮＲ41-Ｗ1-であり、
　　このとき、好ましいＲ41は、水素原子であり、
　　このとき、好ましいＷ1は、Ｃ1-3アルカンジイルであり、
　　より好ましいＷ1は、メタンジイル、エタン－１，１－ジイル、又はエタン－１，２－ジイル、プロパン－２，２－ジイルであり、
　　さらに好ましいＷ1は、メタンジイルである。 In this case, preferable R 41 is a hydrogen atom,
In this case, preferable W 1 is a single bond or C 1-3 alkanediyl,
In this case, preferable R 42 is a hydrogen atom,
At this time, preferable W 2 is C 1-3 alkanediyl,
At this time, a preferable ring B in the formula (β) is pyrrolidine-1,2-diyl,
At this time, preferable W 3 is a single bond,
More preferred Y is the formula -CONR 41 -W 1 - a and,
In this case, preferable R 41 is a hydrogen atom,
At this time, preferable W 1 is C 1-3 alkanediyl,
More preferred W 1 is methanediyl, ethane-1,1-diyl, or ethane-1,2-diyl, propane-2,2-diyl,
More preferred W 1 is methanediyl.
　環Ａの好ましい態様は、以下の（１）～（６）である。
（１）好ましい環Ａは、
　Ｃ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換基群α２から選ばれる１個の基で置換されてもよい。）、
　アリール（該アリールは、置換基群α３から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
　飽和のヘテロシクリル（該飽和のヘテロシクリルは、置換基群α４から選ばれる１個の基で置換されてもよい。）、又は
　ヘテロアリール（該ヘテロアリールは、置換基群α５から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）であり、
　このとき、置換基群α２のうち好ましい基は、Ｃ1-6アルキル、アリール、又は窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルであり、
　このとき、置換基群α３のうち好ましい基は、ハロゲン原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは、１個のヒドロキシ又はＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルキル、アリール、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、１個のＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ、ヘテロアリールオキシ（該アリールオキシ及びヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、飽和のヘテロシクリルＣ1-3アルキル、又は窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルであり、
　このとき、置換基群α４のうち好ましい基は、アリールＣ1-3アルキル、アリールカルボニル（該アリールカルボニルは、１個のＣ1-6アルコキシで置換されてもよい。）、アリールスルホニル（該アリールスルホニルは、１個のＣ1-6アルキル又はハロＣ1-6アルキルで置換されてよい。）、又はオキソであり、
　このとき、置換基群α５のうち好ましい基は、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、飽和のヘテロシクリルＣ1-3アルコキシ、又はオキソである。 Preferred embodiments of ring A are the following (1) to (6).
(1) Preferred ring A is
C 3-8 cycloalkyl (the C 3-8 cycloalkyl may be substituted with one group selected from the substituent group α2);
Aryl (the aryl may be substituted with 1 to 2 groups selected from the same or different from substituent group α3);
Saturated heterocyclyl (the saturated heterocyclyl may be substituted with one group selected from substituent group α4), or heteroaryl (the heteroaryl is the same or different from substituent group α5) And may be substituted with 1 to 2 groups).
At this time, a preferable group in the substituent group α2 is C 1-6 alkyl, aryl, or a 4- to 8-membered saturated heterocyclylcarbonyl containing a nitrogen atom,
At this time, a preferable group in the substituent group α3 is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy or C 1-6 alkoxy), halo. C 1-6 alkyl, aryl, C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 Cycloalkoxy, aryloxy, heteroaryloxy (the aryloxy and heteroaryloxy may be substituted with one C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, or a nitrogen atom 4 to 8 membered saturated heterocyclylcarbonyl,
At this time, preferable groups in the substituent group α4 are aryl C 1-3 alkyl, arylcarbonyl (the arylcarbonyl may be substituted with one C 1-6 alkoxy), arylsulfonyl (the aryl Sulfonyl may be substituted with one C 1-6 alkyl or haloC 1-6 alkyl), or oxo;
At this time, a preferable group in the substituent group α5 is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl is one C 1-6 alkoxy). A saturated heterocyclyl, a C 3-8 cycloalkyl C 1-3 alkyl, an aryl C 1-3 alkyl (wherein the aryl C 1-3 alkyl is substituted with one halogen atom) C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (the aryloxy may be substituted with one halogen atom or C 1-6 alkyl). ), Heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy, with one C 1-6 alkyl It may be conversion.) Saturated heterocyclyl C 1-3 alkoxy, or oxo.
（２）より好ましい環Ａは、
　Ｃ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、Ｃ1-6アルキル、アリール、及び窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルからなる群から選ばれる１個の基で置換されてもよい。）、
　フェニル［該フェニルは、ハロゲン原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは、１個のヒドロキシ又はＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルキル、アリール、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、１個のＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ、ヘテロアリールオキシ（該アリールオキシ及びヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、飽和のヘテロシクリルＣ1-3アルキル、及び窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］、
　ジヒドロインデニル、
　アゼチジニル［該アゼチジニルは、アリールスルホニル（該アリールスルホニルは、１個のハロＣ1-6アルキルで置換されてよい。）］、
　ピペリジニル［該ピペリジニルは、アリールＣ1-3アルキル、アリールカルボニル（該アリールカルボニルは、１個のＣ1-6アルコキシで置換されてもよい。）、アリールスルホニル（該アリールスルホニルは、１個のハロＣ1-6アルキルで置換されてよい。）、及びオキソからなる群から選ばれる１個の基で置換されてもよい。］、
　ピリジル［該ピリジルは、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、及び飽和のヘテロシクリルＣ1-3アルコキシからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］、
　ピリミジニル［該ピリミジニルは、ハロゲン原子及びアリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）からなる群から選ばれる１個の基で置換されてもよい。］、
　ピラゾリル（該ピラゾリルは、Ｃ1-6アルキル及びフェニルからなる群から選ばれる１個の基で置換されてもよい。）、
　チアゾリル（該チアゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、
　ジヒドロピリジニル［該ジヒドロピリジニルは、アリールＣ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、及びオキソからなる群から同一に又は異なって選ばれる１個の基で置換されてもよい。］、
　ベンゾフラニル、
　ジヒドロベンゾフラニル（該ジヒドロベンゾフラニルは、ハロゲン原子、Ｃ1-6アルキルからなる群から同一に選ばれる１から２個の基で置換されてもよい。）、
　クロマニル、
　ジヒドロピラノピリジニル、
　ジヒドロフロピリジニル、
　テトラヒドロキノリル、
　テトラヒドロイソキノリル、
　ジヒドロベンゾジオキシニル、
　テトラヒドロトリアゾロアゼピニル
である。 (2) More preferable ring A is
C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted with one group selected from the group consisting of C 1-6 alkyl, aryl, and a 4- to 8-membered saturated heterocyclylcarbonyl containing nitrogen atom) May be)
Phenyl [the phenyl is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy or C 1-6 alkoxy), halo C 1-6 alkyl, aryl , C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy, hetero Aryloxy (the aryloxy and heteroaryloxy may be substituted with 1 C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, and a 4 to 8 membered saturated nitrogen atom It may be substituted with 1 to 2 groups selected from the group consisting of heterocyclylcarbonyl, the same or different. ],
Dihydroindenyl,
Azetidinyl [wherein the azetidinyl is arylsulfonyl, which may be substituted with one haloC 1-6 alkyl]],
Piperidinyl [wherein piperidinyl is aryl C 1-3 alkyl, arylcarbonyl (the arylcarbonyl may be substituted with 1 C 1-6 alkoxy), arylsulfonyl (wherein arylsulfonyl is 1 halo And optionally substituted with one group selected from the group consisting of oxo. ],
Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy). ), Saturated heterocyclyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (the aryloxy may be substituted with one halogen atom or C 1-6 alkyl) ), Heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy may be substituted with 1 C 1-6 alkyl.), And 1 to 2 groups selected identically or differently from the group consisting of saturated heterocyclyl C 1-3 alkoxy May be substituted. ],
Pyrimidinyl [The pyrimidinyl may be substituted with one group selected from the group consisting of a halogen atom and aryl (the aryl may be substituted with one C 1-6 alkoxy). ],
Pyrazolyl (which may be substituted with one group selected from the group consisting of C 1-6 alkyl and phenyl),
Thiazolyl (which may be substituted with one C 1-6 alkyl),
Dihydropyridinyl [the dihydropyridinyl is aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1-3 alkyl is substituted with one halogen atom And may be substituted with one group selected from the group consisting of oxo and the same or different. ],
Benzofuranyl,
Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups identically selected from the group consisting of a halogen atom and C 1-6 alkyl),
Chromanil,
Dihydropyranopyridinyl,
Dihydrofuropyridinyl,
Tetrahydroquinolyl,
Tetrahydroisoquinolyl,
Dihydrobenzodioxinyl,
Tetrahydrotriazoloazepinyl.
（３）さらに好ましい環Ａは、
　フェニル［該フェニルは、ハロゲン原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは、１個のヒドロキシ又はＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルキル、アリール、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、１個のＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ、ヘテロアリールオキシ（該アリールオキシ及びヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、飽和のヘテロシクリルＣ1-3アルキル、及び窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］、
　ジヒドロインデニル、
　ピリジル［該ピリジルは、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、及び飽和のヘテロシクリルＣ1-3アルコキシからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］、
　ジヒドロピリジニル［該ジヒドロピリジニルは、アリールＣ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、及びオキソからなる群から同一に又は異なって選ばれる１個の基で置換されてもよい。］、
　ベンゾフラニル、
　ジヒドロベンゾフラニル（該ジヒドロベンゾフラニルは、ハロゲン原子、Ｃ1-6アルキルからなる群から同一に選ばれる１から２個の基で置換されてもよい。）、
　クロマニル、
　ジヒドロピラノピリジニル、
　ジヒドロフロピリジニル、
　テトラヒドロキノリル、
　テトラヒドロイソキノリル、
　ジヒドロベンゾジオキシニル
である。 (3) Further preferred ring A is
Phenyl [the phenyl is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy or C 1-6 alkoxy), halo C 1-6 alkyl, aryl , C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy, hetero Aryloxy (the aryloxy and heteroaryloxy may be substituted with 1 C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, and a 4 to 8 membered saturated nitrogen atom It may be substituted with 1 to 2 groups selected from the group consisting of heterocyclylcarbonyl, the same or different. ],
Dihydroindenyl,
Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy). ), Saturated heterocyclyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (the aryloxy may be substituted with one halogen atom or C 1-6 alkyl) ), Heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy may be substituted with 1 C 1-6 alkyl.), And 1 to 2 groups selected identically or differently from the group consisting of saturated heterocyclyl C 1-3 alkoxy May be substituted. ],
Dihydropyridinyl [wherein dihydropyridinyl is aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (wherein aryl C 1-3 alkyl is substituted with one halogen atom) And may be substituted with one group selected from the group consisting of oxo and the same or different. ],
Benzofuranyl,
Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups identically selected from the group consisting of a halogen atom and C 1-6 alkyl),
Chromanil,
Dihydropyranopyridinyl,
Dihydrofuropyridinyl,
Tetrahydroquinolyl,
Tetrahydroisoquinolyl,
Dihydrobenzodioxinyl.
（４）ひとつの特に好ましい環Ａは、
　フェニル［該フェニルは、ハロゲン原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは、１個のヒドロキシ又はＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルキル、アリール、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、１個のＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ、ヘテロアリールオキシ（該アリールオキシ及びヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、飽和のヘテロシクリルＣ1-3アルキル、及び窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］
である。 (4) One particularly preferred ring A is
Phenyl [the phenyl is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with one hydroxy or C 1-6 alkoxy), halo C 1-6 alkyl, aryl , C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy, hetero Aryloxy (the aryloxy and heteroaryloxy may be substituted with 1 C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, and a 4 to 8 membered saturated nitrogen atom It may be substituted with 1 to 2 groups selected from the group consisting of heterocyclylcarbonyl, the same or different. ]
It is.
（５）他の特に好ましい環Ａは、
　ピリジル［該ピリジルは、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、及び飽和のヘテロシクリルＣ1-3アルコキシからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］、
　ジヒドロピリジニル［該ジヒドロピリジニルは、アリールＣ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、及びオキソからなる群から同一に又は異なって選ばれる１個の基で置換されてもよい。］
である。 (5) Another particularly preferred ring A is
Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy). ), Saturated heterocyclyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (the aryloxy may be substituted with one halogen atom or C 1-6 alkyl) ), Heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy, one C 1-6 alkyl may be substituted.), and heterocyclyl C 1-3 1 from two groups the same or different and selected from the group consisting of alkoxy of saturated May be substituted. ],
Dihydropyridinyl [wherein dihydropyridinyl is aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (wherein aryl C 1-3 alkyl is substituted with one halogen atom) And may be substituted with one group selected from the group consisting of oxo and the same or different. ]
It is.
（６）他の特に好ましい環Ａは、
　ジヒドロインデニル、
　ベンゾフラニル、
　ジヒドロベンゾフラニル（該ジヒドロベンゾフラニルは、ハロゲン原子、Ｃ1-6アルキルからなる群から同一に選ばれる１から２個の基で置換されてもよい。）、
　クロマニル、
　ジヒドロベンゾジオキシニル、
　ジヒドロピラノピリジニル、又は
　ジヒドロフロピリジニル
である。 (6) Another particularly preferred ring A is
Dihydroindenyl,
Benzofuranyl,
Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups identically selected from the group consisting of a halogen atom and C 1-6 alkyl),
Chromanil,
Dihydrobenzodioxinyl,
Dihydropyranopyridinyl or dihydrofuropyridinyl.
　本発明化合物のひとつの好ましい態様は、下記式（Ｉ－ａ）で示される化合物又はその製薬学的に許容される塩である。 One preferred embodiment of the compound of the present invention is a compound represented by the following formula (Ia) or a pharmaceutically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000006
 　　　　　　　　　（Ｉ－ａ）
Figure JPOXMLDOC01-appb-C000006
 (Ia)
　ここで、Ｒ1、Ｒ2、Ｗ1、及び環Ａの好ましい態様は、
上記に記載した通りである。 Here, preferred embodiments of R 1 , R 2 , W 1 , and ring A are:
As described above.
　式（Ｉ－ａ）において、より好ましい態様は、
　Ｒ1が、水素原子又はメチルであり、
　Ｒ2が、水素原子又はメトキシであり、
　Ｗ1が、メタンジイル、エタン－１，１－ジイル、又はプロパン－２，２－ジイルであり、
　環Ａが、フェニル［該フェニルは、フッ素原子、塩素原子、臭素原子、メチル（該メチルは、１個のメトキシで置換されてもよい。）、及びメトキシからなる群から同一に又は異なって選ばれる１～２個の基で置換されてもよい。］、ピラゾリル（該ピラゾリルは、１個のフェニルで置換されてもよい。）、ピリジル［該ピリジルは、エチル、イソプロピル、トリフルオロメチル、シクロプロピル、メトキシ、エトキシ、イソプロポキシ、シクロプロポキシ（該シクロプロポキシは、１個のメチルで置換されてもよい。）、シクロブトキシ、及びフェニル（該フェニルは、１個のメトキシで置換されてもよい。）からなる群から選ばれる１個の基で置換されてもよい。］、ジヒドロベンゾフラニル、又はジヒドロベンゾジオキシニル
である場合である。 In the formula (Ia), a more preferred embodiment is
R 1 is a hydrogen atom or methyl;
R 2 is a hydrogen atom or methoxy;
W 1 is methanediyl, ethane-1,1-diyl, or propane-2,2-diyl;
Ring A is phenyl [the phenyl is the same or different from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl (the methyl may be substituted with one methoxy), and methoxy. May be substituted with 1 to 2 groups. ], Pyrazolyl (which may be substituted with one phenyl), pyridyl [the pyridyl is ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, cyclopropoxy (the cyclopropoxy Propoxy may be substituted with one methyl group), cyclobutoxy, and phenyl (the phenyl group may be substituted with one methoxy group). May be. ], Dihydrobenzofuranyl, or dihydrobenzodioxinyl.
　式（Ｉ－ａ）において、さらに好ましい態様は、
　Ｒ1が、水素原子又はメチルであり、
　Ｒ2が、水素原子又はメトキシであり、
　Ｗ1が、メタンジイル、エタン－１，１－ジイル、又はプロパン－２，２－ジイルであり、
　環Ａが、フェニル（該フェニルは、フッ素原子、塩素原子、臭素原子、メチル、及びメトキシからなる群から選ばれる１個の基で置換されてもよい。）、ピリジル［該ピリジルは、トリフルオロメチル、イソプロポキシ、シクロプロポキシ（該シクロプロポキシは、１個のメチルで置換されてもよい。）、及びフェニル（該フェニルは、１個のメトキシで置換されてもよい。）からなる群から選ばれる１個の基で置換されてもよい。］、又はジヒドロベンゾフラニル
である場合である。 In the formula (Ia), a more preferred embodiment is
R 1 is a hydrogen atom or methyl;
R 2 is a hydrogen atom or methoxy;
W 1 is methanediyl, ethane-1,1-diyl, or propane-2,2-diyl;
Ring A is phenyl (the phenyl may be substituted with one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, and methoxy), pyridyl [the pyridyl is trifluoro Selected from the group consisting of methyl, isopropoxy, cyclopropoxy (the cyclopropoxy may be substituted with one methyl), and phenyl (the phenyl may be substituted with one methoxy). May be substituted with one group. Or dihydrobenzofuranyl.
　式（Ｉ－ａ）において、ひとつの特に好ましい態様は、
　Ｒ1が、水素原子であり、
　Ｒ2が、水素原子であり、
　Ｗ1が、メタンジイル又はエタン－１，１－ジイルであり、
　環Ａが、フェニル（該フェニルは、フッ素原子、塩素原子、臭素原子、メチル、及びメトキシからなる群から選ばれる１個の基で置換されてもよい。）又はジヒドロベンゾフラニル
である場合である。 In formula (Ia), one particularly preferred embodiment is
R 1 is hydrogen atom,
R 2 is a hydrogen atom,
W 1 is methanediyl or ethane-1,1-diyl;
When ring A is phenyl (the phenyl may be substituted with one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, and methoxy) or dihydrobenzofuranyl. is there.
　式（Ｉ－ａ）において、他の特に好ましい態様は、
　Ｒ1が、水素原子であり、
　Ｒ2が、メトキシであり、
　Ｗ1が、エタン－１，１－ジイル又はプロパン－２，２－ジイルであり、
　環Ａが、フェニル（該フェニルは、１個のフッ素原子で置換されてもよい。）又はピリジル［該ピリジルは、１個のフェニル（該フェニルは、１個のメトキシで置換されてもよい。）で置換されてもよい。］
である場合である。 In formula (Ia), other particularly preferred embodiments are:
R 1 is hydrogen atom,
R 2 is methoxy;
W 1 is ethane-1,1-diyl or propane-2,2-diyl;
Ring A is phenyl (the phenyl may be substituted with one fluorine atom) or pyridyl [the pyridyl is one phenyl (the phenyl may be substituted with one methoxy. ) May be substituted. ]
This is the case.
　本発明化合物の他の好ましい態様は、下記式（Ｉ－ｂ）で示される化合物又はその製薬学的に許容される塩である。 Another preferred embodiment of the compound of the present invention is a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000007
 　　　　　　　　　（Ｉ－ｂ）
Figure JPOXMLDOC01-appb-C000007
 (Ib)
　ここで、Ｒ1、Ｗ1、及び環Ａの好ましい態様は、
上記に記載した通りである。 Here, preferred embodiments of R 1 , W 1 , and ring A are:
As described above.
　式（Ｉ－ｂ）において、より好ましい態様は、
　Ｒ1が、水素原子又はメチルであり、
　Ｗ1が、メタンジイル、エタン－１，１－ジイル、又はプロパン－２，２－ジイルであり、
　環Ａが、フェニル（該フェニルは、フッ素原子、塩素原子、臭素原子、メチル、及びメトキシからなる群から選ばれる１個の基で置換されてもよい。）、ピリジル［該ピリジルは、トリフルオロメチル、イソプロポキシ、シクロプロポキシ（該シクロプロポキシは、１個のメチルで置換されてもよい。）、及びフェニル（該フェニルは、１個のメトキシで置換されてもよい。）からなる群から選ばれる１個の基で置換されてもよい。］、又はジヒドロベンゾフラニル
である場合である。 In the formula (Ib), a more preferred embodiment is
R 1 is a hydrogen atom or methyl;
W 1 is methanediyl, ethane-1,1-diyl, or propane-2,2-diyl;
Ring A is phenyl (the phenyl may be substituted with one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, and methoxy), pyridyl [the pyridyl is trifluoro Selected from the group consisting of methyl, isopropoxy, cyclopropoxy (the cyclopropoxy may be substituted with one methyl), and phenyl (the phenyl may be substituted with one methoxy). May be substituted with one group. Or dihydrobenzofuranyl.
　式（Ｉ－ｂ）において、さらに好ましい態様は、
　Ｒ1が、水素原子であり、
　Ｗ1が、エタン－１，１－ジイルであり、
　環Ａが、フェニル（該フェニルは、１個のメトキシで置換されてもよい。）
である場合である。 In the formula (Ib), a more preferred embodiment is
R 1 is a hydrogen atom,
W 1 is ethane-1,1-diyl,
Ring A is phenyl (the phenyl may be substituted with 1 methoxy)
This is the case.
　本発明の化合物は、トリアゾリルで置換されたヘテロアリールを有する化合物であり、本発明の化合物はその製薬学的に許容される塩でも良い（以下、適宜「本発明の化合物」という。）。 The compound of the present invention is a compound having a heteroaryl substituted with triazolyl, and the compound of the present invention may be a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compound of the present invention” as appropriate).
　本発明の化合物には互変異性体も含まれる。互変異性体の例として、上記式（Ｉ）で表される化合物及びその互変異性体（Ｉ’）及び（Ｉ”）を以下に示す。 The compounds of the present invention include tautomers. As examples of tautomers, compounds represented by the above formula (I) and tautomers (I ′) and (I ″) thereof are shown below.
Figure JPOXMLDOC01-appb-C000008
      
  　 
Figure JPOXMLDOC01-appb-C000008
      
  　 
　製薬学的に許容される塩としては、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩、硫酸塩、硝酸塩のような鉱酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、トリフルオロメタンスルホン酸塩のようなスルホン酸塩、シュウ酸塩、酒石酸塩、クエン酸塩、マレイン酸塩、コハク酸塩、酢酸塩、トリフルオロ酢酸塩、安息香酸塩、マンデル酸塩、アスコルビン酸塩、乳酸塩、グルコン酸塩、リンゴ酸塩のような有機酸塩等の酸付加塩、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩、又は、リチウム塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩のような無機塩若しくはアンモニウム塩、トリエチルアミン塩、ジイソプロピルアミン塩、シクロヘキシルアミン塩のような有機塩基との塩が挙げられる。なお、塩には、含水塩が含まれる。 Examples of pharmaceutically acceptable salts include hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, nitrates, mineral salts such as methanesulfonate, ethanesulfone, and the like. Acid salt, benzene sulfonate, p-toluene sulfonate, sulfonate such as trifluoromethane sulfonate, oxalate, tartrate, citrate, maleate, succinate, acetate, tri Acid addition salts such as organic acid salts such as fluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, malate, glycine salt, lysine salt, arginine salt, ornithine salt, Amino acid salts such as glutamate and aspartate, or inorganic or ammonium salts such as lithium, sodium, potassium, calcium and magnesium salts; Triethylamine salts, diisopropylamine salts, salts with organic bases such as cyclohexylamine salts. The salt includes a hydrated salt.
　本発明の化合物は、不斉中心を持つことがあり、その場合種々の光学異性体が存在する。したがって、本発明の化合物は、（Ｒ）および（Ｓ）の別々の光学活性体として、およびラセミ体又は（ＲＳ）混合物として存在し得る。また、不斉中心を２個以上持つ化合物の場合には、さらにそれぞれの光学異性によるジアステレオマーも存在する。本発明の化合物は、これらすべての型を、任意の割合で含む混合物も含む。たとえば、ジアステレオマーは当業者によく知られた方法、たとえば分別結晶法等によって分離することができ、また、光学活性体はこの目的のためによく知られた有機化学的手法によって得ることができる。また、本発明の化合物には、シス体、トランス体などの幾何異性体が存在することがある。さらに、本発明の化合物は、互変異性を有し、種々の互変異性体が存在する。本発明の化合物は、それらの異性体、及びそれらの異性体を任意の割合で含んだ混合物も含む。 The compound of the present invention may have an asymmetric center, in which case various optical isomers exist. Thus, the compounds of the present invention may exist as separate optically active forms of (R) and (S) and as racemates or (RS) mixtures. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention also include mixtures containing all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can. The compound of the present invention may have geometric isomers such as cis isomer and trans isomer. Furthermore, the compound of the present invention has tautomerism, and various tautomers exist. The compounds of the present invention include those isomers and mixtures containing these isomers in any proportion.
　さらに、本発明化合物又はその塩が水和物又は溶媒和物を形成する場合、それらも本発明化合物又はその塩の範囲内に含まれる。 Furthermore, when the compound of the present invention or a salt thereof forms a hydrate or solvate, they are also included in the scope of the compound of the present invention or a salt thereof.
　ＰＨＤ２（プロリルヒドロキシラーゼドメイン－２）とは、プロリルヒドロキシラーゼファミリーに属するタンパク質である。ＰＨＤ２は、低酸素誘導因子（ＨＩＦ）プロリルヒドロキシラーゼ活性を有する酵素であり、特に、通常の酸素状態においてＨＩＦ－１α、ＨＩＦ－２α、ＨＩＦ－３α分子（以下一括してＨＩＦ－α分子と呼ぶ）の特定のプロリン残基を水酸化（ヒドロキシ化）する作用を有する。 PHD2 (prolyl hydroxylase domain-2) is a protein belonging to the prolyl hydroxylase family. PHD2 is an enzyme having hypoxia-inducible factor (HIF) prolyl hydroxylase activity, and in particular under normal oxygen conditions, HIF-1α, HIF-2α, HIF-3α molecules (hereinafter collectively referred to as HIF-α molecules). Has a function of hydroxylating a specific proline residue.
　ＨＩＦ－α因子は、造血因子であるエリスロポエチンの転写因子である。ＰＨＤ２はＨＩＦを水酸化することで分解へと促し、過剰なエリスロポエチン産生を抑制している。本発明化合物は、前述の通り優れたＰＨＤ２阻害作用を有する。したがって、ＰＨＤ２の阻害によって、ＨＩＦ－α分子の特定のプロリン残基を水酸化することを防ぎ、ＨＩＦ－α分子の安定化に寄与する。これによって体内のＥＰＯの産生を促し、貧血又は貧血に関連する疾患を予防又は治療することができる。 HIF-α factor is a transcription factor for erythropoietin, a hematopoietic factor. PHD2 promotes decomposition by hydroxylating HIF and suppresses excessive erythropoietin production. The compound of the present invention has an excellent PHD2 inhibitory action as described above. Therefore, inhibition of PHD2 prevents hydroxylation of specific proline residues in the HIF-α molecule, contributing to stabilization of the HIF-α molecule. Thereby, production of EPO in the body can be promoted, and anemia or anemia-related disease can be prevented or treated.
　よって、本発明化合物は、ＰＨＤ２阻害剤、ＥＰＯ産生促進剤、又は貧血若しくは貧血に関連する疾患の予防又は治療剤の有効成分として用いることができる。 Therefore, the compound of the present invention can be used as an active ingredient of a PHD2 inhibitor, an EPO production promoter, or an anemia or an anemia-related disease prevention or treatment agent.
　ここで、「貧血」には、腎臓の機能低下によりＥＰＯ産生能が落ちることで発症する「腎性貧血」、鉄代謝の不全による「鉄欠乏性貧血」の他、特定の原因によるその他の型の貧血が含まれる。 Here, “anemia” includes “renal anemia” that develops due to a decrease in EPO production ability due to decreased kidney function, “iron deficiency anemia” due to iron metabolism failure, and other types caused by specific causes. Anemia is included.
　ここで、「貧血に関連する疾患」とは、慢性腎臓病、心不全などが挙げられる。 Here, “diseases related to anemia” include chronic kidney disease, heart failure and the like.
　また本発明化合物により、ＰＨＤ２を阻害しＨＩＦ－αの安定化を促すことで、虚血性疾患の改善、炎症性疾患の改善が期待できる。またＨＩＦ－α安定化によりＶＥＧＦなど血管新生を促す因子の発現増加のほか、発現されたＥＰＯによる臓器保護作用などが期待できる。ここで言う臓器とは、腎臓、すい臓、脳などが含まれる。 Moreover, the compound of the present invention can be expected to improve ischemic disease and inflammatory disease by inhibiting PHD2 and promoting stabilization of HIF-α. In addition to the increase in the expression of factors that promote angiogenesis such as VEGF by stabilizing HIF-α, organ protective action by the expressed EPO can be expected. The organs mentioned here include the kidney, pancreas, brain and the like.
　本発明化合物は、単独又は薬学的あるいは薬剤学的に許容される添加剤と共に投与することができる。 The compound of the present invention can be administered alone or with a pharmaceutically or pharmaceutically acceptable additive.
　本発明の化合物を医薬として用いるためには、固体組成物、液体組成物及びその他の組成物のいずれの形態でもよく、必要に応じて最適のものが選択される。本発明の医薬は、本発明の化合物に薬学的に許容される添加剤を配合して製造することができる。具体的には、常用の賦形剤又は希釈剤、そして、必要に応じて一般に使用される結合剤、崩壊剤、潤滑剤、被覆剤、糖衣剤、pH調整剤、溶解剤又は水性若しくは非水性溶媒などを添加し、常用の製剤技術によって、錠剤、丸剤、カプセル剤、顆粒剤、粉剤、散剤、液剤、乳剤、懸濁剤、注射剤等に調製する事ができる。前記添加剤としては、たとえば、水、乳糖、デキストロース、フラクトース、ショ糖、ソルビトール、マンニトール、ポリエチレングリコール、プロピレングリコール、デンプン、コーンスターチ、ガム、ゼラチン、アルギネート、ケイ酸カルシウム、リン酸カルシウム、セルロース、水シロップ、メチルセルロース、ポリビニルピロリドン、アルキルパラヒドロキシベンゾエート、タルク、ステアリン酸、ステアリン酸マグネシウム、寒天、ペクチン、アラビアゴム、グリセリン、ゴマ油、オリーブ油、大豆油カカオバター、エチレングリコール、低粘度ヒドロキシプロピルセルロース（ＨＰＣ－Ｌ）、微結晶セルロース、カルボキシメチルセルロース（ＣＭＣ）、カルボキシメチルセルロースナトリウム（ＣＭＣ－Ｎａ）等やその他常用されるものを挙げることができる。 In order to use the compound of the present invention as a medicine, any form of a solid composition, a liquid composition and other compositions may be used, and the optimum one is selected as necessary. The medicament of the present invention can be produced by blending the compound of the present invention with a pharmaceutically acceptable additive. Specifically, conventional excipients or diluents, and commonly used binders, disintegrating agents, lubricants, coating agents, dragees, pH adjusting agents, solubilizers, or aqueous or non-aqueous It can be prepared into tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, etc. by adding conventional solvents and the like. Examples of the additive include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, Methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil cocoa butter, ethylene glycol, low viscosity hydroxypropylcellulose (HPC-L) , Microcrystalline cellulose, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), etc. It is what can be mentioned.
　また、本発明化合物は、α、β若しくはγ－シクロデキストリン又はメチル化シクロデキストリン等と包接化合物を形成させて製剤化することができる。 In addition, the compound of the present invention can be formulated by forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin or the like.
　本発明化合物の製剤の製造例を以下に示す。 Examples of the preparation of the compound of the present invention are shown below.
製剤例１
　以下の成分を含有する顆粒剤を製造する。 Formulation Example 1
A granule containing the following ingredients is produced.
　成分：式（Ｉ）で表される化合物又はその製薬学的に許容される塩、乳糖、コーンスターチ、ＨＰＣ－Ｌ。 Component: A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, lactose, corn starch, HPC-L.
　式（Ｉ）で表される化合物又はその製薬学的に許容される塩と乳糖をふるいに通す。コーンスターチをふるいに通す。これらを混合機にて混合する。混合末にＨＰＣ－Ｌ水溶液を添加し、練合、造粒（押し出し造粒）した後、乾燥する。得られた乾燥顆粒を振動ふるいで篩過し顆粒剤を得る。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof and lactose are passed through a sieve. Pass cornstarch through sieve. These are mixed with a mixer. An HPC-L aqueous solution is added to the mixed powder, kneaded, granulated (extruded granulation), and dried. The obtained dried granules are sieved with a vibration sieve to obtain granules.
製剤例２
　以下の成分を含有するカプセル充填用散剤を製造する。 Formulation Example 2
A powder for capsule filling containing the following components is produced.
　成分：式（Ｉ）で表される化合物又はその製薬学的に許容される塩、乳糖、コーンスターチ、ステアリン酸マグネシウム。 Component: Compound represented by formula (I) or a pharmaceutically acceptable salt thereof, lactose, corn starch, magnesium stearate.
　式（Ｉ）で表される化合物又はその製薬学的に許容される塩と乳糖をふるいに通す。コーンスターチをふるいに通す。これらとステアリン酸マグネシウムを混合機にて混合し、散剤を得る。得られた散剤はカプセルに充填することができる。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof and lactose are passed through a sieve. Pass cornstarch through sieve. These and magnesium stearate are mixed in a mixer to obtain a powder. The resulting powder can be filled into capsules.
製剤例３
　以下の成分を含有するカプセル充填用顆粒剤を製造する。 Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
　成分：式（Ｉ）で表される化合物又はその製薬学的に許容される塩、乳糖、コーンスターチ、ＨＰＣ－Ｌ。 Component: A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, lactose, corn starch, HPC-L.
　式（Ｉ）で表される化合物又はその製薬学的に許容される塩と乳糖をふるいに通す。コーンスターチをふるいに通す。これらを混合機にて混合する。混合末にＨＰＣ－Ｌ水溶液を添加し、練合、造粒した後、乾燥する。得られた乾燥顆粒を振動ふるいで篩過し整粒し、顆粒を得る。得られた顆粒はカプセルに充填することができる。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof and lactose are passed through a sieve. Pass cornstarch through sieve. These are mixed with a mixer. An HPC-L aqueous solution is added to the mixed powder, kneaded, granulated, and dried. The obtained dried granule is sieved with a vibration sieve and sized to obtain a granule. The resulting granules can be filled into capsules.
製剤例４
　以下の成分を含有する錠剤を製造する。 Formulation Example 4
A tablet containing the following ingredients is produced.
　成分：式（Ｉ）で表される化合物又はその製薬学的に許容される塩、乳糖、微結晶セルロース、ステアリン酸マグネシウム、ＣＭＣ－Ｎａ。 Component: Compound represented by formula (I) or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, magnesium stearate, CMC-Na.
　式（Ｉ）で表される化合物又はその製薬学的に許容される塩と乳糖と微結晶セルロース、ＣＭＣ－Ｎａをふるいに通し、混合する。混合末にステアリン酸マグネシウムを添加し、製剤用混合末を得る。本混合末を直打し錠剤を得る。 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, and CMC-Na are passed through a sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a tablet.
　本発明化合物をＰＨＤ２阻害剤などとして使用する場合は、本発明化合物をそのまま経口投与、又は非経口投与してもよい。また、本発明化合物を有効成分として含む剤として経口投与、又は非経口投与してもよい。非経口投与としては、静脈内投与、経鼻投与、経皮投与、皮下投与、筋肉内投与、舌下投与があげられる。 When the compound of the present invention is used as a PHD2 inhibitor or the like, the compound of the present invention may be administered orally or parenterally as it is. Moreover, you may administer orally or parenterally as an agent which contains this invention compound as an active ingredient. Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.
　本発明化合物の投与量は、投与対象、投与ルート、対象疾患、症状などによっても異なるが、例えば、成人の貧血を呈した患者に経口投与する場合、通常１回量として０．１ｍｇ～１０００ｍｇ、好ましくは１ｍｇ～２００ｍｇであり、この量を、１日に１回～３回、又は２日～３日に１回投与するのが望ましい。 The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like. For example, when orally administered to a patient with adult anemia, 0.1 mg to 1000 mg as a single dose, The dose is preferably 1 mg to 200 mg, and it is desirable to administer this amount once to three times a day or once every two to three days.
　本発明化合物には、後述の通り、ＰＨＤ２阻害作用が確認された。そして、前記式（Ｉ－ａ）及び（Ｉ－ｂ）で示される好ましい態様の化合物には、その投与により、正常マウスやラットにおいて、エリスロポエチンの産生の増加が確認された。 As described later, the present compound was confirmed to have a PHD2 inhibitory action. In addition, it was confirmed that the administration of the preferred embodiments of the compounds represented by the formulas (Ia) and (Ib) increased erythropoietin production in normal mice and rats.
　エリスロポエチンの産生の増加を確認する方法については、公知の手法に従って行うことができる。例えば、Ｂｌｏｏｄ，１９８９，７４，６４５－６５１に、血中のエリスロポエチンの濃度を測定する方法が開示されている。 The method for confirming the increase in production of erythropoietin can be performed according to a known method. For example, Blood, 1989, 74, 645-651 discloses a method for measuring the concentration of erythropoietin in blood.
　なお、本発明化合物の中には、医薬品として望ましい性質を有している化合物がある。例えば、貧血治療の際、エリスロポエチンの過剰な産生は、二次的多血症等、身体へ悪影響を与えるが、エリスロポエチンの過剰な産生を回避しうる性質が挙げられる。 Among the compounds of the present invention, there are compounds having desirable properties as pharmaceuticals. For example, in the treatment of anemia, excessive production of erythropoietin adversely affects the body, such as secondary polycythemia, but has the property of avoiding excessive production of erythropoietin.
　本発明の化合物のＰＨＤ２阻害作用を評価するには、例えば、本明細書の試験例に記載した方法など、公知の手法に従って行うことができる。 The PHD2 inhibitory action of the compound of the present invention can be evaluated according to a known method such as the method described in Test Examples of the present specification.
　以下に、本発明に係る化合物の製造方法を詳細に説明するが、例示されたものに特に限定されない。また、反応に使用する溶媒においても、各反応を阻害しないものであればよく、特に下記の記載に限定されない。 Hereinafter, the production method of the compound according to the present invention will be described in detail, but it is not particularly limited to those exemplified. Moreover, the solvent used for the reaction is not particularly limited as long as it does not inhibit each reaction.
　以下、式（Ｉ）で表される化合物（以下、化合物（Ｉ）と記載することもある。）の製造法について説明する。 Hereinafter, a method for producing a compound represented by the formula (I) (hereinafter sometimes referred to as compound (I)) will be described.
　化合物（Ｉ）は、自体公知の方法、例えば、以下に示す製造法１～４又はこれらに準ずる方法により製造することができる。なお、以下の各製造方法において、原料化合物は塩として用いてもよく、該塩としては、例えば、前記の「製薬学的に許容される塩」が挙げられる。また、目的化合物も塩として得ることができ、該塩としては、例えば、前記の「製薬学的に許容される塩」が挙げられる。 Compound (I) can be produced by a method known per se, for example, the production methods 1 to 4 shown below or a method analogous thereto. In each of the following production methods, the raw material compound may be used as a salt, and examples of the salt include the above-mentioned “pharmaceutically acceptable salts”. The target compound can also be obtained as a salt, and examples of the salt include the above-mentioned “pharmaceutically acceptable salts”.
　さらに、得られた目的化合物は、未精製のまま、次工程に用いることもできる。 Furthermore, the obtained target compound can be used in the next step without purification.
　本発明の化合物（Ｉ）に属する化合物（Ｉ－１０）は、例えば、下記製造法１又はこれらに準ずる方法により製造することができる。 The compound (I-10) belonging to the compound (I) of the present invention can be produced, for example, by the following production method 1 or a method analogous thereto.
製造法１
Figure JPOXMLDOC01-appb-C000009
      
  　 
［式中、Ｒ１、Ｒ２、Ｒ３、Ｘ、Ｙ（この場合、Ｙは式-ＣＯＮＲ４１-Ｗ１-、式-ＣＯＮＲ４２-Ｗ２-ＣＯ-、式（β）で表される構造を示し、Ｒ４１、Ｗ１、Ｒ４２、Ｗ２、βは前記と同意義である。）、環Ａ、環Ｂ、Ｗ３は前記と同意義であり、Ｒ１’は水素原子又はＣ１－３アルキル（該Ｃ１－３アルキルは、ヒドロキシで置換されてもよい。また、該ヒドロキシは場合によってはアルコールの一般的な保護基、例えば、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　i n　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（第３版、１９９９、 Ｇ. Ｍ. Ｗ u t s 、Ｔ. Ｗ. Ｇｒｅｅｎｅ編）等に記載されている基、具体的にはベンジル、４－メトキシベンジル等で保護されてもよい。）を示し、Ｐ１はカルボキシの一般的な保護基、例えば、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　i n　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（第３版、１９９９、 Ｇ. Ｍ. Ｗ u t s 、Ｔ. Ｗ. Ｇｒｅｅｎｅ編）等に記載されている基を示し、具体的にはＣ１－６アルキル、ベンジル、４－メトキシベンジル、２－（トリメチルシリル）エチル等を示す。Ｐ２はトリアゾールの保護基、例えばテトラヒドロピラニル、トリフェニルメチル等を示す。］ Manufacturing method 1
Figure JPOXMLDOC01-appb-C000009

[Wherein, R 1 , R 2 , R 3 , X, Y (in this case, Y is represented by the formula -CONR 41 -W 1- , the formula -CONR 42 -W 2 -CO-, the formula (β) Wherein R 41 , W 1 , R 42 , W 2 and β are as defined above), ring A, ring B and W 3 are as defined above, and R 1 ′ is a hydrogen atom or C 1-3 alkyl (wherein the C 1-3 alkyl may be substituted with hydroxy. In some cases, the hydroxy may be a common protecting group for alcohol, such as Protective Groups in Organic Synthesis (3rd edition, 1999, G. M. W uts, T . W. Greene ed) like group as described in, specifically, benzyl, may be protected by 4-methoxybenzyl and the like.) indicates, P 1 is carboxy General protecting groups of, for example, Pro ective Groups i n Organic Synthesis (third edition, 1999, G. M. W u t s, T. W. Greene ed) represents a group described in such, in particular C 1-6 alkyl, benzyl, 4- Methoxybenzyl, 2- (trimethylsilyl) ethyl and the like are shown. P 2 represents a protecting group for triazole, such as tetrahydropyranyl, triphenylmethyl and the like. ]
［工程１－１］
　本工程は化合物（Ｉ－１）をアルコキシドと反応させた後、化合物（Ｉ－２）を加えて、１，２，４－トリアゾール環を構築し、化合物（Ｉ－３）を製造する方法である。アルコキシドは通常、ナトリウムメトキシド、ナトリウムエトキシド等が挙げられる。反応に用いられる溶媒は、メタノール、エタノール等のアルコール系溶媒、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒等が挙げられる。 [Step 1-1]
In this step, compound (I-1) is reacted with an alkoxide, then compound (I-2) is added to construct a 1,2,4-triazole ring, and compound (I-3) is produced. is there. Examples of the alkoxide usually include sodium methoxide, sodium ethoxide and the like. Solvents used in the reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, and aromatic hydrocarbon solvents such as toluene and xylene. Is mentioned.
　これらの反応は、通常室温～還流温度で行うことができる。 These reactions can usually be performed at room temperature to reflux temperature.
　このようにして得られる化合物（Ｉ－３）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (I-3) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程１－２］
　本工程は化合物（Ｉ－３）の１，２，４－トリアゾール環を適当な保護基Ｐ２で保護することにより、化合物（Ｉ－４）を製造する方法である。保護基Ｐ２はテトラヒドロピラニル、トリフェニルメチル等が挙げられる。例えば、保護基Ｐ２がテトラヒドロピラニルの場合は、酸触媒下、化合物（Ｉ－３）を３，４－ジヒドロ－２Ｈ－ピランと反応させることで得られる。反応に用いられる酸は、ｐ－トルエンスルホン酸一水和物、メタンスルホン酸などが挙げられる。反応に用いられる溶媒は、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒、酢酸エチル、Ｎ，Ｎ－ジメチルホルムアミド等の非プロトン性極性溶媒が挙げられる。保護基Ｐ２がトリフェニルメチルの場合は、塩基存在下、化合物（Ｉ－３）をトリフェニルメチルクロリド等と反応させることで得られる。反応に用いられる塩基はトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、水素化ナトリウム等が挙げられる。反応に用いられる溶媒は、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド等の非プロトン性極性溶媒が挙げられる。 [Step 1-2]
This step is by protecting the 1,2,4-triazole ring of compound (I-3) with a suitable protecting group P 2, which is a method for producing a compound (I-4). Protecting group P 2 is tetrahydropyranyl, triphenylmethyl, and the like. For example, when the protecting group P 2 is tetrahydropyranyl, it can be obtained by reacting compound (I-3) with 3,4-dihydro-2H-pyran in the presence of an acid catalyst. Examples of the acid used in the reaction include p-toluenesulfonic acid monohydrate and methanesulfonic acid. Solvents used in the reaction are ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, ethyl acetate, N, N-dimethylformamide. And aprotic polar solvents such as When the protecting group P 2 is triphenylmethyl, it can be obtained by reacting compound (I-3) with triphenylmethyl chloride or the like in the presence of a base. Examples of the base used in the reaction include triethylamine, N, N-diisopropylethylamine, sodium hydride and the like. Solvents used in the reaction include ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, N, N-dimethylformamide, N, Examples include aprotic polar solvents such as N-dimethylacetamide.
　これらの反応は、通常０℃～還流温度で行うことができる。 These reactions can usually be performed at 0 ° C. to reflux temperature.
　このようにして得られる化合物（Ｉ－４）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (I-4) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　なお、本発明の化合物には互変異性体が含まれるのと同様に、保護基Ｐ２で保護された化合物（Ｉ－４）等にも異性体が含まれる場合がある。異性体の例として、化合物（Ｉ－４）及びその異性体（Ｉ－４’）及び（Ｉ－４”）を以下に示す。 It should be noted that the compound of the present invention includes tautomers, and the compound (I-4) protected with the protecting group P 2 may contain isomers. As examples of isomers, compound (I-4) and isomers (I-4 ′) and (I-4 ″) are shown below.
Figure JPOXMLDOC01-appb-C000010
      
  　 
Figure JPOXMLDOC01-appb-C000010
      
  　 
［工程１－３］
　本工程は、化合物（Ｉ－４）のカルボキシの保護基Ｐ１を脱保護することにより、化合物（Ｉ－５）を製造する方法である。この反応は例えば、Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　i n　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ（第３版、１９９９、 Ｇ. Ｍ. Ｗ u t s 、Ｔ. Ｗ. Ｇｒｅｅｎｅ編）等に記載された方法又はそれに準じた方法で行うことができる。具体的には、保護基Ｐ１がｔｅｒｔ－ブチル、４－メトキシベンジル、トリメチルシリルの場合は、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒中、塩酸等の鉱酸や酢酸、トリフルオロ酢酸等の有機酸を用い、化合物（Ｉ－５）を製造することができる。保護基Ｐ１がベンジル、４－メトキシベンジルの場合は、メタノール、エタノール等のアルコール系溶媒、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒中、パラジウム－カーボン等の触媒存在下、加水素分解することにより化合物（Ｉ－５）を製造することもできる。保護基Ｐ１が２－（トリメチルシリル）エチル、トリメチルシリル、ｔｅｒｔ－ブチルジメチルシリルの場合は、フッ化カリウム、テトラブチルアンモニウムフルオリド等で処理することで化合物（Ｉ－５）を製造することもできる。 [Step 1-3]
This step is a method for producing compound (I-5) by deprotecting the carboxy-protecting group P 1 of compound (I-4). This reaction can be performed by, for example, the method described in Protective Groups in Organic Synthesis (3rd edition, 1999, edited by GM Wuts, edited by TW Greene), or the like. Specifically, when the protecting group P 1 is tert-butyl, 4-methoxybenzyl or trimethylsilyl, ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, toluene, xylene and the like Compound (I-5) can be produced using a mineral acid such as hydrochloric acid or an organic acid such as acetic acid or trifluoroacetic acid in the above aromatic hydrocarbon solvent. When the protecting group P 1 is benzyl or 4-methoxybenzyl, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, toluene, xylene and the like Compound (I-5) can also be produced by hydrogenolysis in the presence of a catalyst such as palladium-carbon in the above aromatic hydrocarbon solvent. When the protecting group P 1 is 2- (trimethylsilyl) ethyl, trimethylsilyl, tert-butyldimethylsilyl, compound (I-5) can also be produced by treatment with potassium fluoride, tetrabutylammonium fluoride or the like. .
　これらの反応は、通常室温～還流温度で行うことができる。 These reactions can usually be performed at room temperature to reflux temperature.
　このようにして得られる化合物（Ｉ－５）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (I-5) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程１－４］
　本工程は化合物（Ｉ－５）と化合物（Ｉ－６）、化合物（Ｉ－７）、又は化合物（Ｉ－８）との縮合剤を用いた縮合反応により、化合物（Ｉ－９）を製造する方法である。反応に用いられる溶媒はジエチルエーテル、テトラヒドロフラン、ジオキサン、１，２－ジメトキシエタン等のエーテル系溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒、酢酸エチル、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド等の非プロトン性極性溶媒等が挙げられる。 [Step 1-4]
In this step, compound (I-9) is produced by a condensation reaction of compound (I-5) with compound (I-6), compound (I-7), or compound (I-8) using a condensing agent. It is a method to do. Solvents used in the reaction are ether solvents such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, Examples include aprotic polar solvents such as ethyl acetate, acetonitrile, and N, N-dimethylformamide.
　本反応には添加剤として、塩基を用いることができる。塩基の例としてはトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ルチジン、ピリジン等が挙げられる。 In this reaction, a base can be used as an additive. Examples of the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, lutidine, pyridine and the like.
　反応に用いる縮合剤はＯ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ'，Ｎ'－テトラメチルウロニウムヘキサフルオロリン酸塩（ＨＡＴＵ）、Ｏ－ベンゾトリアゾール－１－イル－Ｎ，Ｎ，Ｎ'，Ｎ'－テトラメチルウロニウムヘキサフルオロリン酸塩（ＨＢＴＵ）、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（ＥＤＣＩ）、ジシクロへキシルカルボジイミド（ＤＣＣ）、１，１'－カルボニルビス（１Ｈ－イミダゾール）（ＣＤＩ）、（１Ｈ－ベンゾトリアゾール－１－イルオキシ）（トリピロリジン－１－イル）ホスホニウムヘキサフルオロリン酸塩（ＰｙＢＯＰ）、４－（４，６－ジメ卜キシ－１，３，５－卜リアジン－２－イル）－４－メチルモルホリニウムクロリド（ＤＭＴ－ＭＭ）等を挙げることができる。更に添加剤として、１－ヒドロキシアザベンゾトリアゾール（ＨＯＡｔ）、１－ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、又はＮ，Ｎ－ジメチルアミノピリジン等を加えてもよい。 The condensing agent used in the reaction is O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-1- Ile-N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide ( DCC), 1,1′-carbonylbis (1H-imidazole) (CDI), (1H-benzotriazol-1-yloxy) (tripyrrolidin-1-yl) phosphonium hexafluorophosphate (PyBOP), 4- ( 4,6-Dimethyl-1,3,5-soriadin-2-yl) -4-methylmorpholinium chloride (DMT-MM), etc. It can be mentioned. Further, 1-hydroxyazabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), N, N-dimethylaminopyridine, or the like may be added as an additive.
　これらの反応は通常０℃～還流温度で行うことができる。 These reactions can usually be performed at 0 ° C. to reflux temperature.
　このようにして得られる化合物（Ｉ－９）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (I-9) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程１－５］
　本工程は、化合物（Ｉ－９）のトリアゾールの保護基Ｐ２を脱保護することにより、化合物（Ｉ－１０）を製造する方法である。例えば、保護基Ｐ２がテトラヒドロピラニルの場合は、メタノール、エタノール等のアルコール系溶媒、又はこれらと水との任意の比率の混合溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒中、塩酸等の鉱酸や酢酸、トリフルオロ酢酸等の有機酸を用い、化合物（Ｉ－１０）を製造することができる。保護基Ｐ２がトリフェニルメチルの場合は上記に準ずる方法にて化合物（Ｉ－１０）を製造することもできる。 [Step 1-5]
In this step, by deprotecting the protective group P 2 of the triazole compound (I-9), a method for producing a compound (I-10). For example, when the protecting group P 2 is tetrahydropyranyl, an alcohol solvent such as methanol or ethanol, a mixed solvent of any ratio of these with water, a halogenated hydrocarbon solvent such as methylene chloride or chloroform, toluene Compound (I-10) can be produced by using a mineral acid such as hydrochloric acid or an organic acid such as acetic acid or trifluoroacetic acid in an aromatic hydrocarbon solvent such as xylene. When the protecting group P 2 is triphenylmethyl, the compound (I-10) can also be produced by a method analogous to the above.
　これらの反応は、通常室温～還流温度で行うことができる。 These reactions can usually be performed at room temperature to reflux temperature.
　このようにして得られる化合物（Ｉ－１０）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (I-10) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）に属する化合物（II－７）は、例えば、下記製造法２又はこれらに準ずる方法により製造することができる。 Compound (II-7) belonging to compound (I) of the present invention can be produced, for example, by the following production method 2 or a method analogous thereto.
製造法２
Figure JPOXMLDOC01-appb-C000011
      
  　 
［式中、Ｒ１、Ｒ２、Ｒ３、Ｘ、Ｐ２、環Ａは前記と同意義である。Ｐ３はＣ１－６アルキル、ベンジル、４－メトキシベンジルを示す。Ｚは塩素原子、臭素原子、又はヒドロキシを示す。］ Manufacturing method 2
Figure JPOXMLDOC01-appb-C000011

[Wherein, R 1 , R 2 , R 3 , X, P 2 and ring A are as defined above. P 3 represents C 1-6 alkyl, benzyl, 4-methoxybenzyl. Z represents a chlorine atom, a bromine atom, or hydroxy. ]
［工程２－１］
　本工程は、化合物（II－１）のＣｕｒｔｉｕｓ転位で生成するイソシアネートと、化合物（II－２）とを反応させて化合物（II－３）を製造する方法である。 [Step 2-1]
This step is a method for producing a compound (II-3) by reacting an isocyanate produced by the Curtius rearrangement of the compound (II-1) with the compound (II-2).
　Ｃｕｒｔｉｕｓ転位で用いるアジド化剤には、ジフェニルリン酸アジド、ビス（ｐ－ニトロフェニル）リン酸アジド等が挙げられる。反応に用いる溶媒はトルエン、キシレン等の芳香族炭化水素系溶媒、１，２－ジクロロエタン、クロロホルム等のハロゲン化炭化水素系溶媒等が挙げられる。 Examples of the azidating agent used in the Curtius rearrangement include diphenyl phosphate azide and bis (p-nitrophenyl) phosphate azide. Examples of the solvent used in the reaction include aromatic hydrocarbon solvents such as toluene and xylene, and halogenated hydrocarbon solvents such as 1,2-dichloroethane and chloroform.
　本反応には添加剤として塩基を用いることができる。塩基の例としてはトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等が挙げられる。 In this reaction, a base can be used as an additive. Examples of the base include triethylamine, N, N-diisopropylethylamine and the like.
　これらの反応は、通常室温～還流温度で行うことができる。 These reactions can usually be performed at room temperature to reflux temperature.
　このようにして得られる化合物（II－３）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (II-3) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程２－２］
　本工程は、カルバメートである化合物（II－３）から、化合物（II－４）を製造する方法である。例えば、Ｐ３がベンジル、４－メトキシベンジルの場合は、メタノール、エタノール等のアルコール系溶媒、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒中、パラジウム－カーボン等の触媒存在下、加水素分解することにより化合物（II－４）を製造することができる。Ｐ３がＣ１－６アルキルの場合は、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、酢酸エチル等の非プロトン性極性溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒中、塩酸、臭化水素酸等の鉱酸や酢酸、トリフルオロ酢酸等の有機酸を用い、化合物（II－４）を製造することもできる。 [Step 2-2]
This step is a method for producing compound (II-4) from compound (II-3) which is carbamate. For example, when P 3 is benzyl or 4-methoxybenzyl, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, toluene, xylene and the like Compound (II-4) can be produced by hydrogenolysis in the presence of a catalyst such as palladium-carbon in the above aromatic hydrocarbon solvent. When P 3 is C 1-6 alkyl, ether solvents such as tetrahydrofuran and dioxane, aprotic polar solvents such as ethyl acetate, halogenated hydrocarbon solvents such as methylene chloride and chloroform, and aromatics such as toluene and xylene The compound (II-4) can also be produced using a mineral acid such as hydrochloric acid or hydrobromic acid or an organic acid such as acetic acid or trifluoroacetic acid in an aromatic hydrocarbon solvent.
　これらの反応は、通常室温～還流温度で行うことができる。 These reactions can usually be performed at room temperature to reflux temperature.
　このようにして得られる化合物（II－４）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (II-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程２－３］
　本工程は、化合物（II－４）と化合物（II－５）との縮合反応により、化合物（II－６）を製造する方法である。Ｚが塩素原子、又は臭素原子の場合は、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、酢酸エチル等の非プロトン性極性溶媒、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒中、トリエチルアミン、ピリジン等の塩基を用い、化合物（II－６）を製造することができる。これらの反応は、通常０℃～室温で行うことができる。Ｚがヒドロキシの場合は、製造法１の工程１－４に記載した方法に準じて化合物（II－６）を製造することができる。 [Step 2-3]
This step is a method for producing compound (II-6) by a condensation reaction of compound (II-4) and compound (II-5). When Z is a chlorine atom or a bromine atom, ether solvents such as tetrahydrofuran and dioxane, aprotic polar solvents such as ethyl acetate, halogenated hydrocarbon solvents such as methylene chloride and chloroform, and aromatics such as toluene and xylene Compound (II-6) can be produced using a base such as triethylamine or pyridine in an aromatic hydrocarbon solvent. These reactions can usually be performed at 0 ° C. to room temperature. When Z is hydroxy, compound (II-6) can be produced according to the method described in Step 1-4 of Production Method 1.
　このようにして得られる化合物（II－６）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (II-6) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程２－４］
　本工程は、化合物（II－６）のトリアゾールの保護基Ｐ２を脱保護することにより、化合物（II－７）を製造する方法である。 [Step 2-4]
In this step, by deprotecting the protective group P 2 of the triazole compound (II-6), a method for producing a compound (II-7).
　本反応は、製造法１の工程１－５に記載した方法に準じて行うことができる。 This reaction can be carried out according to the method described in Process 1-5, Step 1-5.
　このようにして得られる化合物（II－７）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (II-7) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）に属する化合物（III－５）は、例えば、下記製造法３又はこれらに準ずる方法により製造することができる。 The compound (III-5) belonging to the compound (I) of the present invention can be produced, for example, by the following production method 3 or a method analogous thereto.
製造法３
Figure JPOXMLDOC01-appb-C000012
      
  　 
［式中、Ｒ１、Ｒ２、Ｒ３、Ｘ、Ｐ１、Ｐ２、環Ａは前記と同意義である。ＬＧは脱離基を意味し、例えば塩素原子、臭素原子、ヨウ素原子等のハロゲン原子を示す。］ Production method 3
Figure JPOXMLDOC01-appb-C000012

[Wherein R 1 , R 2 , R 3 , X, P 1 , P 2 and ring A are as defined above. LG means a leaving group, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom. ]
［工程３－１］
　本工程は、化合物（III－１）の金属水素化物による還元反応により、化合物（III－２）を製造する方法である。反応に用いられる還元剤は、水素化リチウムアルミニウム、水素化ジイソブチルアルミニウム、水素化ホウ素ナトリウム、ジボラン等が挙げられる。反応に用いられる溶媒は、ジエチルエーテル、テトラヒドロフラン、ジオキサン、１，２－ジメトキシエタン等のエーテル系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒等が挙げられる。 [Step 3-1]
This step is a method for producing compound (III-2) by a reduction reaction of compound (III-1) with a metal hydride. Examples of the reducing agent used in the reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, diborane and the like. Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and aromatic hydrocarbon solvents such as toluene and xylene.
　これらの反応は、通常０℃～還流温度で行うことができる。 These reactions can usually be performed at 0 ° C. to reflux temperature.
　このようにして得られる化合物（III－２）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (III-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程３－２］
　本工程は、化合物（III－２）と化合物（III－３）を塩基の存在下反応させることにより、化合物（III－４）を製造する方法である。反応に用いられる塩基は、水素化アルカリ金属、例えば、水素化ナトリウム等が挙げられる。反応に用いられる溶媒はジエチルエーテル、テトラヒドロフラン、ジオキサン、１，２－ジメトキシエタン等のエーテル系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド等の非プロトン性極性溶媒等が挙げられる。 [Step 3-2]
This step is a method for producing compound (III-4) by reacting compound (III-2) with compound (III-3) in the presence of a base. Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride. Solvents used in the reaction are ether solvents such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as toluene and xylene, aprotic such as acetonitrile and N, N-dimethylformamide. Examples include polar solvents.
　これらの反応は、通常０℃～還流温度で行うことができる。 These reactions can usually be performed at 0 ° C. to reflux temperature.
　このようにして得られる化合物（III－４）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (III-4) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程３－３］
　本工程は、化合物（III－４）のトリアゾールの保護基Ｐ２を脱保護することにより、化合物（III－５）を製造する方法である。 [Step 3-3]
In this step, by deprotecting the compound (III-4) protecting group P 2 of the triazole, which is a method for producing a compound (III-5).
　本反応は、製造法１の工程１－５に記載した方法に準じて行うことができる。 This reaction can be carried out according to the method described in Process 1-5, Step 1-5.
　このようにして得られる化合物（III－５）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (III-5) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）に属する化合物（IV－５）は、例えば、下記製造法４又はこれらに準ずる方法により製造することができる。 The compound (IV-5) belonging to the compound (I) of the present invention can be produced, for example, by the following production method 4 or a method analogous thereto.
製造法４
Figure JPOXMLDOC01-appb-C000013
      
  　 
［式中、Ｒ１、Ｒ２、Ｒ３、Ｘ、Ｐ２、環Ａ、Ｚは前記と同意義である。］ Manufacturing method 4
Figure JPOXMLDOC01-appb-C000013

[Wherein, R 1 , R 2 , R 3 , X, P 2 , rings A and Z are as defined above]. ]
［工程４－１］
　本工程は、製造法３の工程３－１で得られる化合物（III－２）をアジド化剤と反応させることにより、化合物（IV－１）を製造する方法である。
反応に用いられるアジド化剤は、ジフェニルリン酸アジド、ビス（ｐ－ニトロフェニル）リン酸アジド等が挙げられる。 [Step 4-1]
This step is a method for producing compound (IV-1) by reacting compound (III-2) obtained in step 3-1 of production method 3 with an azidating agent.
Examples of the azidating agent used in the reaction include diphenyl phosphate azide, bis (p-nitrophenyl) phosphate azide, and the like.
　本反応には添加剤として塩基を用いることができる。塩基の例としては、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エンが挙げられる。また、光延反応により、アジド化を試みる場合は、添加剤として、アゾジカルボン酸ジエチル、トリフェニルホスフィン等を用いる。 In this reaction, a base can be used as an additive. An example of a base is 1,8-diazabicyclo [5.4.0] undec-7-ene. Further, when azidation is attempted by Mitsunobu reaction, diethyl azodicarboxylate, triphenylphosphine, or the like is used as an additive.
　反応に用いられる溶媒は、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド等の非プロトン性極性溶媒等が挙げられる。 Solvents used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as toluene and xylene, aprotic polarities such as N, N-dimethylformamide and N, N-dimethylacetamide. A solvent etc. are mentioned.
　これらの反応は、通常室温～１００℃で行うことができる。 These reactions can usually be performed at room temperature to 100 ° C.
　このようにして得られる化合物（IV－１）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (IV-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程４－２］
　本工程は、化合物（IV－１）を用いて還元反応を行うことにより、化合物（IV－２）を製造する方法である。反応に用いられる還元剤は、トリメチルホスフィン、トリブチルホスフィン、トリフェニルホスフィン等のリン化合物や、水素化リチウムアルミニウム、水素化ホウ素ナトリウム等の金属水素化物が挙げられる。反応に用いられる溶媒は、還元剤にリン化合物を用いる場合は、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル系溶媒と水との任意の比率の混合溶媒等が挙げられる。還元剤に金属水素化物を用いる場合は、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒等が挙げられる。 [Step 4-2]
This step is a method for producing compound (IV-2) by carrying out a reduction reaction using compound (IV-1). Examples of the reducing agent used in the reaction include phosphorus compounds such as trimethylphosphine, tributylphosphine, and triphenylphosphine, and metal hydrides such as lithium aluminum hydride and sodium borohydride. Examples of the solvent used in the reaction include a mixed solvent of an ether solvent such as diethyl ether, tetrahydrofuran and dioxane and water in an arbitrary ratio when a phosphorus compound is used as the reducing agent. When a metal hydride is used as the reducing agent, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as toluene and xylene, and the like can be given.
　これらの反応は、通常室温～１００℃で行うことができる。 These reactions can usually be performed at room temperature to 100 ° C.
　このようにして得られる化合物（IV－２）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (IV-2) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程４－３］
　本工程は、化合物（IV－２）と化合物（IV－３）との縮合反応により、化合物（IV－４）を製造する方法である。 [Step 4-3]
This step is a method for producing compound (IV-4) by a condensation reaction between compound (IV-2) and compound (IV-3).
　本反応は、製造法２の工程２－３に記載した方法に準じて行うことができる。 This reaction can be carried out according to the method described in Step 2-3 of Production Method 2.
　このようにして得られる化合物（IV－４）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (IV-4) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程４－４］
　本工程は、化合物（IV－４）のトリアゾールの保護基Ｐ２を脱保護することにより、化合物（IV－５）を製造する方法である。 [Step 4-4]
In this step, by deprotecting the protective group P 2 of the triazole compound (IV-4), a method for producing a compound (IV-5).
　本反応は、製造法１の工程１－５に記載した方法に準じて行うことができる。 This reaction can be carried out according to the method described in Process 1-5, Step 1-5.
　このようにして得られる化合物（IV－５）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 The compound (IV-5) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明は、以下の参考例、実施例及び試験例によってさらに詳しく説明されるが、これらは本発明を限定するものではなく、また、本発明の範囲を逸脱しない範囲で変化させてもよい。 The present invention will be described in more detail with reference to the following reference examples, examples and test examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
　本明細書中で用いられている略語は下記の意味を示す。
ｓ　：　シングレット（ｓｉｎｇｌｅｔ）
ｄ　：　ダブレット（ｄｏｕｂｌｅｔ）
ｔ　：　トリプレット（ｔｒｉｐｌｅｔ）
ｑ　：　クァルテット（ｑｕａｒｔｅｔ）
ｑｕｉｎ　：　クィンテット（ｑｕｉｎｔｅｔ）
ｓｐｔ　：　セプテット（ｓｅｐｔｅｔ）
ｄｄ　：　ダブルダブレット（ｄｏｕｂｌｅ　ｄｏｕｂｌｅｔ）
ｄｔ　：　ダブルトリプレット（ｄｏｕｂｌｅ　ｔｒｉｐｌｅｔ）
ｔｄ　：　トリプレットダブレット（ｔｒｉｐｌｅｔ　ｄｏｕｂｌｅｔ）
ｍ　：　マルチプレット（ｍｕｌｔｉｐｌｅｔ）
ｂｒ　：　ブロード（ｂｒｏａｄ）
Ｊ　：　カップリング定数（ｃｏｕｐｌｉｎｇ　ｃｏｎｓｔａｎｔ）
Ｈｚ　：　ヘルツ（Ｈｅｒｔｚ）
ＣＨＬＯＲＯＦＯＲＭ－ｄ　：　重クロロホルム
ＤＭＳＯ－ｄ６　：　重ジメチルスルホキシド
ＭＥＴＨＡＮＯＬ－ｄ４　：　重メタノール
ＤＥＵＴＥＲＩＵＭ　ＯＸＩＤＥ　：　重水
　１Ｈ－ＮＭＲ（プロトン核磁気共鳴スペクトル）は下記のフーリエ変換型ＮＭＲで測定した。
２００ＭＨｚ：　Ｇｅｍｉｎｉ２０００　（Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）
３００ＭＨｚ：　Ｉｎｏｖａ３００　（Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）
５００ＭＨｚ：　ＪＮＭ－ＥＣＡ５００　（ＪＥＯＬ）
６００ＭＨｚ：　ＪＮＭ－ＥＣＡ６００　（ＪＥＯＬ） Abbreviations used in this specification have the following meanings.
s: singlet
d: doublet
t: triplet
q: quartet
quint: quintet
spt: septet
dd: double doublet (double doublet)
dt: double triplet
td: triplet doublet
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CHLOROFORM-d: deuterated chloroform DMSO-d 6 : deuterated dimethyl sulfoxide METHANOL-d 4 : deuterated methanol DEUTERIUM OXIDE: deuterated water 1 H-NMR (proton nuclear magnetic resonance spectrum) was measured by the following Fourier transform NMR.
200 MHz: Gemini 2000 (Agilent Technologies)
300 MHz: Inova300 (Agilent Technologies)
500MHz: JNM-ECA500 (JEOL)
600MHz: JNM-ECA600 (JEOL)
　解析にはＡＣＤ／Ｓｐｅｃｔｒｕｓ　ＰｒｏｃｅｓｓｏｒＴＭなどを用いた。ヒドロキシやアミノ、アミド、トリアゾールなどのプロトンが非常に緩やかなピークについては記載していないこともある。 For the analysis, ACD / Spectros Processor TM or the like was used. Peaks with very gentle protons such as hydroxy, amino, amide, and triazole may not be described.
　ＭＳ（マススペクトル）は以下の装置にて測定した。
ＰｌａｔｆｏｒｍＬＣ　（Ｗａｔｅｒｓ）
ＬＣＭＳ－２０１０ＥＶ　（Ｓｈｉｍａｄｚｕ）
ＬＣＭＳ－ＩＴ－ＴＯＦ　（Ｓｈｉｍａｄｚｕ）
ＧＣＴ　（Ｍｉｃｒｏｍａｓｓ）
Ａｇｉｌｅｎｔ６１３０　（Ａｇｉｌｅｎｔ）
Ａｇｉｌｅｎｔ６１５０　（Ａｇｉｌｅｎｔ）
ＬＣＱ　Ｄｅｃａ　ＸＰ　（ＴｈｅｒｍｏＦｉｓｈｅｒ　Ｓｃｉｅｎｔｉｆｉｃ） MS (mass spectrum) was measured with the following apparatus.
PlatformMLC (Waters)
LCMS-2010EV (Shimadzu)
LCMS-IT-TOF (Shimadzu)
GCT (Micromass)
Agilent 6130 (Agilent)
Agilent 6150 (Agilent)
LCQ Deca XP (ThermoFisher Scientific)
　イオン化法としては、ＥＳＩ（Ｅｌｅｃｔｒｏｓｐｒａｙ　Ｉｏｎｉｚａｔｉｏｎ、エレクトロスプレーイオン化）法、ＥＩ（Ｅｌｅｃｔｒｏｎ　Ｉｏｎｉｚａｔｉｏｎ、電子イオン化）法、又は、ＥＳＩ及びＡＰＣＩ（Ａｔｍｏｓｐｈｅｒｉｃ　Ｐｒｅｓｓｕｒｅ　Ｃｈｅｍｉｃａｌ　Ｉｏｎｉｚａｔｉｏｎ、大気圧化学イオン化）法とのデュアルイオン化法を用いた。データは実測値（ｆｏｕｎｄ）を記載した。通常、分子イオンピークが観測されるが、ヒドロキシ（－ＯＨ）を有する化合物の場合、フラグメントピークとしてＨ２Ｏが脱離したピークが観測されることもある。塩の場合は、通常、フリー体の分子イオンピーク若しくはフラグメントイオンピークが観測される。 As an ionization method, an ESI (Electrospray Ionization) method, an EI (Electron Ionization) method, or an ESI and APCI (Atmospheric Pressure Chemical Ionization) method and a dual method using an atmospheric pressure chemical ionization method are used. It was. The data described the actual value (found). Usually, a molecular ion peak is observed, but in the case of a compound having hydroxy (—OH), a peak from which H 2 O is eliminated may be observed as a fragment peak. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
　以下の参考例、及び実施例において、高速液体クロマトグラフィーマススペクトル（ＬＣＭＳ）は、以下の方法を用いた。 In the following Reference Examples and Examples, the following method was used for high performance liquid chromatography mass spectrum (LCMS).
（方法Ａ－１）
測定機械：Ａｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ１２９０及びＡｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ６１３０
カラム：Ｗａｔｅｒｓ社　Ａｃｑｕｉｔｙ　ＣＳＨ　Ｃ１８　１．７μｍ　２．１ｘ５０ｍｍ
検出法：ＵＶ　２５４ｎｍ
イオン化法：ＥＳＩ及びＡＰＣＩとのデュアルイオン化法
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
グラジェント：０分（Ａ液／Ｂ液＝８０：２０）、１．２～１．４分（Ａ液／Ｂ液＝１：９９）（流速：０．８ｍＬ／ｍｉｎ） (Method A-1)
Measuring machine: Agilent Agilent 1290 and Agilent Agilent 6130
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Detection method: UV 254 nm
Ionization method: Dual ionization method with ESI and APCI Solvent: A solution; 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 min (A solution / B solution = 80: 20) 1.2 to 1.4 minutes (A liquid / B liquid = 1: 99) (flow rate: 0.8 mL / min)
（方法Ａ－２）
測定機械：Ａｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ１２９０及びＡｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ６１３０
カラム：Ｗａｔｅｒｓ社　Ａｃｑｕｉｔｙ　ＣＳＨ　Ｃ１８　１．７μｍ　２．１ｘ５０ｍｍ
検出法：ＵＶ　２５４ｎｍ
イオン化法：ＥＳＩ及びＡＰＣＩとのデュアルイオン化法
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
グラジェント：０分（Ａ液／Ｂ液＝９５：５）、１．２分（Ａ液／Ｂ液＝５０：５０）（流速：０．８ｍＬ／ｍｉｎ）、１．３８分（Ａ液／Ｂ液＝３：９７） (Method A-2)
Measuring machine: Agilent Agilent 1290 and Agilent Agilent 6130
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Detection method: UV 254 nm
Ionization method: Dual ionization method with ESI and APCI Solvent: A solution; 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 95: 5) 1.2 minutes (liquid A / liquid B = 50: 50) (flow rate: 0.8 mL / min), 1.38 minutes (liquid A / liquid B = 3: 97)
（方法Ｂ－１）
測定機械：Ａｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ１２９０及びＡｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ６１５０
カラム：Ｗａｔｅｒｓ社　Ａｃｑｕｉｔｙ　ＣＳＨ　Ｃ１８　１．７μｍ　２．１ｘ５０ｍｍ
検出法：ＵＶ　２５４ｎｍ
イオン化法：ＥＳＩ及びＡＰＣＩとのデュアルイオン化法
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
グラジェント：０分（Ａ液／Ｂ液＝８０：２０）、１．２～１．４分（Ａ液／Ｂ液＝１：９９）（流速：０．８ｍＬ／ｍｉｎ） (Method B-1)
Measuring machine: Agilent Agilent 1290 and Agilent Agilent 6150
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Detection method: UV 254 nm
Ionization method: Dual ionization method with ESI and APCI Solvent: A solution; 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 min (A solution / B solution = 80: 20) 1.2 to 1.4 minutes (A liquid / B liquid = 1: 99) (flow rate: 0.8 mL / min)
（方法Ｂ－２）
測定機械：Ａｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ１２９０及びＡｇｉｌｅｎｔ社　Ａｇｉｌｅｎｔ６１５０
カラム：Ｗａｔｅｒｓ社　Ａｃｑｕｉｔｙ　ＣＳＨ　Ｃ１８　１．７μｍ　２．１ｘ５０ｍｍ
検出法：ＵＶ　２５４ｎｍ
イオン化法：ＥＳＩ及びＡＰＣＩとのデュアルイオン化法
溶媒：Ａ液；０．１％ギ酸含有水、Ｂ液；０．１％ギ酸含有アセトニトリル
グラジェント：０分（Ａ液／Ｂ液＝９５：５）、１．２分（Ａ液／Ｂ液＝５０：５０）（流速：０．８ｍＬ／ｍｉｎ）、１．３８分（Ａ液／Ｂ液＝３：９７） (Method B-2)
Measuring machine: Agilent Agilent 1290 and Agilent Agilent 6150
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Detection method: UV 254 nm
Ionization method: Dual ionization method with ESI and APCI Solvent: A solution; 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 95: 5) 1.2 minutes (liquid A / liquid B = 50: 50) (flow rate: 0.8 mL / min), 1.38 minutes (liquid A / liquid B = 3: 97)
　分取高速液体クロマトグラフィー（分取ＨＰＬＣ）による精製は以下の条件により行った。ただし、塩基性官能基を有する化合物の場合、本操作でトリフルオロ酢酸を用いたときには、フリー体を得るための中和操作等を行う場合がある。
機械：Ｇｉｌｓｏｎ社　ｐｒｅｐａｒａｔｉｖｅ　ＨＰＬＣ　ｓｙｓｔｅｍ
カラム：Ｗａｔｅｒｓ　ＳｕｎＦｉｒｅＴＭ　Ｐｒｅｐ　Ｃ１８　ＯＢＤＴＭ　５μｍ　３０ｘ５０ｍｍ
流速：４０ｍＬ／ｍｉｎ、検出法：ＵＶ　２５４ｎｍ
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジエント：０分（Ａ液／Ｂ液＝９０／１０）、２分（Ａ液／Ｂ液＝９０／１０）、１２分（Ａ液／Ｂ液＝２０／８０）、１３．５分（Ａ液／Ｂ液＝５／９５）、１５分（Ａ液／Ｂ液＝５／９５）
フェーズセパレーターは、バイオタージ社のＩＳＯＬＵＴＥ（登録商標）　Ｐｈａｓｅ　Ｓｅｐａｒａｔｏｒを用いた。 Purification by preparative high performance liquid chromatography (preparative HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation for obtaining a free form may be performed.
Machine: Gilson preparative HPLC system
Column: Waters SunFire ™ Prep C18 OBD ™ 5μm 30x50mm
Flow rate: 40 mL / min, detection method: UV 254 nm
Solvent: Solution A; 0.1% trifluoroacetic acid-containing water, Solution B; 0.1% trifluoroacetic acid-containing acetonitrile Gradient: 0 minutes (A solution / B solution = 90/10), 2 minutes (A solution / B Liquid = 90/10), 12 minutes (liquid A / liquid B = 20/80), 13.5 minutes (liquid A / liquid B = 5/95), 15 minutes (liquid A / liquid B = 5/95)
As the phase separator, ISOLUTE (registered trademark) Phase Separator manufactured by Biotage was used.
　マイクロウェーブ反応装置はＢｉｏｔａｇｅ社Ｉｎｉｔｉａｔｏｒを用いた。 The microwave reactor used was Biotage Initiator.
　化合物名はＡＣＤ／Ｎａｍｅ　（ＡＣＤ／Ｌａｂｓ　２０１２，　Ａｄｖａｎｃｅｄ　Ｃｈｅｍｉｓｔｒｙ　Ｄｅｖｅｌｏｐｍｅｎｔ　Ｉｎｃ．）により命名した。 The compound name was named by ACD / Name (ACD / Labs 2012, Advanced Chemistry Development Inc.).
　参考例及び実施例中の表において、塩情報が空白の化合物はフリー体で得たことを意味する。又、参考例の本文、及び実施例中の表において、測定方法がＡ－１、Ａ－２、Ｂ－１、又はＢ－２とある場合は、前記のＬＣ－ＭＳによる分析の測定方法が、それぞれ方法Ａ－１、方法Ａ－２、方法Ｂ－１、又は方法Ｂ－２であることを意味する。 In the tables in Reference Examples and Examples, compounds with blank salt information mean that they were obtained in free form. In the text of the reference examples and the tables in the examples, when the measurement method is A-1, A-2, B-1, or B-2, the measurement method for analysis by the LC-MS is as follows. Means Method A-1, Method A-2, Method B-1, or Method B-2, respectively.
参考例１
６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボン酸 Reference example 1
6- [1- (Tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000014
  　 
Figure JPOXMLDOC01-appb-C000014
  　 
（１）メチル　６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキシラートの合成 (1) Synthesis of methyl 6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000015
  　 
Figure JPOXMLDOC01-appb-C000015
  　 
　メチル　６－シアノピリジン－３－カルボキシラート（７３．０ｇ）のメタノール懸濁液（９００ｍＬ）にナトリウムメ卜キシド（約２８％、メタノ一ル溶液、８．６９ｇ)を加え、６０℃で３０分間攪拌した。更にホルモヒドラジド（２８．４ｇ）、酢酸（５．２０ｍＬ）を加え、同温度で３０分間攪拌した。室温まで冷却した後、析出物を濾取し、これを酢酸（９００ｍＬ）に加えて還流した。室温まで冷却した後、減圧下濃縮して得られた残渣へメタノールを加え、析出物を濾取した。濾取物を減圧下乾燥し、メチル　６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキシラートを黄色固体（７５．６ｇ）として得た。
LCMS（測定方法　Ａ－１）0.357min，ESI/APCI Dual posi: 205[M+H]+. Sodium methanol (about 28%, methanol solution, 8.69 g) was added to a methanol suspension (900 mL) of methyl 6-cyanopyridine-3-carboxylate (73.0 g), and the mixture was stirred at 60 ° C. for 30 minutes. Stir. Further, formohydrazide (28.4 g) and acetic acid (5.20 mL) were added, and the mixture was stirred at the same temperature for 30 minutes. After cooling to room temperature, the precipitate was collected by filtration, added to acetic acid (900 mL), and refluxed. After cooling to room temperature, methanol was added to the residue obtained by concentration under reduced pressure, and the precipitate was collected by filtration. The filtered product was dried under reduced pressure to obtain methyl 6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxylate as a yellow solid (75.6 g).
LCMS (Measurement method A-1) 0.357min, ESI / APCI Dual posi: 205 [M + H] + .
（２）メチル　６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキシラートの合成 (2) Synthesis of methyl 6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000016
  　 
Figure JPOXMLDOC01-appb-C000016
  　 
　上記（１）で得られた化合物（７５．６ｇ）のクロロホルム懸濁液（７４０ｍＬ）へ、３，４－ジヒドロ－２Ｈ－ピラン（１７０ｍＬ）、ｐ－トルエンスルホン酸一水和物（３．５２ｇ）を加え６０℃で４時間攪拌した。室温まで冷却した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、乾燥剤を濾別し、濾液を減圧下濃縮した。得られた残渣にジイソプロピルエーテル（５００ｍＬ）を加えて氷冷下で１時間攪拌し、沈殿物を濾取した。この粗結晶を酢酸エチル（５００ｍＬ）で再結晶して、濾液からの回収分と合わせてジエチルエーテルに懸濁させた。得られた結晶を濾取して、減圧下乾燥し、メチル　６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキシラートを淡褐色固体（８３．３ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.61 - 1.83 (m, 3 H) 1.97 - 2.19 (m, 2 H) 2.20 - 2.30 (m, 1 H) 3.69 - 3.81 (m, 1 H) 3.98 (s, 3 H) 4.08 - 4.18 (m, 1 H) 5.58 (dd, J=9.2, 2.8 Hz, 1 H) 8.25 (dd, J=8.2, 0.8 Hz, 1 H) 8.35 - 8.46 (m, 2 H) 
9.32 (dd, J=2.2, 0.8 Hz, 1 H).
MS ESI/APCI Dual posi: 289[M+H]+. To a chloroform suspension (740 mL) of the compound (75.6 g) obtained in (1) above, 3,4-dihydro-2H-pyran (170 mL), p-toluenesulfonic acid monohydrate (3.52 g) ) And stirred at 60 ° C. for 4 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (500 mL) was added to the resulting residue, and the mixture was stirred for 1 hour under ice cooling, and the precipitate was collected by filtration. The crude crystals were recrystallized from ethyl acetate (500 mL), combined with the fraction recovered from the filtrate, and suspended in diethyl ether. The obtained crystals were collected by filtration, dried under reduced pressure, and methyl 6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3. The carboxylate was obtained as a light brown solid (83.3 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.61-1.83 (m, 3 H) 1.97-2.19 (m, 2 H) 2.20-2.30 (m, 1 H) 3.69-3.81 (m, 1 H) 3.98 (s, 3 H) 4.08-4.18 (m, 1 H) 5.58 (dd, J = 9.2, 2.8 Hz, 1 H) 8.25 (dd, J = 8.2, 0.8 Hz, 1 H) 8.35-8.46 (m, 2 H)
9.32 (dd, J = 2.2, 0.8 Hz, 1 H).
MS ESI / APCI Dual posi: 289 [M + H] +.
（３）表題化合物の合成
　上記（２）で得られた化合物（２５．８ｇ）のメタノール溶液（１８０ｍＬ）へ１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（９０．０ｍＬ）を加え、６０℃で１時間攪拌した。室温まで冷却した後、塩化アンモニウム（４．８２ｇ）を加えて攪拌し、減圧下濃縮した。得られた残渣にアセトンを加え、析出物を濾取して表題化合物を粗生成物（淡褐色固体　３０．７ｇ）として得た。なお、表題化合物は粗生成物のまま、次の反応に用いた。
1H NMR (300 MHz, DEUTERIUM OXIDE) δ ppm 1.62 - 1.86 (m, 3 H) 1.98 - 2.29 (m, 3 H) 3.77 - 3.89 (m, 1 H) 4.02 - 4.13 (m, 1 H) 5.68 (dd, J=9.1, 3.3 Hz, 1 H) 8.03 (d, J=8.2 Hz, 1 H) 8.32 (dd, J=8.2, 2.1 Hz, 1 H) 8.70 (s, 1 H) 9.02 (d, J=1.9 Hz, 1 H).
MS ESI/APCI Dual posi: 275[M+H]+.
MS ESI/APCI Dual nega: 273[M-H]-. (3) Synthesis of title compound A 1 mol / L aqueous sodium hydroxide solution (90.0 mL) was added to a methanol solution (180 mL) of the compound (25.8 g) obtained in (2) above, and the mixture was stirred at 60 ° C for 1 hour. . After cooling to room temperature, ammonium chloride (4.82 g) was added and stirred, and concentrated under reduced pressure. Acetone was added to the resulting residue, and the precipitate was collected by filtration to give the title compound as a crude product (light brown solid 30.7 g). The title compound was used in the next reaction as a crude product.
1 H NMR (300 MHz, DEUTERIUM OXIDE) δ ppm 1.62-1.86 (m, 3 H) 1.98-2.29 (m, 3 H) 3.77-3.89 (m, 1 H) 4.02-4.13 (m, 1 H) 5.68 ( dd, J = 9.1, 3.3 Hz, 1 H) 8.03 (d, J = 8.2 Hz, 1 H) 8.32 (dd, J = 8.2, 2.1 Hz, 1 H) 8.70 (s, 1 H) 9.02 (d, J = 1.9 Hz, 1 H).
MS ESI / APCI Dual posi: 275 [M + H] + .
MS ESI / APCI Dual nega: 273 [MH] - .
参考例２
６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボン酸 Reference example 2
6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000017
  　 
Figure JPOXMLDOC01-appb-C000017
  　 
　参考例１（２）で得られた化合物の代わりに参考例１（１）で得られた化合物（１．３９ｇ）を用いて、参考例１（３）に準ずる手法にて表題化合物を無色固体（１．１８ｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (d, J=8.7 Hz, 1 H) 8.30 - 8.61 (m, 2 H) 9.15 (dd, J=2.1, 0.7 Hz, 1 H).
MS ESI/APCI Dual posi: 191[M+H]+.
MS ESI/APCI Dual nega: 189[M-H]-. Using the compound (1.39 g) obtained in Reference Example 1 (1) instead of the compound obtained in Reference Example 1 (2), the title compound was obtained as a colorless solid by the method according to Reference Example 1 (3). (1.18 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 8.21 (d, J = 8.7 Hz, 1 H) 8.30-8.61 (m, 2 H) 9.15 (dd, J = 2.1, 0.7 Hz, 1 H).
MS ESI / APCI Dual posi: 191 [M + H] + .
MS ESI / APCI Dual nega: 189 [MH] - .
参考例３
２－（５－ブロモピリジン－２－イル）プロパン－２－アミン Reference example 3
2- (5-Bromopyridin-2-yl) propan-2-amine
Figure JPOXMLDOC01-appb-C000018
  　 
Figure JPOXMLDOC01-appb-C000018
  　 
（１）２－（トリメチルシリル）エチル［２－（５－ブロモピリジン－２－イル）プロパン－２－イル］カルバメートの合成 (1) Synthesis of 2- (trimethylsilyl) ethyl [2- (5-bromopyridin-2-yl) propan-2-yl] carbamate
Figure JPOXMLDOC01-appb-C000019
  　 
Figure JPOXMLDOC01-appb-C000019
  　 
　２－（５－ブロモピリジン－２－イル）－２－メチルプロパン酸（９．７７ｇ）のトルエン懸濁液（８０ｍＬ）にジイソプロピルエチルアミン（３５．０ｍＬ）、ジフェニルリン酸アジド（９．５０ｍＬ）を室温で加えた後、８０℃で1時間攪拌した。これに２－（トリメチルシリル）エタノール（２３．７ｇ）、４－（ジメチルアミノ）ピリジン（０．４９ｇ）を加えて、１５時間還流した。室温まで冷却した後、水を加えてトルエンで２回抽出した。合わせた有機層へ無水硫酸ナトリウムを加えて乾燥した。乾燥剤を濾別した後、濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～８０：２０）で精製し、２－（トリメチルシリル）エチル［２－（５－ブロモピリジン－２－イル）プロパン－２－イル］カルバメートを無色油状状物質（１１．１ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.03 (s, 9 H) 0.90 - 1.02 (m, 2 H) 1.68 (s, 6 H) 4.05 - 4.14 (m, 2 H) 6.04 (br. s., 1 H) 7.32 (dd, J=8.5, 0.7 Hz, 1 H) 7.79 (dd, J=8.5, 2.3 Hz, 1 H) 8.57 (dd, J=2.4, 0.7 Hz, 1 H).
MS ESI/APCI Dual posi: 359[M+H]+, 361[M+H]+. To a toluene suspension (80 mL) of 2- (5-bromopyridin-2-yl) -2-methylpropanoic acid (9.77 g) was added diisopropylethylamine (35.0 mL) and diphenylphosphoric acid azide (9.50 mL). After adding at room temperature, it stirred at 80 degreeC for 1 hour. 2- (Trimethylsilyl) ethanol (23.7 g) and 4- (dimethylamino) pyridine (0.49 g) were added thereto, and the mixture was refluxed for 15 hours. After cooling to room temperature, water was added and extracted twice with toluene. To the combined organic layers, anhydrous sodium sulfate was added and dried. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-80: 20) to give 2- (trimethylsilyl) ethyl. [2- (5-Bromopyridin-2-yl) propan-2-yl] carbamate was obtained as a colorless oil (11.1 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.03 (s, 9 H) 0.90-1.02 (m, 2 H) 1.68 (s, 6 H) 4.05-4.14 (m, 2 H) 6.04 (br. S ., 1 H) 7.32 (dd, J = 8.5, 0.7 Hz, 1 H) 7.79 (dd, J = 8.5, 2.3 Hz, 1 H) 8.57 (dd, J = 2.4, 0.7 Hz, 1 H).
MS ESI / APCI Dual posi: 359 [M + H] + , 361 [M + H] + .
（２）表題化合物の合成
　上記（１）で得られた化合物（１．８０ｇ）のクロロホルム溶液（１０．０ｍＬ）にトリフルオロ酢酸（１０．０ｍＬ）を加え、室温で１時間攪拌した。反応液を減圧下濃縮し、得られた残渣をトルエンで共沸した。これに１ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加え、クロロホルムで３回抽出した。合わせた有機層へ無水硫酸ナトリウムを加えて乾燥した。乾燥剤を濾別した後、濾液を減圧下濃縮し、表題化合物を褐色油状物質（１．０８ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 6 H) 1.91 (s, 2 H) 7.38 (dd, J=8.5, 0.7 Hz, 1 H) 7.75 (dd, J=8.5, 2.4 Hz, 1 H) 8.60 (dd, J=2.4, 0.7 Hz, 1 H).
MS ESI/APCI Dual posi: 215[M+H]+. (2) Synthesis of title compound To a chloroform solution (10.0 mL) of the compound (1.80 g) obtained in (1) above was added trifluoroacetic acid (10.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was azeotroped with toluene. To this was added a 1 mol / L aqueous sodium hydroxide solution, and the mixture was extracted 3 times with chloroform. To the combined organic layers, anhydrous sodium sulfate was added and dried. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound as a brown oil (1.08 g).
1 H NMR (300 MHz, CHLOROFORM -d) δ ppm 1.49 (s, 6 H) 1.91 (s, 2 H) 7.38 (dd, J = 8.5, 0.7 Hz, 1 H) 7.75 (dd, J = 8.5, 2.4 (Hz, 1 H) 8.60 (dd, J = 2.4, 0.7 Hz, 1 H).
MS ESI / APCI Dual posi: 215 [M + H] + .
参考例４
２－［５－（４－メトキシフェニル）ピリジン－２－イル］プロパン－２－アミン Reference example 4
2- [5- (4-Methoxyphenyl) pyridin-2-yl] propan-2-amine
Figure JPOXMLDOC01-appb-C000020
  　 
Figure JPOXMLDOC01-appb-C000020
  　 
（１）２－（トリメチルシリル）エチル｛２－［５－（４－メトキシフェニル）ピリジン－２－イル］プロパン－２－イル｝カルバメートの合成 (1) Synthesis of 2- (trimethylsilyl) ethyl {2- [5- (4-methoxyphenyl) pyridin-2-yl] propan-2-yl} carbamate
Figure JPOXMLDOC01-appb-C000021
  　 
Figure JPOXMLDOC01-appb-C000021
  　 
　参考例３（１）で得られた化合物（１．８０ｇ）のエタノール溶液（２０．０ｍＬ）に（４－メトキシフェニル）ボロン酸（１．１４ｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（０．５８ｇ）及び２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（５．００ｍＬ）を加え、８０℃で１時間攪拌した。室温まで冷却した後、水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムを加えて乾燥した。乾燥剤を濾別した後、濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～８０：２０）で精製し、２－（トリメチルシリル）エチル｛２－［５－（４－メトキシフェニル）ピリジン－２－イル］プロパン－２－イル｝カルバメートを無色粘性油状物質（１．６１ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.03 (s, 9 H) 0.87 - 1.09 (m, 2 H) 1.74 (s, 6 H) 3.86 (s, 3 H) 4.04 - 4.22 (m, 2 H) 6.44 (br. s., 1 H) 6.93 - 7.08 (m, 2 H) 7.51 (s, 3 H) 7.83 (dd, J=8.3, 2.4 Hz, 1 H) 8.70 (dd, J=2.3, 0.8 Hz, 1 H).
MS ESI/APCI Dual posi: 387[M+H]+. To the ethanol solution (20.0 mL) of the compound (1.80 g) obtained in Reference Example 3 (1) was added (4-methoxyphenyl) boronic acid (1.14 g), tetrakis (triphenylphosphine) palladium (0) ( 0.58 g) and a 2 mol / L aqueous sodium carbonate solution (5.00 mL) were added, and the mixture was stirred at 80 ° C. for 1 hour. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-80: 20) to give 2- (trimethylsilyl) ethyl. {2- [5- (4-Methoxyphenyl) pyridin-2-yl] propan-2-yl} carbamate was obtained as a colorless viscous oil (1.61 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.03 (s, 9 H) 0.87-1.09 (m, 2 H) 1.74 (s, 6 H) 3.86 (s, 3 H) 4.04-4.22 (m, 2 H) 6.44 (br. S., 1 H) 6.93-7.08 (m, 2 H) 7.51 (s, 3 H) 7.83 (dd, J = 8.3, 2.4 Hz, 1 H) 8.70 (dd, J = 2.3, 0.8 Hz, 1 H).
MS ESI / APCI Dual posi: 387 [M + H] + .
（２）表題化合物の合成
　上記（１）で得られた化合物（１．６１ｇ）を用いて参考例３（２）と同様の手法にて表題化合物を無色固体（１．０１ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.55 (s, 6 H) 1.91 (s, 2 H) 3.86 (s, 3 H) 6.96 - 7.06 (m, 2 H) 7.44 - 7.58 (m, 3 H) 7.79 (dd, J=8.2, 2.5 Hz, 1 H) 8.75 (dd, J=2.4, 0.9 Hz, 1 H).
MS ESI/APCI Dual posi: 243[M+H]+. (2) Synthesis of title compound The title compound was obtained as a colorless solid (1.01 g) in the same manner as in Reference Example 3 (2) using the compound (1.61 g) obtained in (1) above.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.55 (s, 6 H) 1.91 (s, 2 H) 3.86 (s, 3 H) 6.96-7.06 (m, 2 H) 7.44-7.58 (m, 3 H) 7.79 (dd, J = 8.2, 2.5 Hz, 1 H) 8.75 (dd, J = 2.4, 0.9 Hz, 1 H).
MS ESI / APCI Dual posi: 243 [M + H] + .
参考例５
２－（５－ブロモピリミジン－２－イル）プロパン－２－アミン Reference Example 5
2- (5-Bromopyrimidin-2-yl) propan-2-amine
Figure JPOXMLDOC01-appb-C000022
  　 
Figure JPOXMLDOC01-appb-C000022
  　 
（１）エチル　２－（５－ブロモピリミジン－２－イル）－２－メチルプロパノアートの合成 (1) Synthesis of ethyl 2- (5-bromopyrimidin-2-yl) -2-methylpropanoate
Figure JPOXMLDOC01-appb-C000023
  　 
Figure JPOXMLDOC01-appb-C000023
  　 
　エチル（５－ブロモピリミジン－２－イル）アセタート（１４．６ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（２４．０ｍＬ）に室温で水素化ナトリウム（６０％鉱油分散物、１４．４ｇ）を少量ずつ加え、同温度で１５分間攪拌した。これにヨウ化メチル（２２．５ｍＬ）を少量ずつ滴下し、同温度で１８時間攪拌した。反応液に塩化アンモニウム水溶液を加え、１０分間攪拌した。これに水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムを加えて乾燥した。乾燥剤を濾別した後、濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～８０：２０）で精製し、エチル　２－（５－ブロモピリミジン－２－イル）－２－メチルプロパノアートを黄色油状物質（１２．４ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J=7.1 Hz, 3 H) 1.63 (s, 6 H) 4.17 (q, J=7.1 Hz, 2 H) 8.73 (s, 2 H).
MS ESI/APCI Dual posi: 273[M+H]+, 275[M+H]+. Sodium hydride (60% mineral oil dispersion, 14.4 g) was added in portions to a solution of ethyl (5-bromopyrimidin-2-yl) acetate (14.6 g) in N, N-dimethylformamide (24.0 mL) at room temperature. In addition, the mixture was stirred at the same temperature for 15 minutes. To this was added methyl iodide (22.5 mL) dropwise, and the mixture was stirred at the same temperature for 18 hours. Aqueous ammonium chloride solution was added to the reaction solution and stirred for 10 minutes. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 to 80:20) to give ethyl 2- (5- Bromopyrimidin-2-yl) -2-methylpropanoate was obtained as a yellow oil (12.4 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J = 7.1 Hz, 3 H) 1.63 (s, 6 H) 4.17 (q, J = 7.1 Hz, 2 H) 8.73 (s, 2 H ).
MS ESI / APCI Dual posi: 273 [M + H] + , 275 [M + H] + .
（２）２－（５－ブロモピリミジン－２－イル）－２－メチルプロパン酸の合成 (2) Synthesis of 2- (5-bromopyrimidin-2-yl) -2-methylpropanoic acid
Figure JPOXMLDOC01-appb-C000024
  　 
Figure JPOXMLDOC01-appb-C000024
  　 
　上記（１）で得られた化合物（１２．４ｇ）のエタノール溶液（２７０ｍＬ）へ１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（９０.０ｍＬ)を加え、室温で４８時間攪拌した。反応液を減圧下濃縮して得られた残渣を水に溶解し、氷冷下で１ｍｏｌ／Ｌ硫酸水素カリウム水溶液（１００ｍＬ）を滴下して１０分間攪拌した。析出物を濾取して水で洗浄した。濾取物を減圧下乾燥し、２－（５－ブロモピリミジン－２－イル）－２－メチルプロパン酸を無色固体（１０．１ｇ）として得た。
LCMS（測定方法　Ａ－１）0.674min， ESI/APCI Dual posi: 245[M+H]+, 247[M+H]+. A 1 mol / L aqueous sodium hydroxide solution (90.0 mL) was added to an ethanol solution (270 mL) of the compound (12.4 g) obtained in (1) above, and the mixture was stirred at room temperature for 48 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in water, and 1 mol / L aqueous potassium hydrogen sulfate solution (100 mL) was added dropwise under ice cooling, followed by stirring for 10 minutes. The precipitate was collected by filtration and washed with water. The filtered product was dried under reduced pressure to obtain 2- (5-bromopyrimidin-2-yl) -2-methylpropanoic acid as a colorless solid (10.1 g).
LCMS (Measurement Method A-1) 0.674min, ESI / APCI Dual posi: 245 [M + H] +, 247 [M + H] +.
（３）２－（トリメチルシリル）エチル［２－（５－ブロモピリミジン－２－イル）プロパン－２－イル］カルバメートの合成 (3) Synthesis of 2- (trimethylsilyl) ethyl [2- (5-bromopyrimidin-2-yl) propan-2-yl] carbamate
Figure JPOXMLDOC01-appb-C000025
  　 
Figure JPOXMLDOC01-appb-C000025
  　 
　２－（５－ブロモピリジン－２－イル）－２－メチルプロパン酸の代わりに上記（２）で得られた化合物（１０．１ｇ）を用いて、参考例３（１）と同様の手法にて２－（トリメチルシリル）エチル［２－（５－ブロモピリミジン－２－イル）プロパン－２－イル］カルバメートを無色油状物質（７．２６ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.03 (s, 9 H) 0.92 - 1.03 (m, 2 H) 1.73 (s, 6 H) 4.00 - 4.20 (m, 2 H) 6.07 (br. s., 1 H) 8.75 (s, 2 H).
MS ESI/APCI Dual posi: 332[M+H]+, 334[M+H]+. Using the compound (10.1 g) obtained in (2) above instead of 2- (5-bromopyridin-2-yl) -2-methylpropanoic acid, the same procedure as in Reference Example 3 (1) was performed. Thus, 2- (trimethylsilyl) ethyl [2- (5-bromopyrimidin-2-yl) propan-2-yl] carbamate was obtained as a colorless oily substance (7.26 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.03 (s, 9 H) 0.92-1.03 (m, 2 H) 1.73 (s, 6 H) 4.00-4.20 (m, 2 H) 6.07 (br. S ., 1 H) 8.75 (s, 2 H).
MS ESI / APCI Dual posi: 332 [M + H] + , 334 [M + H] + .
（４）表題化合物の合成
　参考例３（１）で得られた化合物の代わりに上記（３）で得られた化合物（１．８１ｇ）を用いて参考例３（２）と同様の手法にて表題化合物を無色固体（１．０９ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.53 (s, 6 H) 1.94 (s, 2 H) 8.73 (s, 2 H). (4) Synthesis of title compound Using the compound (1.81 g) obtained in (3) above instead of the compound obtained in Reference Example 3 (1), the same procedure as in Reference Example 3 (2) was used. The title compound was obtained as a colorless solid (1.09 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.53 (s, 6 H) 1.94 (s, 2 H) 8.73 (s, 2 H).
参考例６
２－［５－（４－メトキシフェニル）ピリミジン－２－イル］プロパン－２－アミン Reference Example 6
2- [5- (4-Methoxyphenyl) pyrimidin-2-yl] propan-2-amine
Figure JPOXMLDOC01-appb-C000026
  　 
Figure JPOXMLDOC01-appb-C000026
  　 
　参考例３（１）で得られた化合物の代わりに参考例５（３）で得られた化合物（１．８０ｇ）用いて、参考例４（１）～（２）と同様の手法にて表題化合物を無色固体（１．１３ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.59 (s, 6 H) 1.98 (s, 2 H) 3.87 (s, 3 H) 6.99 - 7.09 (m, 2 H) 7.46 - 7.56 (m, 2 H) 8.86 (s, 2 H).
MS ESI/APCI Dual posi: 244[M+H]+. Using the compound (1.80 g) obtained in Reference Example 5 (3) instead of the compound obtained in Reference Example 3 (1), the title was prepared in the same manner as in Reference Examples 4 (1) to (2). The compound was obtained as a colorless solid (1.13 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.59 (s, 6 H) 1.98 (s, 2 H) 3.87 (s, 3 H) 6.99-7.09 (m, 2 H) 7.46-7.56 (m, 2 H) 8.86 (s, 2 H).
MS ESI / APCI Dual posi: 244 [M + H] + .
参考例７－１
１－（６－メトキシピリジン－２－イル）メタンアミン塩酸塩　 Reference Example 7-1
1- (6-Methoxypyridin-2-yl) methanamine hydrochloride
Figure JPOXMLDOC01-appb-C000027
  　 
Figure JPOXMLDOC01-appb-C000027
  　 
　６－メトキシピリジン－２－カルボニトリル（１．００ｇ）のメタノール溶液（３０．０ｍＬ）に２０％水酸化パラジウム/炭素（１００ｍｇ）、４ｍｏｌ／Ｌ塩化水素－酢酸エチル溶液（５．５９ｍＬ）を加え、水素雰囲気下、室温で４時間攪拌した。反応液をセライ卜（登録商標）濾過した後、濾液を減圧下濃縮して得られた残渣にメタノールを加えて加熱溶解した。そこにｎ－ヘキサン、酢酸エチルを加えて攪拌し、析出物を濾取して表題化合物を無色固体（１．４４ｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.92 (s, 3 H) 3.99 - 4.14 (m, 2 H) 6.80 (dd, J=8.3, 0.6 Hz, 1 H) 7.10 (dd, J=7.3, 0.6 Hz, 1 H) 7.75 (dd, J=8.3, 7.3 Hz, 1 H).
MS ESI/APCI Dual posi: 139[M+H]+, 161[M+Na]+. To a methanol solution (30.0 mL) of 6-methoxypyridine-2-carbonitrile (1.00 g) was added 20% palladium hydroxide / carbon (100 mg), 4 mol / L hydrogen chloride-ethyl acetate solution (5.59 mL). The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction solution was filtered through Celai® (registered trademark), and then the filtrate was concentrated under reduced pressure. Methanol was added to the resulting residue and dissolved by heating. Thereto, n-hexane and ethyl acetate were added and stirred, and the precipitate was collected by filtration to give the title compound as a colorless solid (1.44 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.92 (s, 3 H) 3.99-4.14 (m, 2 H) 6.80 (dd, J = 8.3, 0.6 Hz, 1 H) 7.10 (dd, J = (7.3, 0.6 Hz, 1 H) 7.75 (dd, J = 8.3, 7.3 Hz, 1 H).
MS ESI / APCI Dual posi: 139 [M + H] + , 161 [M + Na] + .
参考例７－２
１－（５－エチルピリジン－２－イル）メタンアミン Reference Example 7-2
1- (5-Ethylpyridin-2-yl) methanamine
Figure JPOXMLDOC01-appb-C000028
  　 
Figure JPOXMLDOC01-appb-C000028
  　 
　６－メトキシピリジン－２－カルボニトリルの代わりに５－エチルピリジン－２－カルボニトリル（５００ｍｇ）を用いて、参考例７－１に準ずる手法にて表題化合物を褐色軟性油状物質（３３９ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.12 - 1.25 (m, 3 H) 2.53 - 2.66 (m, 2 H) 3.75 (s, 2 H) 7.33 (d, J=8.1 Hz, 1 H) 7.55 - 7.63 (m, 1 H) 8.30 - 8.37 (m, 1 H).
MS ESI/APCI Dual posi: 137[M+H]+, 159[M+Na]+. Using 5-ethylpyridine-2-carbonitrile (500 mg) instead of 6-methoxypyridine-2-carbonitrile, the title compound was obtained as a brown soft oily substance (339 mg) by the method according to Reference Example 7-1. It was.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.12-1.25 (m, 3 H) 2.53-2.66 (m, 2 H) 3.75 (s, 2 H) 7.33 (d, J = 8.1 Hz, 1 H 7.55-7.63 (m, 1 H) 8.30-8.37 (m, 1 H).
MS ESI / APCI Dual posi: 137 [M + H] + , 159 [M + Na] + .
参考例８－１
１－［２－（プロパン－２－イルオキシ）ピリジン－４－イル］メタンアミン塩酸塩　 Reference Example 8-1
1- [2- (propan-2-yloxy) pyridin-4-yl] methanamine hydrochloride
Figure JPOXMLDOC01-appb-C000029
  　 
Figure JPOXMLDOC01-appb-C000029
  　 
（１）２－（プロパン－２－イルオキシ）ピリジン－４－カルボニトリルの合成 (1) Synthesis of 2- (propan-2-yloxy) pyridine-4-carbonitrile
Figure JPOXMLDOC01-appb-C000030
  　 
Figure JPOXMLDOC01-appb-C000030
  　 
　氷冷したイソプロパノール（１．３４ｍＬ）のテトラヒドロフラン溶液（９０．０ｍＬ）に窒素雰囲気下で水素化ナトリウム（６０％鉱油分散物、６９３ｍｇ）を加え、室温に戻して３０分間攪拌した。そこに２－クロロピリジン－４－カルボニトリル（２．００ｇ）を加えて、同温度で２時間攪拌した。反応液に水を加え、酢酸エチルで２回抽出した。合わせた有機層をフェーズセパレーターに通し、減圧下濃縮した。得られた残渣をｎ－ヘキサンと酢酸エチルの混合溶媒に溶解させ、不溶物を除いた。濾液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～５０：５０）で精製し、２－（プロパン－２－イルオキシ）ピリジン－４－カルボニトリルを無色油状物質（１．６４ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35 (d, J=6.2 Hz, 6 H) 5.32 (spt, J=6.2 Hz, 1 H) 6.90 - 6.93 (m, 1 H) 7.01 (dd, J=5.1, 1.4 Hz, 1 H) 8.27 (dd, J=5.1, 0.8 Hz, 1 H).
MS ESI/APCI Dual posi: 163[M+H]+. Sodium hydride (60% mineral oil dispersion, 693 mg) was added to a solution (90.0 mL) of ice-cooled isopropanol (1.34 mL) in a nitrogen atmosphere, and the mixture was warmed to room temperature and stirred for 30 minutes. 2-Chloropyridine-4-carbonitrile (2.00 g) was added thereto and stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were passed through a phase separator and concentrated under reduced pressure. The obtained residue was dissolved in a mixed solvent of n-hexane and ethyl acetate to remove insoluble matters. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-50: 50) to give 2- (propan-2-yloxy) pyridine-4-carbohydrate. The nitrile was obtained as a colorless oil (1.64 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35 (d, J = 6.2 Hz, 6 H) 5.32 (spt, J = 6.2 Hz, 1 H) 6.90-6.93 (m, 1 H) 7.01 (dd, J = 5.1, 1.4 Hz, 1 H) 8.27 (dd, J = 5.1, 0.8 Hz, 1 H).
MS ESI / APCI Dual posi: 163 [M + H] +.
（２）表題化合物の合成
　上記（１）で得られた化合物（１．６３ｇ）を用いて、参考例７－１と同様の手法にて表題化合物を無色固体（２．２４ｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.2 Hz, 6 H) 3.96 - 4.08 (m, 2 H) 5.24 (spt, J=6.2 Hz, 1 H) 6.90 - 6.96 (m, 1 H) 7.08 (dd, J=5.3, 1.4 Hz, 1 H) 8.17 (d, J=5.3 Hz, 1 H).
MS ESI/APCI Dual posi: 167[M+H]+. (2) Synthesis of title compound Using the compound (1.63 g) obtained in (1) above, the title compound was obtained as a colorless solid (2.24 g) in the same manner as in Reference Example 7-1.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.29 (d, J = 6.2 Hz, 6 H) 3.96-4.08 (m, 2 H) 5.24 (spt, J = 6.2 Hz, 1 H) 6.90-6.96 (m, 1 H) 7.08 (dd, J = 5.3, 1.4 Hz, 1 H) 8.17 (d, J = 5.3 Hz, 1 H).
MS ESI / APCI Dual posi: 167 [M + H] + .
　以下の参考例８－２～８－１６は、対応する市販のハロゲン化ピリジンカルボニトリル、ヒドロキシピリジンカルボニトリル、又はヒドロキシベンゾニトリル及び対応する市販のアルコール、ハロゲン化アルキル、ハロゲン化アリール又はヒドロキシピリジンを用いて、参考例８－１（１）～（２）に記載の方法又はこれに準ずる方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表１－１～表１－２に示す。 Reference Examples 8-2 to 8-16 below show the corresponding commercially available halogenated pyridinecarbonitrile, hydroxypyridinecarbonitrile, or hydroxybenzonitrile and the corresponding commercially available alcohol, alkyl halide, aryl halide or hydroxypyridine. And synthesized according to the method described in Reference Example 8-1 (1) to (2) or a method analogous thereto. Their structures, NMR data, and MS data are shown in Table 1-1 to Table 1-2.
Figure JPOXMLDOC01-appb-T000031
      
  　 
Figure JPOXMLDOC01-appb-T000031
      
  　 
Figure JPOXMLDOC01-appb-T000032
      
  　 
Figure JPOXMLDOC01-appb-T000032
      
  　 
参考例９－１
１－｛４－［（５－メチルピラジン－２－イル）オキシ］フェニル｝メタンアミン塩酸塩 Reference Example 9-1
1- {4-[(5-Methylpyrazin-2-yl) oxy] phenyl} methanamine hydrochloride
Figure JPOXMLDOC01-appb-C000033
  　 
Figure JPOXMLDOC01-appb-C000033
  　 
（１）ｔｅｒｔ－ブチル｛４－［（５－メチルピラジン－２－イル）オキシ］ベンジル｝カルバメートの合成 (1) Synthesis of tert-butyl {4-[(5-methylpyrazin-2-yl) oxy] benzyl} carbamate
Figure JPOXMLDOC01-appb-C000034
  　 
Figure JPOXMLDOC01-appb-C000034
  　 
　２－ブロモ－５－メチルピラジン（７３０ｍｇ）のジメチルスルホキシド溶液（１０．０ｍＬ）にｔｅｒｔ－ブチル（４－ヒドロキシベンジル）カルバメート（１．１３ｇ）、炭酸カリウム（８５６ｍｇ）を加え、１２０℃で６時間攪拌した。室温まで冷却した後、反応液に水を加えて酢酸エチルで２回抽出した。合わせた有機層をフェーズセパレーターに通し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～５０：５０）で精製し、粗精製物を回収した。 To a dimethylsulfoxide solution (10.0 mL) of 2-bromo-5-methylpyrazine (730 mg), tert-butyl (4-hydroxybenzyl) carbamate (1.13 g) and potassium carbonate (856 mg) were added, and the mixture was heated at 120 ° C. for 6 hours. Stir. After cooling to room temperature, water was added to the reaction solution and extracted twice with ethyl acetate. The combined organic layers were passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 to 50:50), and a crude product was recovered.
　続いて、ＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～５０：５０）で精製し、ｔｅｒｔ－ブチル｛４－［（５－メチルピラジン－２－イル）オキシ］ベンジル｝カルバメートを無色油状物質（５３２ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9 H) 2.51 (s, 3 H) 4.33 (d, J=5.8 Hz, 2 H) 4.75 - 4.93 (m, 1 H) 7.05 - 7.14 (m, 2 H) 7.28 - 7.37 (m, 2 H) 7.92 - 7.99 (m, 1 H) 8.31 (d, J=1.4 Hz, 1 H).
MS ESI/APCI Dual posi: 338[M+Na]+.
MS ESI/APCI Dual nega: 314[M-H]-. Subsequently, it was purified by NH silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 to 50:50), and tert-butyl {4-[(5-methylpyrazin-2-yl) oxy] benzyl} carbamate. As a colorless oil (532 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9 H) 2.51 (s, 3 H) 4.33 (d, J = 5.8 Hz, 2 H) 4.75-4.93 (m, 1 H) 7.05- 7.14 (m, 2 H) 7.28-7.37 (m, 2 H) 7.92-7.99 (m, 1 H) 8.31 (d, J = 1.4 Hz, 1 H).
MS ESI / APCI Dual posi: 338 [M + Na] + .
MS ESI / APCI Dual nega: 314 [MH] - .
（２）表題化合物の合成
　上記（１）で得られた化合物（５３０ｍｇ）の酢酸エチル溶液（１０．０ｍＬ）に４ｍｏｌ／Ｌ塩化水素－酢酸エチル溶液（１０．０ｍＬ）を加え、室温で３０分間攪拌した。析出物を濾取し、表題化合物を無色固体（４３０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (s, 3 H) 3.94 - 4.10 (m, 2 H) 7.17 - 7.25 (m, 2 H) 7.51 - 7.60 (m, 2 H) 8.05 - 8.13 (m, 1 H) 8.43 (d, J=1.2 Hz, 1 H).
MS ESI/APCI Dual posi: 216[M+H]+. (2) Synthesis of title compound A 4 mol / L hydrogen chloride-ethyl acetate solution (10.0 mL) was added to an ethyl acetate solution (10.0 mL) of the compound (530 mg) obtained in (1) above, and the mixture was stirred at room temperature for 30 minutes. Stir. The precipitate was collected by filtration to give the title compound as a colorless solid (430 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 2.45 (s, 3 H) 3.94-4.10 (m, 2 H) 7.17-7.25 (m, 2 H) 7.51-7.60 (m, 2 H) 8.05- 8.13 (m, 1 H) 8.43 (d, J = 1.2 Hz, 1 H).
MS ESI / APCI Dual posi: 216 [M + H] + .
参考例９－２
１－｛４－［（５－メチルピリミジン－２－イル）オキシ］フェニル｝メタンアミン塩酸塩 Reference Example 9-2
1- {4-[(5-Methylpyrimidin-2-yl) oxy] phenyl} methanamine hydrochloride
Figure JPOXMLDOC01-appb-C000035
  　 
Figure JPOXMLDOC01-appb-C000035
  　 
　２－ブロモ－５－メチルピラジンの代わりに２－クロロ－５－メチルピリミジン（４００ｍｇ）を用いて参考例９－１（１）～（２）と同様の手法にて表題化合物を無色固体（５９３ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 2.22 (s, 3 H) 3.93 - 4.09 (m, 2 H) 7.12 - 7.30 (m, 2 H) 7.51 - 7.59 (m, 2 H) 8.44 - 8.50 (m, 2 H).
MS ESI/APCI Dual posi: 216[M+H]+. Using the same procedure as in Reference Example 9-1 (1) to (2) using 2-chloro-5-methylpyrimidine (400 mg) instead of 2-bromo-5-methylpyrazine, the title compound was obtained as a colorless solid (593 mg ).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 2.22 (s, 3 H) 3.93-4.09 (m, 2 H) 7.12-7.30 (m, 2 H) 7.51-7.59 (m, 2 H) 8.44- 8.50 (m, 2 H).
MS ESI / APCI Dual posi: 216 [M + H] + .
参考例１０
［４－（アミノメチル）フェニル］メタノール Reference Example 10
[4- (Aminomethyl) phenyl] methanol
Figure JPOXMLDOC01-appb-C000036
  　 
Figure JPOXMLDOC01-appb-C000036
  　 
　氷冷した水素化リチウムアルミニウム（２．３６ｇ）のテトラヒドロフラン懸濁液（８０．０ｍＬ）に窒素雰囲気下で、メチル４－シアノベンゾアート（２．００ｇ）のテトラヒドロフラン溶液（２０．０ｍＬ）を少量ずつ滴下した。氷冷下で１時間攪拌後、５０℃で一晩攪拌した。氷冷した反応液に水（２．４０ｍＬ）、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（２．４０ｍＬ）を少量ずつ滴下した。そこに酢酸エチルを加えて攪拌した後、セライ卜（登録商標）濾過した。濾液を減圧下濃縮して、表題化合物を無色固体（１．５０ｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.68 (s, 2 H) 4.46 (s, 2 H) 7.15 - 7.34 (m, 4 H).
MS ESI/APCI Dual posi: 138[M+H]+. To a tetrahydrofuran suspension (80.0 mL) of ice-cooled lithium aluminum hydride (2.36 g) under a nitrogen atmosphere, a tetrahydrofuran solution (20.0 mL) of methyl 4-cyanobenzoate (2.00 g) was added little by little. It was dripped. After stirring for 1 hour under ice cooling, the mixture was stirred overnight at 50 ° C. Water (2.40 mL) and a 1 mol / L aqueous sodium hydroxide solution (2.40 mL) were added dropwise to the ice-cooled reaction mixture. Ethyl acetate was added thereto and stirred, and then filtered through Celai® (registered trademark). The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (1.50 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.68 (s, 2 H) 4.46 (s, 2 H) 7.15-7.34 (m, 4 H).
MS ESI / APCI Dual posi: 138 [M + H] + .
参考例１１－１
１－［４－（エトキシメチル）フェニル］メタンアミン Reference Example 11-1
1- [4- (Ethoxymethyl) phenyl] methanamine
Figure JPOXMLDOC01-appb-C000037
  　 
Figure JPOXMLDOC01-appb-C000037
  　 
（１）４－（エトキシメチル）ベンゾニトリルの合成 (1) Synthesis of 4- (ethoxymethyl) benzonitrile
Figure JPOXMLDOC01-appb-C000038
  　 
Figure JPOXMLDOC01-appb-C000038
  　 
　氷冷したエタノール（０．４８ｍＬ）のテトラヒドロフラン溶液（３０．０ｍＬ）に窒素雰囲気下で水素化ナトリウム（６０％鉱油分散物、３０６ｍｇ）を加え、室温に戻して３０分間攪拌した。そこに４－（ブロモメチル）ベンゾニトリル（１．００ｇ）を加えて、同温度で一晩攪拌した。反応液に水、飽和食塩水を加えて、酢酸エチルで抽出した。有機層をフェーズセパレーターに通し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９５：５～７０：３０）で精製し、４－（エトキシメチル）ベンゾニトリルを無色油状物質（６８２ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.0 Hz, 3 H) 3.58 (q, J=7.0 Hz, 2 H) 4.56 (s, 2 H) 7.42 - 7.48 (m, 2 H) 7.61- 7.66 (m, 2 H).
MS ESI/APCI Dual posi: 162[M+H]+, 184[M+Na]+. Sodium hydride (60% mineral oil dispersion, 306 mg) was added to a tetrahydrofuran solution (30.0 mL) of ice-cooled ethanol (0.48 mL) under a nitrogen atmosphere, and the mixture was returned to room temperature and stirred for 30 minutes. 4- (Bromomethyl) benzonitrile (1.00 g) was added thereto, and the mixture was stirred overnight at the same temperature. Water and saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 to 70:30) to obtain 4- (ethoxymethyl) benzonitrile as a colorless oil (682 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.0 Hz, 3 H) 3.58 (q, J = 7.0 Hz, 2 H) 4.56 (s, 2 H) 7.42-7.48 (m, 2 H) 7.61-7.66 (m, 2 H).
MS ESI / APCI Dual posi: 162 [M + H] + , 184 [M + Na] + .
（２）表題化合物の合成
　上記（１）で得られた化合物（６８０ｍｇ）を用いて参考例１０と同様の手法にて表題化合物を無色油状物質（６５７ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J=7.0 Hz, 3 H) 3.54 (q, J=7.0 Hz, 2 H) 3.86 (s, 2 H) 4.49 (s, 2 H) 7.23 - 7.37 (m, 4 H).
MS ESI/APCI Dual posi: 166[M+H]+, 188[M+Na]+.
　以下の参考例１１－２～１１－７は、対応する市販のハロゲン化メチルベンゾニトリル、又はヒドロキシメチルベンゾニトリル及び対応する市販のアルコール、又はハロゲン化アルキルを用いて、参考例１１－１（１）～（２）に記載の方法又はこれに準ずる方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表２－１に示す。 (2) Synthesis of title compound The title compound was obtained as a colorless oil (657 mg) in the same manner as in Reference Example 10 using the compound (680 mg) obtained in (1) above.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.0 Hz, 3 H) 3.54 (q, J = 7.0 Hz, 2 H) 3.86 (s, 2 H) 4.49 (s, 2 H ) 7.23-7.37 (m, 4 H).
MS ESI / APCI Dual posi: 166 [M + H] + , 188 [M + Na] + .
The following Reference Examples 11-2 to 11-7 were prepared by using the corresponding commercially available halogenated methylbenzonitrile or hydroxymethylbenzonitrile and the corresponding commercially available alcohol or alkyl halide. ) To (2) or a method analogous thereto. Their structures, NMR data, and MS data are shown in Table 2-1.
Figure JPOXMLDOC01-appb-T000039
      
  　 
Figure JPOXMLDOC01-appb-T000039
      
  　 
参考例１２－１
１－［５－（プロパン－２－イル）ピリジン－２－イル］メタンアミン塩酸塩 Reference Example 12-1
1- [5- (propan-2-yl) pyridin-2-yl] methanamine hydrochloride
Figure JPOXMLDOC01-appb-C000040
  　 
Figure JPOXMLDOC01-appb-C000040
  　 
（１）５－（プロパ－１－エン－２－イル）ピリジン－２－カルボニトリルの合成 (1) Synthesis of 5- (prop-1-en-2-yl) pyridine-2-carbonitrile
Figure JPOXMLDOC01-appb-C000041
  　 
Figure JPOXMLDOC01-appb-C000041
  　 
　５－ブロモピリジン－２－カルボニトリル（５００ｍｇ）、４，４，５，５－テトラメチル－２－（プロパ－１－エン－２－イル）－１，３，２－ジオキサボロラン（６８９μＬ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（３１６ｍｇ）、炭酸セシウム（１．７８ｇ）、水（５．００ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（１５．０ｍＬ）の混合物を封管中１００℃で一晩攪拌した。反応液に水、飽和食塩水を加えて、酢酸エチルで抽出した。有機層をフェーズセパレーターに通し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９５：５～７０：３０）で精製し、５－（プロパ－１－エン－２－イル）ピリジン－２－カルボニトリルを無色油状物質（３００ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.19 (dd, J=1.5, 0.8 Hz, 3 H) 5.36 (dd, J=1.5, 0.8 Hz, 1 H) 5.51 - 5.59 (m, 1 H) 7.66 (dd, J=8.2, 0.9 Hz, 1 H) 7.84 (dd, J=8.2, 2.3 Hz, 1 H) 8.82 (dd, J=2.3, 0.9 Hz, 1 H).
MS ESI/APCI Dual posi: 145[M+H]+, 167[M+Na]+. 5-bromopyridine-2-carbonitrile (500 mg), 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2-dioxaborolane (689 μL), tetrakis A mixture of (triphenylphosphine) palladium (0) (316 mg), cesium carbonate (1.78 g), water (5.00 mL) and N, N-dimethylformamide (15.0 mL) in a sealed tube at 100 ° C. overnight. Stir. Water and saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5-70: 30) to give 5- (prop-1-en-2-yl) pyridine-2-carbonitrile colorless. Obtained as an oil (300 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.19 (dd, J = 1.5, 0.8 Hz, 3 H) 5.36 (dd, J = 1.5, 0.8 Hz, 1 H) 5.51-5.59 (m, 1 H) 7.66 (dd, J = 8.2, 0.9 Hz, 1 H) 7.84 (dd, J = 8.2, 2.3 Hz, 1 H) 8.82 (dd, J = 2.3, 0.9 Hz, 1 H).
MS ESI / APCI Dual posi: 145 [M + H] + , 167 [M + Na] + .
（２）表題化合物の合成
　上記（１）で得られた化合物（３００ｍｇ）を用いて参考例７－１と同様の手法にて表題化合物を淡黄色油状物質（３１３ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (d, J=7.0 Hz, 6 H) 2.98 - 3.14 (m, 1 H) 4.18 - 4.38 (m, 2 H) 7.76 - 7.90 (m, 1 H) 8.08 - 8.23 (m, 1 H) 8.62 - 8.72 (m, 1 H).
MS ESI/APCI Dual posi: 151[M+H]+, 173[M+Na]+. (2) Synthesis of title compound The title compound was obtained as a pale yellow oil (313 mg) in the same manner as in Reference Example 7-1 using the compound (300 mg) obtained in (1) above.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.26 (d, J = 7.0 Hz, 6 H) 2.98-3.14 (m, 1 H) 4.18-4.38 (m, 2 H) 7.76-7.90 (m, 1 H) 8.08-8.23 (m, 1 H) 8.62-8.72 (m, 1 H).
MS ESI / APCI Dual posi: 151 [M + H] + , 173 [M + Na] + .
参考例１２－２
１－（５－シクロプロピルピリジン－２－イル）メタンアミン塩酸塩 Reference Example 12-2
1- (5-Cyclopropylpyridin-2-yl) methanamine hydrochloride
Figure JPOXMLDOC01-appb-C000042
  　 
Figure JPOXMLDOC01-appb-C000042
  　 
　５－ブロモピリジン－２－カルボニトリル（１．００ｇ）と４，４，５，５－テトラメチル－２－（プロパ－１－エン－２－イル）－１，３，２－ジオキサボロランの代わりに対応するシクロプロピルボロン酸（７５１ｍｇ）を用いて、参考例１２－１（１）～（２）に準ずる手法にて表題化合物を油状物質（４９７ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 0.81 - 0.99 (m, 2 H) 1.09 - 1.23 (m, 2 H) 2.03 - 2.19 (m, 1 H) 4.22 - 4.39 (m, 2 H) 7.83 - 8.02 (m, 2 H) 8.64 - 8.73 (m, 1 H). Instead of 5-bromopyridine-2-carbonitrile (1.00 g) and 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2-dioxaborolane Using the corresponding cyclopropylboronic acid (751 mg), the title compound was obtained as an oily substance (497 mg) by a method according to Reference Example 12-1 (1) to (2).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 0.81-0.99 (m, 2 H) 1.09-1.23 (m, 2 H) 2.03-2.19 (m, 1 H) 4.22-4.39 (m, 2 H) 7.83-8.02 (m, 2 H) 8.64-8.73 (m, 1 H).
参考例１３－１
２－アミノ－２－（４－クロロフェニル）－Ｎ，Ｎ－ジメチルアセトアミド塩酸塩 Reference Example 13-1
2-Amino-2- (4-chlorophenyl) -N, N-dimethylacetamide hydrochloride
Figure JPOXMLDOC01-appb-C000043
  　 
Figure JPOXMLDOC01-appb-C000043
  　 
（１）アミノ（４－クロロフェニル）酢酸の合成 (1) Synthesis of amino (4-chlorophenyl) acetic acid
Figure JPOXMLDOC01-appb-C000044
  　 
Figure JPOXMLDOC01-appb-C000044
  　 
　塩化アンモニウム（３．８５ｇ）、シアン化ナトリウム（３．４９ｇ）の水溶液（１５．０ｍＬ）に４－クロロベンズアルデヒド（１０．０ｇ）のメタノール溶液（１５．０ｍＬ）を少量ずつ滴下した。室温で２時間攪拌後、反応液に水（４０．０ｍＬ）を加えた。トルエンで２回抽出し、合わせた有機層を水で洗浄した。有機層を氷冷し、６ｍｏｌ／Ｌ塩酸（２０．０ｍＬ)を加えた。水層を分離し、有機層を６ｍｏｌ／Ｌ塩酸で抽出した。合わせた水層を１００℃で一晩攪拌した。析出したガム状の固体を濾別し、濾液へ２８％アンモニア水溶液を加えて中和した。析出物にエタノール、メタノール、及び酢酸エチルを加えて６０℃でしばらく攪拌した。室温に戻して濾取し、アミノ（４－クロロフェニル）酢酸を粗生成物（淡黄色固体　１．５５ｇ）として得、粗生成物のまま次の反応に用いた。 A methanol solution (15.0 mL) of 4-chlorobenzaldehyde (10.0 g) was added dropwise to an aqueous solution (15.0 mL) of ammonium chloride (3.85 g) and sodium cyanide (3.49 g). After stirring at room temperature for 2 hours, water (40.0 mL) was added to the reaction solution. Extraction was performed twice with toluene, and the combined organic layers were washed with water. The organic layer was ice-cooled and 6 mol / L hydrochloric acid (20.0 mL) was added. The aqueous layer was separated and the organic layer was extracted with 6 mol / L hydrochloric acid. The combined aqueous layer was stirred at 100 ° C. overnight. The precipitated gummy solid was filtered off and neutralized by adding 28% aqueous ammonia solution to the filtrate. Ethanol, methanol, and ethyl acetate were added to the precipitate and stirred at 60 ° C. for a while. The reaction mixture was returned to room temperature and collected by filtration to obtain amino (4-chlorophenyl) acetic acid as a crude product (pale yellow solid, 1.55 g), which was used in the next reaction as the crude product.
（２）［（ｔｅｒｔ－ブトキシカルボニル）アミノ］（４－クロロフェニル）酢酸の合成 (2) Synthesis of [(tert-butoxycarbonyl) amino] (4-chlorophenyl) acetic acid
Figure JPOXMLDOC01-appb-C000045
  　 
Figure JPOXMLDOC01-appb-C000045
  　 
　上記（１）で得られた化合物（１．４５ｇ）の１，４－ジオキサン（２０．０ｍＬ）、水（１０．０ｍＬ）混合溶液に１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（７．８１ｍＬ）、二炭酸ジ－ｔｅｒｔ－ブチル（２．５６ｇ）、及び炭酸水素ナトリウム（０．６６ｇ）を加えて、室温で３時間攪拌した。反応液に飽和硫酸水素カリウム溶液を加え、酢酸エチルで２回抽出した。合わせた有機層をフェーズセパレーターに通して減圧下濃縮し、［（ｔｅｒｔ－ブトキシカルボニル）アミノ］（４－クロロフェニル）酢酸を粗生成物（淡黄色油状物質　３．５９ｇ）として得、粗生成物のまま次の反応に用いた。 To a mixed solution of the compound obtained in (1) (1.45 g) in 1,4-dioxane (20.0 mL) and water (10.0 mL), a 1 mol / L aqueous sodium hydroxide solution (7.81 mL), dicarbonate Di-tert-butyl (2.56 g) and sodium hydrogen carbonate (0.66 g) were added, and the mixture was stirred at room temperature for 3 hours. A saturated potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were passed through a phase separator and concentrated under reduced pressure to obtain [(tert-butoxycarbonyl) amino] (4-chlorophenyl) acetic acid as a crude product (pale yellow oily substance 3.59 g). Used as is in the next reaction.
（３）ｔｅｒｔ－ブチル［１－（４－クロロフェニル）－２－（ジメチルアミノ）－２－オキソエチル］カルバメートの合成 (3) Synthesis of tert-butyl [1- (4-chlorophenyl) -2- (dimethylamino) -2-oxoethyl] carbamate
Figure JPOXMLDOC01-appb-C000046
  　 
Figure JPOXMLDOC01-appb-C000046
  　 
　上記（２）で得られた化合物（５００ｍｇ）のクロロホルム溶液（２．００ｍＬ）に１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（３１３ｍｇ）、１－ヒドロキシベンゾ卜リアゾール一水和物（２５０ｍｇ）、及びジメチルアミン（約５０％、水溶液、１４７ｍｇ)を加えて、室温で１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて、二層を分離した。水層を酢酸エチルで抽出し、合わせた有機層をフェーズセパレーターに通して減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～５０：５０）で精製し、ｔｅｒｔ－ブチル［１－（４－クロロフェニル）－２－（ジメチルアミノ）－２－オキソエチル］カルバメートを淡黄色固体（２８４ｍｇ）として得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9 H) 2.89 (s, 3 H) 2.97 (s, 3 H) 5.51 (d, J=7.5 Hz, 1 H) 6.05 (d, J=7.5 Hz, 1 H) 7.32 (s, 4 H).
MS ESI/APCI Dual posi: 335[M+Na]+. To a chloroform solution (2.00 mL) of the compound (500 mg) obtained in (2) above, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (313 mg), 1-hydroxybenzotriazole monohydrate (250 mg) and dimethylamine (about 50%, aqueous solution, 147 mg) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the two layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-50: 50) and tert-butyl [1- (4-chlorophenyl) -2- (dimethylamino) -2- Oxoethyl] carbamate was obtained as a pale yellow solid (284 mg).
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9 H) 2.89 (s, 3 H) 2.97 (s, 3 H) 5.51 (d, J = 7.5 Hz, 1 H) 6.05 (d, J = 7.5 Hz, 1 H) 7.32 (s, 4 H).
MS ESI / APCI Dual posi: 335 [M + Na] + .
（４）表題化合物の合成
　上記（３）で得られた化合物（２８０ｍｇ）を用いて参考例９－１（２）と同様の手法にて表題化合物を粗生成物（無色固体　１９５ｍｇ）として得た。表題化合物は粗生成物のまま次の反応に用いた。 (4) Synthesis of title compound The title compound was obtained as a crude product (195 mg of colorless solid) using the compound (280 mg) obtained in (3) above in the same manner as in Reference Example 9-1 (2). . The title compound was used in the next reaction as a crude product.
参考例１３－２
２－アミノ－２－（４－クロロフェニル）－１－（モルホリン－４－イル）エタノン塩酸塩 Reference Example 13-2
2-Amino-2- (4-chlorophenyl) -1- (morpholin-4-yl) ethanone hydrochloride
Figure JPOXMLDOC01-appb-C000047
  　 
Figure JPOXMLDOC01-appb-C000047
  　 
　参考例１３－１（２）で得られた化合物とジメチルアミン（約５０％、水溶液）の代わりにモルホリン（７１μＬ）を用いて参考例１３－１（３）～（４）に準ずる手法にて表題化合物を淡黄色油状物質（１８４ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 2.98 - 3.21 (m, 2 H) 3.35 - 3.73 (m, 6 H) 5.62 (s, 1 H) 7.40 - 7.68 (m, 4 H).
MS ESI/APCI Dual posi: 255[M+H]+, 277[M+Na]+. In the same manner as in Reference Examples 13-1 (3) to (4), using morpholine (71 μL) instead of the compound obtained in Reference Example 13-1 (2) and dimethylamine (about 50%, aqueous solution). The title compound was obtained as a pale yellow oil (184 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 2.98-3.21 (m, 2 H) 3.35-3.73 (m, 6 H) 5.62 (s, 1 H) 7.40-7.68 (m, 4 H).
MS ESI / APCI Dual posi: 255 [M + H] + , 277 [M + Na] + .
参考例１４
２－アミノ－２－（４－クロロフェニル）エタノール塩酸塩 Reference Example 14
2-Amino-2- (4-chlorophenyl) ethanol hydrochloride
Figure JPOXMLDOC01-appb-C000048
  　 
Figure JPOXMLDOC01-appb-C000048
  　 
（１）ｔｅｒｔ－ブチル［１－（４－クロロフェニル）－２－ヒドロキシエチル］カルバメートの合成 (1) Synthesis of tert-butyl [1- (4-chlorophenyl) -2-hydroxyethyl] carbamate
Figure JPOXMLDOC01-appb-C000049
  　 
Figure JPOXMLDOC01-appb-C000049
  　 
　参考例１３－１（２）で得られた化合物（２．００ｇ）のテトラヒドロフラン溶液（４０．０ｍＬ）に氷冷下でクロロギ酸イソブチル（６３０μＬ）、４－メチルモルホリン（５２７μＬ）を加えて、１５分間攪拌した。続いて水素化ホウ素ナトリウム（４９５ｍｇ）、水（２．００ｍＬ）を加え、室温で１時間攪拌した。更に水素化ホウ素ナトリウム（５００ｍｇ）を加えて、同温度で２時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで抽出した。有機層をフェーズセパレーターに通して減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～５０：５０）で精製した。得られた粗精製物にｎ－ヘキサン、酢酸エチルを加えて、得られた析出物を濾取した。濾取物を減圧下乾燥し、ｔｅｒｔ－ブチル［１－（４－クロロフェニル）－２－ヒドロキシエチル］カルバメートを無色固体（５０９ｍｇ）として得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 3.66 - 3.94 (m, 2 H) 4.65 - 4.81 (m, 1 H) 5.16 - 5.30 (m, 1 H) 7.19 - 7.28 (m, 2 H) 7.29 - 7.37 (m, 2 H).
MS ESI/APCI Dual posi: 294[M+Na]+. To a tetrahydrofuran solution (40.0 mL) of the compound (2.00 g) obtained in Reference Example 13-1 (2), isobutyl chloroformate (630 μL) and 4-methylmorpholine (527 μL) were added under ice-cooling. Stir for minutes. Subsequently, sodium borohydride (495 mg) and water (2.00 mL) were added, and the mixture was stirred at room temperature for 1 hour. Further, sodium borohydride (500 mg) was added and stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-50: 50). N-Hexane and ethyl acetate were added to the obtained crude product, and the resulting precipitate was collected by filtration. The filtered product was dried under reduced pressure to obtain tert-butyl [1- (4-chlorophenyl) -2-hydroxyethyl] carbamate as a colorless solid (509 mg).
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 3.66-3.94 (m, 2 H) 4.65-4.81 (m, 1 H) 5.16-5.30 (m, 1 H) 7.19-7.28 (m, 2 H) 7.29-7.37 (m, 2 H).
MS ESI / APCI Dual posi: 294 [M + Na] + .
（２）表題化合物の合成
　上記（１）で得られた化合物（２００ｍｇ）を用いて参考例９－１（２）と同様の手法にて表題化合物を粗生成物（無色固体　１５２ｍｇ）として得た。表題化合物は粗生成物のまま次の反応に用いた。 (2) Synthesis of title compound Using the compound (200 mg) obtained in (1) above, the title compound was obtained as a crude product (colorless solid 152 mg) in the same manner as in Reference Example 9-1 (2). . The title compound was used in the next reaction as a crude product.
参考例１５
１－（４－クロロフェニル）－２－メトキシエタンアミン塩酸塩 Reference Example 15
1- (4-Chlorophenyl) -2-methoxyethanamine hydrochloride
Figure JPOXMLDOC01-appb-C000050
  　 
Figure JPOXMLDOC01-appb-C000050
  　 
（１）ｔｅｒｔ－ブチル［１－（４－クロロフェニル）－２－メトキシエチル］カルバメートの合成 (1) Synthesis of tert-butyl [1- (4-chlorophenyl) -2-methoxyethyl] carbamate
Figure JPOXMLDOC01-appb-C000051
  　 
Figure JPOXMLDOC01-appb-C000051
  　 
　参考例１４（１）で得られた化合物（３００ｍｇ）のテトラヒドロフラン溶液（４０．０ｍＬ）へ氷冷下、水素化ナトリウム（６０％鉱油分散物、５３．０ｍｇ）を加えた。同温度で１０分間攪拌した後、ヨウ化メチル（８２．０μＬ）を加えた。同温度で１時間、室温で４時間攪拌した後、水、酢酸エチルを加えた。生成したエマルジョンに希塩酸を加えて有機層を分離した。水層を酢酸エチルで抽出し、合わせた有機層をフェーズセパレーターに通して減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～６０：４０）で精製し、ｔｅｒｔ－ブチル［１－（４－クロロフェニル）－２－メトキシエチル］カルバメートを無色固体（２６４ｍｇ）として得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.41 (s, 9 H) 3.33 (s, 3 H) 3.44 - 3.68 (m, 2 H) 4.67 - 4.83 (m, 1 H) 5.17 - 5.34 (m, 1 H) 7.18 - 7.36 (m, 4 H).
MS ESI/APCI Dual posi: 308[M+Na]+.
MS ESI/APCI Dual nega: 284[M-H]-. Sodium hydride (60% mineral oil dispersion, 53.0 mg) was added to a tetrahydrofuran solution (40.0 mL) of the compound (300 mg) obtained in Reference Example 14 (1) under ice cooling. After stirring at the same temperature for 10 minutes, methyl iodide (82.0 μL) was added. After stirring at the same temperature for 1 hour and at room temperature for 4 hours, water and ethyl acetate were added. Dilute hydrochloric acid was added to the resulting emulsion to separate the organic layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 to 60:40) to give tert-butyl [1- (4-chlorophenyl) -2-methoxyethyl] carbamate as a colorless solid. (264 mg).
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.41 (s, 9 H) 3.33 (s, 3 H) 3.44-3.68 (m, 2 H) 4.67-4.83 (m, 1 H) 5.17-5.34 (m , 1 H) 7.18-7.36 (m, 4 H).
MS ESI / APCI Dual posi: 308 [M + Na] + .
MS ESI / APCI Dual nega: 284 [MH] - .
（２）表題化合物の合成
上記（１）で得られた化合物（２６４ｍｇ）を用いて参考例９－１（２）と同様の手法にて表題化合物を無色固体（１５４ｍｇ）として得た。
1H NMR (200 MHz, DMSO-d6) δ ppm 3.32 (s, 3 H) 3.53 - 3.77 (m, 2 H) 4.40 - 4.59 (m, 1 H) 7.39 - 7.63 (m, 4 H).
MS ESI/APCI Dual posi: 186[M+H]+. (2) Synthesis of title compound Using the compound (264 mg) obtained in (1) above, the title compound was obtained as a colorless solid (154 mg) in the same manner as in Reference Example 9-1 (2).
1 H NMR (200 MHz, DMSO-d 6 ) δ ppm 3.32 (s, 3 H) 3.53-3.77 (m, 2 H) 4.40-4.59 (m, 1 H) 7.39-7.63 (m, 4 H).
MS ESI / APCI Dual posi: 186 [M + H] + .
参考例１６－１
　５－（アミノメチル）－１－ベンジルピリジン－２（１Ｈ）－オントリフルオロアセタート Reference Example 16-1
5- (Aminomethyl) -1-benzylpyridine-2 (1H) -one trifluoroacetate
Figure JPOXMLDOC01-appb-C000052
  　 
Figure JPOXMLDOC01-appb-C000052
  　 
（１）５－（アミノメチル）ピリジン－２（１Ｈ）－オン塩酸塩の合成 (1) Synthesis of 5- (aminomethyl) pyridin-2 (1H) -one hydrochloride
Figure JPOXMLDOC01-appb-C000053
  　 
Figure JPOXMLDOC01-appb-C000053
  　 
　６－メトキシピリジン－２－カルボニトリルの代わりに６－オキソ－１，６－ジヒドロピリジン－３－カルボニトリル（４００ｍｇ）を用いて参考例７－１に準ずる手法にて５－（アミノメチル）ピリジン－２（１Ｈ）－オン塩酸塩を淡褐色固体（６３０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.68 - 3.87 (m, 2 H) 6.27 - 6.46 (m, 1 H) 7.48 - 7.67 (m, 2 H) 8.23 (br. s., 3 H).
MS ESI/APCI Dual posi: 125[M+H]+, 147[M+Na]+.
MS ESI/APCI Dual nega: 123[M-H]-. Using 5-oxo-1,6-dihydropyridine-3-carbonitrile (400 mg) instead of 6-methoxypyridine-2-carbonitrile in the same manner as in Reference Example 7-1, 5- (aminomethyl) pyridine- 2 (1H) -one hydrochloride was obtained as a light brown solid (630 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.68-3.87 (m, 2 H) 6.27-6.46 (m, 1 H) 7.48-7.67 (m, 2 H) 8.23 (br. S., 3 H ).
MS ESI / APCI Dual posi: 125 [M + H] + , 147 [M + Na] + .
MS ESI / APCI Dual nega: 123 [MH] - .
（２）ｔｅｒｔ－ブチル［（６－オキソ－１，６－ジヒドロピリジン－３－イル）メチル］カルバメートの合成 (2) Synthesis of tert-butyl [(6-oxo-1,6-dihydropyridin-3-yl) methyl] carbamate
Figure JPOXMLDOC01-appb-C000054
  　 
Figure JPOXMLDOC01-appb-C000054
  　 
　上記（１）で得られた化合物（６３０ｍｇ）を用いて参考例１３－１（２）に準ずる手法にてｔｅｒｔ－ブチル［（６－オキソ－１，６－ジヒドロピリジン－３－イル）メチル］カルバメートを無色固体（６０９ｍｇ）として得た。 Using the compound (630 mg) obtained in (1) above, tert-butyl [(6-oxo-1,6-dihydropyridin-3-yl) methyl] carbamate in the same manner as in Reference Example 13-1 (2) Was obtained as a colorless solid (609 mg).
（３）ｔｅｒｔ－ブチル［（１－ベンジル－６－オキソ－１，６－ジヒドロピリジン－３－イル）メチル］カルバメートの合成 (3) Synthesis of tert-butyl [(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl) methyl] carbamate
Figure JPOXMLDOC01-appb-C000055
  　 
Figure JPOXMLDOC01-appb-C000055
  　 
　上記（２）で得られた化合物（２００ｍｇ）、炭酸カリウム（３７０ｍｇ）のアセトニトリル懸濁液（７．５０ｍＬ）にベンジルブロミド（１０７μＬ）を加え、室温で３日間攪拌した。反応液にクロロホルムを加えて析出物を溶解した。得られた溶液に無水硫酸マグネシウムを加えて攪拌後、不溶物を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=１００：０～９２：８）で精製し、ｔｅｒｔ－ブチル［（１－ベンジル－６－オキソ－１，６－ジヒドロピリジン－３－イル）メチル］カルバメートを無色油状物質（２３０ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H) 3.98 (d, J=5.9 Hz, 2 H) 4.88 (br. s., 1 H) 5.11 (s, 2 H) 6.59 (d, J=9.3 Hz, 1 H) 7.21 (br. s., 1 H) 7.24 - 7.40 (m, 6 H).
MS ESI/APCI Dual posi: 315[M+H]+. Benzyl bromide (107 μL) was added to an acetonitrile suspension (7.50 mL) of the compound (200 mg) obtained above (2) and potassium carbonate (370 mg), and the mixture was stirred at room temperature for 3 days. Chloroform was added to the reaction solution to dissolve the precipitate. Anhydrous magnesium sulfate was added to the resulting solution and stirred, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 92: 8), and tert-butyl [(1-benzyl-6-oxo-1,6- Dihydropyridin-3-yl) methyl] carbamate was obtained as a colorless oil (230 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H) 3.98 (d, J = 5.9 Hz, 2 H) 4.88 (br. S., 1 H) 5.11 (s, 2 H) 6.59 (d, J = 9.3 Hz, 1 H) 7.21 (br. s., 1 H) 7.24-7.40 (m, 6 H).
MS ESI / APCI Dual posi: 315 [M + H] + .
（４）表題化合物の合成
　上記（３）で得られた化合物（２３０ｍｇ）のクロロホルム溶液（７．３０ｍＬ）に室温でトリフルオロ酢酸（７３２μＬ）を加えた。同温度で３０分間攪拌した後、トリフルオロ酢酸（４．００ｍＬ）を加えて、更に４０分間攪拌した。反応液を減圧下濃縮して、表題化合物を無色油状物質（４９９ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.75 - 3.85 (m, 2 H) 5.08 (s, 2 H) 6.50 (d, J=9.3 Hz, 1 H) 7.25 - 7.40 (m, 5 H) 7.49 - 7.56 (m, 1 H) 7.90 (d, J=2.5 Hz, 1 H) 8.00 (br. s., 3 H).
MS ESI/APCI Dual posi: 215[M+H]+. (4) Synthesis of title compound To a chloroform solution (7.30 mL) of the compound (230 mg) obtained in (3) above, trifluoroacetic acid (732 μL) was added at room temperature. After stirring at the same temperature for 30 minutes, trifluoroacetic acid (4.00 mL) was added, and the mixture was further stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound as a colorless oil (499 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.75-3.85 (m, 2 H) 5.08 (s, 2 H) 6.50 (d, J = 9.3 Hz, 1 H) 7.25-7.40 (m, 5 H ) 7.49-7.56 (m, 1 H) 7.90 (d, J = 2.5 Hz, 1 H) 8.00 (br. S., 3 H).
MS ESI / APCI Dual posi: 215 [M + H] + .
　以下の参考例１６－２～１６－３は、参考例１６－１（２）で得られた化合物と対応する市販のハロゲン化アラルキル、又はハロゲン化アルキルを用いて、参考例１６－１（３）～（４）に記載の方法又はこれに準ずる方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを参考例表３－１に示す。 The following Reference Examples 16-2 to 16-3 were prepared by using Reference Example 16-1 (3) using the compound obtained in Reference Example 16-1 (2) and the corresponding commercially available aralkyl halide or alkyl halide. ) To (4) or a method analogous thereto. Their structures, NMR data, and MS data are shown in Reference Example Table 3-1.
Figure JPOXMLDOC01-appb-T000056
  　 
Figure JPOXMLDOC01-appb-T000056
  　 
参考例１７
３－（アミノメチル）－１－ベンジルピリジン－２（１Ｈ）－オントリフルオロアセタート Reference Example 17
3- (Aminomethyl) -1-benzylpyridine-2 (1H) -one trifluoroacetate
Figure JPOXMLDOC01-appb-C000057
  　 
Figure JPOXMLDOC01-appb-C000057
  　 
　６－オキソ－１，６－ジヒドロピリジン－３－カルボニトリルの代わりに２－オキソ－１，２－ジヒドロピリジン－３－カルボニトリル（５００ｍｇ）を用いて参考例１６－１（１）～（４）に準ずる手法にて表題化合物を褐色油状物質（３２９ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.04 (s, 2 H) 5.11 (s, 2 H) 6.23 (t, J=6.9 Hz, 1 H) 7.19 - 7.25 (m, 2 H) 7.28 - 7.38 (m, 4 H) 7.48 (dd, J=6.9, 1.8 Hz, 1 H).
MS ESI/APCI Dual posi: 215[M+H]+, 237[M+Na]+. Reference Examples 16-1 (1) to (4) were substituted with 2-oxo-1,2-dihydropyridine-3-carbonitrile (500 mg) instead of 6-oxo-1,6-dihydropyridine-3-carbonitrile. The title compound was obtained as a brown oil (329 mg) by a similar method.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.04 (s, 2 H) 5.11 (s, 2 H) 6.23 (t, J = 6.9 Hz, 1 H) 7.19-7.25 (m, 2 H) 7.28- 7.38 (m, 4 H) 7.48 (dd, J = 6.9, 1.8 Hz, 1 H).
MS ESI / APCI Dual posi: 215 [M + H] + , 237 [M + Na] + .
参考例１８－１
４－（アミノメチル）－１－ベンジルピリジン－２（１Ｈ）－オントリフルオロアセタート Reference Example 18-1
4- (Aminomethyl) -1-benzylpyridine-2 (1H) -one trifluoroacetate
Figure JPOXMLDOC01-appb-C000058
  　 
Figure JPOXMLDOC01-appb-C000058
  　 
（１）４－（アミノメチル）ピリジン－２（１Ｈ）－オン塩酸塩の合成 (1) Synthesis of 4- (aminomethyl) pyridin-2 (1H) -one hydrochloride
Figure JPOXMLDOC01-appb-C000059
  　 
Figure JPOXMLDOC01-appb-C000059
  　 
　１－（２－メトキシピリジン－４－イル）メタンアミン（５００ｍｇ）を２ｍｏｌ／Ｌ塩化水素－メタノール溶液（９．０５ｍＬ）に溶解し、７０℃で１９時間攪拌した。反応液を減圧下濃縮し、得られた残渣に水（１０．０ｍＬ）、濃塩酸（２．００ｍＬ）を加えて４時間還流した。再度反応液を減圧下濃縮し、得られた残渣に濃塩酸（５．００ｍＬ）を加えて１３時間還流した。反応液を減圧下濃縮し、４－（アミノメチル）ピリジン－２（１Ｈ）－オン塩酸塩を淡黄色固体（７４０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.83 - 3.95 (m, 2 H) 6.36 (dd, J=6.7, 1.7 Hz, 1 H) 6.42 - 6.54 (m, 1 H) 7.47 (d, J=6.7 Hz, 1 H) 8.58 (br. s., 3 H).
MS ESI/APCI Dual posi: 125[M+H]+, 147[M+Na]+.
MS ESI/APCI Dual nega: 123[M-H]-. 1- (2-methoxypyridin-4-yl) methanamine (500 mg) was dissolved in a 2 mol / L hydrogen chloride-methanol solution (9.05 mL), and the mixture was stirred at 70 ° C. for 19 hours. The reaction solution was concentrated under reduced pressure, water (10.0 mL) and concentrated hydrochloric acid (2.00 mL) were added to the resulting residue, and the mixture was refluxed for 4 hours. The reaction solution was concentrated again under reduced pressure, concentrated hydrochloric acid (5.00 mL) was added to the resulting residue, and the mixture was refluxed for 13 hours. The reaction mixture was concentrated under reduced pressure to give 4- (aminomethyl) pyridin-2 (1H) -one hydrochloride as a pale yellow solid (740 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.83-3.95 (m, 2 H) 6.36 (dd, J = 6.7, 1.7 Hz, 1 H) 6.42-6.54 (m, 1 H) 7.47 (d, J = 6.7 Hz, 1 H) 8.58 (br.s., 3 H).
MS ESI / APCI Dual posi: 125 [M + H] + , 147 [M + Na] + .
MS ESI / APCI Dual nega: 123 [MH] - .
（２）表題化合物の合成
　上記（１）で得られた化合物（７４０ｍｇ）を用いて参考例１６－１（２）～（４）と同様の手法にて表題化合物を淡黄色油状物質（８４５ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.85 - 3.99 (m, 2 H) 5.09 (s, 2 H) 6.25 - 6.33 (m, 1 H) 6.46 - 6.52 (m, 1 H) 7.22 - 7.40 (m, 5 H) 7.86 (d, J=7.1 Hz, 1 H) 8.21 (br. s., 3 H).
MS ESI/APCI Dual posi: 215[M+H]+. (2) Synthesis of title compound Using the compound (740 mg) obtained in (1) above, the title compound was converted to a pale yellow oily substance (845 mg) in the same manner as in Reference Examples 16-1 (2) to (4). Got as.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.85-3.99 (m, 2 H) 5.09 (s, 2 H) 6.25-6.33 (m, 1 H) 6.46-6.52 (m, 1 H) 7.22- 7.40 (m, 5 H) 7.86 (d, J = 7.1 Hz, 1 H) 8.21 (br. S., 3 H).
MS ESI / APCI Dual posi: 215 [M + H] + .
参考例１８－２
　４－（アミノメチル）－１－（シクロブチルメチル）ピリジン－２（１Ｈ）－オントリフルオロアセタート Reference Example 18-2
4- (Aminomethyl) -1- (cyclobutylmethyl) pyridin-2 (1H) -one trifluoroacetate
Figure JPOXMLDOC01-appb-C000060
  　 
Figure JPOXMLDOC01-appb-C000060
  　 
　参考例１８－１（１）で得られた化合物（２００ｍｇ）とベンジルブロミドの代わりに（ブロモメチル）シクロブタン（１００μＬ）を用いて参考例１６－１（３）～（４）と同様の手法にて表題化合物を淡褐色油状物質（２３５ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.64 - 2.01 (m, 6 H) 2.59 - 2.72 (m, 1 H) 3.83 - 3.95 (m, 4 H) 6.18 - 6.27 (m, 1 H) 6.40 - 6.46 (m, 1 H) 7.72 (d, J=7.0 Hz, 1 H) 8.18 (br. s., 3 H).
MS ESI/APCI Dual posi: 193[M+H]+. The compound (200 mg) obtained in Reference Example 18-1 (1) and (bromomethyl) cyclobutane (100 μL) instead of benzyl bromide were used in the same manner as in Reference Example 16-1 (3) to (4). The title compound was obtained as a light brown oil (235 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.64-2.01 (m, 6 H) 2.59-2.72 (m, 1 H) 3.83-3.95 (m, 4 H) 6.18-6.27 (m, 1 H) 6.40-6.46 (m, 1 H) 7.72 (d, J = 7.0 Hz, 1 H) 8.18 (br. S., 3 H).
MS ESI / APCI Dual posi: 193 [M + H] + .
参考例１９
５－（アミノメチル）－１－フェニルピリジン－２（１Ｈ）－オン塩酸塩 Reference Example 19
5- (Aminomethyl) -1-phenylpyridin-2 (1H) -one hydrochloride
Figure JPOXMLDOC01-appb-C000061
  　 
Figure JPOXMLDOC01-appb-C000061
  　 
（１）メチル６－オキソ－１－フェニル－１，６－ジヒドロピリジン－３－カルボキシラートの合成 (1) Synthesis of methyl 6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000062
  　 
Figure JPOXMLDOC01-appb-C000062
  　 
　メチル２－オキソ－２Ｈ－ピラン－５－カルボキシラート（５．００ｇ）のメタノール溶液（３２０ｍＬ）にアニリン（２．９６ｍＬ）を加えて、６０℃で２時間、８０℃で３時間攪拌した。室温まで冷却した後、一晩攪拌した。反応液を減圧下濃縮して、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～３０：７０）で精製し、メチル６－オキソ－１－フェニル－１，６－ジヒドロピリジン－３－カルボキシラートを黄色油状物質（０．９９ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.87 (s, 3 H) 6.64 (dd, J=9.6, 0.6 Hz, 1 H) 7.33 - 7.43 (m, 2 H) 7.43 - 7.58 (m, 3 H) 7.92 (dd, J=9.6, 2.6 Hz, 1 H) 8.24 (dd, J=2.6, 0.6 Hz, 1 H).
MS ESI/APCI Dual posi: 230[M+H]+. Aniline (2.96 mL) was added to a methanol solution (320 mL) of methyl 2-oxo-2H-pyran-5-carboxylate (5.00 g), and the mixture was stirred at 60 ° C. for 2 hours and at 80 ° C. for 3 hours. After cooling to room temperature, the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 30:70) to give methyl 6-oxo-1-phenyl-1, 6-Dihydropyridine-3-carboxylate was obtained as a yellow oil (0.99 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.87 (s, 3 H) 6.64 (dd, J = 9.6, 0.6 Hz, 1 H) 7.33-7.43 (m, 2 H) 7.43-7.58 (m, 3 H) 7.92 (dd, J = 9.6, 2.6 Hz, 1 H) 8.24 (dd, J = 2.6, 0.6 Hz, 1 H).
MS ESI / APCI Dual posi: 230 [M + H] + .
（２）６－オキソ－１－フェニル－１，６－ジヒドロピリジン－３－カルボン酸の合成 (2) Synthesis of 6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000063
  　 
Figure JPOXMLDOC01-appb-C000063
  　 
　上記（１）で得られた化合物（９８０ｍｇ）のテトラヒドロフラン溶液（４９.０ｍＬ）に水（３３．０ｍＬ）、水酸化リチウム一水和物（３５９ｍｇ）を加えて、室温で２時間攪拌した。反応液に水、酢酸エチルを加えた後、２層を分離した。有機層を水で抽出し、合わせた水層に２ｍｏｌ／Ｌ塩酸（５．００ｍＬ）を加えた。酢酸エチルで２回抽出し、合わせた有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、濾液を減圧下濃縮して、６－オキソ－１－フェニル－１，６－ジヒドロピリジン－３－カルボン酸を褐色固体（８９０ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.54 (dd, J=9.6, 0.6 Hz, 1 H) 7.41 - 7.63 (m, 5 H) 7.83 - 7.92 (m, 1 H) 8.08 - 8.25 (m, 1 H) 12.90 (br. s., 1 H).
MS ESI/APCI Dual posi: 216[M+H]+.
MS ESI/APCI Dual nega: 214[M-H]-. Water (33.0 mL) and lithium hydroxide monohydrate (359 mg) were added to a tetrahydrofuran solution (49.0 mL) of the compound (980 mg) obtained in (1) above, and the mixture was stirred at room temperature for 2 hours. After adding water and ethyl acetate to the reaction solution, the two layers were separated. The organic layer was extracted with water, and 2 mol / L hydrochloric acid (5.00 mL) was added to the combined aqueous layer. Extraction was performed twice with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to give 6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylic acid as a brown solid (890 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.54 (dd, J = 9.6, 0.6 Hz, 1 H) 7.41-7.63 (m, 5 H) 7.83-7.92 (m, 1 H) 8.08-8.25 (m , 1 H) 12.90 (br.s., 1 H).
MS ESI / APCI Dual posi: 216 [M + H] + .
MS ESI / APCI Dual nega: 214 [MH] - .
（３）６－オキソ－１－フェニル－１，６－ジヒドロピリジン－３－カルボキサミドの合成 (3) Synthesis of 6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000064
  　 
Figure JPOXMLDOC01-appb-C000064
  　 
　上記（２）で得られた化合物（９４０ｍｇ）のトルエン懸濁液（４４．０ｍＬ）に塩化チオニル（６３０μＬ）を加えて、１００℃で２時間攪拌した。室温まで冷却した後、反応液を減圧下濃縮した。得られた残渣（９１５ｍｇ）に氷冷下で２８％アンモニア水溶液を滴下し、激しく攪拌した。析出物を濾取して水で洗浄した。濾取物を減圧下乾燥し、６－オキソ－１－フェニル－１，６－ジヒドロピリジン－３－カルボキサミドを褐色固体（６９５ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 6.52 (d, J=9.6 Hz, 1 H) 7.41 - 7.59 (m, 5 H) 7.93 (dd, J=9.6, 2.6 Hz, 1 H) 8.29 (d, J=2.6 Hz, 1 H).
MS ESI/APCI Dual posi: 215[M+H]+. Thionyl chloride (630 μL) was added to a toluene suspension (44.0 mL) of the compound (940 mg) obtained in (2) above, and the mixture was stirred at 100 ° C. for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. A 28% aqueous ammonia solution was added dropwise to the resulting residue (915 mg) under ice cooling, and the mixture was vigorously stirred. The precipitate was collected by filtration and washed with water. The filtered product was dried under reduced pressure to obtain 6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxamide as a brown solid (695 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 6.52 (d, J = 9.6 Hz, 1 H) 7.41-7.59 (m, 5 H) 7.93 (dd, J = 9.6, 2.6 Hz, 1 H) 8.29 (d, J = 2.6 Hz, 1 H).
MS ESI / APCI Dual posi: 215 [M + H] + .
（４）６－オキソ－１－フェニル－１，６－ジヒドロピリジン－３－カルボニトリルの合成 (4) Synthesis of 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonitrile
Figure JPOXMLDOC01-appb-C000065
  　 
Figure JPOXMLDOC01-appb-C000065
  　 
　上記（３）で得られた化合物（６９０ｍｇ）のクロロホルム懸濁液（３２．０ｍＬ）にトリエチルアミン（２．２４ｍＬ）を加えた後、氷冷下でトリフルオロ酢酸無水物（１．３４ｍＬ）を滴下した。室温で２時間攪拌した後、氷冷下で水（３２．０ｍＬ）を加えた。室温でしばらく攪拌後、２層を分離した。水層をクロロホルムで抽出し、合わせた有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～１５：８５）で精製し、６－オキソ－１－フェニル－１，６－ジヒドロピリジン－３－カルボニトリルを淡褐色固体（３９８ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.69 (dd, J=9.6, 0.6 Hz, 1 H) 7.31 - 7.40 (m, 2 H) 7.40 - 7.64 (m, 4 H) 7.88 (dd, J=2.5, 0.6 Hz, 1 H).
MS ESI/APCI Dual posi: 197[M+H]+. Triethylamine (2.24 mL) was added to a chloroform suspension (32.0 mL) of the compound (690 mg) obtained in (3) above, and then trifluoroacetic anhydride (1.34 mL) was added dropwise under ice cooling. did. After stirring at room temperature for 2 hours, water (32.0 mL) was added under ice cooling. After stirring for a while at room temperature, the two layers were separated. The aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 15:85), and 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonitrile was pale brown Obtained as a solid (398 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.69 (dd, J = 9.6, 0.6 Hz, 1 H) 7.31-7.40 (m, 2 H) 7.40-7.64 (m, 4 H) 7.88 (dd, J = 2.5, 0.6 Hz, 1 H).
MS ESI / APCI Dual posi: 197 [M + H] + .
（５）表題化合物の合成
上記（４）で得られた化合物（４００ｍｇ）を用いて参考例７－１に準ずる手法にて表題化合物を褐色固体（５７０ｍｇ）として得た。なお、表題化合物は、合成後、すぐに次の反応に用いた。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.80 - 3.93 (m, 2 H) 6.54 (d, J=9.5 Hz, 1 H) 7.38 - 7.58 (m, 5 H) 7.68 (dd, J=9.5, 2.6 Hz, 1 H) 7.87 (d, J=2.6 Hz, 1 H) 8.39 (br. s., 3 H).
MS ESI/APCI Dual posi: 201[M+H]+, 223[M+Na]+. (5) Synthesis of title compound The title compound was obtained as a brown solid (570 mg) by the method according to Reference Example 7-1 using the compound (400 mg) obtained in (4) above. The title compound was used in the next reaction immediately after synthesis.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.80-3.93 (m, 2 H) 6.54 (d, J = 9.5 Hz, 1 H) 7.38-7.58 (m, 5 H) 7.68 (dd, J = (9.5, 2.6 Hz, 1 H) 7.87 (d, J = 2.6 Hz, 1 H) 8.39 (br.s., 3 H).
MS ESI / APCI Dual posi: 201 [M + H] + , 223 [M + Na] + .
参考例２０
１－（２，３－ジヒドロフロ［２，３－ｂ］ピリジン－５－イル）メタンアミン塩酸塩 Reference Example 20
1- (2,3-Dihydrofuro [2,3-b] pyridin-5-yl) methanamine hydrochloride
Figure JPOXMLDOC01-appb-C000066
  　 
Figure JPOXMLDOC01-appb-C000066
  　 
　参考例１９（１）で得られた化合物の代わりにエチルフロ［２，３－ｂ］ピリジン－５－カルボキシラート（ＧＢ２２８９２７６Ａ　実施例１参照）（１７５ｍｇ）を用いて、参考例１９（２）～（５）と同様の手法にて表題化合物を淡褐色油状物質（１５０ｍｇ）として得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 2.98 (t, J=6.8 Hz, 2 H) 3.26 - 3.34 (m, 2 H) 3.79 (t, J=6.8 Hz, 2 H) 4.00 (s, 2 H) 7.66 (s, 1 H) 7.73 (s, 1 H).
MS ESI/APCI Dual posi: 151[M+H]+, 173[M+Na]+. By using ethyl furo [2,3-b] pyridine-5-carboxylate (GB228289276A, see Example 1) (175 mg) instead of the compound obtained in Reference Example 19 (1), Reference Examples 19 (2) to ( The title compound was obtained as a pale-brown oil (150 mg) by a method similar to 5).
1 H NMR (600 MHz, DMSO-d 6 ) δ ppm 2.98 (t, J = 6.8 Hz, 2 H) 3.26-3.34 (m, 2 H) 3.79 (t, J = 6.8 Hz, 2 H) 4.00 (s , 2 H) 7.66 (s, 1 H) 7.73 (s, 1 H).
MS ESI / APCI Dual posi: 151 [M + H] + , 173 [M + Na] + .
参考例２１
１－（２，３－ジヒドロ－１－ベンゾフラン－６－イル）メタンアミン塩酸塩 Reference Example 21
1- (2,3-Dihydro-1-benzofuran-6-yl) methanamine hydrochloride
Figure JPOXMLDOC01-appb-C000067
  　 
Figure JPOXMLDOC01-appb-C000067
  　 
（１）２－（２，５－ジブロモフェノキシ）エタノールの合成 (1) Synthesis of 2- (2,5-dibromophenoxy) ethanol
Figure JPOXMLDOC01-appb-C000068
  　 
Figure JPOXMLDOC01-appb-C000068
  　 
　１，４－ジブロモ－２－フルオロベンゼン（８．００ｇ）にエチレングリコール（４０．８ｍＬ）、Ｎ－メチル－２－ピロリドン（４．０８ｍＬ）、及びカリウムｔｅｒｔ－ブ卜キシド（１２．４ｇ）を加えて、１００℃で１０時間攪拌した。室温まで冷却した後、反応液に水（１６．０ｍＬ）を加えて１時間攪拌した。不溶物を濾別し、濾液に水（１４０ｍＬ）を加えて、室温で３０分間、氷冷下で３０分間攪拌した。析出物を濾取して水で洗浄した。濾取物を減圧下乾燥し、２－（２，５－ジブロモフェノキシ）エタノールを褐色固体（７．８８ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.16 (t, J=6.4 Hz, 1 H) 3.93 - 4.07 (m, 2 H) 4.07 - 4.20 (m, 2 H) 6.98 - 7.07 (m, 2 H) 7.40 (d, J=8.4 Hz, 1 H).
MS ESI/APCI Dual posi: 317[M+Na]+. 1,4-Dibromo-2-fluorobenzene (8.00 g) was charged with ethylene glycol (40.8 mL), N-methyl-2-pyrrolidone (4.08 mL), and potassium tert-butoxide (12.4 g). In addition, the mixture was stirred at 100 ° C. for 10 hours. After cooling to room temperature, water (16.0 mL) was added to the reaction solution and stirred for 1 hour. Insoluble matters were filtered off, water (140 mL) was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes and under ice-cooling for 30 minutes. The precipitate was collected by filtration and washed with water. The filtered product was dried under reduced pressure to obtain 2- (2,5-dibromophenoxy) ethanol as a brown solid (7.88 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.16 (t, J = 6.4 Hz, 1 H) 3.93-4.07 (m, 2 H) 4.07-4.20 (m, 2 H) 6.98-7.07 (m, 2 H) 7.40 (d, J = 8.4 Hz, 1 H).
MS ESI / APCI Dual posi: 317 [M + Na] + .
（２）２－ブロモエチル２，５－ジブロモフェニルエーテルの合成 (2) Synthesis of 2-bromoethyl 2,5-dibromophenyl ether
Figure JPOXMLDOC01-appb-C000069
  　 
Figure JPOXMLDOC01-appb-C000069
  　 
　上記（１）で得られた化合物（７．８８ｇ）のトルエン溶液（５３．０ｍＬ）に三臭化リン（１．１４ｍＬ）を加え、９０℃で２時間攪拌した。室温まで冷却した後、水（２６．０ｍＬ）を少しずつ加えた。９０℃で３時間攪拌した後、室温まで冷却して１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（４７．０ｍＬ）を滴下し、同温度で３時間攪拌した。２層を分離し、有機層を水で洗浄して、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～５０：５０）で精製し、２－ブロモエチル２，５－ジブロモフェニルエーテルを無色油状物質（５．０４ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.68 (t, J=6.4 Hz, 2 H) 4.33 (t, J=6.4 Hz, 2 H) 6.93 - 7.11 (m, 2 H) 7.37 - 7.45 (m, 1 H).
MS EI: 358[M]+. Phosphorus tribromide (1.14 mL) was added to a toluene solution (53.0 mL) of the compound (7.88 g) obtained in (1) above, and the mixture was stirred at 90 ° C. for 2 hours. After cooling to room temperature, water (26.0 mL) was added in small portions. After stirring at 90 ° C. for 3 hours, the mixture was cooled to room temperature, 1 mol / L aqueous sodium hydroxide solution (47.0 mL) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. The two layers were separated and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 50:50) to give 2-bromoethyl 2,5-dibromophenyl ether as a colorless oil (5.04 g). It was.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.68 (t, J = 6.4 Hz, 2 H) 4.33 (t, J = 6.4 Hz, 2 H) 6.93-7.11 (m, 2 H) 7.37-7.45 ( m, 1 H).
MS EI: 358 [M] + .
（３）６－ブロモ－２，３－ジヒドロ－１－ベンゾフランの合成 (3) Synthesis of 6-bromo-2,3-dihydro-1-benzofuran
Figure JPOXMLDOC01-appb-C000070
  　 
Figure JPOXMLDOC01-appb-C000070
  　 
　上記（２）で得られた化合物（５．０２ｇ）にトルエン（４０．０ｍＬ）、テトラヒドロフラン（８０．０ｍＬ）を加えて溶解し、窒素雰囲気下、－７８℃でｎ－ブチルリチウム（２．６９ｍｏｌ／Ｌ、ｎ－ヘキサン溶液、５．２０ｍＬ）を滴下した。同温度で３０分間攪拌した後、酢酸（２００μＬ）、水（１０．０ｍＬ）を順次加えた。室温まで戻した後、水を加えた。２層を分離後、有機層を０．５ｍｏｌ／Ｌ水酸化ナトリウム水溶液、水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９８：２～９２：８）で精製し、６－ブロモ－２，３－ジヒドロ－１－ベンゾフランを粗生成物（無色固体　２．３３ｇ）として得た。なお、６－ブロモ－２，３－ジヒドロ－１－ベンゾフランは粗生成物のまま、次の反応に用いた。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.10 - 3.20 (m, 2 H) 4.58 (t, J=8.7 Hz, 2 H) 6.91 - 6.99 (m, 2 H) 7.01 - 7.07 (m, 1 H).
MS EI: 198[M]+. Toluene (40.0 mL) and tetrahydrofuran (80.0 mL) are added and dissolved in the compound (5.02 g) obtained in (2) above, and n-butyllithium (2.69 mol) at −78 ° C. in a nitrogen atmosphere. / L, n-hexane solution, 5.20 mL) was added dropwise. After stirring at the same temperature for 30 minutes, acetic acid (200 μL) and water (10.0 mL) were sequentially added. After returning to room temperature, water was added. After separating the two layers, the organic layer was washed successively with 0.5 mol / L sodium hydroxide aqueous solution and water. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 98: 2-92: 8) to give 6-bromo-2,3-dihydro-1-benzofuran. Obtained as a crude product (2.33 g of colorless solid). 6-Bromo-2,3-dihydro-1-benzofuran was used in the next reaction as a crude product.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.10-3.20 (m, 2 H) 4.58 (t, J = 8.7 Hz, 2 H) 6.91-6.99 (m, 2 H) 7.01-7.07 (m, 1 H).
MS EI: 198 [M] + .
（４）２，３－ジヒドロ－１－ベンゾフラン－６－カルボニトリルの合成 (4) Synthesis of 2,3-dihydro-1-benzofuran-6-carbonitrile
Figure JPOXMLDOC01-appb-C000071
  　 
Figure JPOXMLDOC01-appb-C000071
  　 
　上記（３）で得られた化合物（２．０７ｇ）、シアン化亜鉛（０．９２ｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（１．２０ｇ）及びＮ，Ｎ－ジメチルホルムアミド（６．００ｍＬ）の混合物をアルゴン雰囲気下、１２０℃で２時間攪拌した。反応液をｎ－ヘキサン、酢酸エチルで希釈し、水で２回洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～７５：２５）で精製し、２，３－ジヒドロ－１－ベンゾフラン－６－カルボニトリルを無色固体（０．９２ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.19 - 3.36 (m, 2 H) 4.64 (t, J=8.8 Hz, 2 H) 6.95 - 7.07 (m, 1 H) 7.12 - 7.19 (m, 1 H) 7.23 - 7.30 (m, 1 H). Compound (2.07 g) obtained in (3) above, zinc cyanide (0.92 g), tetrakis (triphenylphosphine) palladium (0) (1.20 g) and N, N-dimethylformamide (6.00 mL) The mixture was stirred at 120 ° C. for 2 hours under an argon atmosphere. The reaction solution was diluted with n-hexane and ethyl acetate, and washed twice with water. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 75:25) to give 2,3-dihydro-1-benzofuran-6-carbonitrile. As a colorless solid (0.92 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.19-3.36 (m, 2 H) 4.64 (t, J = 8.8 Hz, 2 H) 6.95-7.07 (m, 1 H) 7.12-7.19 (m, 1 H) 7.23-7.30 (m, 1 H).
（５）表題化合物の合成
　上記（４）で得られた化合物（０．９２ｇ）を用いて参考例７－１に準ずる手法にて表題化合物を無色固体（１．０７ｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.01 - 3.26 (m, 2 H) 3.94 (s, 2 H) 4.54 (t, J=8.7 Hz, 2 H) 6.73 - 7.07 (m, 2 H) 7.25 (d, J=8.1 Hz, 1 H) 8.14 (br. s., 3 H).
MS ESI/APCI Dual posi: 150[M+H]+. (5) Synthesis of title compound The title compound was obtained as a colorless solid (1.07 g) by the method according to Reference Example 7-1 using the compound (0.92 g) obtained in (4) above.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.01-3.26 (m, 2 H) 3.94 (s, 2 H) 4.54 (t, J = 8.7 Hz, 2 H) 6.73-7.07 (m, 2 H ) 7.25 (d, J = 8.1 Hz, 1 H) 8.14 (br.s., 3 H).
MS ESI / APCI Dual posi: 150 [M + H] + .
参考例２２
１－（２，２－ジメチル－２，３－ジヒドロ－１－ベンゾフラン－５－イル）メタンアミン Reference Example 22
1- (2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl) methanamine
Figure JPOXMLDOC01-appb-C000072
  　 
Figure JPOXMLDOC01-appb-C000072
  　 
（１）３－ブロモ－４－ｔｅｒｔ－ブトキシベンゾニトリルの合成 (1) Synthesis of 3-bromo-4-tert-butoxybenzonitrile
Figure JPOXMLDOC01-appb-C000073
  　 
Figure JPOXMLDOC01-appb-C000073
  　 
　３－ブロモ－４－フルオロベンゾニトリル（２．００ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（３２．０ｍＬ）にカリウムｔｅｒｔ－ブ卜キシド（１．６８ｇ）を加えて、窒素雰囲気下、１３５℃で１７時間攪拌した。室温まで冷却した後、氷冷した反応液に水を加えた。酢酸エチルで抽出し、有機層を水で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～９１：９）で精製し、３－ブロモ－４－ｔｅｒｔ－ブトキシベンゾニトリルを淡黄色油状物質（１．４９ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9 H) 7.16 (d, J=8.5 Hz, 1 H) 7.51 (dd, J=8.5, 2.0 Hz, 1 H) 7.85 (d, J=2.0 Hz, 1 H).
MS ESI/APCI Dual posi: 276[M+Na]+. To a solution of 3-bromo-4-fluorobenzonitrile (2.00 g) in N, N-dimethylformamide (32.0 mL) was added potassium tert-butoxide (1.68 g), and a nitrogen atmosphere at 135 ° C. Stir for 17 hours. After cooling to room temperature, water was added to the ice-cooled reaction solution. Extraction with ethyl acetate was performed, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 91: 9), and 3-bromo-4-tert-butoxybenzonitrile was pale yellow. Obtained as an oil (1.49 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9 H) 7.16 (d, J = 8.5 Hz, 1 H) 7.51 (dd, J = 8.5, 2.0 Hz, 1 H) 7.85 (d, J = 2.0 Hz, 1 H).
MS ESI / APCI Dual posi: 276 [M + Na] + .
（２）２，２－ジメチル－２，３－ジヒドロ－１－ベンゾフラン－５－カルボニトリルの合成 (2) Synthesis of 2,2-dimethyl-2,3-dihydro-1-benzofuran-5-carbonitrile
Figure JPOXMLDOC01-appb-C000074
  　 
Figure JPOXMLDOC01-appb-C000074
  　 
　上記（１）で得られた化合物（１．４９ｇ）、テトラフルオロホウ酸トリシクロヘキシルホスホニウム（２１６ｍｇ）、ピバル酸（１８０ｍｇ）、及び炭酸セシウム（２．１０ｇ）のメシチレン懸濁液（２５．０ｍＬ）に酢酸パラジウム（II）（６６．０ｍｇ）を加えて、アルゴン雰囲気下、１３５℃で１４時間攪拌した。室温まで冷却した後、反応液をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～９１：９）で精製し、２，２－ジメチル－２，３－ジヒドロ－１－ベンゾフラン－５－カルボニトリルを淡褐色油状物質（１２３ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 6 H) 3.03 (s, 2 H) 6.76 (d, J=8.2 Hz, 1 H) 7.35 - 7.49 (m, 2 H).
MS ESI/APCI Dual posi: 196[M+Na]+.
MS ESI/APCI Dual nega: 172[M-H]-. A mesitylene suspension (25.0 mL) of the compound (1.49 g) obtained in (1) above, tricyclohexylphosphonium tetrafluoroborate (216 mg), pivalic acid (180 mg), and cesium carbonate (2.10 g) To the solution, palladium (II) acetate (66.0 mg) was added, and the mixture was stirred at 135 ° C. for 14 hours under an argon atmosphere. After cooling to room temperature, the reaction solution was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 91: 9) to give 2,2-dimethyl-2,3-dihydro-1-benzofuran-5. Carbonitrile was obtained as a light brown oil (123 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 6 H) 3.03 (s, 2 H) 6.76 (d, J = 8.2 Hz, 1 H) 7.35-7.49 (m, 2 H).
MS ESI / APCI Dual posi: 196 [M + Na] + .
MS ESI / APCI Dual nega: 172 [MH] - .
（３）表題化合物の合成
　上記（２）で得られた化合物（１２０ｍｇ）を用いて、参考例１０に準ずる手法にて表題化合物を淡黄色油状物質（１１０ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 6 H) 3.00 (s, 2 H) 3.77 (s, 2 H) 6.68 (d, J=8.1 Hz, 1 H) 6.99 - 7.06 (m, 1 H) 7.06 - 7.15 (m, 1 H).
MS ESI/APCI Dual posi: 178[M+H]+. (3) Synthesis of title compound Using the compound (120 mg) obtained in (2) above, the title compound was obtained as a pale yellow oily substance (110 mg) by a method according to Reference Example 10.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 6 H) 3.00 (s, 2 H) 3.77 (s, 2 H) 6.68 (d, J = 8.1 Hz, 1 H) 6.99-7.06 ( m, 1 H) 7.06-7.15 (m, 1 H).
MS ESI / APCI Dual posi: 178 [M + H] + .
参考例２３
４－メトキシ－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボン酸 Reference Example 23
4-Methoxy-6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000075
  　 
Figure JPOXMLDOC01-appb-C000075
  　 
（１）メチル　６－クロロ－４－メトキシピリジン－３－カルボキシラートの合成 (1) Synthesis of methyl 6-chloro-4-methoxypyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000076
  　 
Figure JPOXMLDOC01-appb-C000076
  　 
　メチル　４，６－ジクロロピリジン－３－カルボキシラート（４１．３ｇ）のテトラヒドロフラン溶液（４００ｍＬ）に氷冷下でナトリウムメ卜キシド（約２８％、メタノ一ル溶液、３８．６ｇ）を加えた後、室温で１６時間攪拌した。反応液を減圧下濃縮し、得られた残渣に飽和塩化アンモニウム水溶液を加えた。クロロホルムで２回抽出し、合わせた有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別し、濾液を減圧下濃縮した。残渣をジイソプロピルエーテルで再結晶し、析出物を濾取してメチル　６－クロロ－４－メトキシピリジン－３－カルボキシラートを無色固体（３１．１ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3 H) 3.98 (s, 3 H) 6.93 (s, 1 H) 8.71 (s, 1 H).
MS ESI/APCI Dual posi: 202[M+H]+, 204[M+H]+. After adding sodium methoxide (about 28%, methanol solution, 38.6 g) to a tetrahydrofuran solution (400 mL) of methyl 4,6-dichloropyridine-3-carboxylate (41.3 g) under ice-cooling. And stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the resulting residue. Extraction was performed twice with chloroform, and the combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether, and the precipitate was collected by filtration to give methyl 6-chloro-4-methoxypyridine-3-carboxylate as a colorless solid (31.1 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3 H) 3.98 (s, 3 H) 6.93 (s, 1 H) 8.71 (s, 1 H).
MS ESI / APCI Dual posi: 202 [M + H] + , 204 [M + H] + .
（２）メチル　６－シアノ－４－メトキシピリジン－３－カルボキシラートの合成 (2) Synthesis of methyl 6-cyano-4-methoxypyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000077
  　 
Figure JPOXMLDOC01-appb-C000077
  　 
　上記（１）で得られた化合物（３０．３ｇ）を用いて参考例２１（４）と同様の手法にてメチル　６－シアノ－４－メトキシピリジン－３－カルボキシラートを無色固体（１９．７ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.95 (s, 3 H) 4.03 (s, 3 H) 7.30 (s, 1 H) 8.94 (s, 1 H).
MS ESI/APCI Dual posi: 193[M+H]+. Using the compound (30.3 g) obtained in (1) above, methyl 6-cyano-4-methoxypyridine-3-carboxylate was obtained as a colorless solid (19.7 g) in the same manner as in Reference Example 21 (4). ).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.95 (s, 3 H) 4.03 (s, 3 H) 7.30 (s, 1 H) 8.94 (s, 1 H).
MS ESI / APCI Dual posi: 193 [M + H] + .
（３）メチル　４－メトキシ－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキシラートの合成 (3) Synthesis of methyl 4-methoxy-6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000078
  　 
Figure JPOXMLDOC01-appb-C000078
  　 
　上記（２）で得られた化合物（６．５０ｇ）を用いて参考例１（１）と同様の手法にてメチル　４－メトキシ－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキシラートを黄色固体（５．５４ｇ）として得た。
LCMS（測定方法　Ａ－２）0.692min， 
ESI/APCI Dual posi: 235[M+H]+.
ESI/APCI Dual nega: 233[M-H]-. Using the compound (6.50 g) obtained in (2) above, methyl 4-methoxy-6- (1H-1,2,4-triazol-5-yl) was prepared in the same manner as in Reference Example 1 (1). ) Pyridine-3-carboxylate was obtained as a yellow solid (5.54 g).
LCMS (Measurement method A-2) 0.692min,
ESI / APCI Dual posi: 235 [M + H] + .
ESI / APCI Dual nega: 233 [MH] - .
（４）表題化合物の合成
　上記（３）で得られた化合物（５．５４ｇ）を用いて参考例１（３）に準ずる手法にて表題化合物を黄色固体（４．９３ｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 4.02 (s, 3 H) 7.78 (s, 1 H) 8.15 (br. s., 1 H) 8.82 (s, 1 H).
MS ESI/APCI Dual posi: 221[M+H]+.
MS ESI/APCI Dual nega: 219[M-H]-. (4) Synthesis of title compound The title compound was obtained as a yellow solid (4.93 g) by the method according to Reference Example 1 (3) using the compound (5.54 g) obtained in (3) above.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 4.02 (s, 3 H) 7.78 (s, 1 H) 8.15 (br. S., 1 H) 8.82 (s, 1 H).
MS ESI / APCI Dual posi: 221 [M + H] + .
MS ESI / APCI Dual nega: 219 [MH] - .
参考例２４
４－エトキシ－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボン酸 Reference Example 24
4-Ethoxy-6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000079
  　 
Figure JPOXMLDOC01-appb-C000079
  　 
（１）メチル　４－クロロ－６－シアノピリジン－３－カルボキシラートの合成 (1) Synthesis of methyl 4-chloro-6-cyanopyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000080
  　 
Figure JPOXMLDOC01-appb-C000080
  　 
　参考例２１（３）で得られた化合物の代わりにメチル　４，６－ジクロロピリジン－３－カルボキシラート（７．０４ｇ）を用いて参考例２１（４）と同様の手法にてメチル　４－クロロ－６－シアノピリジン－３－カルボキシラートを無色固体（２．５０ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.02 (s, 3 H) 7.80 (s, 1 H) 9.09 (s, 1 H).
MS ESI/APCI Dual posi: 197[M+H]+. Using methyl 4,6-dichloropyridine-3-carboxylate (7.04 g) in place of the compound obtained in Reference Example 21 (3) in the same manner as in Reference Example 21 (4), methyl 4-chloro -6-Cyanopyridine-3-carboxylate was obtained as a colorless solid (2.50 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.02 (s, 3 H) 7.80 (s, 1 H) 9.09 (s, 1 H).
MS ESI / APCI Dual posi: 197 [M + H] + .
（２）メチル　４－クロロ－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキシラートの合成 (2) Synthesis of methyl 4-chloro-6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000081
  　 
Figure JPOXMLDOC01-appb-C000081
  　 
　上記（１）で得られた化合物（２．５０ｇ）を用いて参考例１（１）～（２）と同様の手法にてメチル　４－クロロ－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキシラートを黄色固体（３４１ｍｇ）として得た。
LCMS（測定方法　Ａ－１）0.790min， ESI/APCI Dual posi: 323[M+H]+.   Using the compound (2.50 g) obtained in (1) above, methyl 4-chloro-6- [1- (tetrahydro-2H-pyran--) in the same manner as in Reference Examples 1 (1) to (2) 2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylate was obtained as a yellow solid (341 mg).
LCMS (Measurement method A-1) 0.790min, ESI / APCI Dual posi: 323 [M + H] + .
（３）表題化合物の合成
　上記（２）で得られた化合物（２００ｍｇ）のエタノール溶液（５．００ｍＬ）にナトリウムエ卜キシド（約２０％、エタノ一ル溶液、１２７ｍｇ）を加え、室温で３時間攪拌した。ナトリウムエ卜キシド（約２０％、エタノ一ル溶液、２５４ｍｇ）を加え、６０℃で１時間攪拌した。反応液を減圧下濃縮して得られた残渣にエタノールを加え、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．６０ｍＬ)を加え、６０℃で１時間攪拌した。室温まで冷却した後、反応液を減圧下濃縮して表題化合物を粗生成物として得た。なお、表題化合物は、粗生成物のまま、次の反応に用いた。
LCMS（測定方法　Ａ－１）0.437min，
ESI/APCI Dual posi: 319[M+H]+.
ESI/APCI Dual nega: 317[M-H]-. (3) Synthesis of title compound Sodium ethoxide (about 20%, ethanol solution, 127 mg) was added to an ethanol solution (5.00 mL) of the compound (200 mg) obtained in (2) above, and 3 Stir for hours. Sodium ethoxide (about 20%, ethanol solution, 254 mg) was added, and the mixture was stirred at 60 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, ethanol was added to the resulting residue, 1 mol / L aqueous sodium hydroxide solution (0.60 mL) was added, and the mixture was stirred at 60 ° C. for 1 hr. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain the title compound as a crude product. The title compound was used in the next reaction as a crude product.
LCMS (Measurement method A-1) 0.437min,
ESI / APCI Dual posi: 319 [M + H] + .
ESI / APCI Dual nega: 317 [MH] - .
参考例２５
５－クロロ－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボン酸 Reference Example 25
5-Chloro-6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000082
  　 
Figure JPOXMLDOC01-appb-C000082
  　 
（１）メチル　５，６－ジクロロピリジン－３－カルボキシラートの合成 (1) Synthesis of methyl 5,6-dichloropyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000083
  　 
Figure JPOXMLDOC01-appb-C000083
  　 
　５，６－ジクロロピリジン－３－カルボン酸（１０．０ｇ）のメタノール溶液（１５０ｍＬ）に氷冷下で塩化チオニル（３．９４ｍＬ）を滴下した後、室温で４日間攪拌した。反応液を減圧下濃縮し、得られた残渣をクロロホルムに溶解した。クロロホルム溶液を飽和炭酸水素ナトリウム水溶液で２回、飽和食塩水で順次洗浄して無水硫酸マグネシウムで乾燥した。乾燥剤を濾別し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=１００：０～９５：５）で精製し、メチル　５，６－ジクロロピリジン－３－カルボキシラートを無色固体（９．７０ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.97 (s, 3 H) 8.38 (d, J=2.0 Hz, 1 H) 8.89 (d, J=2.0 Hz, 1 H).
MS ESI/APCI Dual posi: 206[M+H]+. To a methanol solution (150 mL) of 5,6-dichloropyridine-3-carboxylic acid (10.0 g) was added dropwise thionyl chloride (3.94 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. The chloroform solution was washed successively with saturated aqueous sodium hydrogen carbonate solution twice and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 95: 5) to obtain methyl 5,6-dichloropyridine-3-carboxylate as a colorless solid (9.70 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.97 (s, 3 H) 8.38 (d, J = 2.0 Hz, 1 H) 8.89 (d, J = 2.0 Hz, 1 H).
MS ESI / APCI Dual posi: 206 [M + H] + .
（２）メチル　５－クロロ－６－シアノピリジン－３－カルボキシラートの合成 (2) Synthesis of methyl 5-chloro-6-cyanopyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000084
  　 
Figure JPOXMLDOC01-appb-C000084
  　 
　上記（１）で得られた化合物（９．１６ｇ）を用いて、参考例２１（４）と同様の手法にてメチル　５－クロロ－６－シアノピリジン－３－カルボキシラートを無色固体（２．９８ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.02 (s, 3 H) 8.45 (d, J=1.7 Hz, 1 H) 9.16 (d, J=1.7 Hz, 1 H).
MS ESI/APCI Dual posi: 197[M+H]+. Using the compound (9.16 g) obtained in (1) above, methyl 5-chloro-6-cyanopyridine-3-carboxylate was obtained as a colorless solid (2. 98 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.02 (s, 3 H) 8.45 (d, J = 1.7 Hz, 1 H) 9.16 (d, J = 1.7 Hz, 1 H).
MS ESI / APCI Dual posi: 197 [M + H] + .
（３）表題化合物の合成
　上記（２）で得られた化合物（１．００ｇ）を用いて、参考例１（１）～（３）に準ずる手法にて表題化合物を無色固体（３４０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.51 - 1.83 (m, 3 H) 1.90 - 2.26 (m, 3 H) 3.63 - 3.76 (m, 1 H) 3.90 - 4.03 (m, 1 H) 5.69 (dd, J=9.3, 2.8 Hz, 1 H) 8.41 (d, J=1.7 Hz, 1 H) 8.92 (s, 1 H) 9.07 (d, J=1.7 Hz, 1 H) 13.89 (br. s., 1 H).
MS ESI/APCI Dual nega: 307[M-H]-. (3) Synthesis of title compound Using the compound (1.00 g) obtained in (2) above, the title compound was obtained as a colorless solid (340 mg) by the method according to Reference Examples 1 (1) to (3). It was.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.51-1.83 (m, 3 H) 1.90-2.26 (m, 3 H) 3.63-3.76 (m, 1 H) 3.90-4.03 (m, 1 H) 5.69 (dd, J = 9.3, 2.8 Hz, 1 H) 8.41 (d, J = 1.7 Hz, 1 H) 8.92 (s, 1 H) 9.07 (d, J = 1.7 Hz, 1 H) 13.89 (br. S ., 1 H).
MS ESI / APCI Dual nega: 307 [MH] - .
参考例２６
５－フルオロ－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボン酸 Reference Example 26
5-Fluoro-6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000085
  　 
Figure JPOXMLDOC01-appb-C000085
  　 
　参考例２５（１）で得られた化合物の代わりにメチル　６－クロロ－５－フルオロピリジン－３－カルボキシラート（２．０４ｇ）を用いて、参考例２５（２）～（３）と同様の手法にて表題化合物を淡褐色固体（６０９ｍｇ）として得た。
LCMS（測定方法　Ａ－１）0.596min， ESI/APCI Dual nega: 291[M-H]-.  The same procedure as in Reference Examples 25 (2) to (3) was carried out using methyl 6-chloro-5-fluoropyridine-3-carboxylate (2.04 g) instead of the compound obtained in Reference Example 25 (1). The procedure gave the title compound as a light brown solid (609 mg).
LCMS (Measurement method A-1) 0.596min, ESI / APCI Dual nega: 291 [MH] - .
参考例２７
４－メチル－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボン酸 Reference Example 27
4-Methyl-6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000086
  　 
Figure JPOXMLDOC01-appb-C000086
  　 
（１）メチル　４，６－ジメチルピリジン－３－カルボキシラート　１－オキシドの合成 (1) Synthesis of methyl 4,6-dimethylpyridine-3-carboxylate 1-oxide
Figure JPOXMLDOC01-appb-C000087
  　 
Figure JPOXMLDOC01-appb-C000087
  　 
　メチル　４，６－ジメチルピリジン－３－カルボキシラート（４８６ｍｇ）のクロロホルム溶液へ、メタクロロ過安息香酸（６５８ｍｇ）を室温で少量ずつ加え、同温で３時間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチルのみ　さらにクロロホルム：メタノール=９０：１０）で精製し、メチル　４，６－ジメチルピリジン－３－カルボキシラート　１－オキシドを無色固体（５００ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54 (s, 3 H) 2.57 (s, 3 H) 3.92 (s, 3 H) 7.14 (s, 1 H) 8.80 (s, 1 H).
MS ESI/APCI Dual posi: 182[M+H]+. To a chloroform solution of methyl 4,6-dimethylpyridine-3-carboxylate (486 mg), metachloroperbenzoic acid (658 mg) was added little by little at room temperature and stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate alone and further chloroform: methanol = 90: 10) to obtain methyl 4,6-dimethylpyridine-3-carboxylate 1-oxide. Obtained as a colorless solid (500 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54 (s, 3 H) 2.57 (s, 3 H) 3.92 (s, 3 H) 7.14 (s, 1 H) 8.80 (s, 1 H).
MS ESI / APCI Dual posi: 182 [M + H] + .
（２）メチル　６－（ヒドロキシメチル）－４－メチルピリジン－３－カルボキシラートの合成 (2) Synthesis of methyl 6- (hydroxymethyl) -4-methylpyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000088
  　 
Figure JPOXMLDOC01-appb-C000088
  　 
　上記（１）で得られた化合物（５００ｍｇ）のクロロホルム溶液（１０．０ｍＬ）に、氷冷下でトリフルオロ酢酸無水物（１．９０ｍＬ）を加えた。室温で４時間攪拌後、反応液へ飽和炭酸水素ナトリウム水溶液を加えて、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥した。乾燥剤を濾別して、濾液を減圧下濃縮した。得られた残渣をメタノール（１０．０ｍＬ）に溶解し、ナトリウムメ卜キシド（約２５％、メタノ一ル溶液、２００ｍｇ）を加えて、室温で１時間攪拌した。反応液へ飽和塩化アンモニウム水溶液を加え、溶媒を減圧下留去した。得られた混合物にクロロホルムを加え、有機層を分離した。有機層を無水硫酸ナトリウムで乾燥した。乾燥剤を濾別して、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル= ６０：４０～０：１００　さらにクロロホルム：メタノール= ９０：１０）で精製し、メチル　６－（ヒドロキシメチル）－４－メチルピリジン－３－カルボキシラートを無色固体（４２５ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.64 (s, 3 H) 3.45 - 3.58 (m, 1 H) 3.94 (s, 3 H) 4.74 - 4.80 (m, 2 H) 7.13 - 7.17 (m, 1 H) 9.04 (s, 1 H).
MS ESI/APCI Dual posi: 182[M+H]+. Trichloroacetic anhydride (1.90 mL) was added to a chloroform solution (10.0 mL) of the compound (500 mg) obtained in (1) above under ice-cooling. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (10.0 mL), sodium methoxide (about 25%, methanol solution, 200 mg) was added, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the solvent was evaporated under reduced pressure. Chloroform was added to the obtained mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40 to 0: 100, further chloroform: methanol = 90: 10), and methyl 6- (hydroxymethyl) -4-methylpyridine- 3-carboxylate was obtained as a colorless solid (425 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.64 (s, 3 H) 3.45-3.58 (m, 1 H) 3.94 (s, 3 H) 4.74-4.80 (m, 2 H) 7.13-7.17 (m , 1 H) 9.04 (s, 1 H).
MS ESI / APCI Dual posi: 182 [M + H] + .
（３）メチル　６－ホルミル－４－メチルピリジン－３－カルボキシラートの合成 (3) Synthesis of methyl 6-formyl-4-methylpyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000089
  　 
Figure JPOXMLDOC01-appb-C000089
  　 
　上記（２）で得られた化合物（４２５ｍｇ）のクロロホルム溶液（５．００ｍＬ）に、氷冷下でデス－マーチンペルヨージナン（１．２０ｇ）を加え、１時間攪拌した。反応液へ飽和炭酸水素ナトリウム水溶液を加えて、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥した。乾燥剤を濾別して、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～０：１００）で精製し、メチル　６－ホルミル－４－メチルピリジン－３－カルボキシラートを黄色固体（３３７ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.71 (s, 3 H) 3.98 (s, 3 H) 7.81 - 7.85 (m, 1 H) 9.17 - 9.22 (m, 1 H) 10.08 - 10.13 (m, 1 H).
MS ESI/APCI Dual posi: 180[M+H]+. Dess-Martin periodinane (1.20 g) was added to a chloroform solution (5.00 mL) of the compound (425 mg) obtained in (2) above under ice-cooling and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 0: 100) to give methyl 6-formyl-4-methylpyridine-3-carboxylate as a yellow solid (337 mg). Obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.71 (s, 3 H) 3.98 (s, 3 H) 7.81-7.85 (m, 1 H) 9.17-9.22 (m, 1 H) 10.08-10.13 (m , 1 H).
MS ESI / APCI Dual posi: 180 [M + H] + .
（４）メチル　６－［（ヒドロキシイミノ）メチル］－４－メチルピリジン－３－カルボキシラートの合成 (4) Synthesis of methyl 6-[(hydroxyimino) methyl] -4-methylpyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000090
  　 
Figure JPOXMLDOC01-appb-C000090
  　 
　上記（３）で得られた化合物（３３７ｍｇ）のメタノール溶液（１０．０ｍＬ）へ室温で、ヒドロキシルアミン塩酸塩（１９６ｍｇ）、及びトリエチルアミン（３９３μＬ）を加え、同温で３０分攪拌した。析出物を濾別し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル=１００：０～０：１００）で精製し、メチル　６－［（ヒドロキシイミノ）メチル］－４－メチルピリジン－３－カルボキシラートを淡紫色固体（３５９ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 2.57 (s, 3 H) 3.87 (s, 3 H) 7.72 - 7.76 (m, 1 H) 8.10 (s, 1 H) 8.92 (s, 1 H) 11.95 (s, 1 H).
MS ESI/APCI Dual posi: 195[M+H]+. Hydroxylamine hydrochloride (196 mg) and triethylamine (393 μL) were added to a methanol solution (10.0 mL) of the compound (337 mg) obtained in (3) above at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 100: 0 to 0: 100), and methyl 6-[(hydroxyimino) methyl] -4-methylpyridine-3-carboxylate was pale purple. Obtained as a solid (359 mg).
1 H NMR (300 MHz, DMSO-d6) δ ppm 2.57 (s, 3 H) 3.87 (s, 3 H) 7.72-7.76 (m, 1 H) 8.10 (s, 1 H) 8.92 (s, 1 H) 11.95 (s, 1 H).
MS ESI / APCI Dual posi: 195 [M + H] + .
（５）メチル　６－シアノ－４－メチルピリジン－３－カルボキシラートの合成 (5) Synthesis of methyl 6-cyano-4-methylpyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000091
  　 
Figure JPOXMLDOC01-appb-C000091
  　 
　上記（４）で得られた化合物（３５９ｍｇ）、及びトリエチルアミン（１．３０ｍＬ）のクロロホルム懸濁液（１０．０ｍＬ）に、氷冷下でトリフルオロメタンスルホン酸無水物（７７８μＬ）を少量ずつ滴下し、３０分間攪拌した。更にトリエチルアミン（６５０μＬ）、及びトリフルオロメタンスルホン酸無水物（３８９μＬ）を滴下し、氷冷下で３０分間攪拌した。反応液に水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥した。乾燥剤を濾別して、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～０：１００）で精製し、メチル　６－シアノ－４－メチルピリジン－３－カルボキシラートを淡黄色固体（２６８ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.69 (s, 3 H) 3.98 (s, 3 H) 7.58 - 7.61 (m, 1 H) 9.10 - 9.14 (m, 1 H).
MS ESI/APCI Dual posi: 177[M+H]+. To a chloroform suspension (10.0 mL) of the compound (359 mg) obtained in (4) above and triethylamine (1.30 mL), trifluoromethanesulfonic anhydride (778 μL) was added dropwise little by little under ice cooling. And stirred for 30 minutes. Further, triethylamine (650 μL) and trifluoromethanesulfonic anhydride (389 μL) were added dropwise and stirred for 30 minutes under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 0: 100), and methyl 6-cyano-4-methylpyridine-3-carboxylate was obtained as a pale yellow solid (268 mg). Got as.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.69 (s, 3 H) 3.98 (s, 3 H) 7.58-7.61 (m, 1 H) 9.10-9.14 (m, 1 H).
MS ESI / APCI Dual posi: 177 [M + H] + .
（６）表題化合物の合成
　上記（５）で得られた化合物（２６８ｍｇ）を用いて参考例１（１）～（３）に準ずる手法にて、表題化合物を粗生成物（２５４ｍｇ）として得た。なお、表題化合物は、粗生成物のまま、次の反応に用いた。
LCMS（測定方法　Ａ－１）0.569min，
ESI/APCI Dual posi: 289[M+H]+.
ESI/APCI Dual nega: 287[M-H]-. (6) Synthesis of title compound The title compound was obtained as a crude product (254 mg) by the method according to Reference Examples 1 (1) to (3) using the compound (268 mg) obtained in (5) above. . The title compound was used in the next reaction as a crude product.
LCMS (Measurement method A-1) 0.569min,
ESI / APCI Dual posi: 289 [M + H] + .
ESI / APCI Dual nega: 287 [MH] - .
参考例２８
ナトリウム　４－（ベンジルオキシ）－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキシラート Reference Example 28
Sodium 4- (benzyloxy) -6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000092
  　 
Figure JPOXMLDOC01-appb-C000092
  　 
（１）ベンジル　４－（ベンジルオキシ）－６－メチルピリジン－３－カルボキシラートの合成 (1) Synthesis of benzyl 4- (benzyloxy) -6-methylpyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000093
  　 
Figure JPOXMLDOC01-appb-C000093
  　 
　４－ヒドロキシ－６－メチルピリジン－３－カルボン酸（１５．４ｇ）、ベンジルアルコール（２７．１ｇ）、及びトリフェニルホスフィン（６５．６ｇ）のテトラヒドロフラン溶液（４００ｍＬ）に、アゾジカルボン酸ジエチル（２．２ｍｏｌ／Ｌ、トルエン溶液、１１０ｍＬ）を氷冷下で少量ずつ滴下した。室温で１８時間撹拌した後、溶媒を減圧下留去し、得られた残渣にジイソプロピルエーテルを加えて３０分間加熱撹拌した。析出物を濾別し、濾液を減圧下濃縮した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル= ５０：５０）で粗精製した。得られた粗精製物をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=５０：５０～２５：７５）で精製した。回収物をジイソプロピルエーテルで再結晶した。析出物を濾取して、ベンジル　４－（ベンジルオキシ）－６－メチルピリジン－３－カルボキシラートを粗生成物（無色固体　３５．６ｇ）として得た。なお、ベンジル　４－（ベンジルオキシ）－６－メチルピリジン－３－カルボキシラートは、粗生成物のまま、次の反応に用いた。
LCMS（測定方法　Ａ－１）0.876min ，ESI/APCI Dual posi: 334[M+H]+. To a tetrahydrofuran solution (400 mL) of 4-hydroxy-6-methylpyridine-3-carboxylic acid (15.4 g), benzyl alcohol (27.1 g), and triphenylphosphine (65.6 g) was added diethyl azodicarboxylate (2 .2 mol / L, toluene solution, 110 mL) was added dropwise little by little under ice cooling. After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, diisopropyl ether was added to the resulting residue, and the mixture was stirred with heating for 30 minutes. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was roughly purified by NH silica gel column chromatography (n-hexane: ethyl acetate = 50: 50). The obtained crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 to 25:75). The recovered material was recrystallized from diisopropyl ether. The precipitate was collected by filtration to give benzyl 4- (benzyloxy) -6-methylpyridine-3-carboxylate as a crude product (35.6 g of colorless solid). Benzyl 4- (benzyloxy) -6-methylpyridine-3-carboxylate was used in the next reaction as a crude product.
LCMS (measurement method A-1) 0.876min, ESI / APCI Dual posi: 334 [M + H] + .
（２）表題化合物の合成
　上記（１）で得られた化合物（３５．６ｇ）を用いて、参考例２７（１）～（６）に準じた手法にて表題化合物を粗生成物（褐色アモルファス　１．０９ｇ）として得た。なお、表題化合物は、粗生成物のまま、次の反応に用いた。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.59 - 1.82 (m, 3 H) 1.96 - 2.16 (m, 2 H) 2.21 - 2.36 (m, 1 H) 3.67 - 3.83 (m, 1 H) 3.94 (s, 3 H) 4.03 - 4.21 (m, 1 H) 5.36 (s, 2 H) 5.57 (dd, J=9.4, 2.7 Hz, 1 H) 7.29 - 7.59 (m, 5 H) 7.88 (s, 1 H) 8.39 (s, 1 H) 9.07 (s, 1 H).
MS ESI/APCI Dual posi: 395[M+H]+. (2) Synthesis of title compound Using the compound (35.6 g) obtained in (1) above, the title compound was obtained as a crude product (brown amorphous) according to the procedure of Reference Examples 27 (1) to (6). 1.09 g). The title compound was used in the next reaction as a crude product.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.59-1.82 (m, 3 H) 1.96-2.16 (m, 2 H) 2.21-2.36 (m, 1 H) 3.67-3.83 (m, 1 H) 3.94 (s, 3 H) 4.03-4.21 (m, 1 H) 5.36 (s, 2 H) 5.57 (dd, J = 9.4, 2.7 Hz, 1 H) 7.29-7.59 (m, 5 H) 7.88 (s, 1 H) 8.39 (s, 1 H) 9.07 (s, 1 H).
MS ESI / APCI Dual posi: 395 [M + H] + .
参考例２９－１
Ｎ－（ジフェニルメチル）－４－ヒドロキシ－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Reference Example 29-1
N- (diphenylmethyl) -4-hydroxy-6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000094
  　 
Figure JPOXMLDOC01-appb-C000094
  　 
（１）４－（ベンジルオキシ）－Ｎ－（ジフェニルメチル）－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキサミドの合成 (1) 4- (Benzyloxy) -N- (diphenylmethyl) -6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine- Synthesis of 3-carboxamide
Figure JPOXMLDOC01-appb-C000095
  　 
Figure JPOXMLDOC01-appb-C000095
  　 
　参考例２８で得られた化合物（８１．０ｍｇ）、及びジフェニルメタンアミン（９２．０ｍｇ）を用いて、後述の実施例１－１（１）に準じた手法にて４－（ベンジルオキシ）－Ｎ－（ジフェニルメチル）－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキサミドを淡黄色アモルファス（８０．０ｍｇ）として得た。
LCMS（測定方法　Ａ－１）1.123min，ESI/APCI Dual posi: 546[M+H]+. Using the compound (81.0 mg) obtained in Reference Example 28 and diphenylmethanamine (92.0 mg), 4- (benzyloxy) -N was prepared by the method according to Example 1-1 (1) described later. -(Diphenylmethyl) -6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxamide was converted to a pale yellow amorphous (80.0 mg ).
LCMS (Measurement method A-1) 1.123min, ESI / APCI Dual posi: 546 [M + H] + .
（２）表題化合物の合成
　上記の（１）で得られた化合物（８０．０ｍｇ）をエタノール（３．００ｍＬ）、及びテトラヒドロフラン（３．００ｍＬ）で溶解して１０％パラジウム／炭素（３０．０ｍｇ）を加え、水素雰囲気下、室温で１８時間撹拌した。不溶物をセライ卜（登録商標）濾過にて濾別した。濾液を減圧下濃縮し、得られた残渣を用いて、後述の実施例１－１（２）と同様の手法にて表題化合物を無色固体（３８．０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 6.29 (d, J=8.1 Hz, 1 H) 7.03 (s, 1 H) 7.17 - 7.46 (m, 10 H) 8.39 (d, J=6.4 Hz, 1 H) 8.87 (s, 1 H) 11.38 (d, J=8.2 Hz, 1 H) 12.65 - 12.83 (m, 1 H) 14.76 (br. s., 1 H).
MS ESI/APCI Dual posi: 372[M+H]+. (2) Synthesis of title compound The compound (80.0 mg) obtained in (1) above was dissolved in ethanol (3.00 mL) and tetrahydrofuran (3.00 mL), and 10% palladium / carbon (30.0 mg) was dissolved. ) And stirred at room temperature for 18 hours under a hydrogen atmosphere. Insoluble matter was filtered off by Celai® (registered trademark) filtration. The filtrate was concentrated under reduced pressure, and the title compound was obtained as a colorless solid (38.0 mg) by the same method as in Example 1-1 (2) described later using the obtained residue.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 6.29 (d, J = 8.1 Hz, 1 H) 7.03 (s, 1 H) 7.17-7.46 (m, 10 H) 8.39 (d, J = 6.4 Hz , 1 H) 8.87 (s, 1 H) 11.38 (d, J = 8.2 Hz, 1 H) 12.65-12.83 (m, 1 H) 14.76 (br. S., 1 H).
MS ESI / APCI Dual posi: 372 [M + H] + .
　以下の参考例２９－２～２９－４は参考例２８で得られた化合物と市販の対応するアミンを用いて、参考例２９－１（１）～（２）に記載の方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表４－１に示す。 The following Reference Examples 29-2 to 29-4 were synthesized by the method described in Reference Example 29-1 (1) to (2) using the compound obtained in Reference Example 28 and a commercially available corresponding amine. Their structures, NMR data, and MS data are shown in Table 4-1.
Figure JPOXMLDOC01-appb-T000096
      
  　 
Figure JPOXMLDOC01-appb-T000096
      
  　 
　なお、上記参考例２９－１～２９－４は、後述の試験例１又は２において、以下のヒトＰＨＤ２阻害活性を有する。
参考例２９－１　試験例１、阻害率、９７％（ａｔ　１μＭ）
参考例２９－２　試験例１、阻害率、８５％（ａｔ　１μＭ）
参考例２９－３　試験例１、阻害率、９６％（ａｔ　１μＭ）
参考例２９－４　試験例１、阻害率、１０５％（ａｔ　１μＭ）
　　　　　　　　試験例２、阻害率、８９％（ａｔ　１μＭ） The above Reference Examples 29-1 to 29-4 have the following human PHD2 inhibitory activity in Test Example 1 or 2 described later.
Reference Example 29-1 Test Example 1, inhibition rate, 97% (at 1 μM)
Reference Example 29-2 Test Example 1, inhibition rate, 85% (at 1 μM)
Reference Example 29-3 Test Example 1, inhibition rate, 96% (at 1 μM)
Reference Example 29-4 Test Example 1, inhibition rate, 105% (at 1 μM)
Test example 2, inhibition rate, 89% (at 1 μM)
　なお、参考例２９－４は、５０ｎｇ／ｗｅｌｌのヒトＰＨＤ２酵素溶液で試験例２を実施した。 In Reference Example 29-4, Test Example 2 was carried out with a 50 ng / well human PHD2 enzyme solution.
参考例３０
ナトリウム　６－｛５－［（ベンジルオキシ）メチル］－１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル｝ピリジン－３－カルボキシラート Reference Example 30
Sodium 6- {5-[(Benzyloxy) methyl] -1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl} pyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000097
  　 
Figure JPOXMLDOC01-appb-C000097
  　 
（１）メチル　６－｛３－［（ベンジルオキシ）メチル］－１Ｈ－１，２，４－トリアゾール－５－イル｝ピリジン－３－カルボキシラートの合成 (1) Synthesis of methyl 6- {3-[(benzyloxy) methyl] -1H-1,2,4-triazol-5-yl} pyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000098
  　 
Figure JPOXMLDOC01-appb-C000098
  　 
　メチル　６－シアノピリジン－３－カルボキシラート（１９５ｍｇ）とホルモヒドラジドの代わりに２－（ベンジルオキシ）アセトヒドラジド（２１７ｍｇ）を用いて、参考例１（１）と同様の手法にてメチル　６－｛３－［（ベンジルオキシ）メチル］－１Ｈ－１，２，４－トリアゾール－５－イル｝ピリジン－３－カルボキシラートを黄色固体（２１６ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.00 (s, 3 H) 4.71 (s, 2 H) 4.78 (s, 2 H) 7.24 - 7.46 (m, 5 H) 8.31 (d, J=8.2 Hz, 1 H) 8.45 (dd, J=8.2, 2.2 Hz, 1 H) 9.34 (dd, J=2.2, 0.8 Hz, 1 H).
MS ESI/APCI Dual posi: 325[M+H]+.
MS ESI/APCI Dual nega: 323[M-H]-. Using methyl 6-cyanopyridine-3-carboxylate (195 mg) and 2- (benzyloxy) acetohydrazide (217 mg) in place of formohydrazide in the same manner as in Reference Example 1 (1), methyl 6- { 3-[(Benzyloxy) methyl] -1H-1,2,4-triazol-5-yl} pyridine-3-carboxylate was obtained as a yellow solid (216 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.00 (s, 3 H) 4.71 (s, 2 H) 4.78 (s, 2 H) 7.24-7.46 (m, 5 H) 8.31 (d, J = 8.2 (Hz, 1 H) 8.45 (dd, J = 8.2, 2.2 Hz, 1 H) 9.34 (dd, J = 2.2, 0.8 Hz, 1 H).
MS ESI / APCI Dual posi: 325 [M + H] + .
MS ESI / APCI Dual nega: 323 [MH] - .
（２）表題化合物の合成
　上記の（１）で得られた化合物（２１６ｍｇ）を用いて、参考例１（２）～（３）に準ずる手法にて表題化合物を粗生成物（無色アモルファス　３１６ｍｇ）として得た。なお、表題化合物は、粗生成物のまま、次の反応に用いた。 (2) Synthesis of title compound Using the compound (216 mg) obtained in (1) above, the title compound was obtained in a crude product (colorless amorphous 316 mg) by the method according to Reference Examples 1 (2) to (3). Got as. The title compound was used in the next reaction as a crude product.
参考例３１
６－［５－メチル－１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボン酸 Reference Example 31
6- [5-Methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000099
  　 
Figure JPOXMLDOC01-appb-C000099
  　 
　メチル　６－シアノピリジン－３－カルボキシラート（３．２５ｇ）とホルモヒドラジドの代わりにアセトヒドラジド（１．６３ｇ）を用いて、参考例１（１）～（３）に準ずる手法にて表題化合物を粗生成物（無色固体　２．９１ｇ）として得た。なお、表題化合物は、粗生成物のまま、次の反応に用いた。
1H NMR (300 MHz, DEUTERIUM OXIDE) δ ppm 1.59 - 1.88 (m, 3 H) 1.95 - 2.17 (m, 2 H) 2.20 - 2.38 (m, 1 H) 2.57 (s, 3 H) 3.78 - 3.92 (m, 1 H) 4.03 - 4.18 (m, 1 H) 5.63 (dd, J=10.3, 2.3 Hz, 1 H) 7.98 (dd, J=8.1, 0.8 Hz, 1 H) 8.30 (dd, J=8.2, 2.1 Hz, 1 H) 9.00 (dd, J=2.0, 0.8 Hz, 1 H).
MS ESI/APCI Dual posi: 289[M+H]+.
MS ESI/APCI Dual nega: 287[M-H]-. The title compound was prepared in the same manner as in Reference Examples 1 (1) to (3) using methyl 6-cyanopyridine-3-carboxylate (3.25 g) and acetohydrazide (1.63 g) instead of formohydrazide. Obtained as a crude product (2.91 g of colorless solid). The title compound was used in the next reaction as a crude product.
1 H NMR (300 MHz, DEUTERIUM OXIDE) δ ppm 1.59-1.88 (m, 3 H) 1.95-2.17 (m, 2 H) 2.20-2.38 (m, 1 H) 2.57 (s, 3 H) 3.78-3.92 ( m, 1 H) 4.03-4.18 (m, 1 H) 5.63 (dd, J = 10.3, 2.3 Hz, 1 H) 7.98 (dd, J = 8.1, 0.8 Hz, 1 H) 8.30 (dd, J = 8.2, 2.1 Hz, 1 H) 9.00 (dd, J = 2.0, 0.8 Hz, 1 H).
MS ESI / APCI Dual posi: 289 [M + H] +.
MS ESI / APCI Dual nega: 287 [MH] - .
参考例３２
４－メトキシ－６－（３－メチル－１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボン酸 Reference Example 32
4-Methoxy-6- (3-methyl-1H-1,2,4-triazol-5-yl) pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000100
  　 
Figure JPOXMLDOC01-appb-C000100
  　 
　参考例２３（２）で得られた化合物（３．８５ｇ）と、ホルモヒドラジドの代わりにアセトヒドラジド（１．６３ｇ）を用いて、参考例２３（３）～（４）と同様の手法にて表題化合物を黄色固体（１．４１ｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.99 (s, 3 H) 7.71 (s, 1 H) 8.77 (s, 1 H).
MS ESI/APCI Dual posi: 235[M+H]+.
MS ESI/APCI Dual nega: 233[M-H]-. Using the compound (3.85 g) obtained in Reference Example 23 (2) and acetohydrazide (1.63 g) instead of formohydrazide, the same procedure as in Reference Examples 23 (3) to (4) was used. The title compound was obtained as a yellow solid (1.41 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.99 (s, 3 H) 7.71 (s, 1 H) 8.77 (s, 1 H).
MS ESI / APCI Dual posi: 235 [M + H] + .
MS ESI / APCI Dual nega: 233 [MH] - .
参考例３３
ナトリウム　５－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピラジン－２－カルボキシラート Reference Example 33
Sodium 5- [1- (Tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyrazin-2-carboxylate
Figure JPOXMLDOC01-appb-C000101
  　 
Figure JPOXMLDOC01-appb-C000101
  　 
　参考例２７（３）で得られた化合物の代わりにメチル　５－ホルミルピラジン－２－カルボキシラート（ＷＯ２００４／０５２８６９号　実施例２１参照）（２．３１ｇ）を用いて、参考例２７（４）～（６）に準ずる手法にて表題化合物を粗生成物（淡黄色固体　３３４ｍｇ）として得た。なお、表題化合物は、粗生成物のまま、次の反応に用いた。
LCMS（測定方法　Ａ－２）0.917min，
ESI/APCI Dual posi: 276[M+H]+.
ESI/APCI Dual nega: 274[M-H]-. Instead of the compound obtained in Reference Example 27 (3), methyl 5-formylpyrazine-2-carboxylate (see WO 2004/052869, Example 21) (2.31 g) was used. The title compound was obtained as a crude product (334 mg of pale yellow solid) by a method according to (6). The title compound was used in the next reaction as a crude product.
LCMS (Measurement method A-2) 0.917min,
ESI / APCI Dual posi: 276 [M + H] + .
ESI / APCI Dual nega: 274 [MH] - .
参考例３４
６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－アミン Reference Example 34
6- [1- (Tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridin-3-amine
Figure JPOXMLDOC01-appb-C000102
  　 
Figure JPOXMLDOC01-appb-C000102
  　 
（１）ベンジル｛６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－イル｝カルバメートの合成 (1) Synthesis of benzyl {6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridin-3-yl} carbamate
Figure JPOXMLDOC01-appb-C000103
  　 
Figure JPOXMLDOC01-appb-C000103
  　 
　参考例１（３）で得られた化合物（６００ｍｇ）のトルエン懸濁液（６．００ｍＬ）にジフェニルリン酸アジド（４２７μＬ）、トリエチルアミン（５０２μＬ）、及びベンジルアルコール（５５８μＬ）を加えて、３時間還流した。室温まで冷却した後、反応液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル=１００：０～０：１００　さらにクロロホルム：メタノール=９５：５～９０：１０）で精製し、ベンジル｛６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－イル｝カルバメートを淡黄色固体（２５８ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60 - 1.79 (m, 3 H) 1.95 - 2.31 (m, 3 H) 3.66 - 3.80 (m, 1 H) 4.05 - 4.17 (m, 1 H) 5.24 (s, 2 H) 5.48 - 5.58 (m, 1 H) 6.76 - 6.87 (m, 1 H) 7.31 - 7.46 (m, 5 H) 8.07 - 8.19 (m, 2 H) 8.34 (s, 1 H) 8.52 - 8.58 (m, 1 H).
MS ESI/APCI Dual posi: 380[M+H]+. Diphenyl phosphate azide (427 μL), triethylamine (502 μL), and benzyl alcohol (558 μL) were added to a toluene suspension (6.00 mL) of the compound (600 mg) obtained in Reference Example 1 (3) for 3 hours. Refluxed. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 100: 0 to 0: 100 and further chloroform: methanol = 95: 5 to 90:10), and benzyl {6- [1- (tetrahydro-2H -Pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridin-3-yl} carbamate was obtained as a pale yellow solid (258 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60-1.79 (m, 3 H) 1.95-2.31 (m, 3 H) 3.66-3.80 (m, 1 H) 4.05-4.17 (m, 1 H) 5.24 (s, 2 H) 5.48-5.58 (m, 1 H) 6.76-6.87 (m, 1 H) 7.31-7.46 (m, 5 H) 8.07-8.19 (m, 2 H) 8.34 (s, 1 H) 8.52 -8.58 (m, 1 H).
MS ESI / APCI Dual posi: 380 [M + H] + .
（２）表題化合物の合成
　上記（１）で得られた化合物（２５８ｍｇ）のメタノール溶液（５．００ｍＬ）に１０％パラジウム／炭素（１３０ｍｇ）を加え、水素雰囲気下、室温で一晩攪拌した。不溶物をセライ卜（登録商標）濾過にて濾別した。濾液を減圧下濃縮し、表題化合物を無色固体（１６７ｍｇ）として得た。
MS ESI/APCI Dual posi: 246[M+H]+, 268[M+Na]+.
MS ESI/APCI Dual nega: 244[M-H]-. (2) Synthesis of title compound To a methanol solution (5.00 mL) of the compound (258 mg) obtained in (1) above was added 10% palladium / carbon (130 mg), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. Insoluble matter was filtered off by Celai® (registered trademark) filtration. The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (167 mg).
MS ESI / APCI Dual posi: 246 [M + H] + , 268 [M + Na] + .
MS ESI / APCI Dual nega: 244 [MH] - .
参考例３５
｛６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－イル｝メタノール Reference Example 35
{6- [1- (Tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridin-3-yl} methanol
Figure JPOXMLDOC01-appb-C000104
  　 
Figure JPOXMLDOC01-appb-C000104
  　 
　参考例１（２）で得られた化合物（１．１７ｇ）のテトラヒドロフラン懸濁液（１２．０ｍＬ）に氷冷下で水素化リチウムアルミニウム（２．３６ｇ）を加え、同温で２時間攪拌した。氷冷下で反応液に硫酸ナトリウム１０水和物（６．５０ｇ）を少しずつ加えて、１５分間攪拌した。室温に昇温して１．５時間攪拌した後、不溶物をセライ卜（登録商標）濾過にて濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=１００：０～８５：１５）で精製し、表題化合物を黄色油状物質（６８０ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.55 - 1.84 (m, 3 H) 1.95 - 2.33 (m, 3 H) 3.67 - 3.80 (m, 1 H) 3.94 - 4.28 (m, 1 H) 4.79 (s, 2 H) 5.55 (dd, J=9.2, 2.9 Hz, 1 H) 7.61 - 7.90 (m, 1 H) 8.14 (dd, J=8.1, 0.8 Hz, 1 H) 8.36 (s, 1 H) 8.65 - 8.72 (m, 1 H).
MS ESI/APCI Dual posi: 261[M+H]+. Lithium aluminum hydride (2.36 g) was added to a tetrahydrofuran suspension (12.0 mL) of the compound (1.17 g) obtained in Reference Example 1 (2) under ice cooling, and the mixture was stirred at the same temperature for 2 hours. . Under ice cooling, sodium sulfate decahydrate (6.50 g) was added little by little to the reaction solution, and the mixture was stirred for 15 minutes. After warming to room temperature and stirring for 1.5 hours, the insoluble material was filtered off by Celai® (registered trademark) filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 85:15) to give the title compound as a yellow oil (680 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.55-1.84 (m, 3 H) 1.95-2.33 (m, 3 H) 3.67-3.80 (m, 1 H) 3.94-4.28 (m, 1 H) 4.79 (s, 2 H) 5.55 (dd, J = 9.2, 2.9 Hz, 1 H) 7.61-7.90 (m, 1 H) 8.14 (dd, J = 8.1, 0.8 Hz, 1 H) 8.36 (s, 1 H) 8.65-8.72 (m, 1 H).
MS ESI / APCI Dual posi: 261 [M + H] + .
参考例３６
１－｛６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－イル｝メタンアミン Reference Example 36
1- {6- [1- (Tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridin-3-yl} methanamine
Figure JPOXMLDOC01-appb-C000105
  　 
Figure JPOXMLDOC01-appb-C000105
  　 
（１）５－（アジドメチル）－２－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジンの合成 (1) Synthesis of 5- (azidomethyl) -2- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine
Figure JPOXMLDOC01-appb-C000106
  　 
Figure JPOXMLDOC01-appb-C000106
  　 
　参考例３５で得られた化合物（３７０ｍｇ）にトルエン（１．００ｍＬ）、及びテトラヒドロフラン（３．００ｍＬ）を加えて溶解し、室温で、ジフェニルリン酸アジド（３９７μＬ）、及び１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（２７６μＬ）を滴下した。室温で４時間攪拌後、溶液にジフェニルリン酸アジド（７９４μＬ）、及び１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（５５２μＬ）を滴下し、更に同温で２３時間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～０：１００）で精製し、５－（アジドメチル）－２－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジンを無色油状物質（２８５ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.55 - 1.79 (m, 3 H) 1.97 - 2.27 (m, 3 H) 3.66 - 3.78 (m, 1 H) 4.06 - 4.15 (m, 1 H) 4.44 (s, 2 H) 5.55 (dd, J=9.3, 3.0 Hz, 1 H) 7.77 (dd, J=8.2, 2.3 Hz, 1 H) 8.19 (d, J=8.2 Hz, 1 H) 8.39 (s, 1 H) 8.68 (dd, J=1.5, 0.7 Hz, 1 H).
MS ESI/APCI Dual posi: 286[M+H]+. Toluene (1.00 mL) and tetrahydrofuran (3.00 mL) were added and dissolved in the compound (370 mg) obtained in Reference Example 35, and diphenylphosphoric acid azide (397 μL) and 1,8-diazabicyclo [ 5.4.0] Undec-7-ene (276 μL) was added dropwise. After stirring at room temperature for 4 hours, diphenyl phosphate azide (794 μL) and 1,8-diazabicyclo [5.4.0] undec-7-ene (552 μL) were added dropwise to the solution, and the mixture was further stirred at the same temperature for 23 hours. . The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 0: 100) to give 5- (azidomethyl) -2- [1- (tetrahydro -2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine was obtained as a colorless oil (285 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.55-1.79 (m, 3 H) 1.97-2.27 (m, 3 H) 3.66-3.78 (m, 1 H) 4.06-4.15 (m, 1 H) 4.44 (s, 2 H) 5.55 (dd, J = 9.3, 3.0 Hz, 1 H) 7.77 (dd, J = 8.2, 2.3 Hz, 1 H) 8.19 (d, J = 8.2 Hz, 1 H) 8.39 (s, 1 H) 8.68 (dd, J = 1.5, 0.7 Hz, 1 H).
MS ESI / APCI Dual posi: 286 [M + H] + .
（２）表題化合物の合成
　上記の（１）で得られた化合物（２８５ｍｇ）のテトラヒドロフラン溶液（１０．０ｍＬ）にトリフェニルホスフィン（１７５ｍｇ）、及び水（１００μＬ）を加えて、室温で１３時間攪拌した。更にトリフェニルホスフィン（１７５ｍｇ）、及び水（１００μＬ）を加えて、６０℃で７５分間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=１００：０～７０：３０）で精製し、表題化合物を淡黄色油状物質（２５５ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.59 - 1.81 (m, 3 H) 1.97 - 2.32 (m, 3 H) 3.64 - 3.81 (m, 1 H) 3.96 (s, 2 H) 4.04 - 4.20 (m, 1 H) 5.55 (dd, J=9.2, 2.9 Hz, 1 H) 7.78 (dd, J=8.1, 2.3 Hz, 1 H) 8.13 (d, J=8.1 Hz, 1 H) 8.36 (s, 1 H) 8.67 (d, J=1.7 Hz, 1 H).
MS ESI/APCI Dual posi: 260[M+H]+. (2) Synthesis of title compound To a tetrahydrofuran solution (10.0 mL) of the compound (285 mg) obtained in (1) above was added triphenylphosphine (175 mg) and water (100 μL), and the mixture was stirred at room temperature for 13 hours. did. Triphenylphosphine (175 mg) and water (100 μL) were further added, and the mixture was stirred at 60 ° C. for 75 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 70:30) to give the title compound as a pale yellow oil (255 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.59-1.81 (m, 3 H) 1.97-2.32 (m, 3 H) 3.64-3.81 (m, 1 H) 3.96 (s, 2 H) 4.04-4.20 (m, 1 H) 5.55 (dd, J = 9.2, 2.9 Hz, 1 H) 7.78 (dd, J = 8.1, 2.3 Hz, 1 H) 8.13 (d, J = 8.1 Hz, 1 H) 8.36 (s, 1 H) 8.67 (d, J = 1.7 Hz, 1 H).
MS ESI / APCI Dual posi: 260 [M + H] + .
参考例３７－１
１－（２，４－ジメトキシフェニル）－Ｎ－［４－（ピリミジン－２－イルオキシ）ベンジル］メタンアミン Reference Example 37-1
1- (2,4-Dimethoxyphenyl) -N- [4- (pyrimidin-2-yloxy) benzyl] methanamine
Figure JPOXMLDOC01-appb-C000107
  　 
Figure JPOXMLDOC01-appb-C000107
  　 
　４－（ピリミジン－２－イルオキシ）ベンズアルデヒド（５００ｍｇ）のクロロホルム溶液（１０．０ｍＬ）に１－（２，４－ジメトキシフェニル）メタンアミン（４５１μＬ）、及びナトリウムトリアセトキシボロヒドリド（７９４ｍｇ）を加えて、室温で一晩攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層をフェーズセパレーターに通し、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=９９：１～９０：１０）で精製し、表題化合物を淡黄色油状物質（９０４ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.46 (s, 2 H) 3.81 (s, 8 H) 6.35 - 6.51 (m, 2 H) 7.03 (t, J=4.8 Hz, 1 H) 7.10 - 7.21 (m, 3 H) 7.36 - 7.43 (m, 2 H) 8.56 (d, J=4.8 Hz, 2 H).
MS ESI/APCI Dual posi: 352[M+H]+, 374[M+Na]+. To a chloroform solution (10.0 mL) of 4- (pyrimidin-2-yloxy) benzaldehyde (500 mg) was added 1- (2,4-dimethoxyphenyl) methanamine (451 μL) and sodium triacetoxyborohydride (794 mg). Stir overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 99: 1 to 90:10) to give the title compound as a pale yellow oil (904 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.46 (s, 2 H) 3.81 (s, 8 H) 6.35-6.51 (m, 2 H) 7.03 (t, J = 4.8 Hz, 1 H) 7.10- 7.21 (m, 3 H) 7.36-7.43 (m, 2 H) 8.56 (d, J = 4.8 Hz, 2 H).
MS ESI / APCI Dual posi: 352 [M + H] + , 374 [M + Na] + .
　以下の参考例３７－２～３７－３は１－（２，４－ジメトキシフェニル）メタンアミンと市販の対応するアルデヒドを、また、参考例３７－４～３７－５は１－（２，４－ジメトキシフェニル）メタンアミンと既知の方法（ＷＯ２０１４／０２１２８１号　参考例１３－３、及び参考例１３－１５参照）で合成した対応するアルデヒドを用いて、参考例３７－１に記載の方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表５－１に示す。 Reference Examples 37-2 to 37-3 below show 1- (2,4-dimethoxyphenyl) methanamine and a commercially available corresponding aldehyde, and Reference Examples 37-4 to 37-5 show 1- (2,4- The compound was synthesized by the method described in Reference Example 37-1 using dimethoxyphenyl) methanamine and the corresponding aldehyde synthesized by a known method (see WO 2014/021281, Reference Example 13-3 and Reference Example 13-15). Their structures, NMR data, and MS data are shown in Table 5-1.
Figure JPOXMLDOC01-appb-T000108
      
  　 
Figure JPOXMLDOC01-appb-T000108
      
  　 
参考例３８
１－ベンジル－６－｛［（２，４－ジメトキシベンジル）アミノ］メチル｝ピリジン－２（１Ｈ）－オン Reference Example 38
1-benzyl-6-{[(2,4-dimethoxybenzyl) amino] methyl} pyridin-2 (1H) -one
Figure JPOXMLDOC01-appb-C000109
  　 
Figure JPOXMLDOC01-appb-C000109
  　 
（１）エチル　６－オキソ－１，６－ジヒドロピリジン－２－カルボキシラートの合成 (1) Synthesis of ethyl 6-oxo-1,6-dihydropyridine-2-carboxylate
Figure JPOXMLDOC01-appb-C000110
  　 
Figure JPOXMLDOC01-appb-C000110
  　 
　６－メトキシピリジン－２－カルボン酸（１．４４ｇ）のエタノール溶液（４５．０ｍＬ）に室温で塩化チオニル（３．３９ｍＬ）を滴下した後、７０℃で１６時間攪拌した。室温まで冷却した後、反応液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=９９：１～９１：９）で精製し、エチル　６－オキソ－１，６－ジヒドロピリジン－２－カルボキシラートを無色固体（１．５８ｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 - 1.41 (m, 3 H) 4.23 - 4.40 (m, 2 H)6.64 - 6.79 (m, 1 H) 7.02 - 7.22 (m, 1 H) 7.53 - 7.72 (m, 1 H).
MS ESI/APCI Dual posi: 168[M+H]+, 190[M+Na]+.
MS ESI/APCI Dual nega: 166[M-H]-. Thionyl chloride (3.39 mL) was added dropwise at room temperature to an ethanol solution (45.0 mL) of 6-methoxypyridine-2-carboxylic acid (1.44 g), and the mixture was stirred at 70 ° C. for 16 hours. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (chloroform: methanol = 99: 1 to 91: 9) to give ethyl 6-oxo-1,6-dihydropyridine. -2-Carboxylate was obtained as a colorless solid (1.58 g).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.24-1.41 (m, 3 H) 4.23-4.40 (m, 2 H) 6.64-6.79 (m, 1 H) 7.02-7.22 (m, 1 H) 7.53-7.72 (m, 1 H).
MS ESI / APCI Dual posi: 168 [M + H] + , 190 [M + Na] + .
MS ESI / APCI Dual nega: 166 [MH] - .
（２）エチル　１－ベンジル－６－オキソ－１，６－ジヒドロピリジン－２－カルボキシラートの合成 (2) Synthesis of ethyl 1-benzyl-6-oxo-1,6-dihydropyridine-2-carboxylate
Figure JPOXMLDOC01-appb-C000111
  　 
Figure JPOXMLDOC01-appb-C000111
  　 
　上記の（１）で得られた化合物（１．３６ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（４０．０ｍＬ）に室温で炭酸カリウム（３．３７ｇ）、及びベンジルブロミド（０．９７ｍＬ）を加え、同温で２０時間攪拌した。反応液に酢酸エチルを加え、しばらく攪拌した後、不溶物をセライ卜（登録商標）濾過にて濾別した。濾液を水、飽和食塩水で順次洗浄した後、フェーズセパレーターに通して減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=１００：０～３３：６７）で精製し、エチル　１－ベンジル－６－オキソ－１，６－ジヒドロピリジン－２－カルボキシラートを淡黄色油状物質（６６２ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18 (t, J=7.1 Hz, 3 H) 4.18 (q, J=7.1 Hz, 2 H) 5.66 (s, 2 H) 6.69 (dd, J=6.8, 1.5 Hz, 1 H) 6.80 (dd, J=9.3, 1.5 Hz, 1 H) 7.11 - 7.17 (m, 2 H) 7.18 - 7.37 (m, 4 H). To a N, N-dimethylformamide solution (40.0 mL) of the compound (1.36 g) obtained in (1) above was added potassium carbonate (3.37 g) and benzyl bromide (0.97 mL) at room temperature, The mixture was stirred at the same temperature for 20 hours. Ethyl acetate was added to the reaction mixture, and the mixture was stirred for a while, and then insoluble matters were filtered off by Celai® (registered trademark) filtration. The filtrate was washed successively with water and saturated brine, then passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 100: 0 to 33:67) to give ethyl 1-benzyl-6-oxo-1,6-dihydropyridine-2-carboxylate as a pale salt. Obtained as a yellow oil (662 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18 (t, J = 7.1 Hz, 3 H) 4.18 (q, J = 7.1 Hz, 2 H) 5.66 (s, 2 H) 6.69 (dd, J = (6.8, 1.5 Hz, 1 H) 6.80 (dd, J = 9.3, 1.5 Hz, 1 H) 7.11-7.17 (m, 2 H) 7.18-7.37 (m, 4 H).
（３）１－ベンジル－６－（ヒドロキシメチル）ピリジン－２（１Ｈ）－オンの合成 (3) Synthesis of 1-benzyl-6- (hydroxymethyl) pyridin-2 (1H) -one
Figure JPOXMLDOC01-appb-C000112
  　 
Figure JPOXMLDOC01-appb-C000112
  　 
　上記の（２）で得られた化合物（６６０ｍｇ）のテトラヒドロフラン溶液（１０．０ｍＬ）に室温で水素化ホウ素リチウム（２２３ｍｇ）を加え、同温で１６時間攪拌した。反応液にメタノールを加えて攪拌した後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=９７：３～９０：１０）で精製し、１－ベンジル－６－（ヒドロキシメチル）ピリジン－２（１Ｈ）－オンを無色油状物質（４１９ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 4.31 (d, J=5.3 Hz, 2 H) 5.29 (s, 2 H) 5.65 (t, J=5.6 Hz, 1 H) 6.31 - 6.38 (m, 1 H) 6.39 - 6.45 (m, 1 H) 7.05 - 7.12 (m, 2 H) 7.20 - 7.37 (m, 3 H) 7.42 - 7.53 (m, 1 H). To a tetrahydrofuran solution (10.0 mL) of the compound (660 mg) obtained in (2) above was added lithium borohydride (223 mg) at room temperature, and the mixture was stirred at the same temperature for 16 hours. After adding methanol to the reaction solution and stirring, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3-90: 10) to give 1-benzyl-6- (hydroxymethyl) pyridin-2 (1H) -one as a colorless oil (419 mg). ).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 4.31 (d, J = 5.3 Hz, 2 H) 5.29 (s, 2 H) 5.65 (t, J = 5.6 Hz, 1 H) 6.31-6.38 (m , 1 H) 6.39-6.45 (m, 1 H) 7.05-7.12 (m, 2 H) 7.20-7.37 (m, 3 H) 7.42-7.53 (m, 1 H).
（４）１－ベンジル－６－オキソ－１，６－ジヒドロピリジン－２－カルバルデヒドの合成 (4) Synthesis of 1-benzyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde
Figure JPOXMLDOC01-appb-C000113
  　 
Figure JPOXMLDOC01-appb-C000113
  　 
　上記の（３）で得られた化合物（３９９ｍｇ）のクロロホルム溶液（１０．０ｍＬ）に氷冷下でデス－マーチンペルヨージナン（８６４ｍｇ）を加え、室温に昇温して、１．５時間攪拌した。反応液にチオ硫酸ナトリウム水溶液を加えて３０分間攪拌した後、有機層を分離した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別した後、濾液を減圧下濃縮した。１－ベンジル－６－オキソ－１，６－ジヒドロピリジン－２－カルバルデヒドを粗生成物（褐色油状物質　４４４ｍｇ）として得た。なお、１－ベンジル－６－オキソ－１，６－ジヒドロピリジン－２－カルバルデヒドは粗生成物のまま、次の反応に用いた。
MS ESI/APCI Dual posi: 214[M+H]+, 236[M+Na]+.
MS ESI/APCI Dual nega: 212[M-H]-. Dess-Martin periodinane (864 mg) was added to a chloroform solution (10.0 mL) of the compound (399 mg) obtained in (3) above under ice cooling, and the mixture was warmed to room temperature and stirred for 1.5 hours. did. An aqueous sodium thiosulfate solution was added to the reaction solution and stirred for 30 minutes, and then the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. 1-Benzyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde was obtained as a crude product (444 mg of brown oil). 1-Benzyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde was used in the next reaction as a crude product.
MS ESI / APCI Dual posi: 214 [M + H] + , 236 [M + Na] + .
MS ESI / APCI Dual nega: 212 [MH] - .
（５）表題化合物の合成
　上記の（４）で得られた化合物（３９５ｍｇ）、及び１－（２，４－ジメトキシフェニル）メタンアミン（３３５μＬ）を用いて、参考例３７－１と同様の手法にて表題化合物を褐色油状物質（５５５ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.51 (s, 2 H) 3.71 (s, 2 H) 3.79 (s, 3 H) 3.81 (s, 3 H) 5.55 (s, 2 H) 6.21 (dd, J=6.8, 1.3 Hz, 1 H) 6.39 - 6.41 (m, 1 H) 6.42 - 6.44 (m, 1 H) 6.46 (d, J=2.3 Hz, 1 H) 6.60 (dd, J=9.1, 1.3 Hz, 1 H) 7.00 - 7.07 (m, 3 H) 7.17 - 7.35 (m, 4 H).
MS ESI/APCI Dual posi: 365[M+H]+, 387[M+Na]+. (5) Synthesis of title compound Using the compound (395 mg) obtained in (4) above and 1- (2,4-dimethoxyphenyl) methanamine (335 μL), the same procedure as in Reference Example 37-1 was performed. To give the title compound as a brown oil (555 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.51 (s, 2 H) 3.71 (s, 2 H) 3.79 (s, 3 H) 3.81 (s, 3 H) 5.55 (s, 2 H) 6.21 ( dd, J = 6.8, 1.3 Hz, 1 H) 6.39-6.41 (m, 1 H) 6.42-6.44 (m, 1 H) 6.46 (d, J = 2.3 Hz, 1 H) 6.60 (dd, J = 9.1, 1.3 Hz, 1 H) 7.00-7.07 (m, 3 H) 7.17-7.35 (m, 4 H).
MS ESI / APCI Dual posi: 365 [M + H] + , 387 [M + Na] + .
参考例３９
１－（２，４－ジメトキシフェニル）－Ｎ－［（６－フルオロ－２，３－ジヒドロ－１－ベンゾフラン－５－イル）メチル］メタンアミン Reference Example 39
1- (2,4-Dimethoxyphenyl) -N-[(6-fluoro-2,3-dihydro-1-benzofuran-5-yl) methyl] methanamine
Figure JPOXMLDOC01-appb-C000114
  　 
Figure JPOXMLDOC01-appb-C000114
  　 
（１）６－フルオロ－２，３－ジヒドロ－１－ベンゾフランの合成 (1) Synthesis of 6-fluoro-2,3-dihydro-1-benzofuran
Figure JPOXMLDOC01-appb-C000115
  　 
Figure JPOXMLDOC01-appb-C000115
  　 
　１，４－ジブロモ－２－フルオロベンゼンの代わりに１－ブロモ－２，４－ジフルオロベンゼン（５．００ｇ）を用いて、参考例２１（１）～（３）に準じた手法にて、６－フルオロ－２，３－ジヒドロ－１－ベンゾフランを黄色油状物質（１．６０ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.11 - 3.20 (m, 2 H) 4.56 - 4.65 (m, 2 H) 6.46 - 6.58 (m, 2 H) 7.04 - 7.12 (m, 1 H).
MS ESI/APCI Dual posi: 161[M+Na]+.
MS ESI/APCI Dual nega: 137[M-H]-. Using 1-bromo-2,4-difluorobenzene (5.00 g) instead of 1,4-dibromo-2-fluorobenzene, a method according to Reference Example 21 (1) to (3) was used. -Fluoro-2,3-dihydro-1-benzofuran was obtained as a yellow oil (1.60 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.11-3.20 (m, 2 H) 4.56-4.65 (m, 2 H) 6.46-6.58 (m, 2 H) 7.04-7.12 (m, 1 H).
MS ESI / APCI Dual posi: 161 [M + Na] + .
MS ESI / APCI Dual nega: 137 [MH] - .
（２）６－フルオロ－２，３－ジヒドロ－１－ベンゾフラン－５－カルバルデヒドの合成 (2) Synthesis of 6-fluoro-2,3-dihydro-1-benzofuran-5-carbaldehyde
Figure JPOXMLDOC01-appb-C000116
  　 
Figure JPOXMLDOC01-appb-C000116
  　 
　上記の（１）で得られた化合物（１．６０ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（１．９７ｍＬ）に塩化ホスホリル（２．１６ｍＬ）を滴下して、８５℃で１２時間攪拌した。反応液を室温まで冷却した後、氷水を加えて一晩攪拌した。酢酸エチルで抽出し、合わせた有機層をフェーズセパレーターに通して減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９９：１～８０：２０）で精製し、６－フルオロ－２，３－ジヒドロ－１－ベンゾフラン－５－カルバルデヒドを無色固体（８４９ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.22 (t, J=8.8 Hz, 2 H) 4.72 (t, J=8.8 Hz, 2 H) 6.44 - 6.61 (m, 1 H) 7.64 - 7.75 (m, 1 H) 10.17 (s, 1 H).
MS ESI/APCI Dual posi: 167[M+H]+, 189[M+Na]+. Phosphoryl chloride (2.16 mL) was added dropwise to an N, N-dimethylformamide solution (1.97 mL) of the compound (1.60 g) obtained in (1) above, and the mixture was stirred at 85 ° C. for 12 hours. After cooling the reaction solution to room temperature, ice water was added and stirred overnight. The mixture was extracted with ethyl acetate, and the combined organic layers were passed through a phase separator and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 99: 1-80: 20) to give 6-fluoro-2,3-dihydro-1-benzofuran-5-carbaldehyde as a colorless solid. (849 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.22 (t, J = 8.8 Hz, 2 H) 4.72 (t, J = 8.8 Hz, 2 H) 6.44-6.61 (m, 1 H) 7.64-7.75 ( m, 1 H) 10.17 (s, 1 H).
MS ESI / APCI Dual posi: 167 [M + H] + , 189 [M + Na] + .
（３）表題化合物の合成
　上記の（２）で得られた化合物（８４０ｍｇ）、及び１－（２，４－ジメトキシフェニル）メタンアミン（９１４μＬ）を用いて、参考例３７－１と同様の手法にて表題化合物を無色油状物質（１．００ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.14 (t, J=8.7 Hz, 2 H) 3.68 - 3.75 (m, 4 H) 3.80 (s, 6 H) 4.59 (t, J=8.7 Hz, 2 H) 6.38 - 6.54 (m, 3 H) 7.10 - 7.17 (m, 2 H).
MS ESI/APCI Dual posi: 318[M+H]+.
MS ESI/APCI Dual nega: 316[M-H]-. (3) Synthesis of title compound Using the compound (840 mg) obtained in (2) above and 1- (2,4-dimethoxyphenyl) methanamine (914 μL), the same procedure as in Reference Example 37-1 was performed. To give the title compound as a colorless oil (1.00 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.14 (t, J = 8.7 Hz, 2 H) 3.68-3.75 (m, 4 H) 3.80 (s, 6 H) 4.59 (t, J = 8.7 Hz, 2 H) 6.38-6.54 (m, 3 H) 7.10-7.17 (m, 2 H).
MS ESI / APCI Dual posi: 318 [M + H] + .
MS ESI / APCI Dual nega: 316 [MH] - .
　以下の参考例３９－２～３９－３は、市販の対応する２－ブロモ－１，３－ジフルオロベンゼン、及び１－ブロモ－２，３－ジフルオロベンゼンを用いて、参考例３９（１）～（３）に記載の方法又はこれに準ずる方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表６－１に示す。 Reference Examples 39-2 to 39-3 below were prepared using Reference Examples 39 (1) to 39-3 using commercially available corresponding 2-bromo-1,3-difluorobenzene and 1-bromo-2,3-difluorobenzene. It was synthesized by the method described in (3) or a method analogous thereto. Their structures, NMR data, and MS data are shown in Table 6-1.
Figure JPOXMLDOC01-appb-T000117
      
  　 
Figure JPOXMLDOC01-appb-T000117
      
  　 
参考例４０－１
１－（２，３－ジヒドロフロ［２，３－ｃ］ピリジン－５－イル）－Ｎ－（２，４－ジメトキシベンジル）メタンアミン Reference Example 40-1
1- (2,3-Dihydrofuro [2,3-c] pyridin-5-yl) -N- (2,4-dimethoxybenzyl) methanamine
Figure JPOXMLDOC01-appb-C000118
  　 
Figure JPOXMLDOC01-appb-C000118
  　 
　参考例３８（２）で得られた化合物の代わりにエチル　２，３－ジヒドロフロ［２，３－ｃ］ピリジン－５－カルボキシラート（ＯｒｇａｎｉｃＬｅｔｔｅｒｓ ｖｏｌ．１４　Ｎｏ６，２０１２　１６０４－１６０７参照）（４６８ｍｇ）を用いて、参考例３８（３）～（５）と同様の手法にて表題化合物を淡褐色油状物質（２７３ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.21 (t, J=8.6 Hz, 2 H) 3.79 - 3.82 (m, 8 H) 3.85 (s, 2 H) 4.59 (t, J=8.7 Hz, 2 H) 6.41 - 6.46 (m, 2 H) 7.14 - 7.19 (m, 1 H) 7.24 (s, 1 H) 8.07 (s, 1 H).
MS ESI/APCI Dual posi: 301[M+H]+, 323[M+Na]+.
MS ESI/APCI Dual nega: 299[M-H]-. In place of the compound obtained in Reference Example 38 (2), ethyl 2,3-dihydrofuro [2,3-c] pyridine-5-carboxylate (see Organic Letters vol. 14 No. 6, 2012 1604-1607) (468 mg) Was used to give the title compound as a pale brown oil (273 mg) in the same manner as in Reference Examples 38 (3) to (5).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.21 (t, J = 8.6 Hz, 2 H) 3.79-3.82 (m, 8 H) 3.85 (s, 2 H) 4.59 (t, J = 8.7 Hz, 2 H) 6.41-6.46 (m, 2 H) 7.14-7.19 (m, 1 H) 7.24 (s, 1 H) 8.07 (s, 1 H).
MS ESI / APCI Dual posi: 301 [M + H] + , 323 [M + Na] + .
MS ESI / APCI Dual nega: 299 [MH] - .
参考例４０－２
１－（３，４－ジヒドロ－２Ｈ－ピラノ［２，３－ｃ］ピリジン－６－イル）－Ｎ－（２，４－ジメトキシベンジル）メタンアミン Reference Example 40-2
1- (3,4-Dihydro-2H-pyrano [2,3-c] pyridin-6-yl) -N- (2,4-dimethoxybenzyl) methanamine
Figure JPOXMLDOC01-appb-C000119
  　 
Figure JPOXMLDOC01-appb-C000119
  　 
　参考例３８（２）で得られた化合物の代わりにエチル　３，４－ジヒドロ－２Ｈ－ピラノ［２，３－ｃ］ピリジン－６－カルボキシラート（ＯｒｇａｎｉｃＬｅｔｔｅｒｓ ｖｏｌ．１４　Ｎｏ６，２０１２　１６０４－１６０７参照）（２．６０ｇ）を用いて、参考例３８（３）～（５）と同様の手法にて表題化合物を淡褐色油状物質（５９０ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.98 - 2.06 (m, 2 H) 2.75 (t, J=6.6 Hz, 2 H) 3.78 - 3.82 (m, 10 H) 4.16 - 4.23 (m, 2 H) 6.39 - 6.46 (m, 2 H) 7.01 (s, 1 H) 7.12 - 7.19 (m, 1 H) 8.07 (s, 1 H).
MS ESI/APCI Dual posi: 315[M+H]+, 337[M+Na]+. Instead of the compound obtained in Reference Example 38 (2), ethyl 3,4-dihydro-2H-pyrano [2,3-c] pyridine-6-carboxylate (see Organic Letters vol. 14 No. 6, 2012 1604-1607) (2.60 g) was used to give the title compound as a pale brown oil (590 mg) in the same manner as in Reference Examples 38 (3) to (5).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.98-2.06 (m, 2 H) 2.75 (t, J = 6.6 Hz, 2 H) 3.78-3.82 (m, 10 H) 4.16-4.23 (m, 2 H) 6.39-6.46 (m, 2 H) 7.01 (s, 1 H) 7.12-7.19 (m, 1 H) 8.07 (s, 1 H).
MS ESI / APCI Dual posi: 315 [M + H] + , 337 [M + Na] + .
実施例１－１
Ｎ－（２，３－ジヒドロ－１，４－ベンゾジオキシン－６－イルメチル）－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 1-1
N- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000120
  　 
Figure JPOXMLDOC01-appb-C000120
  　 
（１）Ｎ－（２，３－ジヒドロ－１，４－ベンゾジオキシン－６－イルメチル）－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキサミドの合成 (1) N- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazole Synthesis of -3-yl] pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000121
  　 
Figure JPOXMLDOC01-appb-C000121
  　 
　参考例１で得られた化合物（５００ｍｇ）、２，３－ジヒドロ－１，４－ベンゾジオキシン－６－イルメチルアミン（４９６ｍｇ）、及び１－ヒドロキシベンゾトリアゾール一水和物（４６０ｍｇ）のクロロホルム懸濁液（６．００ｍＬ）に１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（５７６ｍｇ）を加えて、６０℃で１時間攪拌した。室温まで冷却した後、反応液に飽和炭酸水素ナトリウム水溶液を加えた。クロロホルムで２回抽出し、合わせた有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=１００：０～９５：５）で精製した。得られた粗精製物に酢酸エチルを加え、析出物を濾取した。濾取物を減圧下乾燥し、Ｎ－（２，３－ジヒドロ－１，４－ベンゾジオキシン－６－イルメチル）－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキサミドを無色固体（５２１ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60 - 1.82 (m, 3 H) 1.96 - 2.32 (m, 3 H) 3.67 - 3.81 (m, 1 H) 4.07 - 4.17 (m, 1 H) 4.25 (s, 4 H) 4.56 (d, J=5.4 Hz, 2 H) 5.56 (dd, J=9.3, 2.8 Hz, 1 H) 6.45 - 6.59 (m, 1 H) 6.79 - 6.93 (m, 3 H) 8.17 - 8.28 (m, 2 H) 8.37 (s, 1 H) 9.07 (t, J=1.6 Hz, 1 H).
MS ESI/APCI Dual posi: 422[M+H]+. Chloroform suspension of the compound (500 mg) obtained in Reference Example 1, 2,3-dihydro-1,4-benzodioxin-6-ylmethylamine (496 mg), and 1-hydroxybenzotriazole monohydrate (460 mg). 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (576 mg) was added to the suspension (6.00 mL), and the mixture was stirred at 60 ° C. for 1 hour. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution. Extraction was performed twice with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 95: 5). Ethyl acetate was added to the obtained crude product, and the precipitate was collected by filtration. The filtered product was dried under reduced pressure to give N- (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) -6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1 , 2,4-Triazol-3-yl] pyridine-3-carboxamide was obtained as a colorless solid (521 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60-1.82 (m, 3 H) 1.96-2.32 (m, 3 H) 3.67-3.81 (m, 1 H) 4.07-4.17 (m, 1 H) 4.25 (s, 4 H) 4.56 (d, J = 5.4 Hz, 2 H) 5.56 (dd, J = 9.3, 2.8 Hz, 1 H) 6.45-6.59 (m, 1 H) 6.79-6.93 (m, 3 H) 8.17-8.28 (m, 2 H) 8.37 (s, 1 H) 9.07 (t, J = 1.6 Hz, 1 H).
MS ESI / APCI Dual posi: 422 [M + H] + .
（２）表題化合物の合成
　上記（１）で得られた化合物（５２１ｍｇ）のメタノール懸濁液（４．００ｍＬ）に、水（２．００ｍＬ）、トリフルオロ酢酸（１．００ｍＬ）を加えて、６０℃で１時間攪拌した。室温まで冷却した後、反応液に水を加え、析出物を濾取した。得られた粗生成物にメタノールを加え、析出物を濾取した。濾取物を減圧下乾燥し、表題化合物を無色固体（３３２ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 4.21 (s, 4 H) 4.34 - 4.47 (m, 2 H) 6.77 - 6.89 (m, 3 H) 8.17 (dd, J=8.2, 0.8 Hz, 1 H) 8.29 - 8.43 (m, 2 H) 9.12 (dd, J=2.2, 0.8 Hz, 1 H) 9.19 - 9.31 (m, 1 H).
MS ESI/APCI Dual posi: 338[M+H]+.
MS ESI/APCI Dual nega: 336[M-H]-. (2) Synthesis of title compound To a methanol suspension (4.00 mL) of the compound (521 mg) obtained in (1) above, water (2.00 mL) and trifluoroacetic acid (1.00 mL) were added, Stir at 60 ° C. for 1 hour. After cooling to room temperature, water was added to the reaction solution, and the precipitate was collected by filtration. Methanol was added to the resulting crude product, and the precipitate was collected by filtration. The filtered product was dried under reduced pressure to give the title compound as a colorless solid (332 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 4.21 (s, 4 H) 4.34-4.47 (m, 2 H) 6.77-6.89 (m, 3 H) 8.17 (dd, J = 8.2, 0.8 Hz, 1 H) 8.29-8.43 (m, 2 H) 9.12 (dd, J = 2.2, 0.8 Hz, 1 H) 9.19-9.31 (m, 1 H).
MS ESI / APCI Dual posi: 338 [M + H] + .
MS ESI / APCI Dual nega: 336 [MH] - .
　以下の実施例１－２～１－３、１－５～１－５０、１－５３～１７２は参考例１で得られた化合物と、参考例３、４、５、６、７－１～７－２、８－１～８－１６、９－１～９－２、１０、１１－１～１１－７、１２－１～１２－２、１３－１～１３－２、１４、１５、１６－１～１６－３、１７、１８－１～１８－２、１９、２０、２１、２２で得られた化合物、又は市販の対応するアミンを原料として実施例１－１（１）～（２）に記載の方法又はこれに準ずる方法で合成した。なお、実施例１－４は参考例１で得られた化合物と既知の方法（ＷＯ２０１１／００２６２４号　Ｅｘａｍｐｌｅ１　１－Ｄ参照）で合成した対応するアミンを用い、実施例１（１）～（２）に記載の方法で合成した。実施例１－５１、１－５２は参考例２で得られた化合物と市販の対応するアミンを用いて実施例１（１）に記載の方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表７－１～表７－２５に示す。 The following Examples 1-2 to 1-3, 1-5 to 1-50, 1-53 to 172 are the compounds obtained in Reference Example 1 and Reference Examples 3, 4, 5, 6, 7-1 to 7-2, 8-1 to 8-16, 9-1 to 9-2, 10, 11-1 to 11-7, 12-1 to 12-2, 13-1 to 13-2, 14, 15, 16-1 to 16-3, 17, 18-1 to 18-2, 19, 20, 21, 22 Example 1-1 (1)-( It was synthesized by the method described in 2) or a method analogous thereto. In addition, Example 1-4 uses the compound obtained in Reference Example 1 and the corresponding amine synthesized by a known method (see WO2011 / 002624, Example 1, 1-D). Examples 1 (1) to (2) It was synthesized by the method described in 1. Examples 1-51 and 1-52 were synthesized by the method described in Example 1 (1) using the compound obtained in Reference Example 2 and a commercially available corresponding amine. Their structures, NMR data, and MS data are shown in Tables 7-1 to 7-25.
Figure JPOXMLDOC01-appb-T000122
      
  　 
Figure JPOXMLDOC01-appb-T000122
      
  　 
Figure JPOXMLDOC01-appb-T000123
      
  　 
Figure JPOXMLDOC01-appb-T000123
      
  　 
Figure JPOXMLDOC01-appb-T000124
      
  　 
Figure JPOXMLDOC01-appb-T000124
      
  　 
Figure JPOXMLDOC01-appb-T000125
      
  　 
Figure JPOXMLDOC01-appb-T000125
      
  　 
Figure JPOXMLDOC01-appb-T000126
      
  　 
Figure JPOXMLDOC01-appb-T000126
      
  　 
Figure JPOXMLDOC01-appb-T000127
      
  　 
Figure JPOXMLDOC01-appb-T000127
      
  　 
Figure JPOXMLDOC01-appb-T000128
      
  　 
Figure JPOXMLDOC01-appb-T000128
      
  　 
Figure JPOXMLDOC01-appb-T000129
      
  　 
Figure JPOXMLDOC01-appb-T000129
      
  　 
Figure JPOXMLDOC01-appb-T000130
      
  　 
Figure JPOXMLDOC01-appb-T000130
      
  　 
Figure JPOXMLDOC01-appb-T000131
  　 
Figure JPOXMLDOC01-appb-T000131
  　 
Figure JPOXMLDOC01-appb-T000132
      
  　 
Figure JPOXMLDOC01-appb-T000132
      
  　 
Figure JPOXMLDOC01-appb-T000133
      
  　 
Figure JPOXMLDOC01-appb-T000133
      
  　 
Figure JPOXMLDOC01-appb-T000134
      
  　 
Figure JPOXMLDOC01-appb-T000134
      
  　 
Figure JPOXMLDOC01-appb-T000135
      
  　 
Figure JPOXMLDOC01-appb-T000135
      
  　 
Figure JPOXMLDOC01-appb-T000136
      
  　 
Figure JPOXMLDOC01-appb-T000136
      
  　 
Figure JPOXMLDOC01-appb-T000137
      
  　 
Figure JPOXMLDOC01-appb-T000137
      
  　 
Figure JPOXMLDOC01-appb-T000138
      
  　 
Figure JPOXMLDOC01-appb-T000138
      
  　 
Figure JPOXMLDOC01-appb-T000139
      
  　 
Figure JPOXMLDOC01-appb-T000139
      
  　 
Figure JPOXMLDOC01-appb-T000140
      
  　 
Figure JPOXMLDOC01-appb-T000140
      
  　 
Figure JPOXMLDOC01-appb-T000141
      
  　 
Figure JPOXMLDOC01-appb-T000141
      
  　 
Figure JPOXMLDOC01-appb-T000142
      
  　 
Figure JPOXMLDOC01-appb-T000142
      
  　 
Figure JPOXMLDOC01-appb-T000143
      
  　 
Figure JPOXMLDOC01-appb-T000143
      
  　 
Figure JPOXMLDOC01-appb-T000144
      
  　 
Figure JPOXMLDOC01-appb-T000144
      
  　 
Figure JPOXMLDOC01-appb-T000145
      
  　 
Figure JPOXMLDOC01-appb-T000145
      
  　 
Figure JPOXMLDOC01-appb-T000146
      
  　 
Figure JPOXMLDOC01-appb-T000146
      
  　 
実施例２－１
Ｎ－（２，３－ジヒドロ－１－ベンゾフラン－５－イルメチル）－４－メトキシ－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 2-1
N- (2,3-dihydro-1-benzofuran-5-ylmethyl) -4-methoxy-6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000147
      
  　 
Figure JPOXMLDOC01-appb-C000147
      
  　 
　参考例２３で得られた化合物（８００ｍｇ）、（２，３－ジヒドロベンゾフラン－５－イル）メタンアミン塩酸塩（４１０ｍｇ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ'，Ｎ'，－テトラメチルウロニウムヘキサフルオロリン酸塩（８３７ｍｇ）、１－ヒドロキシアザベンゾトリアゾール（３００ｍｇ）、及びＮ，Ｎ－ジイソプロピルエチルアミン（８８０μＬ）のＮ，Ｎ－ジメチルホルムアミド懸濁液（４．００ｍＬ）を７０℃で３時間攪拌した。室温まで冷却した後、反応液に水を加えた。析出物を濾取し、分取ＨＰＬＣで精製した。得られた粗精製物にメタノールを加え、析出物を濾取した。濾取物を減圧下乾燥し、表題化合物を淡黄色固体（３１２ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.16 (t, J=8.7 Hz, 2 H) 4.05 (s, 3 H) 4.42 (d, J=6.1 Hz, 2 H) 4.50 (t, J=8.7 Hz, 2 H) 6.71 (d, J=8.1 Hz, 1 H) 7.07 (dd, J=8.2, 1.9 Hz, 1 H) 7.22 (s, 1 H) 7.77 (s, 1 H) 8.68 - 8.75 (m, 1 H) 8.78 (s, 1 H).
MS ESI/APCI Dual posi: 352[M+H]+.
MS ESI/APCI Dual nega: 350[M-H]-. Compound (800 mg) obtained in Reference Example 23, (2,3-dihydrobenzofuran-5-yl) methanamine hydrochloride (410 mg), O- (7-azabenzotriazol-1-yl) -N, N, N N, N-dimethylformamide suspension of ', N',-tetramethyluronium hexafluorophosphate (837 mg), 1-hydroxyazabenzotriazole (300 mg), and N, N-diisopropylethylamine (880 μL) ( 4.00 mL) was stirred at 70 ° C. for 3 hours. After cooling to room temperature, water was added to the reaction solution. The precipitate was collected by filtration and purified by preparative HPLC. Methanol was added to the obtained crude product, and the precipitate was collected by filtration. The filtered product was dried under reduced pressure to give the title compound as a pale yellow solid (312 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.16 (t, J = 8.7 Hz, 2 H) 4.05 (s, 3 H) 4.42 (d, J = 6.1 Hz, 2 H) 4.50 (t, J = 8.7 Hz, 2 H) 6.71 (d, J = 8.1 Hz, 1 H) 7.07 (dd, J = 8.2, 1.9 Hz, 1 H) 7.22 (s, 1 H) 7.77 (s, 1 H) 8.68-8.75 (m, 1 H) 8.78 (s, 1 H).
MS ESI / APCI Dual posi: 352 [M + H] + .
MS ESI / APCI Dual nega: 350 [MH] - .
　以下の実施例２－２は参考例２３で得られた化合物と既知の方法（ＷＯ２０１１／００２６２４号　Ｅｘａｍｐｌｅ１　１－Ｄ参照）で合成した対応するアミンを原料とし、又、実施例２－３～２－１０は参考例２３で得られた化合物と市販の対応するアミンを原料として、実施例２－１に記載の方法又はこれに準ずる方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表８－１に示す。 In the following Example 2-2, the compound obtained in Reference Example 23 and the corresponding amine synthesized by a known method (see WO2011 / 002624, Example 1, 1-D) are used as raw materials, and Examples 2-3 and 2 -10 was synthesized by the method described in Example 2-1 or a method analogous thereto, using the compound obtained in Reference Example 23 and a commercially available corresponding amine as raw materials. Their structures, NMR data, and MS data are shown in Table 8-1.
Figure JPOXMLDOC01-appb-T000148
      
  　 
Figure JPOXMLDOC01-appb-T000148
      
  　 
実施例３
Ｎ－（２，３－ジヒドロ－１－ベンゾフラン－５－イルメチル）－４－エトキシ－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 3
N- (2,3-dihydro-1-benzofuran-5-ylmethyl) -4-ethoxy-6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000149
  　 
Figure JPOXMLDOC01-appb-C000149
  　 
　参考例２４で得られた化合物と（２，３－ジヒドロベンゾフラン－５－イル）メタンアミン（１８５ｍｇ）を用いて実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（７２．０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (t, J=6.9 Hz, 3 H) 3.16 (t, J=8.5 Hz, 2 H) 4.28 - 4.37 (m, 2 H) 4.40 - 4.45 (m, 2 H) 4.47 - 4.55 (m, 2 H) 6.72 (d, J=8.1 Hz, 1 H) 7.05 - 7.12 (m, 1 H) 7.21 - 7.27 (m, 1 H) 7.73 (s, 1 H) 8.25 - 8.31 (m, 1 H) 8.53 - 8.61 (m, 1 H) 8.73 (s, 1 H).
MS ESI/APCI Dual posi: 366[M+H]+.
MS ESI/APCI Dual nega: 364[M-H]-. Using the compound obtained in Reference Example 24 and (2,3-dihydrobenzofuran-5-yl) methanamine (185 mg), the title compound was purified in the same manner as in Example 1-1 (1) to (2). Obtained as a solid (72.0 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.39 (t, J = 6.9 Hz, 3 H) 3.16 (t, J = 8.5 Hz, 2 H) 4.28-4.37 (m, 2 H) 4.40-4.45 (m, 2 H) 4.47-4.55 (m, 2 H) 6.72 (d, J = 8.1 Hz, 1 H) 7.05-7.12 (m, 1 H) 7.21-7.27 (m, 1 H) 7.73 (s, 1 H) 8.25-8.31 (m, 1 H) 8.53-8.61 (m, 1 H) 8.73 (s, 1 H).
MS ESI / APCI Dual posi: 366 [M + H] + .
MS ESI / APCI Dual nega: 364 [MH] - .
実施例４－１
５－クロロ－Ｎ－（２，３－ジヒドロ－１－ベンゾフラン－５－イルメチル）－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 4-1
5-Chloro-N- (2,3-dihydro-1-benzofuran-5-ylmethyl) -6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000150
  　 
Figure JPOXMLDOC01-appb-C000150
  　 
　参考例２５（１００ｍｇ）で得られた化合物と（２，３－ジヒドロベンゾフラン－５－イル）メタンアミン（５８．０ｍｇ）を用いて、実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（９８．０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.10 - 3.21 (m, 2 H) 4.39 - 4.46 (m, 2 H) 4.46 - 4.55 (m, 2 H) 6.67 - 6.76 (m, 1 H) 7.03 - 7.12 (m, 1 H) 7.19 - 7.26 (m, 1 H) 8.42 - 8.54 (m, 2 H) 9.06 (d, J=2.0 Hz, 1 H) 9.26 - 9.38 (m, 1 H).
MS ESI/APCI Dual posi: 356[M+H]+.
MS ESI/APCI Dual nega: 354[M-H]-. Using the compound obtained in Reference Example 25 (100 mg) and (2,3-dihydrobenzofuran-5-yl) methanamine (58.0 mg), the same procedure as in Example 1-1 (1) to (2) Gave the title compound as a colorless solid (98.0 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.10-3.21 (m, 2 H) 4.39-4.46 (m, 2 H) 4.46-4.55 (m, 2 H) 6.67-6.76 (m, 1 H) 7.03-7.12 (m, 1 H) 7.19-7.26 (m, 1 H) 8.42-8.54 (m, 2 H) 9.06 (d, J = 2.0 Hz, 1 H) 9.26-9.38 (m, 1 H).
MS ESI / APCI Dual posi: 356 [M + H] + .
MS ESI / APCI Dual nega: 354 [MH] - .
実施例４－２
５－クロロ－Ｎ－［（１Ｓ）－１－（４－フルオロフェニル）エチル］－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 4-2
5-Chloro-N-[(1S) -1- (4-fluorophenyl) ethyl] -6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000151
  　 
Figure JPOXMLDOC01-appb-C000151
  　 
　参考例２５（２５９ｍｇ）で得られた化合物と（Ｓ）－（－）－１－（４－フルオロフェニル）エチルアミン（１８８ｍｇ）を用いて、実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（１６０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.50 (d, J=7.0 Hz, 3 H) 5.09 - 5.28 (m, 1 H) 7.10 - 7.24 (m, 2 H) 7.41 - 7.50 (m, 2 H) 8.40 - 8.62 (m, 2 H) 9.03 - 9.06 (m, 1 H) 9.15 - 9.22 (m, 1 H).
MS ESI/APCI Dual posi: 346[M+H]+.
MS ESI/APCI Dual nega: 344[M-H]-. Similar to Example 1-1 (1) to (2) using the compound obtained in Reference Example 25 (259 mg) and (S)-(−)-1- (4-fluorophenyl) ethylamine (188 mg) The title compound was obtained as a colorless solid (160 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.50 (d, J = 7.0 Hz, 3 H) 5.09-5.28 (m, 1 H) 7.10-7.24 (m, 2 H) 7.41-7.50 (m, 2 H) 8.40-8.62 (m, 2 H) 9.03-9.06 (m, 1 H) 9.15-9.22 (m, 1 H).
MS ESI / APCI Dual posi: 346 [M + H] + .
MS ESI / APCI Dual nega: 344 [MH] - .
実施例５－１
Ｎ－（２，３－ジヒドロ－１－ベンゾフラン－５－イルメチル）－５－フルオロ－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 5-1
N- (2,3-dihydro-1-benzofuran-5-ylmethyl) -5-fluoro-6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000152
  　 
Figure JPOXMLDOC01-appb-C000152
  　 
　参考例２６で得られた化合物（２００ｍｇ）と（２，３－ジヒドロベンゾフラン－５－イル）メタンアミン（１７０ｍｇ）を用いて、実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（１１９ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.16 (t, J=8.7 Hz, 2 H) 4.41 - 4.46 (m, 2 H) 4.50 (t, J=8.7 Hz, 2 H) 6.72 (d, J=8.1 Hz, 1 H) 7.04 - 7.11 (m, 1 H) 7.21 - 7.25 (m, 1 H) 8.27 (dd, J=11.3, 1.7 Hz, 1 H) 8.44 - 8.53 (m, 1 H) 9.00 (t, J=1.7 Hz, 1 H) 9.23 - 9.36 (m, 1 H).
MS ESI/APCI Dual posi: 340[M+H]+.
MS ESI/APCI Dual nega: 338[M-H]-. Using the compound (200 mg) obtained in Reference Example 26 and (2,3-dihydrobenzofuran-5-yl) methanamine (170 mg), the same procedure as in Example 1-1 (1) to (2) was used. The title compound was obtained as a colorless solid (119 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.16 (t, J = 8.7 Hz, 2 H) 4.41-4.46 (m, 2 H) 4.50 (t, J = 8.7 Hz, 2 H) 6.72 (d , J = 8.1 Hz, 1 H) 7.04-7.11 (m, 1 H) 7.21-7.25 (m, 1 H) 8.27 (dd, J = 11.3, 1.7 Hz, 1 H) 8.44-8.53 (m, 1 H) 9.00 (t, J = 1.7 Hz, 1 H) 9.23-9.36 (m, 1 H).
MS ESI / APCI Dual posi: 340 [M + H] + .
MS ESI / APCI Dual nega: 338 [MH] - .
実施例５－２
５－フルオロ－Ｎ－［（１Ｓ）－１－（４－フルオロフェニル）エチル］－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 5-2
5-Fluoro-N-[(1S) -1- (4-fluorophenyl) ethyl] -6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000153
  　 
Figure JPOXMLDOC01-appb-C000153
  　 
　参考例２６で得られた化合物（２００ｍｇ）と（Ｓ）－（－）－１－（４－フルオロフェニル）エチルアミン（１５９ｍｇ）を用いて、実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（９３．０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.50 (d, J=7.1 Hz, 3 H) 5.19 (quin, J=7.1 Hz, 1 H) 7.09 - 7.23 (m, 2 H) 7.40 - 7.52 (m, 2 H) 8.30 (dd, J=11.2, 1.7 Hz, 1 H) 8.50 (br. s., 1 H) 8.98 (t, J=1.7 Hz, 1 H) 9.12 - 9.19 (m, 1 H).
MS ESI/APCI Dual posi: 330[M+H]+.
MS ESI/APCI Dual nega: 328[M-H]-. Similar to Example 1-1 (1) to (2), using the compound (200 mg) obtained in Reference Example 26 and (S)-(−)-1- (4-fluorophenyl) ethylamine (159 mg). The title compound was obtained as a colorless solid (93.0 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.50 (d, J = 7.1 Hz, 3 H) 5.19 (quin, J = 7.1 Hz, 1 H) 7.09-7.23 (m, 2 H) 7.40-7.52 (m, 2 H) 8.30 (dd, J = 11.2, 1.7 Hz, 1 H) 8.50 (br. s., 1 H) 8.98 (t, J = 1.7 Hz, 1 H) 9.12-9.19 (m, 1 H ).
MS ESI / APCI Dual posi: 330 [M + H] + .
MS ESI / APCI Dual nega: 328 [MH] - .
実施例６－１
Ｎ－（２，３－ジヒドロ－１－ベンゾフラン－５－イルメチル）－４－メチル－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 6-1
N- (2,3-dihydro-1-benzofuran-5-ylmethyl) -4-methyl-6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000154
  　 
Figure JPOXMLDOC01-appb-C000154
  　 
　参考例２７で得られた化合物（２５４ｍｇ）と（２，３－ジヒドロベンゾフラン－５－イル）メタンアミン（２１８ｍｇ）を用いて、実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（４２．０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 2.44 (s, 3 H) 3.17 (t, J=8.9 Hz, 2 H) 4.36 - 4.43 (m, 2 H) 4.51 (t, J=8.9 Hz, 2 H) 6.73 (d, J=8.1 Hz, 1 H) 7.05 - 7.10 (m, 1 H) 7.23 (d, J=1.9 Hz, 1 H) 7.98 (s, 1 H) 8.23 - 8.29 (m, 1 H) 8.59 (s, 1 H) 8.96 - 9.05 (m, 1 H).
MS ESI/APCI Dual posi: 336[M+H]+. Using the compound (254 mg) obtained in Reference Example 27 and (2,3-dihydrobenzofuran-5-yl) methanamine (218 mg), the same procedure as in Example 1-1 (1) to (2) was used. The title compound was obtained as a colorless solid (42.0 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 2.44 (s, 3 H) 3.17 (t, J = 8.9 Hz, 2 H) 4.36-4.43 (m, 2 H) 4.51 (t, J = 8.9 Hz , 2 H) 6.73 (d, J = 8.1 Hz, 1 H) 7.05-7.10 (m, 1 H) 7.23 (d, J = 1.9 Hz, 1 H) 7.98 (s, 1 H) 8.23-8.29 (m, 1 H) 8.59 (s, 1 H) 8.96-9.05 (m, 1 H).
MS ESI / APCI Dual posi: 336 [M + H] + .
実施例６－２
４－メチル－Ｎ－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 6-2
4-Methyl-N-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000155
  　 
Figure JPOXMLDOC01-appb-C000155
  　 
　参考例２７で得られた化合物と［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メタンアミン（２７３ｍｇ）を用いて、実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（８７．０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.2 Hz, 6 H) 2.44 (s, 3 H) 4.36 - 4.46 (m, 2 H) 5.14 - 5.30 (m, 1 H) 6.70 - 6.78 (m, 1 H) 7.63 - 7.74 (m, 1 H) 7.99 (s, 1 H) 8.08 - 8.17 (m, 1 H) 8.23 - 8.33 (m, 1 H) 8.60 (s, 1 H) 9.02 - 9.10 (m, 1 H).
MS ESI/APCI Dual posi: 353[M+H]+.
MS ESI/APCI Dual nega: 351[M-H]-. Using the compound obtained in Reference Example 27 and [6- (propan-2-yloxy) pyridin-3-yl] methanamine (273 mg), the same procedure as in Example 1-1 (1) to (2) was performed. To give the title compound as a colorless solid (87.0 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.28 (d, J = 6.2 Hz, 6 H) 2.44 (s, 3 H) 4.36-4.46 (m, 2 H) 5.14-5.30 (m, 1 H ) 6.70-6.78 (m, 1 H) 7.63-7.74 (m, 1 H) 7.99 (s, 1 H) 8.08-8.17 (m, 1 H) 8.23-8.33 (m, 1 H) 8.60 (s, 1 H ) 9.02-9.10 (m, 1 H).
MS ESI / APCI Dual posi: 353 [M + H] + .
MS ESI / APCI Dual nega: 351 [MH] - .
実施例７
Ｎ－（ジフェニルメチル）－６－［３－（ヒドロキシメチル）－１Ｈ－１，２，４－トリアゾール－５－イル］ピリジン－３－カルボキサミド Example 7
N- (diphenylmethyl) -6- [3- (hydroxymethyl) -1H-1,2,4-triazol-5-yl] pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000156
  　 
Figure JPOXMLDOC01-appb-C000156
  　 
　参考例３０で得られた化合物（３１６ｍｇ）とジフェニルメタンアミン（３６７ｍｇ）を用いて、参考例２９－１（１）～（２）と同様の手法にて表題化合物を無色アモルファス（２６１ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 4.60 (br. s., 2 H) 6.44 (d, J=8.5 Hz, 1 H) 7.19 - 7.50 (m, 10 H) 8.15 (d, J=8.2 Hz, 1 H) 8.33 - 8.54 (m, 1 H) 9.13 (d, J=1.6 Hz, 1 H) 9.58 (d, J=8.4 Hz, 1 H).
MS ESI/APCI Dual posi: 386[M+H]+.
MS ESI/APCI Dual nega: 384[M-H]-. Using the compound (316 mg) obtained in Reference Example 30 and diphenylmethanamine (367 mg), the title compound was obtained as colorless amorphous (261 mg) in the same manner as in Reference Example 29-1 (1) to (2). .
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 4.60 (br. S., 2 H) 6.44 (d, J = 8.5 Hz, 1 H) 7.19-7.50 (m, 10 H) 8.15 (d, J = 8.2 Hz, 1 H) 8.33-8.54 (m, 1 H) 9.13 (d, J = 1.6 Hz, 1 H) 9.58 (d, J = 8.4 Hz, 1 H).
MS ESI / APCI Dual posi: 386 [M + H] + .
MS ESI / APCI Dual nega: 384 [MH] - .
実施例８－１
Ｎ－［（１Ｓ）－１－（４－メトキシフェニル）エチル］－６－（３－メチル－１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 8-1
N-[(1S) -1- (4-methoxyphenyl) ethyl] -6- (3-methyl-1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000157
  　 
Figure JPOXMLDOC01-appb-C000157
  　 
　参考例３１で得られた化合物（５００ｍｇ）と（Ｓ）－１－（４－メトキシフェニル）エチルアミン（２３０ｍｇ）を用いて実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（２６２ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.48 (d, J=7.0 Hz, 3 H) 2.39 (s, 3 H) 3.73 (s, 3 H) 5.07 - 5.24 (m, 1 H) 6.83 - 6.97 (m, 2 H) 7.26 - 7.39 (m, 2 H) 8.11 (d, J=8.2 Hz, 1 H) 8.34 (dd, J=8.2, 2.2 Hz, 1 H) 9.01 (d, J=8.1 Hz, 1 H) 9.07 (dd, J=2.3, 0.7 Hz, 1 H).
MS ESI/APCI Dual posi: 338[M+H]+.
MS ESI/APCI Dual nega: 336[M-H]-. Using the compound (500 mg) obtained in Reference Example 31 and (S) -1- (4-methoxyphenyl) ethylamine (230 mg), the title was prepared in the same manner as in Example 1-1 (1) to (2). The compound was obtained as a colorless solid (262 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.48 (d, J = 7.0 Hz, 3 H) 2.39 (s, 3 H) 3.73 (s, 3 H) 5.07-5.24 (m, 1 H) 6.83 -6.97 (m, 2 H) 7.26-7.39 (m, 2 H) 8.11 (d, J = 8.2 Hz, 1 H) 8.34 (dd, J = 8.2, 2.2 Hz, 1 H) 9.01 (d, J = 8.1 (Hz, 1 H) 9.07 (dd, J = 2.3, 0.7 Hz, 1 H).
MS ESI / APCI Dual posi: 338 [M + H] + .
MS ESI / APCI Dual nega: 336 [MH] - .
　以下の実施例８－２～８－４は参考例３１で得られた化合物と市販の対応するアミンを用いて、実施例１－１（１）～（２）に記載の方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表９－１に示す。 The following Examples 8-2 to 8-4 were synthesized by the method described in Example 1-1 (1) to (2) using the compound obtained in Reference Example 31 and a commercially available corresponding amine. Their structures, NMR data, and MS data are shown in Table 9-1.
Figure JPOXMLDOC01-appb-T000158
      
  　 
Figure JPOXMLDOC01-appb-T000158
      
  　 
実施例９－１
４－メトキシ－Ｎ－［（１Ｓ）－１－（４－メトキシフェニル）エチル］－６－（３－メチル－１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 9-1
4-Methoxy-N-[(1S) -1- (4-methoxyphenyl) ethyl] -6- (3-methyl-1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000159
  　 
Figure JPOXMLDOC01-appb-C000159
  　 
　参考例３２で得られた化合物（３５２ｍｇ）と（Ｓ）－１－（４－メトキシフェニル）エチルアミン（２７３ｍｇ）を用いて、実施例２－１に準ずる手法にて４－メトキシ－Ｎ－［（１Ｓ）－１－（４－メトキシフェニル）エチル］－６－（３－メチル－１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミドを無色固体（１９７ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (d, J=7.0 Hz, 3 H) 2.38 (s, 3 H) 3.74 (s, 3 H) 4.03 (s, 3 H) 5.03 - 5.19 (m, 1 H) 6.85 - 6.98 (m, 1 H) 7.26 - 7.39 (m, 1 H) 7.71 (s, 1 H) 8.53 (d, J=8.2 Hz, 1 H) 8.63 (s, 1 H).
MS ESI/APCI Dual posi: 368[M+H]+.
MS ESI/APCI Dual nega: 366[M-H]-. Using the compound (352 mg) obtained in Reference Example 32 and (S) -1- (4-methoxyphenyl) ethylamine (273 mg), 4-methoxy-N-[(( 1S) -1- (4-Methoxyphenyl) ethyl] -6- (3-methyl-1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide was obtained as a colorless solid (197 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.44 (d, J = 7.0 Hz, 3 H) 2.38 (s, 3 H) 3.74 (s, 3 H) 4.03 (s, 3 H) 5.03-5.19 (m, 1 H) 6.85-6.98 (m, 1 H) 7.26-7.39 (m, 1 H) 7.71 (s, 1 H) 8.53 (d, J = 8.2 Hz, 1 H) 8.63 (s, 1 H) .
MS ESI / APCI Dual posi: 368 [M + H] + .
MS ESI / APCI Dual nega: 366 [MH] - .
　以下の実施例９－２～９－３は参考例３２で得られた化合物と市販の対応するアミンを用いて、実施例２－１に準ずる手法にて合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表１０－１に示す。 The following Examples 9-2 to 9-3 were synthesized by the method according to Example 2-1 using the compound obtained in Reference Example 32 and a commercially available corresponding amine. Their structures, NMR data, and MS data are shown in Table 10-1.
Figure JPOXMLDOC01-appb-T000160
  　 
Figure JPOXMLDOC01-appb-T000160
  　 
実施例１０－１
Ｎ－［（１Ｓ）－１－（４－メトキシフェニル）エチル］－５－（１Ｈ－１，２，４－トリアゾール－５－イル）ピラジン－２－カルボキサミド Example 10-1
N-[(1S) -1- (4-methoxyphenyl) ethyl] -5- (1H-1,2,4-triazol-5-yl) pyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000161
  　 
Figure JPOXMLDOC01-appb-C000161
  　 
　参考例３３で得られた化合物（３３４ｍｇ）と（Ｓ）－１－（４－メトキシフェニル）エチルアミン（２３０ｍｇ）を用いて実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（２９４ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.52 (d, J=7.0 Hz, 3 H) 3.73 (s, 3 H) 5.11 - 5.26 (m, 1 H) 6.81 - 6.95 (m, 2 H) 7.31 - 7.45 (m, 2 H) 8.61 (br. s., 1 H) 9.17 - 9.27 (m, 2 H) 9.30 (d, J=1.6 Hz, 1 H).
MS ESI/APCI Dual posi: 325[M+H]+.
MS ESI/APCI Dual nega: 323[M-H]-. Using the compound (334 mg) obtained in Reference Example 33 and (S) -1- (4-methoxyphenyl) ethylamine (230 mg), the title was prepared in the same manner as in Example 1-1 (1) to (2). The compound was obtained as a colorless solid (294 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.52 (d, J = 7.0 Hz, 3 H) 3.73 (s, 3 H) 5.11-5.26 (m, 1 H) 6.81-6.95 (m, 2 H ) 7.31-7.45 (m, 2 H) 8.61 (br. S., 1 H) 9.17-9.27 (m, 2 H) 9.30 (d, J = 1.6 Hz, 1 H).
MS ESI / APCI Dual posi: 325 [M + H] + .
MS ESI / APCI Dual nega: 323 [MH] - .
実施例１０－２
Ｎ－（２，３－ジヒドロ－１－ベンゾフラン－５－イルメチル）－５－（１Ｈ－１，２，４－トリアゾール－５－イル）ピラジン－２－カルボキサミド Example 10-2
N- (2,3-dihydro-1-benzofuran-5-ylmethyl) -5- (1H-1,2,4-triazol-5-yl) pyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000162
  　 
Figure JPOXMLDOC01-appb-C000162
  　 
　参考例３３で得られた化合物（３１８ｍｇ）と（２，３－ジヒドロベンゾフラン－５－イル）メタンアミン（２２４ｍｇ）を用いて実施例１－１（１）～（２）と同様の手法にて表題化合物を無色固体（２７４ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.14 (t, J=8.9 Hz, 2 H) 4.42 (d, J=6.4 Hz, 2 H) 4.49 (t, J=8.7 Hz, 2 H) 6.69 (d, J=8.1 Hz, 1 H) 7.08 (dd, J=8.2, 1.7 Hz, 1 H) 7.23 (s, 1 H) 8.62 (br. s., 1 H) 9.26 (d, J=1.6 Hz, 1 H) 9.29 (d, J=1.6 Hz, 1 H) 9.40 - 9.50 (m, 1 H).
MS ESI/APCI Dual posi: 323[M+H]+.
MS ESI/APCI Dual nega: 321[M-H]-. Using the compound (318 mg) obtained in Reference Example 33 and (2,3-dihydrobenzofuran-5-yl) methanamine (224 mg), the title was prepared in the same manner as in Example 1-1 (1) to (2). The compound was obtained as a colorless solid (274 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.14 (t, J = 8.9 Hz, 2 H) 4.42 (d, J = 6.4 Hz, 2 H) 4.49 (t, J = 8.7 Hz, 2 H) 6.69 (d, J = 8.1 Hz, 1 H) 7.08 (dd, J = 8.2, 1.7 Hz, 1 H) 7.23 (s, 1 H) 8.62 (br. S., 1 H) 9.26 (d, J = 1.6 (Hz, 1 H) 9.29 (d, J = 1.6 Hz, 1 H) 9.40-9.50 (m, 1 H).
MS ESI / APCI Dual posi: 323 [M + H] + .
MS ESI / APCI Dual nega: 321 [MH] - .
実施例１１
２－（２，３－ジヒドロ－１－ベンゾフラン－５－イル）－Ｎ－［６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－イル］アセトアミド Example 11
2- (2,3-Dihydro-1-benzofuran-5-yl) -N- [6- (1H-1,2,4-triazol-5-yl) pyridin-3-yl] acetamide
Figure JPOXMLDOC01-appb-C000163
  　 
Figure JPOXMLDOC01-appb-C000163
  　 
　参考例３４で得られた化合物（１６７ｍｇ）、２，３－ジヒドロ－１－ベンゾフラン－５－イル酢酸（２４２ｍｇ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ'，Ｎ'，－テトラメチルウロニウムヘキサフルオロリン酸塩（５１７ｍｇ）、及びＮ，Ｎ－ジイソプロピルエチルアミン（４７４μＬ）のＮ，Ｎ－ジメチルホルムアミド懸濁液（６．００ｍＬ）を室温で一晩攪拌した。反応液に水を加えて、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、乾燥剤を濾別し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル= ９０：１０～０：１００　さらにクロロホルム：メタノール=９０：１０）で精製し、粗精製物を回収した。続いて、ＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９０：１０～０：１００　さらにクロロホルム：メタノール=９０：１０）で精製し、粗生成物（３０７ｍｇ）を得た。この粗生成物を用いて、実施例１－１（２）と同様の手法にて表題化合物を無色固体（１００ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 3.16 (t, J=8.7 Hz, 2 H) 3.61 (s, 2 H) 4.50 (t, J=8.7 Hz, 2 H) 6.71 (d, J=8.1 Hz, 1 H) 7.02 - 7.07 (m, 1 H) 7.20 (s, 1 H) 8.03 (d, J=8.5 Hz, 1 H) 8.14 - 8.22 (m, 2 H) 8.89 (d, J=2.2 Hz, 1 H) 10.53 (s, 1 H).
MS ESI/APCI Dual posi: 322[M+H]+.
MS ESI/APCI Dual nega: 320[M-H]-. Compound (167 mg) obtained in Reference Example 34, 2,3-dihydro-1-benzofuran-5-ylacetic acid (242 mg), O- (7-azabenzotriazol-1-yl) -N, N, N ′ , N ′,-Tetramethyluronium hexafluorophosphate (517 mg) and N, N-diisopropylethylamine (474 μL) in N, N-dimethylformamide suspension (6.00 mL) were stirred overnight at room temperature. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 90: 10 to 0: 100, further chloroform: methanol = 90: 10), and a crude product was recovered. Subsequently, the product was purified by NH silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 to 0: 100, further chloroform: methanol = 90: 10) to obtain a crude product (307 mg). Using this crude product, the title compound was obtained as a colorless solid (100 mg) in the same manner as in Example 1-1 (2).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 3.16 (t, J = 8.7 Hz, 2 H) 3.61 (s, 2 H) 4.50 (t, J = 8.7 Hz, 2 H) 6.71 (d, J = 8.1 Hz, 1 H) 7.02-7.07 (m, 1 H) 7.20 (s, 1 H) 8.03 (d, J = 8.5 Hz, 1 H) 8.14-8.22 (m, 2 H) 8.89 (d, J = 2.2 Hz, 1 H) 10.53 (s, 1 H).
MS ESI / APCI Dual posi: 322 [M + H] + .
MS ESI / APCI Dual nega: 320 [MH] - .
実施例１２－１
５－｛［（４－クロロベンジル）オキシ］メチル｝－２－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン Example 12-1
5-{[(4-Chlorobenzyl) oxy] methyl} -2- (1H-1,2,4-triazol-5-yl) pyridine
Figure JPOXMLDOC01-appb-C000164
  　 
Figure JPOXMLDOC01-appb-C000164
  　 
（１）５－｛［（４－クロロベンジル）オキシ］メチル｝－２－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジンの合成 (1) 5-{[(4-Chlorobenzyl) oxy] methyl} -2- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine Synthesis of
Figure JPOXMLDOC01-appb-C000165
  　 
Figure JPOXMLDOC01-appb-C000165
  　 
　参考例３５で得られた化合物（２００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（３．８０ｍＬ）に、氷冷下で水素化ナトリウム（６０％鉱油分散物、６１．０ｍｇ）を少量ずつ加え、窒素雰囲気下、同温度で３０分間攪拌した。これに４－クロロベンジルブロミド（３１６ｍｇ）を加えて、同温度で３０分間攪拌した。反応液に水を加えて、酢酸エチルで２回抽出した。合わせた有機層を水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル=９９：１～０：１００　さらにクロロホルム：メタノール=１００：０～９１：９）で精製し、５－｛［（４－クロロベンジル）オキシ］メチル｝－２－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジンを淡黄色油状物質（２４０ｍｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.58 - 1.82 (m, 3 H) 1.94 - 2.33 (m, 3 H) 3.67 - 3.82 (m, 1 H) 4.04 - 4.20 (m, 1 H) 4.55 (s, 2 H) 4.61 (s, 2 H) 5.56 (dd, J=9.2, 2.9 Hz, 1 H) 7.26 - 7.38 (m, 4 H) 7.81 (dd, J=8.1, 2.2 Hz, 1 H) 8.16 (d, J=8.1 Hz, 1 H) 8.37 (s, 1 H) 8.69 (d, J=1.7 Hz, 1 H).
MS ESI/APCI Dual posi: 385[M+H]+. To a solution of the compound (200 mg) obtained in Reference Example 35 (200 mg) in N, N-dimethylformamide (3.80 mL), sodium hydride (60% mineral oil dispersion, 61.0 mg) was added little by little under ice-cooling. The mixture was stirred at the same temperature for 30 minutes under the atmosphere. 4-Chlorobenzyl bromide (316 mg) was added thereto, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 99: 1 to 0: 100 and further chloroform: methanol = 100: 0 to 91: 9) to give 5-{[(4-chlorobenzyl ) Oxy] methyl} -2- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine was obtained as a pale yellow oil (240 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.58-1.82 (m, 3 H) 1.94-2.33 (m, 3 H) 3.67-3.82 (m, 1 H) 4.04-4.20 (m, 1 H) 4.55 (s, 2 H) 4.61 (s, 2 H) 5.56 (dd, J = 9.2, 2.9 Hz, 1 H) 7.26-7.38 (m, 4 H) 7.81 (dd, J = 8.1, 2.2 Hz, 1 H) 8.16 (d, J = 8.1 Hz, 1 H) 8.37 (s, 1 H) 8.69 (d, J = 1.7 Hz, 1 H).
MS ESI / APCI Dual posi: 385 [M + H] + .
（２）表題化合物の合成
　上記の（１）で得られた化合物（２４０ｍｇ）を用いて、実施例１－１（３）と同様の手法にて表題化合物を無色固体（１１８ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 4.59 (s, 2 H) 4.65 (s, 2 H) 7.37 - 7.49 (m, 4 H) 7.90 - 8.01 (m, 1 H) 8.05 - 8.13 (m, 1 H) 8.15 - 8.36 (m, 1 H) 8.67 (d, J=1.7 Hz, 1 H).
MS ESI/APCI Dual posi: 301[M+H]+. (2) Synthesis of title compound Using the compound (240 mg) obtained in (1) above, the title compound was obtained as a colorless solid (118 mg) in the same manner as in Example 1-1 (3).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 4.59 (s, 2 H) 4.65 (s, 2 H) 7.37-7.49 (m, 4 H) 7.90-8.01 (m, 1 H) 8.05-8.13 ( m, 1 H) 8.15-8.36 (m, 1 H) 8.67 (d, J = 1.7 Hz, 1 H).
MS ESI / APCI Dual posi: 301 [M + H] + .
実施例１２－２
５－｛［（４－フルオロベンジル）オキシ］メチル｝－２－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン Example 12-2
5-{[(4-Fluorobenzyl) oxy] methyl} -2- (1H-1,2,4-triazol-5-yl) pyridine
Figure JPOXMLDOC01-appb-C000166
  　 
Figure JPOXMLDOC01-appb-C000166
  　 
　参考例３５で得られた化合物（２００ｍｇ）と４－フルオロベンジルブロミド（１９１ｍｇ）を用いて、実施例１３－１（１）～（２）と同様の手法にて表題化合物を無色油状物質（２０９ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 4.58 (s, 2 H) 4.65 (s, 2 H) 7.14 - 7.27 (m, 2 H) 7.36 - 7.54 (m, 2 H) 7.93 - 8.01 (m, 1 H) 8.07 - 8.14 (m, 1 H) 8.23 - 8.36 (m, 1 H) 8.67 (d, J=1.2 Hz, 1 H).
MS ESI/APCI Dual posi: 285[M+H]+. Using the compound (200 mg) obtained in Reference Example 35 and 4-fluorobenzyl bromide (191 mg), the title compound was purified in the same manner as in Example 13-1 (1) to (2) using a colorless oily substance (209 mg). ).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 4.58 (s, 2 H) 4.65 (s, 2 H) 7.14-7.27 (m, 2 H) 7.36-7.54 (m, 2 H) 7.93-8.01 ( m, 1 H) 8.07-8.14 (m, 1 H) 8.23-8.36 (m, 1 H) 8.67 (d, J = 1.2 Hz, 1 H).
MS ESI / APCI Dual posi: 285 [M + H] + .
実施例１３－１
４－フルオロ－Ｎ－｛［６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－イル］メチル｝ベンズアミド Example 13-1
4-Fluoro-N-{[6- (1H-1,2,4-triazol-5-yl) pyridin-3-yl] methyl} benzamide
Figure JPOXMLDOC01-appb-C000167
  　 
Figure JPOXMLDOC01-appb-C000167
  　 
　参考例３６で得られた化合物（８５．０ｍｇ）と４－フルオロ安息香酸（５５．０ｍｇ）を用いて、実施例１１に準ずる手法にて表題化合物を無色固体（６１．０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 4.57 (d, J=5.9 Hz, 2 H) 7.26 - 7.38 (m, 2 H) 7.86 - 8.03 (m, 3 H) 8.08 (d, J=8.1 Hz, 1 H) 8.20 - 8.36 (m, 1 H) 8.64 - 8.69 (m, 1 H) 9.17 (t, J=5.7 Hz, 1 H).
MS ESI/APCI Dual posi: 298[M+H]+.
MS ESI/APCI Dual nega: 296[M-H]-. Using the compound obtained in Reference Example 36 (85.0 mg) and 4-fluorobenzoic acid (55.0 mg), the title compound was obtained as a colorless solid (61.0 mg) by the same method as in Example 11.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 4.57 (d, J = 5.9 Hz, 2 H) 7.26-7.38 (m, 2 H) 7.86-8.03 (m, 3 H) 8.08 (d, J = 8.1 Hz, 1 H) 8.20-8.36 (m, 1 H) 8.64-8.69 (m, 1 H) 9.17 (t, J = 5.7 Hz, 1 H).
MS ESI / APCI Dual posi: 298 [M + H] + .
MS ESI / APCI Dual nega: 296 [MH] - .
　以下の実施例１３－２～１３－３は参考例３６で得られた化合物と市販の対応するカルボン酸を用いて、実施例１１に準ずる手法にて合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表１１－１に示す。 The following Examples 13-2 to 13-3 were synthesized by the method according to Example 11 using the compound obtained in Reference Example 36 and a commercially available corresponding carboxylic acid. Their structures, NMR data, and MS data are shown in Table 11-1.
Figure JPOXMLDOC01-appb-T000168
      
  　 
Figure JPOXMLDOC01-appb-T000168
      
  　 
実施例１４－１
Ｎ－［４－（ピリミジン－２－イルオキシ）ベンジル］－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 14-1
N- [4- (pyrimidin-2-yloxy) benzyl] -6- (1H-1,2,4-triazol-5-yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000169
  　 
Figure JPOXMLDOC01-appb-C000169
  　 
　参考例１で得られた化合物（５００ｍｇ）、参考例３７－１で得られた化合物（８６８ｍｇ）、及び１－ヒドロキシベンゾトリアゾール一水和物（３４５ｍｇ）のクロロホルム懸濁液（６．００ｍＬ）に１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（４３２ｍｇ）を加えて、室温で一晩攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えた後、有機層を分離した。水層をクロロホルムで抽出し、合わせた有機層をフェーズセパレーターに通して減圧下濃縮した。得られた残渣をクロロホルム（２．００ｍＬ）に溶解し、アニソール（１．００ｍＬ）、及びトリフルオロ酢酸（３．００ｍＬ）を加えて、室温で１時間、６０℃で２時間攪拌した。室温まで冷却した後、反応液を減圧下濃縮し、得られた残渣を分取ＨＰＬＣにて精製し、粗精製物を回収した。このものをアセトンで粉末化させ、表題化合物を無色固体（２５０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 4.55 (d, J=5.9 Hz, 2 H) 7.13 - 7.21 (m, 2 H) 7.26 (t, J=4.8 Hz, 1 H) 7.38 - 7.46 (m, 2 H) 8.19 (d, J=8.9 Hz, 1 H) 8.34 - 8.49 (m, 1 H) 8.63 (d, J=4.7 Hz, 2 H) 9.16 (d, J=1.4 Hz, 1 H) 9.33 - 9.45 (m, 1 H).
MS ESI/APCI Dual posi: 374[M+H]+.
MS ESI/APCI Dual nega: 372[M-H]-. To a chloroform suspension (6.00 mL) of the compound obtained in Reference Example 1 (500 mg), the compound obtained in Reference Example 37-1 (868 mg), and 1-hydroxybenzotriazole monohydrate (345 mg). 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (432 mg) was added and stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and then the organic layer was separated. The aqueous layer was extracted with chloroform, and the combined organic layers were passed through a phase separator and concentrated under reduced pressure. The obtained residue was dissolved in chloroform (2.00 mL), anisole (1.00 mL) and trifluoroacetic acid (3.00 mL) were added, and the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to collect a crude product. This was triturated with acetone to give the title compound as a colorless solid (250 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 4.55 (d, J = 5.9 Hz, 2 H) 7.13-7.21 (m, 2 H) 7.26 (t, J = 4.8 Hz, 1 H) 7.38-7.46 (m, 2 H) 8.19 (d, J = 8.9 Hz, 1 H) 8.34-8.49 (m, 1 H) 8.63 (d, J = 4.7 Hz, 2 H) 9.16 (d, J = 1.4 Hz, 1 H ) 9.33-9.45 (m, 1 H).
MS ESI / APCI Dual posi: 374 [M + H] + .
MS ESI / APCI Dual nega: 372 [MH] - .
　以下の実施例１４－２～１４－１１は参考例１で得られた化合物と参考例３７－２～５、３８、３９－１～３、４０－１～２で得られた化合物を原料として、実施例１４－１に記載の方法で合成した。それらの構造、ＮＭＲデータ、ＭＳデータを表１２－１～表１２－２に示す。 The following Examples 14-2 to 14-11 were prepared using the compound obtained in Reference Example 1 and the compounds obtained in Reference Examples 37-2 to 5, 38, 39-1 to 3, and 40-1 to 2 as raw materials. This was synthesized by the method described in Example 14-1. Their structures, NMR data, and MS data are shown in Tables 12-1 to 12-2.
Figure JPOXMLDOC01-appb-T000170
      
  　 
Figure JPOXMLDOC01-appb-T000170
      
  　 
Figure JPOXMLDOC01-appb-T000171
      
  　 
Figure JPOXMLDOC01-appb-T000171
      
  　 
実施例１５
Ｎ－［１－（３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）－２－メチル－１－オキソプロパン－２－イル］－６－（１Ｈ－１，２，４－トリアゾール－５－イル）ピリジン－３－カルボキサミド Example 15
N- [1- (3,4-Dihydroisoquinolin-2 (1H) -yl) -2-methyl-1-oxopropan-2-yl] -6- (1H-1,2,4-triazole-5 Yl) pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000172
  　 
Figure JPOXMLDOC01-appb-C000172
  　 
（１）メチル　２－メチル－Ｎ－（｛６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－イル｝カルボニル）アラニナートの合成 (1) Methyl 2-methyl-N-({6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridin-3-yl} carbonyl ) Synthesis of alaninate
Figure JPOXMLDOC01-appb-C000173
  　 
Figure JPOXMLDOC01-appb-C000173
  　 
　参考例１で得られた化合物（１．００ｇ）、２－アミノ－２－メチルプロパン酸メチル塩酸塩（０．６９ｇ）、及び１－ヒドロキシベンゾトリアゾール一水和物（０．６９ｇ）のクロロホルム懸濁液（１２．０ｍＬ）に１－（３－ジメチルアミノプロピル）－３－ エチルカルボジイミド塩酸塩（０．８６ｇ）、及びトリエチルアミン（０．８４ｍＬ）を加えて、６０℃で１時間攪拌した。室温まで冷却した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで２回抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=９５：５）で精製し、メチル　２－メチル－Ｎ－（｛６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－イル｝カルボニル）アラニナートを無色固体（０．７０ｇ）として得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.58 - 1.83 (m, 9 H) 1.98 - 2.33 (m, 3 H) 3.68 - 3.84 (m, 4 H) 4.08 - 4.18 (m, 1 H) 5.57 (dd, J=9.3, 2.8 Hz, 1 H) 6.91 (s, 1 H) 8.14 - 8.29 (m, 2 H) 8.39 (s, 1 H) 9.10 (dd, J=2.2, 1.1 Hz, 1 H).
MS ESI/APCI Dual posi: 374[M+H]+. Chloroform suspension of the compound (1.00 g) obtained in Reference Example 1, methyl 2-amino-2-methylpropanoate hydrochloride (0.69 g), and 1-hydroxybenzotriazole monohydrate (0.69 g). 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.86 g) and triethylamine (0.84 mL) were added to the suspension (12.0 mL), and the mixture was stirred at 60 ° C. for 1 hour. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5), and methyl 2-methyl-N-({6- [1- (tetrahydro-2H-pyran-2-yl) -1H- 1,2,4-Triazol-3-yl] pyridin-3-yl} carbonyl) alaninate was obtained as a colorless solid (0.70 g).
1 H NMR (300 MHz, CHLOROFORM-d) δppm 1.58-1.83 (m, 9 H) 1.98-2.33 (m, 3 H) 3.68-3.84 (m, 4 H) 4.08-4.18 (m, 1 H) 5.57 ( dd, J = 9.3, 2.8 Hz, 1 H) 6.91 (s, 1 H) 8.14-8.29 (m, 2 H) 8.39 (s, 1 H) 9.10 (dd, J = 2.2, 1.1 Hz, 1 H).
MS ESI / APCI Dual posi: 374 [M + H] + .
（２）Ｎ－［１－（３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）－２－メチル－１－オキソプロパン－２－イル］－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキサミドの合成 (2) N- [1- (3,4-Dihydroisoquinolin-2 (1H) -yl) -2-methyl-1-oxopropan-2-yl] -6- [1- (tetrahydro-2H-pyran- Synthesis of 2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000174
  　 
Figure JPOXMLDOC01-appb-C000174
  　 
　上記（１）で得られた化合物（７００ｍｇ）のメタノール溶液（１８．０ｍＬ）に１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（３．００ｍＬ）を加えて、２時間還流した。室温まで冷却した後、反応液を減圧下濃縮した。得られた残渣をＮ，Ｎ－ジメチルホルムアミド（１０．０ｍＬ）に溶解し、１，２，３，４－テトラヒドロイソキノリン（８００ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（４６０ｍｇ）、及び１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（５７６ｍｇ）を加えて、室温で２時間攪拌した。反応液に水、及び飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール= ９５：５）で精製し、Ｎ－［１－（３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）－２－メチル－１－オキソプロパン－２－イル］－６－［１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－３－カルボキサミドを無色固体（５６６ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 - 1.81 (m, 9 H) 1.90 - 2.28 (m, 3 H) 2.67 (br. s., 2 H) 3.58 - 4.09 (m, 4 H) 4.70 (br. s., 2 H) 5.65 (dd, J=9.7, 2.6 Hz, 1 H) 6.84 - 7.24 (m, 4 H) 7.92 - 8.34 (m, 2 H) 8.87 (s, 1 H) 8.93 (br. s., 1 H).
MS ESI/APCI Dual posi: 475[M+H]+.
MS ESI/APCI Dual nega: 473[M-H]-. A 1 mol / L aqueous sodium hydroxide solution (3.00 mL) was added to a methanol solution (18.0 mL) of the compound (700 mg) obtained in (1) above and refluxed for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (10.0 mL), and 1,2,3,4-tetrahydroisoquinoline (800 mg), 1-hydroxybenzotriazole monohydrate (460 mg), and 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (576 mg) was added and stirred at room temperature for 2 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5), and N- [1- (3,4-dihydroisoquinolin-2 (1H) -yl) -2-methyl-1-oxo was obtained. Propan-2-yl] -6- [1- (tetrahydro-2H-pyran-2-yl) -1H-1,2,4-triazol-3-yl] pyridine-3-carboxamide as a colorless solid (566 mg) Obtained.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.41-1.81 (m, 9 H) 1.90-2.28 (m, 3 H) 2.67 (br. S., 2 H) 3.58-4.09 (m, 4 H ) 4.70 (br. S., 2 H) 5.65 (dd, J = 9.7, 2.6 Hz, 1 H) 6.84-7.24 (m, 4 H) 7.92-8.34 (m, 2 H) 8.87 (s, 1 H) 8.93 (br. S., 1 H).
MS ESI / APCI Dual posi: 475 [M + H] + .
MS ESI / APCI Dual nega: 473 [MH] - .
（３）表題化合物の合成
　上記の（２）で得られた化合物（５６６ｍｇ）を用いて、参考例１（３）と同様の手法で表題化合物を無色アモルファス（３６０ｍｇ）として得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.53 (s, 6 H) 2.68 (br. s., 2 H) 3.79 (br. s., 2 H) 4.71 (br. s., 2 H) 6.85 - 7.28 (m, 4 H) 8.02 - 8.53 (m, 3 H) 8.82 - 9.17 (m, 2 H).
MS ESI/APCI Dual posi: 391[M+H]+.
MS ESI/APCI Dual nega: 389[M-H]-.
　本発明の化合物のＰＨＤ２に対する阻害活性を、以下に示す試験例１及び２に従って測定した。 (3) Synthesis of title compound Using the compound (566 mg) obtained in (2) above, the title compound was obtained as a colorless amorphous (360 mg) in the same manner as in Reference Example 1 (3).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.53 (s, 6 H) 2.68 (br. S., 2 H) 3.79 (br. S., 2 H) 4.71 (br. S., 2 H ) 6.85-7.28 (m, 4 H) 8.02-8.53 (m, 3 H) 8.82-9.17 (m, 2 H).
MS ESI / APCI Dual posi: 391 [M + H] + .
MS ESI / APCI Dual nega: 389 [MH] - .
The inhibitory activity against PHD2 of the compounds of the present invention was measured according to Test Examples 1 and 2 shown below.
　試験例１
　（１）ヒトＰＨＤ２の発現・調製
　ヒトＰＨＤ２の発現は、昆虫細胞（ＨｉｇｈＦｉｖｅ細胞）にて行った。ヒトＰＨＤ２登録配列（ＮＭ＿０２２０５１）をｐＦａｓｔＢａｃ１ベクター（Ｉｎｖｉｔｒｏｇｅｎ）に導入し、配列を確認した。当該ベクターをＳｆ９昆虫細胞（Ｉｎｖｉｔｒｏｇｅｎ）に導入し、ヒトＰＨＤ２バキュロウィルスを取得した。この組換えウィルスをＨｉｇｈＦｉｖｅ昆虫細胞（Ｉｎｖｉｔｒｏｇｅｎ）に感染させ、２７℃で７２時間培養後、各種プロテアーゼ阻害剤を含んだ細胞溶解溶液を加え破砕懸濁した。破砕懸濁溶液を４℃、１００，０００×ｇ，３０分間遠心し、上清を回収して細胞ライセートとした。ウエスタンブロット解析により、ＰＨＤ２バキュロウィルス感染細胞ライセートにのみ、ヒトＰＨＤ２蛋白質の発現を確認した。 Test example 1
(1) Expression and preparation of human PHD2 Human PHD2 was expressed in insect cells (HighFive cells). The human PHD2 registration sequence (NM — 022051) was introduced into the pFastBac1 vector (Invitrogen), and the sequence was confirmed. The vector was introduced into Sf9 insect cells (Invitrogen) to obtain human PHD2 baculovirus. HighFive insect cells (Invitrogen) were infected with this recombinant virus, and after culturing at 27 ° C. for 72 hours, a cell lysis solution containing various protease inhibitors was added and suspended. The disrupted suspension was centrifuged at 100,000 × g for 30 minutes at 4 ° C., and the supernatant was recovered to obtain a cell lysate. Western Plot analysis confirmed the expression of human PHD2 protein only in PHD2 baculovirus-infected cell lysates.
　（２）ヒトＰＨＤ２阻害活性の測定
　ヒトＰＨＤ２酵素活性は、ＨＩＦ－１αの配列を基にした１９残基の部分ペプチドを基質として測定した。具体的には、ペプチド中に含まれるプロリン残基をＰＨＤ２酵素が水酸化する時に同時に起こる２－ｏｘｏｇｌｕｔａｒａｔｅからｓｕｃｃｉｎｉｃ　ａｃｉｄへの変換反応を利用した。すなわち、［１４Ｃ］－２－ｏｘｏｇｌｕｔａｒａｔｅを反応系に添加して酵素反応を開始し、反応後に残存している［１４Ｃ］－２－ｏｘｏｇｌｕｔａｒａｔｅを２，４－ｄｉｎｉｔｒｏｐｈｅｎｙｌｈｙｄｒａｚｉｎｅ（ＤＮＰＨ）と結合させ沈殿物としてフィルターで除去した。その後、生成した［１４Ｃ］－ ｓｕｃｃｉｎｉｃ　ａｃｉｄの放射カウントを測定した。 (2) Measurement of human PHD2 inhibitory activity Human PHD2 enzyme activity was measured using a 19-residue partial peptide based on the sequence of HIF-1α as a substrate. Specifically, a conversion reaction from 2-oxoglutarate to succinic acid that occurs simultaneously with the PHD2 enzyme hydroxylating a proline residue contained in a peptide was used. That is, [ 14 C] -2-oxoglutarate is added to the reaction system to start the enzymatic reaction, and the remaining [ 14 C] -2-oxoglutarate is combined with 2,4-dinitrophenylhydrate (DNPH) to precipitate The product was removed by a filter. Thereafter, the radiation count of the produced [ 14 C] -succinic acid was measured.
　酵素及び基質は、６．６７ｍＭ　ＫＣｌ、２ｍＭ　ＭｇＣｌ2、１３．３μＭ硫酸鉄、２．６７ｍＭアスコルビン酸、１．３３ｍＭ　ＤＴＴを含む２０ｍＭトリス－塩酸緩衝液（ｐＨ７．５）で希釈し、試験化合物はジメチルスルホキシド（ＤＭＳＯ）で希釈した。 The enzyme and substrate were diluted with 20 mM Tris-HCl buffer (pH 7.5) containing 6.67 mM KCl, 2 mM MgCl 2 , 13.3 μM iron sulfate, 2.67 mM ascorbic acid, 1.33 mM DTT, and the test compound was Diluted with dimethyl sulfoxide (DMSO).
　試験化合物、ＨＩＦ－１αペプチドおよび［１４Ｃ］－２－ｏｘｏｇｌｕｔａｒａｔｅを９６穴プレートにあらかじめ添加し、ヒトＰＨＤ２酵素溶液（４μｇ／ｗｅｌｌ）を添加することにより反応を開始した。３７℃で１５分間インキュベーションした後、ＤＮＰＨを含む停止液を添加し、室温で３０分間静置した。その後過剰量の放射能ラベルしていない２－ｏｘｏｇｌｕｔａｒａｔｅを添加し、室温で６０分間静置した。生成した沈殿物をフィルターで除去し、［１４Ｃ］－ｓｕｃｃｉｎｉｃ　ａｃｉｄの放射カウントを（マイクロベータにて）定量した。各ウェルの放射カウントを測定し、試験化合物のヒトＰＨＤ２阻害活性を、基質無添加群および試験物質無添加群の値に基づいて計算した。 The test compound, HIF-1α peptide and [ 14 C] -2-oxoglutarate were previously added to a 96-well plate, and the reaction was started by adding human PHD2 enzyme solution (4 μg / well). After incubation at 37 ° C. for 15 minutes, a stop solution containing DNPH was added and allowed to stand at room temperature for 30 minutes. Thereafter, an excessive amount of non-radiolabeled 2-oxoglutarate was added and allowed to stand at room temperature for 60 minutes. The produced precipitate was removed by a filter, and the radioactivity count of [ 14 C] -succinic acid was quantified (in microbeta). The radiocount of each well was measured, and the human PHD2 inhibitory activity of the test compound was calculated based on the values of the group without the substrate and the group without the test substance.
　（３）結果
　各化合物のヒトＰＨＤ２阻害率（％、試験化合物濃度は１μＭ）を以下の表１３－１に示す。 (3) Results The human PHD2 inhibition rate (%, test compound concentration is 1 μM) of each compound is shown in the following Table 13-1.
Figure JPOXMLDOC01-appb-T000175
      
  　 
Figure JPOXMLDOC01-appb-T000175
      
  　 
　試験例２
（１）ヒトＰＨＤ２の発現・調製
　ヒトＰＨＤ２の発現は、ヒト細胞（２９３ＦＴ細胞）にて行った。ヒトＰＨＤ２登録配列（ＮＭ＿０２２０５１）をｐｃＤＮＡ３．１／Ｈｙｇｒｏ（＋）ベクター（Ｉｎｖｉｔｒｏｇｅｎ）に導入し、配列を確認した。当該ベクターを２９３ＦＴ細胞（Ｉｎｖｉｔｒｏｇｅｎ）に導入し、３７℃、５％炭酸ガス存在下で４８時間培養後、各種プロテアーゼ阻害剤を含んだ細胞溶解溶液を加え破砕懸濁した。破砕懸濁溶液を４℃、１００，０００×ｇ、３０分間遠心し、上清を回収して細胞ライセートとした。ウエスタンブロット解析により、細胞ライセートにヒトＰＨＤ２蛋白質の発現を確認した。 Test example 2
(1) Expression and preparation of human PHD2 Human PHD2 was expressed in human cells (293FT cells). The human PHD2 registration sequence (NM — 022051) was introduced into pcDNA3.1 / Hygro (+) vector (Invitrogen), and the sequence was confirmed. The vector was introduced into 293FT cells (Invitrogen), cultured at 37 ° C. in the presence of 5% carbon dioxide gas for 48 hours, and then added with a cell lysis solution containing various protease inhibitors and suspended. The disrupted suspension was centrifuged at 4 ° C. and 100,000 × g for 30 minutes, and the supernatant was recovered to obtain a cell lysate. The expression of human PHD2 protein was confirmed in the cell lysate by Western blot analysis.
（２）ヒトＰＨＤ２阻害活性の測定　ヒトＰＨＤ２酵素活性は、ＨＩＦ－１αの配列を基にした１９残基の部分ペプチドを基質として、ペプチド中に含まれるプロリン残基の水酸化をＦＰ（Ｆｌｕｏｒｅｓｃｅｎｃｅ　Ｐｏｌａｒｉｚａｔｉｏｎ）法にて測定した。 (2) Measurement of human PHD2 inhibitory activity The human PHD2 enzyme activity is determined by using FP (Fluorescence Polarization) for hydroxylation of proline residues contained in peptides using a 19-residue partial peptide based on the sequence of HIF-1α as a substrate. ) Method.
　酵素及び基質は、１２．５ｍＭ ＫＣｌ、３．７５ｍＭＭｇＣｌ２、２５μＭ硫酸鉄、５ｍＭアスコルビン酸、２．５ｍＭＤＴＴを含む５０ｍＭトリス－塩酸緩衝液（ｐＨ７．５）で希釈し、試験化合物はジメチルスルホキシド（ＤＭＳＯ）で希釈した。 The enzyme and substrate were diluted with 50 mM Tris-HCl buffer (pH 7.5) containing 12.5 mM KCl, 3.75 mM MgCl 2 , 25 μM iron sulfate, 5 mM ascorbic acid, 2.5 mM DTT, and the test compound was dimethyl sulfoxide (DMSO ).
　試験化合物及び基質溶液を３８４穴プレートにあらかじめ添加し、ヒトＰＨＤ２酵素溶液（４０ｎｇ／ｗｅｌｌまたは５０ｎｇ／ｗｅｌｌ）を添加することにより反応を開始した。３０℃で２０分間インキュベーションした後、ＥＤＴＡを含む停止液を添加し、ＨＩＦ－ＯＨ抗体溶液を添加・結合させて、水酸化されたプロリン残基の量を蛍光偏光測定法により定量した。 The test compound and the substrate solution were previously added to the 384-well plate, and the reaction was started by adding human PHD2 enzyme solution (40 ng / well or 50 ng / well). After incubation at 30 ° C. for 20 minutes, a stop solution containing EDTA was added, a HIF-OH antibody solution was added and bound, and the amount of hydroxylated proline residues was quantified by fluorescence polarization measurement.
　各ウェルの蛍光偏光を測定し、試験化合物のヒトＰＨＤ２阻害活性を、試験物質無添加群の値に基づいて計算した。 The fluorescence polarization of each well was measured, and the human PHD2 inhibitory activity of the test compound was calculated based on the value of the test substance-free group.
　なお、上記試験について、５０ｎｇ／ｗｅｌｌのヒトＰＨＤ２酵素溶液で実施した実施例は、実施例１－５、１－６、１－８、１－９、１－１２～１－１４、１－１８～１－３６、１－４３、１－４４、１－４６～１－５０、１－１２９～１－１４２、２－８～２－１０、３、４－１、４－２、５－１、５－２、６－１、６－２、８－１～８－４、９－１～９－３、１０－１、１０－２、１１、１４－７～１４－１１である。 For the above test, Examples carried out with a 50 ng / well human PHD2 enzyme solution are shown in Examples 1-5, 1-6, 1-8, 1-9, 1-12 to 1-14, 1-18. ~ 1-36, 1-43, 1-44, 1-46 to 1-50, 1-129 to 1-142, 2-8 to 2-10, 3, 4-1, 4-2, 5-1 5-2, 6-1, 6-2, 8-1 to 8-4, 9-1 to 9-3, 10-1, 10-2, 11, 14-7 to 14-11.
　（３）結果
　各化合物のヒトＰＨＤ２阻害活性について、阻害率（％、試験化合物濃度は１μＭ）を以下の表１４－１～表１４－２に示す。また、代表的な化合物については、ＩＣ５０（ｎＭ）を以下の表１５－１に示す。 (3) Results Regarding the human PHD2 inhibitory activity of each compound, the inhibition rates (%, test compound concentration is 1 μM) are shown in Tables 14-1 to 14-2 below. For typical compounds, IC 50 (nM) is shown in Table 15-1.
Figure JPOXMLDOC01-appb-T000176
      
  　 
Figure JPOXMLDOC01-appb-T000176
      
  　 
Figure JPOXMLDOC01-appb-T000177
      
  　 
Figure JPOXMLDOC01-appb-T000177
      
  　 
Figure JPOXMLDOC01-appb-T000178
      
  　 
Figure JPOXMLDOC01-appb-T000178
      
  　 
　本発明化合物は優れたＰＨＤ２阻害作用を有し、本発明により貧血に由来する疾病等の予防又は治療に有効な医薬品を提供するが可能となり、患者の負担を軽減し、医薬品産業の発達に寄与することが期待される。
  The compound of the present invention has an excellent PHD2 inhibitory action, and according to the present invention, it is possible to provide a drug effective for the prevention or treatment of diseases caused by anemia, thereby reducing the burden on patients and contributing to the development of the pharmaceutical industry. Is expected to do.

Claims (7)

  1. 　下記式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
     　（Ｉ）
      　 
    ［式（Ｉ）中、
    　Ｒ1は、水素原子又はＣ1-3アルキル（該Ｃ1-3アルキルは、ヒドロキシで置換されてもよい。）を示し、
    　Ｘは、式ＣＲ2又は窒素原子を示し、
    　Ｒ2は、水素原子、ハロゲン原子、Ｃ1-3アルキル、又はＣ1-3アルコキシを示し、
    　Ｒ3は、水素原子、ハロゲン原子、Ｃ1-3アルキル、又はＣ1-3アルコキシを示し、
    　Ｙは、式-ＣＯＮＲ41-Ｗ1-、式-ＣＯＮＲ42-Ｗ2-ＣＯ-、下記式（β）で表される構造、式-ＣＨ2ＮＨＣＯ-、式-ＣＨ2ＯＣＨ2-、又は式-ＮＨＣＯＣＨ2-を示し、
    Figure JPOXMLDOC01-appb-C000002
     　（β）
      　 
    　Ｒ41は、水素原子又はＣ1-3アルキルを示し、
    　Ｗ1は、単結合、Ｃ1-3アルカンジイル、又は式-ＣＨ2ＣＨ2Ｏ-を示し、
    　このとき、Ｃ1-3アルカンジイルは、置換基群α１から同一に又は異なって選ばれる１～２個の置換基で置換されてもよく、
    　置換基群α１は、ヒドロキシ、カルバモイル、Ｃ1-3アルキル（該Ｃ1-3アルキルは、１個のヒドロキシ又はＣ1-3アルコキシで置換されてもよい。）、Ｃ3-6シクロアルキル、アリール、ヘテロアリール（該ヘテロアリールは、１個のＣ1-3アルキルで置換されてもよい。）、Ｃ1-3アルコキシカルボニル、ジＣ1-3アルキルアミノカルボニル、及び窒素原子を含む４から７員の飽和のヘテロシクリルカルボニルからなる群を示し、
    また、Ｃ1-3アルカンジイルの炭素原子の１つは、Ｃ3-6シクロアルカンジイル又は二価の４から６員の環状エーテルと置き換わってもよく、
    　Ｒ42は、水素原子又はＣ1-3アルキルを示し、
    　Ｗ2は、単結合又はＣ1-3アルカンジイルを示し、
    　上記式（β）中の環Ｂは、窒素原子を含む４から８員の飽和のヘテロ環を示し、
    　Ｗ3は、単結合又はＣ1-3アルカンジイルを示し、
    　環Ａは、
    　Ｃ3-8シクロアルキル、Ｃ3-8シクロアルケニル（該Ｃ3-8シクロアルキル及びＣ3-8シクロアルケニルは、置換基群α２から選ばれる１個の基で置換されてもよい。）、
    　アリール（該アリールは、置換基群α３から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
    　飽和のヘテロシクリル（該飽和のヘテロシクリルは、置換基群α４から選ばれる１個の基で置換されてもよい。）、又は
    　ヘテロアリール（該ヘテロアリールは、置換基群α５から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）を示し、
    　置換基群α２は、Ｃ1-6アルキル、アリール、及び窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルからなる群を示し、
    　置換基群α３は、ハロゲン原子、Ｃ1-6アルキル（該Ｃ1-6アルキルは、１個のヒドロキシ又はＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルキル、アリール、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、１個のＣ1-6アルコキシで置換されてもよい。）、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ、ヘテロアリールオキシ（該アリールオキシ及びヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、飽和のヘテロシクリルＣ1-3アルキル、及び窒素原子を含む４から８員の飽和のヘテロシクリルカルボニルからなる群を示し、
    　置換基群α４は、アリールＣ1-3アルキル、アリールカルボニル（該アリールカルボニルは、１個のＣ1-6アルコキシで置換されてもよい。）、アリールスルホニル（該アリールスルホニルは、１個のＣ1-6アルキル又はハロＣ1-6アルキルで置換されてよい。）、及びオキソからなる群を示し、
    　置換基群α５は、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、飽和のヘテロシクリルＣ1-3アルコキシ、及びオキソからなる群を示す。］
    で表される化合物又はその製薬学的に許容される塩。     Formula (I) below
    Figure JPOXMLDOC01-appb-C000001
     (I)

    [In the formula (I),
    R 1 represents a hydrogen atom or C 1-3 alkyl (the C 1-3 alkyl may be substituted with hydroxy);
    X represents the formula CR 2 or a nitrogen atom;
    R 2 represents a hydrogen atom, a halogen atom, C 1-3 alkyl, or C 1-3 alkoxy,
    R 3 represents a hydrogen atom, a halogen atom, C 1-3 alkyl, or C 1-3 alkoxy,
    Y represents a formula —CONR 41 —W 1 —, a formula —CONR 42 —W 2 —CO—, a structure represented by the following formula (β), a formula —CH 2 NHCO—, a formula —CH 2 OCH 2 —, or The formula —NHCOCH 2 —
    Figure JPOXMLDOC01-appb-C000002
     (Β)

    R 41 represents a hydrogen atom or C 1-3 alkyl,
    W 1 represents a single bond, C 1-3 alkanediyl, or the formula —CH 2 CH 2 O—,
    At this time, the C 1-3 alkanediyl may be substituted with 1 to 2 substituents selected from the same or different from the substituent group α1.
    Substituent group α1 is hydroxy, carbamoyl, C 1-3 alkyl (the C 1-3 alkyl may be substituted with one hydroxy or C 1-3 alkoxy), C 3-6 cycloalkyl, Aryl, heteroaryl (the heteroaryl may be substituted with one C 1-3 alkyl), C 1-3 alkoxycarbonyl, diC 1-3 alkylaminocarbonyl, and 4 containing a nitrogen atom Represents a group consisting of 7-membered saturated heterocyclylcarbonyl;
    Also, one of the carbon atoms of the C 1-3 alkanediyl may be replaced with C 3-6 cycloalkanediyl or a divalent 4- to 6-membered cyclic ether,
    R 42 represents a hydrogen atom or a C 1-3 alkyl,
    W 2 represents a single bond or C 1-3 alkanediyl,
    Ring B in the above formula (β) represents a 4- to 8-membered saturated heterocycle containing a nitrogen atom,
    W 3 represents a single bond or C 1-3 alkanediyl,
    Ring A is
    C 3-8 cycloalkyl, C 3-8 cycloalkenyl (the C 3-8 cycloalkyl and C 3-8 cycloalkenyl may be substituted with one group selected from the substituent group α2),
    Aryl (the aryl may be substituted with 1 to 2 groups selected from the same or different from substituent group α3);
    Saturated heterocyclyl (the saturated heterocyclyl may be substituted with one group selected from substituent group α4), or heteroaryl (the heteroaryl is the same or different from substituent group α5) And may be substituted with 1 to 2 groups
    Substituent group α2 represents a group consisting of C 1-6 alkyl, aryl, and a 4- to 8-membered saturated heterocyclylcarbonyl containing a nitrogen atom,
    Substituent group α3 is a halogen atom, C 1-6 alkyl (the C 1-6 alkyl may be substituted with 1 hydroxy or C 1-6 alkoxy), halo C 1-6 alkyl, aryl , C 1-6 alkoxy (the C 1-6 alkoxy may be substituted with one C 1-6 alkoxy), halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy, hetero Aryloxy (the aryloxy and heteroaryloxy may be substituted with 1 C 1-6 alkyl), saturated heterocyclyl C 1-3 alkyl, and a 4 to 8 membered saturated nitrogen atom Represents a group consisting of heterocyclylcarbonyl,
    Substituent group α4 is aryl C 1-3 alkyl, arylcarbonyl (the arylcarbonyl may be substituted with one C 1-6 alkoxy), arylsulfonyl (the arylsulfonyl is one C And optionally substituted with 1-6 alkyl or haloC 1-6 alkyl), and oxo
    Substituent Group α5 represents a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (said aryl may be substituted with one C 1-6 alkoxy. ), Saturated heterocyclyl, C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1-3 alkyl may be substituted with one halogen atom), C 1 -6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (the aryloxy may be substituted with one halogen atom or C 1-6 alkyl), heteroaryloxy ( The heteroaryloxy may be substituted with one C 1-6 alkyl.), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy is 1 may be substituted with pieces of C 1-6 alkyl.), saturated Heterocyclyl C 1-3 alkoxy, and shows the group consisting of oxo. ]
    Or a pharmaceutically acceptable salt thereof.
  2. 　環Ａが、
    　Ｃ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、前記置換基群α２から選ばれる１個の基で置換されてもよい。）、
    　フェニル（該フェニルは、前記置換基群α３から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
    　ジヒドロインデニル、
    　アゼチジニル［該アゼチジニルは、アリールスルホニル（該アリールスルホニルは、１個のＣ1-6アルキル又はハロＣ1-6アルキルで置換されてよい。）］、
    　ピペリジニル［該ピペリジニルは、アリールＣ1-3アルキル、アリールカルボニル（該アリールカルボニルは、１個のＣ1-6アルコキシで置換されてもよい。）、アリールスルホニル（該アリールスルホニルは、１個のＣ1-6アルキル又はハロＣ1-6アルキルで置換されてよい。）、及びオキソからなる群から選ばれる１個の基で置換されてもよい。］、
    　ピリジル［該ピリジルは、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、及び飽和のヘテロシクリルＣ1-3アルコキシからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］、
    　ピリミジニル［該ピリミジニルは、ハロゲン原子及びアリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）からなる群から選ばれる１個の基で置換されてもよい。］、
    　ピラゾリル（該ピラゾリルは、Ｃ1-6アルキル及びフェニルからなる群から選ばれる１個の基で置換されてもよい。）、
    　チアゾリル（該チアゾリルは、１個のＣ1-6アルキルで置換されてもよい。）、
    　ジヒドロピリジニル［該ジヒドロピリジニルは、Ｃ1-6アルキル、Ｃ3-8シクロアルキル、アリールＣ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、及びオキソからなる群から同一に又は異なって選ばれる１個の基で置換されてもよい。］、
    　ベンゾフラニル、
    　ジヒドロベンゾフラニル（該ジヒドロベンゾフラニルは、ハロゲン原子、Ｃ1-6アルキルからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
    　クロマニル、
    　ジヒドロピラノピリジニル、
    　ジヒドロフロピリジニル、
    　テトラヒドロキノリル、
    　テトラヒドロイソキノリル、
    　ジヒドロベンゾジオキシニル、
    　テトラヒドロトリアゾロアゼピニル
    である請求項１に記載の化合物又はその製薬学的に許容される塩。     Ring A is
    C 3-8 cycloalkyl (the C 3-8 cycloalkyl may be substituted with one group selected from the substituent group α2);
    Phenyl (the phenyl may be substituted with 1 to 2 groups selected from the same or different from the substituent group α3);
    Dihydroindenyl,
    Azetidinyl [wherein the azetidinyl is arylsulfonyl, which may be substituted with one C 1-6 alkyl or haloC 1-6 alkyl]],
    Piperidinyl [wherein the piperidinyl is aryl C 1-3 alkyl, arylcarbonyl (the arylcarbonyl may be substituted with one C 1-6 alkoxy), arylsulfonyl (the arylsulfonyl is one C Optionally substituted with 1-6 alkyl or haloC 1-6 alkyl), and one group selected from the group consisting of oxo. ],
    Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy). ), Saturated heterocyclyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (the aryloxy may be substituted with one halogen atom or C 1-6 alkyl) ), Heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy may be substituted with 1 C 1-6 alkyl.), And 1 to 2 groups selected identically or differently from the group consisting of saturated heterocyclyl C 1-3 alkoxy May be substituted. ],
    Pyrimidinyl [The pyrimidinyl may be substituted with one group selected from the group consisting of a halogen atom and aryl (the aryl may be substituted with one C 1-6 alkoxy). ],
    Pyrazolyl (which may be substituted with one group selected from the group consisting of C 1-6 alkyl and phenyl),
    Thiazolyl (which may be substituted with one C 1-6 alkyl),
    Dihydropyridinyl [wherein the dihydropyridinyl is C 1-6 alkyl, C 3-8 cycloalkyl, aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1- 3 alkyl may be substituted with one halogen atom.), and may be substituted with one group selected identical to or different from the group consisting of oxo. ],
    Benzofuranyl,
    Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom, C 1-6 alkyl, the same or different),
    Chromanil,
    Dihydropyranopyridinyl,
    Dihydrofuropyridinyl,
    Tetrahydroquinolyl,
    Tetrahydroisoquinolyl,
    Dihydrobenzodioxinyl,
    The compound according to claim 1, which is tetrahydrotriazoloazepinyl, or a pharmaceutically acceptable salt thereof.
  3. 　Ｘが、式ＣＲ2であり、
    　Ｒ2が、水素原子又はメトキシであり、
    　Ｙが、式-ＣＯＮＲ41-Ｗ1-であり、
    　Ｒ41が、水素原子であり、
    　Ｗ1が、Ｃ1-3アルカンジイルであり、
    　環Ａが、
    　フェニル（該フェニルは、前記置換基群α３から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
    　ジヒドロインデニル、
    　ピリジル［該ピリジルは、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル、アリール（該アリールは、１個のＣ1-6アルコキシで置換されてもよい。）、飽和のヘテロシクリル、Ｃ1-6アルコキシ、ハロＣ1-6アルコキシ、Ｃ3-8シクロアルコキシ、アリールオキシ（該アリールオキシは、１個のハロゲン原子又はＣ1-6アルキルで置換されてもよい。）、ヘテロアリールオキシ（該ヘテロアリールオキシは、１個のＣ1-6アルキルで置換されてもよい。）、Ｃ3-8シクロアルキルＣ1-3アルコキシ（該Ｃ3-8シクロアルキルＣ1-3アルコキシは、１個のＣ1-6アルキルで置換されてもよい。）、及び飽和のヘテロシクリルＣ1-3アルコキシからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。］、
    　ジヒドロピリジニル［該ジヒドロピリジニルは、Ｃ1-6アルキル、Ｃ3-8シクロアルキル、アリールＣ3-8シクロアルキルＣ1-3アルキル、アリールＣ1-3アルキル（該アリールＣ1-3アルキルは、１個のハロゲン原子で置換されてもよい。）、及びオキソからなる群から同一に又は異なって選ばれる１個の基で置換されてもよい。］、
    　ベンゾフラニル、
    　ジヒドロベンゾフラニル（該ジヒドロベンゾフラニルは、ハロゲン原子、Ｃ1-6アルキルからなる群から同一に又は異なって選ばれる１から２個の基で置換されてもよい。）、
    　クロマニル、
    　ジヒドロピラノピリジニル、
    　ジヒドロフロピリジニル、
    　テトラヒドロキノリル、
    　テトラヒドロイソキノリル、
    　ジヒドロベンゾジオキシニル
    である請求項１又は２に記載の化合物又はその製薬学的に許容される塩。     X is the formula CR 2
    R 2 is a hydrogen atom or methoxy;
    Y is of the formula -CONR 41 -W 1-
    R 41 is a hydrogen atom,
    W 1 is C 1-3 alkanediyl,
    Ring A is
    Phenyl (the phenyl may be substituted with 1 to 2 groups selected from the same or different from the substituent group α3);
    Dihydroindenyl,
    Pyridyl [wherein the pyridyl is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, aryl (the aryl may be substituted with one C 1-6 alkoxy). ), Saturated heterocyclyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 3-8 cycloalkoxy, aryloxy (the aryloxy may be substituted with one halogen atom or C 1-6 alkyl) ), Heteroaryloxy (the heteroaryloxy may be substituted with one C 1-6 alkyl), C 3-8 cycloalkyl C 1-3 alkoxy (the C 3-8 cycloalkyl C 1-3 alkoxy may be substituted with 1 C 1-6 alkyl.), And 1 to 2 groups selected identically or differently from the group consisting of saturated heterocyclyl C 1-3 alkoxy May be substituted. ],
    Dihydropyridinyl [wherein the dihydropyridinyl is C 1-6 alkyl, C 3-8 cycloalkyl, aryl C 3-8 cycloalkyl C 1-3 alkyl, aryl C 1-3 alkyl (the aryl C 1- 3 alkyl may be substituted with one halogen atom.), and may be substituted with one group selected identical to or different from the group consisting of oxo. ],
    Benzofuranyl,
    Dihydrobenzofuranyl (the dihydrobenzofuranyl may be substituted with 1 to 2 groups selected from the group consisting of a halogen atom, C 1-6 alkyl, the same or different),
    Chromanil,
    Dihydropyranopyridinyl,
    Dihydrofuropyridinyl,
    Tetrahydroquinolyl,
    Tetrahydroisoquinolyl,
    The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is dihydrobenzodioxinyl.
  4. 　請求項１から３のいずれかに記載の化合物又はその製薬学的に許容される塩を有効成分として含有する医薬。 A medicament comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  5. 　請求項１から３のいずれかに記載の化合物又はその製薬学的に許容される塩を有効成分として含有するＰＨＤ２阻害剤。 A PHD2 inhibitor comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  6. 　請求項１から３のいずれかに記載の化合物又はその製薬学的に許容される塩を有効成分として含有するＥＰＯ産生促進剤。 An EPO production promoter containing the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  7. 　請求項１から３のいずれかに記載の化合物又はその製薬学的に許容される塩を有効成分として含有する貧血の予防薬又は治療薬。
          A prophylactic or therapeutic agent for anemia comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
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