WO2015163472A1 - Composé hétéroaryle substitué par un groupe triazolyle - Google Patents

Composé hétéroaryle substitué par un groupe triazolyle 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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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

　La présente invention concerne un composé représenté par la formule (I), ayant une action inhibitrice de PHD-2, ou un sel acceptable d'un point de vue pharmacologique de ce composé. (I) (Dans la formule (I), R1 représente un atome d'hydrogène ou un groupe alkyle en C1-3 en option substitué ; X représente la formule CR2 ou un atome d'azote ; R3 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1-3 ou alcoxy en C1-3 ; Y représente la formule -CONR41-W1-, la formule -CONR42-W2-CO-, une structure représentée par la formule (β), la formule -CH2NHCO-, la formule -CH2OCH2- ou la formule -NHCOCH2- ; et le noyau A représente un groupe cycloalkyle en C3-8 en option substitué, cycloalcényle en C3-8 en option substitué, aryle en option substitué, hétérocyclyle saturé en option substitué ou hétéroaryle en option substitué.)
PCT/JP2015/062612 2014-04-25 2015-04-24 Composé hétéroaryle substitué par un groupe triazolyle WO2015163472A1 (fr)

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CN111470994A (zh) * 2019-10-31 2020-07-31 上海开荣化工科技有限公司 对氯苯甘氨酸的制备方法
EP3709986A4 (fr) * 2017-11-14 2021-05-26 Merck Sharp & Dohme Corp. Nouveaux composés biaryles substitués utilisés en tant qu'inhibiteurs de l'indoléamine 2,3-dioxygénase (ido)
US11434249B1 (en) 2018-01-02 2022-09-06 Seal Rock Therapeutics, Inc. ASK1 inhibitor compounds and uses thereof

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