WO2016104451A1 - Novel heterocyclic derivative - Google Patents

Novel heterocyclic derivative Download PDF

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Publication number
WO2016104451A1
WO2016104451A1 PCT/JP2015/085718 JP2015085718W WO2016104451A1 WO 2016104451 A1 WO2016104451 A1 WO 2016104451A1 JP 2015085718 W JP2015085718 W JP 2015085718W WO 2016104451 A1 WO2016104451 A1 WO 2016104451A1
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Prior art keywords
group
triazolo
pyridine
amino
anemia
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PCT/JP2015/085718
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French (fr)
Japanese (ja)
Inventor
隆弘 佐藤
幸帆 永山
泰裕 吉野
勗 井上
宏茂 加藤
淳一郎 雨田
真里 稲葉
典子 矢本
哲也 谷口
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株式会社富士薬品
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Publication of WO2016104451A1 publication Critical patent/WO2016104451A1/en

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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/47—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
    • A61K31/435—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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel heterocyclic derivative having an erythropoietin (EPO) production promoting action.
  • EPO erythropoietin
  • EPO is a glycoprotein hormone consisting of 165 amino acids produced mainly in the kidney and partly in the liver, and promotes differentiation induction of erythroid stem cells (progenitor cells) to produce mature erythrocytes.
  • erythroid stem cells progenitor cells
  • HIF hypoxia-inducible factor
  • HIF- ⁇ ⁇ subunit
  • HIF- ⁇ ⁇ subunit
  • PHD prolyl hydroxylase
  • Non-patent Documents 2 and 3 It has been reported that PHD has 1 to 3 isoforms, and each has different intracellular localization, oxygen partial pressure response, reactivity to HIF isoform, etc. (Non-patent Documents 2 and 3). HIF- ⁇ also has several isoforms. Although HIF-1 ⁇ and HIF-2 ⁇ are very similar in structure, their expression levels and localization are different (Non-patent Document 3). HIF has also been suggested to affect hypoxia-inducible factors other than EPO (glucose transporters 1 and 3, lactate dehydrogenase, hepcidin, etc.) (Non-Patent Documents 3 and 4). It is not fully understood.
  • HIF- ⁇ is stabilized without being degraded by PHD, and moves from the cytoplasm into the nucleus to form a dimer with HIF- ⁇ .
  • the heterodimer of HIF- ⁇ and ⁇ binds to the hypoxia responsive element sequence of the EPO gene to enhance transcription and promote EPO production. It has been confirmed in mammals such as rodents, monkeys, and humans that stabilization of HIF based on PHD inhibition promotes EPO production and increases erythrocytes with increasing EPO concentration.
  • EPO production promoter by PHD inhibition Has been shown to be useful as a therapeutic agent for anemia (Patent Documents 1, 2, 3 and Non-Patent Documents 5, 6).
  • EPO production decreases in the kidney due to kidney damage or the like
  • the EPO concentration in the blood decreases
  • red blood cell production is suppressed
  • anemia renal anemia
  • acute kidney diseases such as renal failure
  • renal anemia with a high probability
  • anemia resulting from a decrease in EPO production is also known regardless of kidney damage or the like.
  • the main treatments for these diseases include anemia treatment in patients with chronic kidney disease (CKD) using genetically modified human EPO preparation (hereinafter referred to as EPO preparation), treatment of self-accumulation and premature infant anemia, AIDS and chemistry. Treatment of anemia for cancer patients undergoing therapy is known.
  • EPO preparation genetically modified human EPO preparation
  • ischemic heart disease such as angina pectoris, myocardial infarction
  • ischemic cerebrovascular disorder cerebral embolism, cerebral infarction, etc.
  • ischemic kidney disease such as ischemic renal failure
  • Ischemic diseases such as lower limb ischemia (obstructive arteriosclerosis, Buerger's disease, diabetic gangrene, etc.), ischemic enteritis (such as ischemic colitis), and metabolic diseases such as fatty liver are also low in the target organ or tissue. Under the oxygen environment, stabilization of HIF based on PHD inhibition is expected to have a preventive or therapeutic effect on these diseases (Non-patent Documents 7 and 8).
  • the above-mentioned EPO preparation has drastically reduced the number of patients who require regular blood transfusion, has improved various symptoms associated with anemia, and has greatly contributed to the improvement of QOL (Quality of life) of anemia patients.
  • the EPO preparation is a glycoprotein, the structure of the sugar chain attached to the EPO surface is complex, and its glycosylation is extensive and diverse. It was difficult to produce human serum EPO with good reproducibility.
  • it since it is a biologic, it is expensive, and it is a burden on the patient from the viewpoint of medical costs.
  • the route of administration is injection, a method and / or compound for increasing endogenous EPO that can be administered orally is also desired from the viewpoint of preventing medical accidents and reducing patient burden.
  • Patent Document 1 triazolopyridine derivatives
  • Patent Documents 4 and 5 pyrimidine derivatives
  • isoquinoline derivatives Patent Documents 3 and 6
  • bicyclic pyridine derivatives Patent Document 7)
  • Bicyclic heteroaromatic N-substituted glycine derivatives Patent Document 8 and the like have been developed.
  • JP 2011-37841 A JP 2006-137763 A Special table 2008-546644 JP2011-88840 Special table 2009-541351 JP2011-148810A Special table 2009-541486 Special table 2009-537558
  • An object of the present invention is to provide a novel compound having an EPO production promoting action, and is useful for the prevention or treatment of a symptom of a disease in which a hypoxic environment occurs in a target organ or tissue, particularly for the prevention or treatment of anemia. Providing a good medicine.
  • the present invention provides the following [1] to [10].
  • X represents an oxygen atom, an imino group, a sulfur atom, sulfinyl or sulfonyl
  • R 1 , R 2 and R 3 each independently represents a hydrogen atom or a C 1 -C 6 alkyl group
  • R 4 represents a hydrogen atom, a C 1 -C 6 alkyl group or an arylalkyl group
  • R 5 is an alkyl group which may be substituted with a group selected from the substituent group, an alkenyl group which may be substituted with a group selected from the substituent group, or a group selected from the substituent group.
  • the substituent group includes an aryl group which may have 1 to 7 substituents (the substituent on the aryl group includes a C 1 -C 6 alkyl group, a trifluoromethyl group, a halogen atom, a methoxy group, A heteromethoxy group which may have 1 to 7 substituents (the substituent on the heteroaryl group includes a C 1 -C 6 alkyl group, trifluoro; Methyl group, halogen atom, methoxy group, trifluoromethoxy group, cyano group or phenyl group), C 1 -C 6 alkyl group (in the case of C 3 -C 6 alkyl group, carbon atoms are bonded to each other) A 3- to 6-membered saturated ring may
  • a pharmaceutical composition comprising the compound according to [1] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a medicament comprising the compound according to [1] above or a pharmaceutically acceptable salt thereof as an active ingredient.
  • An EPO production promoter comprising the compound according to [1] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a method for promoting EPO production comprising administering the compound according to [1] or a pharmaceutically acceptable salt thereof.
  • anemia self-blood storage, premature infant anemia, AIDS or cancer receiving chemotherapy in a patient with chronic renal failure, characterized by administering the compound according to [1] or a pharmaceutically acceptable salt thereof
  • a method for preventing and / or treating anemia selected from patient anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia and megaloblastic anemia.
  • the compound of the present invention Since the compound of the present invention has a sustained and superior EPO production promoting effect than the compound described in Patent Document 1, it has undergone anemia, self-accumulation and premature infant anemia, AIDS and chemotherapy in patients with chronic renal failure. It is useful as a prophylactic and / or therapeutic agent for anemia such as anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, megaloblastic anemia in cancer patients.
  • alkyl group means a saturated hydrocarbon chain that may be linear, branched, cyclic, or a combination thereof.
  • a C 1 -C 18 linear or branched alkyl group, a C 3 -C 18 cyclic alkyl group, or a combination thereof is preferred, and a C 1 -C 4 linear or branched alkyl group, C 3 A —C 12 cyclic alkyl group or a combination thereof is more preferred.
  • alkenyl group means an unsaturated hydrocarbon chain having a double bond, which may be linear, branched, cyclic, or a combination thereof.
  • n-propenyl, n-butenyl, n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl and the like can be mentioned.
  • a C 2 -C 18 linear or branched alkenyl group is preferable, and a C 2 -C 14 linear or branched alkenyl group is more preferable.
  • alkynyl group described in the present specification means an unsaturated hydrocarbon chain having a triple bond which may be linear, branched, cyclic, or a combination thereof.
  • n-pentynyl, n-hexynyl and the like can be mentioned.
  • a C 2 -C 8 linear or branched alkynyl group is preferred.
  • the “aryl group” described in the present specification is a monocyclic, bicyclic or tricyclic aryl group, and includes an aryl group in which some of the rings have an aromatic ring.
  • a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms is used.
  • Specific examples include phenyl group, naphthyl group, tetrahydronaphthyl group, indenyl group, indanyl group, phenanthrenyl group, fluorenyl group and the like.
  • heteroaryl group is a monocyclic, bicyclic or tricyclic heteroaryl group, for example, a monocyclic ring having 1 to 4 heteroatoms (nitrogen atom, oxygen atom or sulfur atom) , Bicyclic or tricyclic heteroaryl groups.
  • Specific examples include pyrrolyl, furanyl, thienyl, pyridyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazyl, quinolyl, isoquinolyl, quinazolyl, indolyl, benzothiophenyl, benzofuranyl.
  • benzoimidazolyl group benzoxazolyl group, benzothiazolyl group, benzodioxanyl group, dibenzothiophenyl group, dibenzofuranyl group, carbazolyl group and the like.
  • the substituent group includes an aryl group which may have 1 to 7 substituents (the substituent on the aryl group includes a C 1 -C 6 alkyl group, a halogen atom, a methoxy group, A heteromethoxy group optionally having 1 to 7 substituents (a substituent on the heteroaryl group includes a C 1 -C 6 alkyl group, a halogen atom) , A methoxy group, a trifluoromethoxy group, a cyano group and a phenyl group), a C 1 -C 6 alkyl group (in the case of a C 3 -C 6 alkyl group, carbon atoms are bonded to each other to form a 3- to 6-membered saturated group) A C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, an arylalkyl group, a C 2 -C 6 alkoxycarbonyl group, a halogen atom
  • X is preferably an oxygen atom, a sulfur atom, sulfinyl or sulfonyl, more preferably an oxygen atom or a sulfur atom.
  • R 1 , R 2 and R 3 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group, and among these, a hydrogen atom is more preferred.
  • C 1 -C 6 alkyl group means a saturated hydrocarbon chain that may be linear, branched, cyclic, or a combination thereof. Preferably, it is a C 1 -C 6 linear or branched alkyl group or a C 3 -C 6 cyclic alkyl group.
  • Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • R 4 represents a hydrogen atom, a C 1 -C 6 alkyl group or an arylalkyl group, and more preferably a hydrogen atom.
  • the “arylalkyl group” is a group in which a C 1 -C 6 alkyl group is bonded to the aryl group, and examples thereof include a C 6 -C 14 aryl-C 1 -C 6 alkyl group. Specifically, a phenyl-C 1 -C 6 alkyl group is preferable, and a benzyl group and a phenethyl group are more preferable.
  • Examples of the alkyl group, alkenyl group, aryl group or heteroaryl group represented by R 5 include a C 1 -C 18 linear or branched alkyl group, a C 3 -C 8 cyclic alkyl group, or a combination thereof.
  • Monocyclic, bicyclic or tricyclic heteroaryl groups having 1 heteroatom (nitrogen atom, oxygen atom or sulfur atom) are preferred.
  • the substituent group which can be substituted with 1 to 7 substituents for R 5 includes a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms which may have 1 to 7 substitutions (on the aryl group).
  • the substituent is a C 1 -C 6 alkyl group, a trifluoromethyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group or a phenyl group) and may have 1 to 7 substituents.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • aryl group examples include phenyl, naphthyl, tetrahydronaphthyl, indanyl, phenanthrenyl, fluorenyl and the like.
  • C 1 -C 6 alkyl group examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, And cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • heteroaryl group examples include pyrrolyl, furanyl, thiophenyl, pyridyl, quinolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzothiazolyl, pyrazyl, benzodioxanyl and the like.
  • alkenyl group examples include vinyl, propenyl, butenyl and the like.
  • C 2 -C 6 alkynyl group examples include ethynyl, propynyl, pentynyl and the like.
  • arylalkyl group examples include benzyl.
  • Examples of the “C 2 -C 6 alkoxycarbonyl group” include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and the like.
  • Examples of the “C 1 -C 6 halogenated alkyl group” include trifluoromethyl, trifluoroethyl and the like.
  • Examples of the “C 1 -C 6 alkoxy group” include methoxy, ethoxy, isopropoxy, t-butoxy and the like.
  • Examples of the “C 1 -C 6 halogenated alkoxy group” include trifluoromethoxy, trifluoroethoxy and the like.
  • Examples of the “aryloxy group, carbamoyl group” include phenoxy, t-butoxycarbamoyl, benzylcarbamoyl and the like.
  • Examples of the “C 2 -C 6 alkylcarbonyl group” include methylcarbonyl and the like.
  • Examples of the “C 1 -C 6 alkylamino group” include dimethylamino, benzylamino and the like.
  • Examples of the “C 1 -C 6 alkylaminocarbonyl group” include dimethylaminocarbonyl and the like.
  • Examples of the “C 1 -C 6 alkylcarbonylamino group” include acetylamino and the like.
  • Examples of the “arylamino group” include phenylamino, diphenylamino and the like.
  • Examples of the “C 1 -C 6 alkylsulfonyl group” include methanesulfonyl and the like.
  • Examples of the “C 1 -C 6 halogenated alkylsulfonyl group” include trifluoromethanesulfonyl and the like.
  • Examples of the “arylsulfonyl group” include phenylsulfonyl and the like.
  • Examples of the “C 1 -C 6 alkylsulfanyl group” include methylsulfanyl, isopropylsulfanyl and the like.
  • C 1 -C 6 halogenated alkylsulfanyl group examples include trifluoromethanesulfanyl and the like.
  • arylsulfanyl group examples include phenylsulfanyl and the like.
  • a preferred embodiment of the general formula (1) is a compound comprising a combination of each of the above-mentioned preferred groups.
  • the compounds described in the examples, their pharmaceutically acceptable salts, or their hydrates, or solvents Japanese products are listed.
  • the compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a geometric isomer or tautomer based on a double bond depending on the type of substituent.
  • optical isomers and diastereomers may exist due to the presence of an asymmetric carbon atom.
  • all isolated isomers or mixtures thereof are included.
  • the production method of the compound of the present invention and pharmaceutically acceptable salts, hydrates and solvates can be produced by various known techniques.
  • the functional group is replaced with an appropriate protective group at the stage of the raw material or intermediate, which is effective in terms of production technology.
  • functional groups include amino groups, hydroxy groups, and carboxy groups.
  • the desired compound can be obtained by removing the protecting group at the appropriate time in each production stage.
  • protective group types and desorption methods include the methods described in Protective Groups In Organic Synthesis: Third Edition (by Greene, Wuts).
  • representative production methods of the compound (1) of the present invention will be described.
  • the production method of the compound of the present invention is not particularly limited, and can be produced, for example, according to the following production method.
  • Y represents a protecting group for a carboxyl group such as a methyl group or a tert-butyl group, and other symbols are as defined above.
  • a compound (3) can be obtained by introduce
  • X is S
  • the compound (2) is heated under a palladium catalyst such as palladium acetate, tris (dibenzylideneacetone) dipalladium, xanthophos, 1,1-bis (di-tert-butylphosphino) ferrocene under heating conditions.
  • a palladium catalyst such as palladium acetate, tris (dibenzylideneacetone) dipalladium, xanthophos, 1,1-bis (di-tert-butylphosphino) ferrocene under heating conditions.
  • a ligand such as bis [2- (diphenylphosphino) phenyl] ether
  • a base such as diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, potassium t-butoxide
  • Compound (3) can be obtained by reacting with thiol (R 5 SH) in a solvent such as N, N-dimethylformamide, toluene, cyclopentyl methyl ether and the like.
  • the compound (2) is subjected to a copper catalyst such as copper iodide, copper bromide, copper chloride, copper oxide, ethyl 2-cyclohexanone carboxylate, 1,10-phenanthroline under low temperature to warming conditions. , Dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, 1,4-dioxane, toluene, etc. in the presence of a ligand such as (2-pyridyl) acetone and picolinic acid and a base such as potassium carbonate, cesium carbonate and potassium phosphate
  • a ligand such as (2-pyridyl) acetone and picolinic acid
  • a base such as potassium carbonate, cesium carbonate and potassium phosphate
  • the compound (3) can be obtained by reacting with phenol (R 5 OH) in the solvent.
  • Second step Compound (4) can be obtained by deprotecting the t-butoxycarbonyl group of compound (3) according to a conventional method.
  • the compound (3) is hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, dimethyl under low temperature to warming conditions.
  • Compound (4) can be obtained by reacting with an acid such as aluminum trichloride, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid or trifluoroacetic acid.
  • Compound (4) can be obtained by reacting with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide in a mixed solvent.
  • Compound (5) can be obtained by condensing compound (4) with a glycine derivative represented by H 2 NCH 2 COOY according to a conventional method.
  • the compound (4) is subjected to dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole in a solvent such as N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene and the like under low temperature to warming conditions.
  • a condensing agent such as diphenylphosphoryl azide and optionally N-hydroxysuccinimide, 1-hydroxybenzotriazole, dimethylaminopyridine and the like
  • potassium carbonate if desired, sodium bicarbonate, cesium carbonate
  • triethylamine, diisopropylethylamine, morpholine a base such as
  • Compound (1) can be obtained by deprotecting the protecting group for the benzyl group and carboxyl group of compound (5) according to a conventional method.
  • Y is a methyl group
  • the compound (5) is reacted in an acid solvent such as trifluoroacetic acid under heating conditions in the presence of anisole, thioanisole, dimethyl sulfide, etc.
  • the group can be deprotected.
  • the compound (5) is heated at room temperature to warming, in a hydrogen atmosphere, at normal pressure to under pressure, hexane, methanol, ethanol, 2-propanol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethyl.
  • a catalyst such as palladium carbon, palladium hydroxide, platinum oxide, platinum carbon, Raney nickel in a single or mixed solvent such as acetamide, ethyl acetate, acetic acid, water, etc.
  • a mixed solvent of water and a solvent such as methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, acetonitrile under low temperature to warming conditions
  • the compound (1) can be obtained by reacting with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • First step When X is S, compound (2) can be reacted with sodium sulfide or the like in a solvent such as N, N-dimethylformamide under low temperature to warming conditions to obtain compound (6). it can.
  • X When X is O, the compound (2) is reacted with a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution or the like in a solvent such as diethylene glycol monoethyl ether under low temperature to warming conditions to obtain the compound (6).
  • a solvent such as N, N-dimethylformamide
  • Second Step When X is S and O, compound (6) is mixed with azodicarboxylic acid ester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, triphenylphosphine, alcohol (R 5 OH) in a solvent such as tetrahydrofuran or toluene. ) Can be reacted to give compound (3).
  • azodicarboxylic acid ester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, triphenylphosphine, alcohol (R 5 OH)
  • R 5 OH a solvent
  • the compound (6) is subjected to low temperature to warming conditions such as triethylamine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, potassium t-butoxide, sodium hydride and the like.
  • the type of the salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • Examples of the pharmaceutically acceptable hydrate of the compound of the general formula (1) include 1/2 hydrate, monohydrate, dihydrate and the like. Moreover, since the compound of General formula (1) may exist as a solvate, a solvate is also included.
  • the compound represented by the general formula (1) of the present invention produced as described above is in a free state or as a salt thereof, which is extraction, concentration, distillation, crystallization, filtration, recrystallization, which is a normal chemical operation. It can be isolated and purified by various chromatographies.
  • compound (1) contains an optical isomer, a stereoisomer, or a regioisomer, each can be isolated by a fractional recrystallization method, a chiral column method, a diastereomer method, or the like.
  • anemia self-blood storage, premature infant anemia in patients with chronic renal failure
  • anemia such as anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, megaloblastic anemia, etc. in cancer patients undergoing chemotherapy It is.
  • a pharmaceutical composition comprising a compound represented by the general formula (1) or a pharmaceutically acceptable salt, hydrate or solvate thereof is carried out in the form of tablets, pills, capsules, granules, powders, liquids Oral administration, etc., or intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalation Any form of parenteral administration by an agent or the like may be used.
  • the kind of additive for the preparation is pharmaceutically acceptable
  • the carrier is not particularly limited as long as it is a carrier, excipient, lubricant, coating agent, sugar coating, wetting agent, binder, disintegrant, solvent, solubilizer, solubilizer, solubilizer, Suspending agents, dispersing agents, emulsifiers, surfactants, tonicity agents, buffers, pH regulators, soothing agents, preservatives, preservatives, stabilizers, antioxidants, coloring agents, sweeteners, etc. It can be used alone or in appropriate combination.
  • the dose and frequency of administration of the compound of the present invention or the pharmaceutical composition containing the compound can be appropriately selected according to symptoms, age, sex, dosage form, type of concomitant drug, etc., but usually 0.1 to 1000 mg / day / person
  • the dose can be administered in the range of 1 to 500 mg / day / person once a day or divided into several times.
  • the pharmaceutical composition of the present invention may be used not only alone but also in combination with other drugs having the same drug effect and / or other drugs having another drug effect.
  • NMR showed a 270 MHz nuclear magnetic resonance spectrum
  • TMS tetramethylsilane
  • MS showed mass spectrometry
  • ESI electrospray ionization method
  • Reference Example 1 7-benzyloxy-5-phenylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester benzenethiol (54 mg), 7-benzyloxy-5 -Iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg), tris (dibenzylideneacetone) dipalladium (10 mg), xanthophos (13 mg), N, N-diisopropylethylamine (120 mg) was mixed in a dioxane solvent (2.0 mL), and heated and stirred at 100 ° C.
  • Reference Example 2 7-Benzyloxy-5-phenylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid
  • the compound (484 mg) obtained in Reference Example 1 was dissolved in toluene (3. 8 mL) and ethyl acetate (1.2 mL) were dissolved, and methanesulfonic acid (429 mg) dissolved in ethyl acetate (0.5 mL) was added over 10 minutes at room temperature. After stirring at room temperature for 3 hours, the precipitated crystals were collected by filtration.
  • Example 1 Methyl [(7-benzyloxy-5-phenylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetate
  • Compound (309 mg) obtained in Reference Example 2 ) was dissolved in DMF (3.0 mL), and glycine methyl ester hydrochloride (113 mg), 1-hydroxybenzotriazole (138 mg) and triethylamine (99 mg) were added at room temperature.
  • To this mixture was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (173 mg), and the mixture was stirred overnight at room temperature.
  • Example 2 Methyl [(7-hydroxy-5-phenylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetate
  • Example 3 [(7-Hydroxy-5-phenylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid
  • the compound (210 mg) obtained in Example 2 was obtained.
  • the suspension was suspended in isopropyl alcohol (4.0 mL), 4 M aqueous lithium hydroxide solution (0.6 mL) was added, and the mixture was heated with stirring at 70 ° C. for 2 hours. After completion of the reaction, the reaction solution was neutralized with 6M hydrochloric acid (0.4 mL) and stirred while gradually cooling. When crystals began to precipitate, water (2.0 mL) was added and collected by filtration to obtain the title compound (189 mg).
  • Reference example 3 ⁇ [7-benzyloxy-5- (3,4-dichlorophenoxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester copper bromide ( 14 mg), ethyl 2-cyclohexanonecarboxylate (36 mg) and cesium carbonate (684 mg) were mixed in DMSO (3 mL) and stirred at room temperature for 30 minutes. 3,4-Dichlorophenol (99 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (452 mg) were added to DMSO (5 mL).
  • Example 4 ⁇ [7-Benzyloxy-5- (3,4-dichlorophenoxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid t-butyl ester Reference The compound (377 mg) obtained in Example 3 was converted to a carboxylic acid in the same manner as in Reference Example 2, and then the title compound (183 mg) was obtained in the same manner as in Example 1 using glycine t-butyl ester hydrochloride. .
  • Example 5 ⁇ [5- (3,4-Dichlorophenoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid obtained in Example 4
  • the compound (183 mg) was dissolved in trifluoroacetic acid (2 mL), thioanisole (83 mg) was added, and the mixture was stirred at 80 ° C. for 2 hr.
  • the solvent was distilled off under reduced pressure, and methanol (0.5 mL) and water (2 mL) were added.
  • Example 6 ⁇ [5- (3,5-Dimethylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3,5-dimethyl Benzenethiol (182 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (500 mg) were used in Reference Example 1 and Example 4. In the same manner as in 5, the title compound (160 mg) was obtained.
  • Example 7 ⁇ [5- (2,3-Dimethylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,3-dimethyl Benzenethiol (138 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (226 mg) were used in Reference Example 1 and Example 4. In the same manner as in 5, the title compound (55 mg) was obtained.
  • Example 8 ⁇ [5- (3-Fluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-fluorobenzenethiol (62 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg), Reference Examples 1, 2, and Examples 1-3 In the same manner as the above, the title compound (160 mg) was obtained.
  • Example 9 ⁇ [5- (3,5-Difluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3,5-difluoro Reference Examples 1 and 2 were carried out using benzenethiol (65 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg). In the same manner as in Examples 1 to 3, the title compound (85 mg) was obtained.
  • Example 10 ⁇ [5- (3,4-Difluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3,4-difluoro Benzenethiol (77 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) were used in Reference Example 1 and Example 4. In the same manner as in 5, the title compound (55 mg) was obtained.
  • Example 11 ⁇ [5- (3,5-Dichlorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3,5-dichlorobenzene Thiol (83 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (199 mg) were used as Reference Examples 1, 2, and Examples. The title compound (112 mg) was obtained in the same manner as in 1-3.
  • Example 12 ⁇ [7-Hydroxy-5- (4-trifluoromethoxyphenylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 4-trifluoromethoxy Reference Examples 1, 2 were carried out using benzenethiol (86 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg). In the same manner as in Examples 1 to 3, the title compound (107 mg) was obtained.
  • Example 13 ⁇ [5- (biphenyl-3-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-phenylbenzenethiol ( 104 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg). In the same manner as in 3, the title compound (99 mg) was obtained.
  • Example 14 ⁇ [5- (2-Chloro-5-fluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-chloro Reference Example 1 was prepared using -5-fluorobenzenethiol (93 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (226 mg). 2, In the same manner as in Examples 1 to 3, the title compound (72 mg) was obtained.
  • Example 15 ⁇ [5- (3-Chloro-5-fluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-chloro Reference Example 1 -5-fluorobenzenethiol (85 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) 2. In the same manner as in Examples 1 to 3, the title compound (30 mg) was obtained.
  • Example 16 ⁇ [5- (3-Chloro-5-methylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-chloro Reference Example 1 -5-methylbenzenethiol (85 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) 2. In the same manner as in Examples 1 to 3, the title compound (104 mg) was obtained.
  • Example 17 ⁇ [5- (3-Fluoro-5-methylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-fluoro Reference Example 1 using -5-methylbenzenethiol (71 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (201 mg) 2, In the same manner as in Examples 1 to 3, the title compound (103 mg) was obtained.
  • Example 18 ⁇ [5- (3-Fluoro-5-trifluoromethylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3 -Fluoro-5- (trifluoromethyl) benzenethiol (72 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester ( 166 mg) in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3, to obtain the title compound (87 mg).
  • Example 19 ( ⁇ 5- [3-Chloro-5- (trifluoromethyl) phenylsulfanyl] -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl ⁇ amino) Acetic acid
  • the title compound (48 mg) was obtained.
  • Example 20 ⁇ [5- (2,3-Dimethylphenoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,3-dimethylphenol (119 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (400 mg), Reference Example 3, Example 4 In the same manner as in 5, the title compound (125 mg) was obtained.
  • Example 21 ⁇ [5- (3,5-dichlorophenoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3,5-dichlorophenol Reference Example 3, Example 4 using (72 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (238 mg). In the same manner as in 5, the title compound (42 mg) was obtained.
  • Example 22 ⁇ [5- (biphenyl-3-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-phenylphenol (135 mg) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) as in Reference Example 3, Examples 4 and 5. To give the title compound (75 mg).
  • Example 23 ⁇ [5- (3-Chloro-4-fluorophenoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-chloro- Reference Example 3 was carried out using 4-fluorophenol (110 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (226 mg). In the same manner as in Examples 4 and 5, the title compound (90 mg) was obtained.
  • Example 24 ⁇ [5- (4-Chloro-2-methylphenoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 4-chloro- Reference Example 3 using 2-methylphenol (113 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Examples 4 and 5, the title compound (30 mg) was obtained.
  • Example 25 ⁇ [5- (4-Fluoro-3-trifluoromethylphenoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 4- Using fluoro-3-trifluoromethylphenol (144 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Reference Example 3 and Examples 4 and 5, the title compound (86 mg) was obtained.
  • Example 26 ⁇ [7-hydroxy-5- (naphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 1-naphthalenethiol (99 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg), Reference Examples 1, 2, and Examples 1-3 In the same manner as the above, the title compound (31 mg) was obtained.
  • Example 27 ⁇ [5- (4-Chloronaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 4-chloro Reference Example 4 was conducted using 1-naphthol (730 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (304 mg). In the same manner as in Example 19, the title compound (50 mg) was obtained.
  • Example 28 ⁇ [7-Hydroxy-5- (naphthalen-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 1-naphthol (192 mg) and 7-Benzyloxy-5-iodo [1,2,4] triazolo “1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) was prepared in the same manner as in Reference Example 3 and Examples 4 and 5. To give the title compound (86 mg).
  • Example 29 ⁇ [7-Hydroxy-5- (5,6,7,8-tetrahydronaphthalen-1-ylsulfanyl) [1,2,4] -triazolo [1,5- ⁇ ] pyridine-8-carbonyl Amino ⁇ acetic acid 5,6,7,8-tetrahydronaphthalene-1-thiol (220 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carvone The title compound (215 mg) was obtained using acid t-butyl ester (500 mg) in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
  • Example 30 ⁇ [7-Hydroxy-5- (indan-4-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid
  • Reference Example 7 Reference example of synthesized indan-4-thiol (100 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (250 mg) 1, 2
  • the title compound (74 mg) was obtained.
  • Example 31 ⁇ [7-Hydroxy-5- (7-trifluoromethylquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridin-8-carbonyl] amino ⁇ acetic acid 7 -Trifluoromethylquinoline-4-thiophenol (183 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Reference Example 1 and Example 4, the title compound (59 mg) was obtained.
  • Reference Example 5 Bis (4-isoquinoline) disulfide 4-bromoisoquinoline (504 mg), 2-ethylhexyl 3-mercaptopropionate (532 mg), tris (dibenzylideneacetone) dipalladium (43 mg), xanthophos (55 mg), N, N-diisopropylethylamine (0.85 mL) was mixed in a dioxane solvent (2.5 mL), and heated and stirred at 100 ° C. for 3.5 hours under an argon atmosphere. After completion of the reaction, insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure.
  • Example 32 ⁇ [7-Hydroxy-5- (isoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid obtained in Reference Example 6
  • the title compound (168 mg) was obtained in the same manner as in Reference Example 2 and Examples 1 to 3 using the compound (297 mg).
  • Reference Example 8 Bis (5-fluoro-1,2,3-trimethyl-1H-indol-7-yl) disulfide Dissolve the compound (310 mg) obtained in Reference Example 7 in N, N-dimethylformamide (3 mL) Under ice-cooling, sodium hydride (60%, 77 mg) and methyl iodide (96 ⁇ L) were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 33 ⁇ [5- (5-Fluoro-1,2,3-trimethyl-1H-indol-7-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine -8-Carbonyl] amino ⁇ acetic acid
  • the compound (436 mg) obtained in Reference Example 8 and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t -Butyl ester (521 mg) was obtained in the same manner as in Reference Example 6 and Example 32 to obtain the title compound (230 mg).
  • Example 34 ⁇ [7-Hydroxy-5- (thiophen-2-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-thiophenethiol (116 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (421 mg), Reference Examples 1, 2, and Examples 1-3 In the same manner as the above, the title compound (194 mg) was obtained.
  • Example 35 ⁇ [5- (5-chlorothiophen-2-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5-chloro Thiophene-2-thiol (117 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (181 mg) were used in Reference Example 1, 2. The title compound (79 mg) was obtained in the same manner as in Examples 1 to 3.
  • Example 36 ⁇ [5- (Benzo [b] thiophen-3-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Benzo [ b] Thiophene-3-thiol (89 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (201 mg) 1, 2 In the same manner as in Examples 1 to 3, the title compound (109 mg) was obtained.
  • Example 37 ⁇ [5- (Benzo [b] thiophen-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Benzo [ b] Thiophene-4-thiol (76 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (188 mg) 1, 2 In the same manner as in Examples 1 to 3, the title compound (90 mg) was obtained.
  • Example 38 ⁇ [7-hydroxy-5- (2-methylfuran-3-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-methyl Furan-3-thiol (75 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) were used in Reference Example 1, 2. In the same manner as in Examples 1 to 3, the title compound (48 mg) was obtained.
  • Example 39 ⁇ [5- (5-Chloronaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5-chloro Reference Example 4 was carried out using 1-naphthol (168 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (250 mg). In the same manner as in Example 19, the title compound (128 mg) was obtained.
  • Example 40 ⁇ [5- (6-Chloronaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 6-chloro Reference Example 4 was carried out using 1-naphthol (120 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (250 mg). In the same manner as in Example 19, the title compound (109 mg) was obtained.
  • Example 41 ⁇ [5- (5-Chloronaphthalen-1-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5-chloro- Reference Example 3, Example 1-naphthol (388 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (400 mg) In the same manner as in 4 and 5, the title compound (75 mg) was obtained.
  • Example 42 ⁇ [7-Hydroxy-5- (8-trifluoromethylquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 4 -Hydroxy-8-trifluoromethylquinoline (739 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (180 mg) In the same manner as in Reference Example 4 and Example 19, the title compound (140 mg) was obtained.
  • Example 43 ⁇ [5- (Dibenzothiophen-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid dibenzothiophene-4- All (165 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (379 mg) were used as Reference Example 4, Example 19 and In the same manner, the title compound (73 mg) was obtained.
  • Example 44 ⁇ [5-hydroxy-5- (1-trifluoromethylisoquinolin-5-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 1 Using trifluoromethyl-5-hydroxyisoquinoline (183 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Reference Example 3 and Examples 4 and 5, the title compound (58 mg) was obtained.
  • Example 45 [7-Hydroxy-5- (5-trifluoromethylnaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5- See trifluoromethylnaphthalene-1-thiol (219 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (433 mg) In the same manner as in Examples 1, 2, and Examples 4, 5, the title compound (195 mg) was obtained.
  • Example 46 [7-hydroxy-5- (5-methylnaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5-methylnaphthalene See 1-thiol (0.58 g) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (1.6 g) In the same manner as in Examples 1 and 2, and Examples 4 and 5, the title compound (141 mg) was obtained.
  • Example 47 [[5- (5-Cyanonaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5-cyano Reference examples: naphthalen-1-ol (2 g) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (1.2 g) 4. In the same manner as in Example 19, the title compound (199 mg) was obtained.
  • Example 48 ⁇ [7-Hydroxy-5- (6-trifluoromethylnaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 6 -Trifluoromethylnaphthalene-1-thiol (603 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Reference Example 1 and Examples 4 and 5, the title compound (150 mg) was obtained.
  • Example 49 ⁇ [7-Hydroxy-5- (7-trifluoromethylnaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 7 -Trifluoromethylnaphthalene-1-thiol (603.6 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) The title compound (198 mg) was obtained in the same manner as in Reference Example 1, Examples 4 and 5.
  • Example 50 ⁇ [7-Hydroxy-5- (5-trifluoromethylnaphthalen-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5- See trifluoromethylnaphthalen-1-ol (80 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (208 mg) In the same manner as in Example 9 and Examples 4 and 5, the title compound (68 mg) was obtained.
  • Example 51 ⁇ [7-Hydroxy-5- (5-methoxynaphthalen-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5-methoxynaphthalene
  • Reference Example 9 was carried out using 1-ol (106 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (329 mg). In the same manner as in Examples 4 and 5, the title compound (45 mg) was obtained.
  • Example 52 ⁇ [7-hydroxy-5- (5-methylnaphthalen-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5-methylnaphthalene
  • Reference Example 9 was carried out using 1-ol (146 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (487 mg). In the same manner as in Examples 4 and 5, the title compound (50 mg) was obtained.
  • Example 53 ⁇ [7-hydroxy-5- (6-methylnaphthalen-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 6-methylnaphthalene
  • Reference Example 9 was carried out using 1-ol (100 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (316 mg). In the same manner as in Examples 4 and 5, the title compound (97 mg) was obtained.
  • Example 54 ⁇ [7-hydroxy-5- (6-trifluoromethylnaphthalen-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 6- Using trifluoromethylnaphthalen-1-ol (189 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (400 mg) In the same manner as in Reference Example 3 and Examples 4 and 5, the title compound (98 mg) was obtained.
  • Example 55 ⁇ [5- (6-Chloronaphthalen-1-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 6-chloronaphthalene
  • Reference Example 3 using 1-ol (121 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Examples 4 and 5, the title compound (73 mg) was obtained.
  • Example 56 ⁇ [7-Hydroxy-5- (8-trifluoromethylisoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 8 Trifluoromethylisoquinoline-4-thiol (307 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (252 mg) The title compound (159 mg) was obtained in the same manner as in Reference Examples 2 and 3 and Examples 1 to 3.
  • Example 57 ⁇ [7-Hydroxy-5- (8-methylisoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 8-methyl
  • isoquinoline-4-thiol 64 mg
  • Example 58 ⁇ [5- (8-Fluoroisoquinolin-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 8-fluoro Reference example using isoquinoline-4-thiol (70 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (202 mg) 1, In the same manner as in Examples 4 and 5, the title compound (24 mg) was obtained.
  • Example 59 ⁇ [5- (8-chloroisoquinolin-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 8-chloro Reference example using isoquinoline-4-thiol (152 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (404 mg) 1, In the same manner as in Examples 4 and 5, the title compound (125 mg) was obtained.
  • Example 60 ⁇ [7-Hydroxy-5- (7-trifluoromethylisoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridin-8-carbonyl] amino ⁇ acetic acid 7 -Trifluoromethylisoquinoline-4-thiol (642 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (339 mg) In the same manner as in Reference Example 1 and Examples 4 and 5, the title compound (40 mg) was obtained.
  • Example 61 ⁇ [7-Hydroxy-5- (8-methylisoquinolin-4-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 8-methylisoquinoline Reference Example 2 using -4-ol (78 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) 3. In the same manner as in Examples 1 to 3, the title compound (25 mg) was obtained.
  • Example 62 ⁇ [5- (8-Fluoroisoquinolin-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 8-fluoroisoquinoline Reference Example 3 using -4-ol (152 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (420 mg) In the same manner as in Examples 4 and 5, the title compound (46 mg) was obtained.
  • Example 63 ⁇ [5- (8-Chloroisoquinolin-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 8-chloroisoquinoline Reference Example 3 using 4-ol (250 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (690 mg) In the same manner as in Examples 4 and 5, the title compound (90 mg) was obtained.
  • Example 64 ⁇ [5- (7-chloroquinolin-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 7-chloro Reference example using quinoline-4-thiol (120 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) 3. In the same manner as in Examples 4 and 5, the title compound (55 mg) was obtained.
  • Example 65 ⁇ [7-hydroxy-5- (2-trifluoromethylquinazolin-5-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2 -Trifluoromethylquinazoline-5-thiol (155 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (334 mg) And the title compound (135 mg) was obtained in the same manner as in Reference Example 1, Examples 4 and 5.
  • Example 66 ⁇ [5- (2-Chlorobenzo [b] thiophen-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-chlorobenzo [b] thiophene-4-thiol (87 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (180 mg)
  • the title compound (92 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
  • Example 67 ⁇ [7-Hydroxy-5- (2-trifluoromethylbenzo [b] thiophen-4-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] Amino ⁇ acetic acid 2-trifluoromethylbenzo [b] thiophene-4-thiol (186 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid The title compound (190 mg) was obtained using t-butyl ester (249 mg) in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
  • Example 68 ⁇ [5- (Benzo [b] thiophen-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Reference Example 9 The title compound (146 mg) was obtained in the same manner as in Reference Example 2 and Examples 1 to 3 using the compound obtained in step (220 mg).
  • Example 69 ⁇ [7-Hydroxy-5- (3-methylbenzo [b] thiophen-7-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-methylbenzo [b] thiophene-7-thiol (108 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (213 mg)
  • the title compound (155 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
  • Example 70 ⁇ [7-hydroxy-5- (3-trifluoromethylbenzo [b] thiophen-7-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] Amino ⁇ acetic acid 3-trifluoromethylbenzo [b] thiophene-7-thiol (404 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid The title compound (155 mg) was obtained using t-butyl ester (231 mg) in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
  • Example 71 ⁇ [5- (Benzo [b] thiophen-7-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Benzo [b ] Using thiophen-7-ol (110 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (255 mg) In the same manner as in Examples 9 and 2 and Examples 1 to 3, the title compound (91 mg) was obtained.
  • Example 72 ⁇ [7-hydroxy-5- (3-methylbenzo [b] thiophen-7-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3 -Methylbenzo [b] thiophen-7-ol (117 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (247 mg) In the same manner as in Reference Examples 9 and 2 and Examples 1 to 3, the title compound (105 mg) was obtained.
  • Example 73 ⁇ [7-Hydroxy-5- (3-trifluoromethylbenzo [b] thiophen-7-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ Acetic acid 3-trifluoromethylbenzo [b] thiophen-7-ol (227 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t Using butyl ester (246 mg), the title compound (88 mg) was obtained in the same manner as in Reference Examples 9 and 2 and Examples 1 to 3.
  • Example 74 ⁇ [5- (4-Chlorobenzo [b] thiophen-7-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 4 -Chlorobenzo [b] thiophen-7-ol (123 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (252 mg) In the same manner as in Reference Examples 9 and 2 and Examples 1 to 3, the title compound (114 mg) was obtained.
  • Example 75 ⁇ [7-hydroxy-5- (7-trifluoromethylbenzo [b] thiophen-3-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] Amino ⁇ acetic acid 7-trifluoromethylbenzo [b] thiophene-3-thiol (201 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid Using the t-butyl ester (301 mg), the title compound (214 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
  • Example 76 ⁇ [5- (Benzo [b] thiophen-3-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Benzo [b ] Using thiophen-3-one (554 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (987 mg) In the same manner as in Example 9 and Examples 4 and 5, the title compound (76 mg) was obtained.
  • Example 77 ⁇ [5- (6-Chlorobenzofuran-3-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 6-chloro Reference example using benzofuran-3-thiol (113 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (214 mg) 1, In the same manner as in Examples 4 and 5, the title compound (136 mg) was obtained.
  • Example 78 ⁇ [7-Hydroxy-5- (1,2,3-trimethyl-1H-indol-7-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl Amino ⁇ acetic acid 1,2,3-trimethyl-1H-indole-7-thiol (138 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8- The title compound (111 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3, using carboxylic acid t-butyl ester (288 mg).
  • Example 79 ⁇ [5- (3-Chloro-1-methyl-1H-indol-7-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl Amino ⁇ acetic acid 3-chloro-1-methyl-1H-indole-7-thiol (198 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8- The title compound (90 mg) was obtained in the same manner as in Reference Example 1, Example 4, and 5 using carboxylic acid t-butyl ester (200 mg).
  • Example 80 ⁇ [7-Hydroxy-5- (1,2,3-trimethyl-1H-indol-4-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl Amino ⁇ acetic acid 1,2,3-trimethyl-1H-indole-4-thiol (132 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8- The title compound (159 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3, using carboxylic acid t-butyl ester (279 mg).
  • Example 81 ⁇ [7-Hydroxy-5- (1,2,3-trimethyl-1H-indol-4-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] Amino ⁇ acetic acid 1,2,3-trimethyl-1H-indole-4-ol (254 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carvone
  • the title compound (41 mg) was obtained in the same manner as in Reference Examples 2 and 3, and Examples 1 to 3, using acid t-butyl ester (550 mg).
  • Example 82 ⁇ [5- (9H-fluoren-1-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 9H-fluorene-1 -Ol (165 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (474 mg) were used in Reference Example 9 and Example 4. In the same manner as in 5, the title compound (31 mg) was obtained.
  • Example 83 ⁇ [5- (Dibenzofuran-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid dibenzofuran-4-ol (164 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (400 mg), Reference Example 3, Examples 4, 5 In the same manner as the above, the title compound (177 mg) was obtained.
  • Example 84 ⁇ [5- (Dibenzothiophen-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid dibenzothiophen-4-ol (178 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (400 mg), Reference Example 3, Example 4 In the same manner as in 5, the title compound (78 mg) was obtained.
  • Example 85 ⁇ [5- (dibenzofuran-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid dibenzofuran-4-thiol ( 603 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner, the title compound (78 mg) was obtained.
  • Example 86 ⁇ [7-hydroxy-5- (phenanthren-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid phenanthren-1-ol (173 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (400 mg), Reference Example 3, Examples 4, 5 In the same manner as the above, the title compound (125 mg) was obtained.
  • Example 87 ⁇ [7-Hydroxy-5- (5,6,7,8-tetrahydronaphthalen-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ Acetic acid 5,6,7,8-tetrahydronaphthalen-1-ol (1 g) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t -The title compound (667 mg) was obtained by treating the butyl ester (2 g) in the same manner as in Reference Example 9, Examples 4 and 5.
  • Example 88 ⁇ [7-hydroxy-5- (5-methyl-5,6,7,8-tetrahydronaphthalen-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8 -Carbonyl] amino ⁇ acetic acid 5-methyl-5,6,7,8-tetrahydronaphthalen-1-ol (100 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] Pyridine-8-carboxylic acid t-butyl ester (316 mg) was treated in the same manner as in Reference Example 9, Examples 4 and 5 to give the title compound (97 mg).
  • Example 89 ⁇ [7-hydroxy-5- (indan-4-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid indan-4-ol (120 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (350 mg), and Reference Example 3, Examples 4, 5 In the same manner as described above, the title compound (149 mg) was obtained.
  • Example 90 ⁇ [5- (3,5-dimethylphenoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3,5-dimethylphenol (81 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (250 mg) were used. In the same manner as in Examples 1 to 3, the title compound (70 mg) was obtained.
  • Example 91 ⁇ [5- (5-Fluorobiphenyl-3-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5-fluoro Biphenyl-3-thiol (135 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) were used in Reference Example 1, In the same manner as in Examples 4 and 5, the title compound (55 mg) was obtained.
  • Reference Example 11 7-Benzyloxy-5- (2-cyclopentylethoxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester
  • Compound obtained in Reference Example 10 200 mg was mixed with tetrahydrofuran (10 mL), and 2-cyclopentaneethanol (114 ⁇ l), diisopropyl azodicarboxylate (235 ⁇ l), and triphenylphosphine (315 mg) were sequentially added under ice cooling. After stirring at room temperature for 2 hours, the solvent was distilled under reduced pressure.
  • Example 92 [[7-Hydroxy-5- (2-methylbutylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-methylbutanethiol (63 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (250 mg) in the same manner as in Example 8, Compound (71 mg) was obtained.
  • Example 93 (S)-[[7-hydroxy-5- (2-methylbutylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid (S) After using -2-methylbutanol (71 mg) and the compound (200 mg) obtained in Reference Example 15 in the same manner as in Reference Example 11 and Example 2, the resulting residue was placed in isopropyl alcohol (1.5 mL). Suspended, 4M aqueous lithium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 4 hours.
  • reaction mixture was neutralized with 2M hydrochloric acid, and the organic layer extracted with ethyl acetate was washed with water and saturated brine. After washing with water, drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure to obtain the title compound (35 mg).
  • Example 94 [[7-Hydroxy-5-methylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid obtained in methanol (1 mL) and Reference Example 15 Using the compound (200 mg), the title compound (42 mg) was obtained in the same manner as in Reference Example 11, Examples 2 and 3.
  • Example 95 [(7-hydroxy-5-propylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid propanethiol (40 mg) and 7-benzyloxy-5 Using the iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg), the title compound (28 mg) was obtained in the same manner as in Example 8.
  • Example 96 ⁇ [7-hydroxy-5- (3,3,3-trifluoropropylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3, Using 3,3-trifluoropropanethiol (173 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (201 mg) In the same manner as in Example 8, the title compound (74 mg) was obtained.
  • Example 97 [(7-hydroxy-5-butylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid obtained in butanol (80 mg) and Reference Example 15 The title compound (117 mg) was obtained in the same manner as in Example 94, using the compound (200 mg).
  • Example 98 [[7-Hydroxy-5- (3-methylbutylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 3-methylbutanethiol (55 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, Compound (40 mg) was obtained.
  • Example 99 ⁇ [5- (3,3-dimethylbutylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3,3-dimethyl
  • the title compound (39 mg) was obtained in the same manner as in Example 152, using butyl-4-methylbenzenesulfonate (95 mg) and the compound (125 mg) obtained in Reference Example 15.
  • Example 100 [[7-Hydroxy-5- (2,2-dimethylbutylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2,2-dimethyl
  • the title compound (95 mg) was obtained in the same manner as in Reference Example 11 and Example 5, using butanol (110 mg) and the compound (200 mg) obtained in Reference Example 13.
  • Reference Example 13 [(7-Benzyloxy-5-mercapto [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid t-butyl ester
  • Compound obtained in Reference Example 12 (15.7 g) was dissolved in methanol (60 mL) and stirred at 0 ° C. for 30 minutes. Thereafter, sodium methoxide (2.6 g) was added, the mixture was further stirred for 30 minutes, and aqueous citric acid was added. The precipitated crystals were collected by filtration and washed with water to give the title compound (8.0 g).
  • Reference Example 14 3- [7-Benzyloxy-8- (methoxycarbonylmethylcarbamoyl)-[1,2,4] triazolo [1,5- ⁇ ] pyridin-5-ylsulfanyl] propionic acid 3-ethylhexyl ester 3 -Mercaptopropionic acid 3-ethylhexyl ester (2.7 g) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (5.
  • the title compound (3.85 g) was obtained in the same manner as in Reference Examples 1 and 2 and Example 1.
  • Example 101 [[5- (2-Ethylbutylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-ethylbutanol (87 mg)
  • the title compound (48 mg) was obtained in the same manner as in Example 93, using the compound (250 mg) obtained in Reference Example 15.
  • Example 102 [[5- (1,3-Dimethylbutylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 4-methyl-2 -The title compound (30 mg) was obtained in the same manner as in Example 100 using pentanol (105 mg) and the compound (200 mg) obtained in Reference Example 13.
  • Example 103 [[7-hydroxy-5- (4,4,4-trifluorobutylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid methanesulfone Using the acid 4,4,4-trifluoro-butyl ester (309 mg) and the compound (279 mg) obtained in Reference Example 15, the title compound (104 mg) was obtained in the same manner as in Example 152.
  • Example 104 [(7-Hydroxy-5-pentylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid pentanethiol (125 mg) and 7-benzyloxy-5 Using iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (451 mg), the title compound (48 mg) was obtained in the same manner as in Example 6.
  • Example 105 [(7-hydroxy-5- (4-methylpentylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 4-methylpentanol (100 mg ) And the compound (200 mg) obtained in Reference Example 13 were used in the same manner as in Example 100 to obtain the title compound (100 mg).
  • Example 106 [(7-Hydroxy-5- (3-methylpentylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 3-methylpentanol (100 mg ) And the compound (200 mg) obtained in Reference Example 13 were used in the same manner as in Example 100 to obtain the title compound (70 mg).
  • Example 107 [[7-Hydroxy-5- (2-propylpentylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-propylpentene-1-
  • the title compound (102 mg) was obtained in the same manner as in Example 100, using all (147 mg) and the compound (311 mg) obtained in Reference Example 13.
  • Example 108 [[5- (3-Ethylpentylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 3-ethylpentane-1 Using the ol (131 mg) and the compound (311 mg) obtained in Reference Example 13, the title compound (135 mg) was obtained in the same manner as in Example 100.
  • Example 109 [[7-Hydroxy-5- (pent-3-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 3-pentyne-1- Using all (32 mg) and the compound (130 mg) obtained in Reference Example 15, the title compound (69 mg) was obtained in the same manner as in Reference Example 11, Example 5, and 3.
  • Example 110 [[7-Hydroxy-5- (4,4,5,5,5-pentafluoropentylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ] Acetic acid Toluenesulfonic acid 4,4,5,5,5-pentafluoropentane ester (332 mg) and the compound obtained in Reference Example 15 (279 mg) were used in the same manner as in Example 152 to give the titled compound (210 mg) Got.
  • Example 111 [(5-Hexylsulfanyl-7-hydroxy- [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid hexanethiol (88 mg) and 7-benzyloxy-
  • the title compound (60 mg) was obtained in the same manner as in Example 8 using 5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg). .
  • Example 112 [(5-hex-3-yn-1-ylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 3-hexyne-
  • the title compound (57 mg) was obtained in the same manner as in Example 152, using 1-hydroxymethanesulfonic acid ester (143 mg) and the compound (350 mg) obtained in Reference Example 15.
  • Example 113 [(7-Hydroxy-5-isopropylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 2-propanethiol (92 mg) and 7-benzyloxy Using -5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (250 mg), the title compound (32 mg) was obtained in the same manner as in Example 8. It was.
  • Example 114 [(5-tert-butylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 2-methylpropane-2-thiol (48 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, Compound (60 mg) was obtained.
  • Example 115 [(7-hydroxy-5-isobutylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 2-methylpropane-1-thiol (48 mg) and Using 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, the title compound ( 73 mg) was obtained.
  • Example 116 [[5- (1,2-Dimethylpropylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 1,2-dimethyl
  • the title compound (40 mg) was obtained.
  • Example 117 [(5-allylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid allyl mercaptan (53.8 mg) and 7-benzyloxy Using 5--5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid methyl ester (300 mg) in the same manner as in Reference Examples 1, 2, and Example 1, 5-allyl Sulfanyl-7-benzyloxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonylaminoacetic acid methyl ester (104 mg) was obtained.
  • Example 118 [(5-Cyclopentylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid cyclopentanethiol (45 mg) and 7-benzyloxy- Using 5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, the title compound (72 mg) was obtained. .
  • Example 119 [(5-cyclohexylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid cyclohexanethiol (61 mg) and 7-benzyloxy-5
  • the title compound (55 mg) was obtained in the same manner as in Example 8 using iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (250 mg).
  • Example 120 [[5- (adamantan-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 1-adamantanethiol (400 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (400 mg) in the same manner as in Example 8, Compound (110 mg) was obtained.
  • Example 121 ⁇ [5-Cyclopropylmethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Bromomethylcyclopropane (87 mg) and Reference Example The title compound (56 mg) was obtained in the same manner as in Example 152, using the compound (81 mg) obtained in 15.
  • Example 122 ⁇ [5-cyclobutylmethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Bromomethylcyclobutane (39 mg) and Reference Example 15 The title compound (50 mg) was obtained in the same manner as in Example 152 using the compound obtained in (76 mg).
  • Example 123 ⁇ [5-Cyclopentylmethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Toluene-4-sulfonic acid cyclopentylmethyl ester (254 mg ) And the compound (250 mg) obtained in Reference Example 15 were used to obtain the title compound (111 mg) in the same manner as in Example 152.
  • Example 124 ⁇ [5-cyclohexylmethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid toluene-4-sulfonic acid cyclohexylmethyl ester (75 ⁇ L ) And the compound (200 mg) obtained in Reference Example 15 were used to obtain the title compound (85 mg) in the same manner as in Example 152.
  • Example 125 ⁇ [5- (2-cyclohexylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid toluene-4-sulfonic acid cyclohexyl
  • the title compound (136 mg) was obtained in the same manner as in Example 152, using ethyl ester (251 mg) and the compound (300 mg) obtained in Reference Example 15.
  • Example 126 ⁇ [5- (2-cyclohexylpropylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-cyclohexylpropanol ( 102 mg) and the compound obtained in Reference Example 13 (200 mg) were used in the same manner as in Example 100 to obtain the title compound (119 mg).
  • Example 127 [[5- (2-Cyclopropylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid Toluene-4-sulfonic acid
  • the title compound (95 mg) was obtained in the same manner as in Example 152, using 2-cyclopropylethyl ester (132 mg) and the compound (207 mg) obtained in Reference Example 15.
  • Example 128 ⁇ [5- (2-cyclobutylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Toluene-4-sulfonic acid
  • the title compound (40 mg) was obtained in the same manner as in Example 152, using -2-cyclobutylethyl ester (165 mg) and the compound (200 mg) obtained in Reference Example 15.
  • Example 129 ⁇ [5- (2-Cyclopentylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Toluene-4-sulfonic acid
  • the title compound (56 mg) was obtained in the same manner as in Example 152, using 2-cyclopentylethyl ester (217 mg) and the compound (200 mg) obtained in Reference Example 15.
  • Example 130 ⁇ [5- (2-bicyclo [2.2.1] hept-2-ylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8- Carbonyl] amino ⁇ acetic acid
  • (2-bicyclo [2,2,1] hept-2-ylethanol (144 mg) and triethylamine (101 mg) was dissolved in THF (2 mL), and mesyl chloride (112 mg) was added under ice cooling. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Example 131 ⁇ [5- (2-adamantan-1-ylethyl) sulfanyl-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Toluene-4-
  • the title compound (71 mg) was obtained in the same manner as in Example 152, using sulfonic acid-2-adamantan-1-ylethyl ester (234 mg) and the compound (200 mg) obtained in Reference Example 15.
  • Example 132 ⁇ (7-hydroxy-5-phenethylsulfanyl [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino ⁇ acetic acid 2-phenylethanethiol (92 mg) and 7-benzyl Using oxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (250 mg) in the same manner as in Reference Example 3 and Example 32, the title compound ( 60 mg) was obtained.
  • Example 133 ([5- [2- (3,4-Dichlorophenyl) ethylsulfanyl] -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino) acetic acid 3 , 4-Dichlorophenylethanol (110 mg) and the compound obtained in Reference Example 13 (200 mg) were used in the same manner as in Example 100 to obtain the title compound (120 mg).
  • Example 134 ([7-hydroxy-5- [2- (4-methoxyphenyl) ethylsulfanyl] [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino) acetic acid 2-
  • the title compound (100 mg) was obtained in the same manner as in Example 100, using (4-methoxyphenyl) ethanol (150 mg) and the compound (200 mg) obtained in Reference Example 13.
  • Example 135 [(7-hydroxy-5- (2-phenylpropylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 2-phenylpropanol (90 mg)
  • the title compound (90 mg) was obtained in the same manner as in Example 94, using the compound (200 mg) obtained in Reference Example 15.
  • Example 136 [(7-Hydroxy-5- (2-methyl-2-phenylpropylsulfanyl)-[1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 2-
  • the title compound (90 mg) was obtained in the same manner as in Example 94, using methyl-2-phenylpropanol (90 mg) and the compound (200 mg) obtained in Reference Example 15.
  • Example 137 [(7-hydroxy-5- (2-thiophen-2-ylethylsulfanyl)-[1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 2-
  • the title compound (84 mg) was obtained in the same manner as in Example 94, using thiophene ethanol (71 mg) and the compound (200 mg) obtained in Reference Example 15.
  • Example 138 ⁇ [5- (3-cyclohexylpropylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid toluene-4-sulfonic acid 3 -
  • the title compound (50 mg) was obtained in the same manner as in Example 152, using cyclohexylpropyl ester (112 mg) and the compound (200 mg) obtained in Reference Example 15.
  • Example 139 [[7-hydroxy-5- (3-phenylpropylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 3-phenylpropanol (110 mg)
  • the title compound (89 mg) was obtained in the same manner as in Example 100 using the compound (200 mg) obtained in Reference Example 13.
  • Example 140 ⁇ [7-hydroxy-5- (2-methoxyethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 1-bromo-2-methoxy
  • the title compound (105 mg) was obtained in the same manner as in Example 152, using ethane (76 ⁇ L) and the compound (200 mg) obtained in Reference Example 15.
  • Example 141 [[7-Hydroxy-5- (2-isopropoxyethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-isopropoxyethanol ( 73 mg) and the compound obtained in Reference Example 17 (200 mg) were used in the same manner as in Reference Examples 11 and 2 and Examples 1 to 3, to obtain the title compound (44 mg).
  • Example 142 [(7-hydroxy-5- (2-phenoxyethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 2-phenoxyethanol (90 mg) and The title compound (40 mg) was obtained in the same manner as in Example 94, using the compound (200 mg) obtained in Reference Example 15.
  • Example 143 [[5- (2,3-dihydrobenzo [b] [1,4] dioxin-2-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] [Pyridine-8-carbonyl] amino] acetic acid 2-hydroxymethyl-1,4-benzodioxane (150 mg) and the compound obtained in Reference Example 15 (200 mg) were used in the same manner as in Example 94 to obtain the title compound (20 mg )
  • Example 144 ⁇ [5- (2,3-diphenylpropylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,3-diphenyl 2,3-Diphenylpropanol methanesulfonate (1.4 g) was obtained in the same manner as in Example 130, using propanol (1.0 g). Using this compound (190 mg) and the compound (200 mg) obtained in Reference Example 17, the title compound (55 mg) was obtained in the same manner as in Reference Example 16 and Example 32.
  • Example 145 ( ⁇ 5- [2- (2-ethylhexyloxycarbonyl) ethylsulfanyl] -7-hydroxy [1,2,4] triazolo [1,5, ⁇ ] pyridine-8-carbonyl] amino) acetic acid 3 -Using mercaptopropanoic acid 2-ethylhexyl ester (72 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (137 mg) In the same manner as in Example 94, the title compound (90 mg) was obtained.
  • Example 146 [(5-Benzylsulfanyl-7-hydroxy- [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid benzyl mercaptan (49 mg) and 7-benzyloxy- Use 5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (150 mg) in the same manner as Reference Example 3, Reference Example 2, and Examples 1 to 3. To give the title compound (21 mg).
  • Example 147 ⁇ [7-hydroxy-5- (2-methylbenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid (2-methylphenyl) methane Using thiol (67 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) as in Example 8. To give the title compound (44 mg).
  • Example 148 ⁇ [7-hydroxy-5- (2-trifluoromethylbenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2- (trifluoro
  • the title compound (46 mg) was obtained in the same manner as in Example 152, using methyl) benzyl bromide (57 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 149 ⁇ [5- (2-Fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-fluorobenzyl bromide (45 mg ) And the compound (80 mg) obtained in Reference Example 15 were used to obtain the title compound (56 mg) in the same manner as in Example 152.
  • Example 150 ⁇ [5- (2-chlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid (2-chlorophenyl) methanethiol (77 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) as in Example 8. The title compound (66 mg) was obtained.
  • Example 151 1 [[7-Hydroxy-5- (2-methoxybenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid obtained in Reference Example 16
  • the title compound (48 mg) was obtained in the same manner as in Examples 2 and 3 using the compound (100 mg).
  • Example 152 [[7-hydroxy-5- (2-trifluoromethoxybenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2- (trifluoro
  • the title compound (70 mg) was obtained in the same manner as in Reference Example 16 and Example 151 using (methoxy) benzyl bromide (65 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 153 ⁇ [7-Hydroxy-5- (3-methylbenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-methylbenzyl bromide (44 mg ) And the compound (80 mg) obtained in Reference Example 15 were used to obtain the title compound (51 mg) in the same manner as in Example 152.
  • Example 154 ⁇ [7-hydroxy-5- (3-trifluoromethylbenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3- (trifluoro
  • the title compound (60 mg) was obtained in the same manner as in Example 152, using (methyl) benzyl bromide (57 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 155 ⁇ [5- (3-Fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-fluorobenzyl bromide (45 mg ) And the compound (80 mg) obtained in Reference Example 15 were used to obtain the title compound (60 mg) in the same manner as in Example 152.
  • Example 156 ⁇ [5- (3-chlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-chlorobenzyl bromide (49 mg ) And the compound (80 mg) obtained in Reference Example 15 were used to obtain the title compound (60 mg) in the same manner as in Example 152.
  • Example 157 [[7-hydroxy-5- (4-methylbenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 4-methylbenzyl mercaptan (66 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, Compound (66 mg) was obtained.
  • Example 158 ⁇ [7-hydroxy-5- (4-trifluoromethylbenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid [4- (tri Fluoromethyl) phenyl] methanethiol (108 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (230 mg) In the same manner as in Example 8, the title compound (89 mg) was obtained.
  • Example 159 ⁇ [5- (4-Fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid (4-fluorophenyl) methane Using thiol (69 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) as in Example 8. To give the title compound (88 mg).
  • Example 160 [[5- (4-Chlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 4-chlorobenzyl mercaptan (168 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (400 mg) in the same manner as in Example 6, Compound (48 mg) was obtained.
  • Example 161 ⁇ [5- (4-Cyanobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 4- (mercaptomethyl) benzo Similar to Example 6 using nitrile (73 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg). To give the title compound (97 mg).
  • Example 162 ⁇ [5- (4-t-butylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid (4-t- Examples using butylphenyl) methanethiol (144 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as 146, the title compound (24 mg) was obtained.
  • Example 163 ⁇ [5- (biphenyl-4-ylmethylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid biphenyl-4-
  • Example 146 with ylmethanethiol (117 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (220 mg) In the same manner, the title compound (42 mg) was obtained.
  • Example 164 ⁇ [7-hydroxy-5- (4-methoxybenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 4-methoxybenzyl alcohol (134 mg ) And the compound (300 mg) obtained in Reference Example 15 were used to obtain the title compound (53 mg) in the same manner as in Reference Example 11, Examples 2 and 3.
  • Example 165 ⁇ [5- (2-Fluoro-3-methylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-fluoro
  • the title compound (47 mg) was obtained in the same manner as in Example 152, using -3-methylbenzyl bromide (48 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 166 ⁇ [5- (2,3-difluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,3-difluoro
  • the title compound (56 mg) was obtained in the same manner as in Example 152, using benzyl bromide (49 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 167 ⁇ [5- (2,4-dichlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid (2,4- Example 8 using dichlorophenyl) methanethiol (94 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg) To give the title compound (65 mg).
  • Example 168 ⁇ [5- (2,4-dimethylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,4-dimethyl Benzyl alcohol (50 mg) and tetrahydrofuran (2.0 mL) were mixed, and triethylamine (45 mg) and methanesulfonyl chloride (42 mg) were sequentially added under ice cooling. After stirring at the same temperature for 2 hours and confirming the completion of the reaction, triethylamine (45 mg) and the compound obtained in Reference Example 13 (152 mg) were further added. After stirring for 1 hour at room temperature, the completion of the reaction was confirmed.
  • Example 169 ⁇ [5- (2,5-dimethylbenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,5-
  • the title compound (71 mg) was obtained in the same manner as in Example 152, using dimethylphenylmethyl methanesulfonate (57 mg) and the compound (90 mg) obtained in Reference Example 15.
  • Example 170 ⁇ [5- (2,5-difluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,5-difluoro
  • the title compound (50 mg) was obtained in the same manner as in Example 152, using benzyl bromide (43 mg) and the compound (70 mg) obtained in Reference Example 15.
  • Example 171 ⁇ [5- (2,5-dichlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,5-dichloro
  • the title compound (52 mg) was obtained in the same manner as in Example 152, using benzyl bromide (57 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 172 ⁇ [5- (5-chloro-2-fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 5-chloro
  • the title compound (57 mg) was obtained in the same manner as in Example 152, using -2-fluorobenzyl bromide (53 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 173 ⁇ [5- (2-chloro-5-fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-chloro
  • the title compound (51 mg) was obtained in the same manner as in Example 152, using -5-fluorobenzyl bromide (53 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 174 ⁇ [5- (2-Fluoro-5-methylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-fluoro
  • the title compound (70 mg) was obtained in the same manner as in Example 130, using -5-methylbenzyl alcohol (80 mg) and the compound (90 mg) obtained in Reference Example 15.
  • Example 175 ⁇ [5- (2-Chloro-3,6-difluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2
  • the title compound (63 mg) was obtained in the same manner as in Example 152, using -chloro-3,6-difluorobenzyl bromide (57 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 176 ⁇ [5- (2,6-dichlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,6-dichloro
  • the title compound (56 mg) was obtained in the same manner as in Example 152, using benzyl bromide (50 mg) and the compound (70 mg) obtained in Reference Example 15.
  • Example 177 ⁇ [5- (3-Chloro-4-fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-chloro
  • the title compound (68 mg) was obtained in the same manner as in Example 152, using -4-fluorobenzyl bromide (53 mg) and the compound obtained in Reference Example 15 (80 mg).
  • Example 178 ⁇ [5- (3,5-bistrifluoromethylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3,5 Using the bis (trifluoromethyl) benzyl bromide (95 mg) and the compound (92 mg) obtained in Reference Example 17, the title compound (67 mg) was obtained in the same manner as in Example 32.
  • Example 179 [[5- (2,6-dimethylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2,6-dimethyl
  • the title compound (75 mg) was obtained in the same manner as in Example 152, using benzyl iodide (159 mg) and the compound (200 mg) obtained in Reference Example 15.
  • Example 180 ⁇ [7-hydroxy-5- (2,4,6-trimethylbenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid (2, 4,6-trimethylphenyl) methanethiol (81 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (200 mg). And the title compound (64 mg) was obtained as in Example 8.
  • Example 181 ⁇ [7-hydroxy-5- (2,3,6-trifluorobenzylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,
  • the title compound (48 mg) was obtained in the same manner as in Example 152, using 3,6-trifluorobenzyl bromide (53 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 182 ⁇ [7-hydroxy-5- (2,3,4,5,6-pentafluorobenzylsulfanyl)-[1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] Amino ⁇ acetic acid 2,3,4,5,6-pentafluorobenzyl bromide (46 mg) and the compound obtained in Reference Example 15 (60 mg) were used in the same manner as in Example 152 to obtain the title compound (33 mg). .
  • Example 183 ⁇ [5- (3,6-difluoro-2-methylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 1 , 4-Difluoro-2,3-dimethylbenzene (100 mg) and monochlorobenzene (1.0 mL) were added, and N-bromosuccinimide (150 mg) and azobisisobutyronitrile (6 mg) were added to the mixture. Stir at 4 ° C. for 4 hours. After completion of the reaction, the insoluble material was filtered through Celite, and the solvent was concentrated under reduced pressure. The title compound (73 mg) was obtained in the same manner as in Example 152, using the obtained 2-bromomethyl-1,4-difluoro-3-methylbenzene and the compound (80 mg) obtained in Reference Example 15.
  • Example 184 ⁇ [5- (2,6-difluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2,6-difluoro
  • the title compound (30 mg) was obtained in the same manner as in Example 100 using benzyl alcohol (110 mg) and the compound (200 mg) obtained in Reference Example 13.
  • Example 185 ( ⁇ )-[[7-hydroxy-5- (1-phenylethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid ( ⁇ )
  • the title compound (113 mg) was obtained in the same manner as in Example 152, using 1-phenylethyl chloride (106 mg) and the compound (140 mg) obtained in Reference Example 15.
  • Example 186 [[7-hydroxy-5- (1,2,3,4-tetrahydronaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] Amino] acetic acid 1-chloro-1,2,3,4-tetrahydronaphthalene (80 mg) and the compound obtained in Reference Example 15 (94 mg) were used in the same manner as in Example 152 to obtain the title compound (40 mg). It was.
  • Example 187 ⁇ [7-Hydroxy-5- (5,6,7,8-tetrahydronaphthalen-2-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl Amino ⁇ acetic acid 5,6,7,8-tetrahydronaphthalen-2-ylmethanol (274 mg)
  • the title compound (65 mg) was obtained in the same manner as in Example 130, using the compound (80 mg) obtained in Reference Example 15. It was.
  • Example 188 ⁇ [5- (benzothiazol-2-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-benzothiazole
  • the title compound (62 mg) was obtained in the same manner as in Example 152, using methanol 2-methanesulfonate (57 mg) and the compound (80 mg) obtained in Reference Example 15.
  • Example 189 ⁇ [7-hydroxy-5- (pyridin-2-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-bromomethylpyridine
  • the title compound (53 mg) was obtained in the same manner as in Example 152, using bromate (112 mg) and the compound (150 mg) obtained in Reference Example 15.
  • Example 190 ⁇ [7-Hydroxy-5- (pyridin-3-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid Pyridin-3-yl
  • the title compound (35 mg) was obtained in the same manner as in Example 152, using methylmethanesulfonate (83 mg) and the compound (150 mg) obtained in Reference Example 15.
  • Example 191 1 ⁇ [7-Hydroxy-5- (pyridin-4-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 4-Bromomethylpyridine
  • the title compound (101 mg) was obtained in the same manner as in Example 152, using bromate (136 mg) and the compound (200 mg) obtained in Reference Example 15.
  • Example 192 ⁇ [7-hydroxy-5- (6-methylpyridin-2-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 6- ⁇ [7-Benzyloxy-5- (6-methylpyridin-2-ylmethyl) was prepared in the same manner as in Example 168 using methyl-2-pyridinemethanol (49 mg) and the compound obtained in Reference Example 15 (135 mg). Sulfanyl)-[1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid methyl ester was obtained. The title compound (70 mg) was obtained from the obtained compound in the same manner as in Examples 2 and 3.
  • Example 193 [[7-hydroxy-5- (6-trifluoromethylpyridin-3-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid
  • the title compound (109 mg) was obtained in the same manner as in Example 130, using 6-trifluoromethylpyridin-3-ylmethanol (255 mg) and the compound (311 mg) obtained in Reference Example 15.
  • Example 194 [[5- (2,6-dichloropyridin-3-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid
  • the title compound (185 mg) was obtained in the same manner as in Example 152, using methanesulfonic acid 2,6-dichloropyridin-3-ylmethyl ester (256 mg) and the compound (311 mg) obtained in Reference Example 15.
  • Example 195 [[7-hydroxy-5- (2-trifluoromethylpyridin-4-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid
  • the title compound (160 mg) was obtained in the same manner as in Example 130, using (2-trifluoromethylpyridin-4-yl) methanol (177 mg) and the compound (311 mg) obtained in Reference Example 15.
  • Example 196 [[5- (2,6-Dimethylpyridin-4-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid Using the methanesulfonic acid 2,6-dimethylpyridin-4-ylmethyl ester (161 mg) and the compound obtained in Reference Example 15 (250 mg), the title compound (120 mg) was obtained in the same manner as in Example 152.
  • Example 197 [[5- (2,6-dichloropyridin-4-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid
  • the title compound (180 mg) was obtained in the same manner as in Example 152, using methanesulfonic acid 2,6-dichloropyridin-4-ylmethyl ester (256 mg) and the compound (311 mg) obtained in Reference Example 15.
  • Example 198 ⁇ [7-Hydroxy-5- (quinolin-4-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridin-8-carbonyl] amino ⁇ acetic acid quinolin-4-yl
  • the title compound (70 mg) was obtained in the same manner as Example 192 using methanol (94 mg) and the compound (200 mg) obtained in Reference Example 15.
  • Example 199 [[7-Hydroxy-5- (8-trifluoromethylquinolin-4-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid Sodium borohydride (86 mg) was added to a methanol solution (4 mL) of 8-trifluoromethylquinoline-4-carbaldehyde (341 mg), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Example 200 [[7-Hydroxy-5- (quinolin-2-ylmethylsulfanyl) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-quinoline methanol ( 230 mg) and the compound obtained in Reference Example 15 (300 mg) were used in the same manner as in Example 94 to obtain the title compound (130 mg).
  • Example 201 [[7-Hydroxy-5- (2-methylbutoxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-methylbutanol (22 mg) and The title compound (50 mg) was obtained in the same manner as in Reference Example 11, Example 4 and 5, using the compound (93.7 mg) obtained in Reference Example 10.
  • Example 202 (S)-[(7-hydroxy-5- (2-methylbutoxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid (S)-
  • the title compound (35 mg) was obtained in the same manner as in Example 201, using 2-methylbutanol (22 mg) and the compound (94 mg) obtained in Reference Example 10.
  • Example 203 [(5-butoxy-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid obtained in n-butanol (108 mg) and Reference Example 10
  • the title compound (123 mg) was obtained in the same manner as in Example 201 using the obtained compound (250 mg).
  • Example 204 ⁇ [5- (3,3-dimethylbutoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3,3-dimethylbutanol (72 mg) and the compound obtained in Reference Example 10 (200 mg) were used in the same manner as Reference Example 11, Reference Example 2 and Example 1, ⁇ [7-benzyloxy-5- (3,3-dimethylbutoxy) -[1,2,4] Triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid methyl ester was obtained.
  • Example 205 [[5- (2-Ethylbutoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-ethylbutanol (90 mg) and The title compound (90 mg) was obtained in the same manner as in Example 201 using the compound (200 mg) obtained in Reference Example 10.
  • Example 206 [[5- (2,3-Dimethylbutoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2,3-dimethylbutane
  • the title compound (35 mg) was obtained in the same manner as in Example 201, using -1-ol (77 mg) and the compound (200 mg) obtained in Reference Example 10.
  • Example 207 [[5- (1,2-dimethylbutoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 1,2-dimethylbutanol (185 mg) and the compound (500 mg) obtained in Reference Example 10 were used in the same manner as in Reference Example 11 to obtain an ether form (216 mg). Subsequently, it melt
  • Example 208 [[7-Hydroxy-5- (4-methylpentyloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 4-methylpentanol (72 mg ) And the compound (200 mg) obtained in Reference Example 10 were used in the same manner as in Example 201 to obtain the title compound (83 mg).
  • Example 209 [[7-Hydroxy-5- (3-methylpentyloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid-methylpentan-1-ol (72 mg) and the compound (200 mg) obtained in Reference Example 10 were used, and the title compound (75 mg) was obtained in the same manner as in Example 201.
  • Example 210 [(7-Hydroxy-5- (pent-3-ynyloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 3-pentyn-1-ol (59 mg) and the compound (200 mg) obtained in Reference Example 10 were used, and the title compound (36 mg) was obtained in the same manner as in Example 201.
  • Example 211 [[5- (1,4-Dimethylpentyloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 1,4-dimethyl
  • the title compound (50 mg) was obtained in the same manner as in Example 201, using -1-pentanol (116 mg) and the compound (300 mg) obtained in Reference Example 10.
  • Example 212 [(5-Hexyloxy-7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid 1-hexanol (85 mg) and Reference Example 10
  • the title compound (25 mg) was obtained in the same manner as in Example 201 using the obtained compound (122 mg).
  • Example 213 [[5- (Hex-4-en-1-yloxy) -7-hydroxy- [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid cis- Using 4-hexen-1-ol (70.3 mg) and the compound obtained in Reference Example 10 (200 mg), the title compound (57 mg) was obtained in the same manner as in Example 201.
  • Example 214 [[7-Hydroxy-5- (oct-3-en-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid cis-3 Using the -octen-1-ol (90 mg) and the compound (250 mg) obtained in Reference Example 10, the title compound (310 mg) was obtained in the same manner as in Example 201.
  • Example 215 [[7-hydroxy-5- (non-3-yn-1-yloxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 3-nonine
  • the title compound (35 mg) was obtained in the same manner as in Example 201, using -1-ol (98.5 mg) and the compound (200 mg) obtained in Reference Example 10.
  • Example 216 ([5- [2- (2-ethoxyethoxy) ethoxy] -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino) acetic acid diethylene glycol monoethyl
  • the title compound (40 mg) was obtained in the same manner as in Example 201 using ether (100 mg) and the compound (200 mg) obtained in Reference Example 10.
  • Example 217 [[5- (2-cyclohexylethoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-cyclohexane-1-ethanol ( The title compound (44 mg) was obtained in the same manner as in Example 201 using 46 mg) and the compound (102 mg) obtained in Reference Example 10.
  • Example 218 ⁇ [5- (2-cyclobutylethoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-cyclobutylethanol (60 mg ) And the compound (200 mg) obtained in Reference Example 10 were used in the same manner as in Example 201 to obtain the title compound (25 mg).
  • Example 219 ⁇ [5- (2-Cyclopentylethoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-cyclopentylethanol (114 mg) and The title compound (66 mg) was obtained in the same manner as in Example 201 using the compound (200 mg) obtained in Reference Example 10.
  • Example 220 [[5- (2-bicyclo [2.2.1] hept-2-ylethoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] Amino ⁇ acetic acid 2-bicyclo [2,2,1] hept-2-ylethanol (164 mg) and the compound obtained in Reference Example 10 (200 mg) were used in the same manner as in Example 201 to give the title compound (40 mg). Got.
  • Example 221 [[5- (2-adamantan-1-ylethoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 2-adamantane-1 -The title compound (67 mg) was obtained in the same manner as in Example 201 using ylethanol (128 mg) and the compound (200 mg) obtained in Reference Example 10.
  • Example 222 [(7-hydroxy-5-phenethyloxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl) amino] acetic acid obtained in 2-phenylethanol (90 mg) and Reference Example 10 Using the obtained compound (200 mg), the title compound (70 mg) was obtained in the same manner as in Example 201.
  • Example 223 ([5- [2- (2-Fluorophenyl) ethoxy] -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino) acetic acid 2- ( Using 2-fluorophenyl) -1-ethanol (139 mg) and the compound (300 mg) obtained in Reference Example 10, the title compound (73 mg) was obtained in the same manner as in Example 201.
  • Example 224 [[7-hydroxy-5- (2-thiophen-2-ylethoxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-thiophene ethanol ( 81 mg) and the compound (200 mg) obtained in Reference Example 10 were used, and the title compound (35 mg) was obtained in the same manner as in Example 201.
  • Example 225 ⁇ [5- (3-cyclohexylpropoxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino ⁇ acetic acid 3-cyclohexylpropanol (139 ⁇ L) and Using the compound (200 mg) obtained in Reference Example 10, the title compound (60 mg) was obtained in the same manner as in Reference Example 11, Example 4 and Example 5.
  • Example 226 [[7-Hydroxy-5- (2-phenoxyethoxy) [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-phenoxyethanol (90 mg) and reference Using the compound (200 mg) obtained in Example 10, the title compound (70 mg) was obtained in the same manner as in Example 201.
  • Example 227 [[5- (2,6-Dimethylbenzyloxy) -7-hydroxy [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carbonyl] amino] acetic acid 2-fluoro-5 -Methylbenzyl alcohol (3.34 g) was dissolved in HMPA (35 mL), NaH (866 mg) was added with stirring in an ice bath, stirred at 65 ° C. for 2 hours, and cooled in an ice bath with cooling and stirring.
  • 5-Iodo [1,2,4] triazolo [1,5- ⁇ ] pyridine-8-carboxylic acid t-butyl ester (3.26 g) was added, and the mixture was stirred at 15 ° C.
  • Tables 1 to 35 below list the chemical structural formulas and physical property data in the above examples for the compounds represented by the general formula (1).
  • EPO increase rate (%) (EPO concentration when test substance is added / EPO concentration when medium is added ⁇ 1) ⁇ 100
  • the compound of the present invention has a sustained and strong EPO production promoting action at a concentration of 1 ⁇ M, and is significantly superior to the compound described in Patent Document 1.
  • Formulation example (tablet manufacturing method) 1) Example 11 5.0 mg 2) Lactose 94.0mg 3) Corn starch 20.0mg 4) Hydroxypropylcellulose 4.0mg 5) Magnesium stearate 0.5mg 6) Carboxymethylcellulose 6.5mg Total (1 tablet) 130.0mg
  • the above 1), 2) and 3) are dispersed with a stirring granulator, the aqueous solution of 4) is added to this powder, kneaded, dried and sized, and 5) and 6) are added and mixed. Tablet using a tablet machine.
  • the compound of the present invention has a sustained and excellent EPO production-promoting action, and is useful for the prevention or treatment of diseases in which a hypoxic environment occurs in a target organ or tissue, particularly for the prevention or treatment of anemia.

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Abstract

The present invention relates to a compound represented by the following general formula (1) [wherein X represents an oxygen atom, an imino group, a sulfur atom, sulfinyl, or sulfonyl, R1, R2, and R3 each independently represent a hydrogen atom or a C1-6 alkyl group, R4 represents a hydrogen atom, a C1-6 alkyl group, or an arylalkyl group, R5 represents an alkyl, alkenyl, alkynyl, aryl, or heteroaryl group]. This compound has excellent EPO-production acceleration activity and is useful as a pharmaceutical.

Description

新規複素環誘導体New heterocyclic derivatives
　本発明は、エリスロポエチン（Ｅｒｙｔｈｒｏｐｏｉｅｔｉｎ：ＥＰＯ）産生促進作用を有する新規複素環誘導体に関する。 The present invention relates to a novel heterocyclic derivative having an erythropoietin (EPO) production promoting action.
　ＥＰＯは主に腎臓、一部肝臓で産生されるアミノ酸１６５個からなる糖タンパク質ホルモンであり、赤芽球系幹細胞（前駆細胞）の分化誘導を促進し成熟赤血球を産生する。血中のＥＰＯ濃度と赤血球産生には正の相関関係があり、また、赤血球数の増加には、ＥＰＯ濃度の持続の重要性が示唆されている（非特許文献１)。 EPO is a glycoprotein hormone consisting of 165 amino acids produced mainly in the kidney and partly in the liver, and promotes differentiation induction of erythroid stem cells (progenitor cells) to produce mature erythrocytes. There is a positive correlation between EPO concentration in blood and erythrocyte production, and it is suggested that the increase in the number of erythrocytes is important in maintaining EPO concentration (Non-patent Document 1).
　ＥＰＯの産生は転写因子である低酸素誘導性因子（ｈｙｐｏｘｉａ　ｉｎｄｕｃｉｂｌｅ　ｆａｃｔｏｒ：ＨＩＦ）により制御される。ＨＩＦはαサブユニット（ＨＩＦ－α）とβサブユニット（ＨＩＦ－β）から構成され、組織内の酸素濃度によって異なる反応を示す。正常酸素圧下ではＨＩＦ－αはプロリルヒドロキシラーゼ（ＰＨＤ）によりプロリン残基がヒドロキシル化され、ユビキチン－プロテアソーム系により分解される。 EPO production is controlled by a transcription factor, hypoxia-inducible factor (HIF). HIF is composed of an α subunit (HIF-α) and a β subunit (HIF-β), and shows different responses depending on the oxygen concentration in the tissue. Under normoxia, HIF-α is hydroxylated at the proline residue by prolyl hydroxylase (PHD) and is degraded by the ubiquitin-proteasome system.
　ＰＨＤには１～３のアイソフォームが存在し、細胞内における局在、酸素分圧応答、ＨＩＦアイソフォームに対する反応性などがそれぞれ異なることが報告されている（非特許文献２、３）。又、ＨＩＦ－αにもいくつかのアイソフォームがあり、ＨＩＦ－１αおよびＨＩＦ－２αは構造上きわめて類似しているものの、発現量・局在は異なる（非特許文献３）。ＨＩＦについてはＥＰＯ以外の低酸素誘導性因子（グルコーストランスポーター１および３、乳酸脱水素酵素、ヘプシジンなど）への影響も示唆されている（非特許文献３、４）が、その生理機能については十分解明されていない。 It has been reported that PHD has 1 to 3 isoforms, and each has different intracellular localization, oxygen partial pressure response, reactivity to HIF isoform, etc. (Non-patent Documents 2 and 3). HIF-α also has several isoforms. Although HIF-1α and HIF-2α are very similar in structure, their expression levels and localization are different (Non-patent Document 3). HIF has also been suggested to affect hypoxia-inducible factors other than EPO (glucose transporters 1 and 3, lactate dehydrogenase, hepcidin, etc.) (Non-Patent Documents 3 and 4). It is not fully understood.
　一方、低酸素下ではＨＩＦ－αはＰＨＤによる分解を受けずに安定化し、細胞質から核内に移行してＨＩＦ－βと二量体を形成する。ＨＩＦ－αとβのヘテロ二量体はＥＰＯ遺伝子のｈｙｐｏｘｉａ　ｒｅｓｐｏｎｓｉｂｌｅ　ｅｌｅｍｅｎｔ配列に結合して転写を亢進し、ＥＰＯ産生を促進する。ＰＨＤ阻害に基づくＨＩＦの安定化がＥＰＯ産生を促進し、ＥＰＯ濃度の上昇とともに赤血球の増加をもたらすことが、げっ歯類、サル或いはヒトなどの哺乳動物で確認され、ＰＨＤ阻害によるＥＰＯ産生促進剤は貧血治療薬としての有用性が示されている（特許文献１、２、３及び非特許文献５、６）。 On the other hand, under hypoxia, HIF-α is stabilized without being degraded by PHD, and moves from the cytoplasm into the nucleus to form a dimer with HIF-β. The heterodimer of HIF-α and β binds to the hypoxia responsive element sequence of the EPO gene to enhance transcription and promote EPO production. It has been confirmed in mammals such as rodents, monkeys, and humans that stabilization of HIF based on PHD inhibition promotes EPO production and increases erythrocytes with increasing EPO concentration. EPO production promoter by PHD inhibition Has been shown to be useful as a therapeutic agent for anemia (Patent Documents 1, 2, 3 and Non-Patent Documents 5, 6).
　例えば、腎臓障害等により、腎臓においてＥＰＯの産生低下が起こると、血液中のＥＰＯ濃度は低下し、赤血球の産生が抑制され、貧血（腎性貧血）が生じる。腎不全などの急性腎疾患では、高い確率で腎性貧血を起こすことが知られている。なお、腎臓障害等とは関係なく、ＥＰＯ産生低下に起因する貧血も知られている。 For example, when EPO production decreases in the kidney due to kidney damage or the like, the EPO concentration in the blood decreases, red blood cell production is suppressed, and anemia (renal anemia) occurs. In acute kidney diseases such as renal failure, it is known to cause renal anemia with a high probability. In addition, anemia resulting from a decrease in EPO production is also known regardless of kidney damage or the like.
　これら疾患に対する主な治療方法としては、遺伝子組み換えヒトＥＰＯ製剤（以下、ＥＰＯ製剤）による、慢性腎臓病（ｃｈｒｏｎｉｃ　ｋｉｄｎｅｙ　ｄｉｓｅａｓｅ：ＣＫＤ）患者における貧血治療、自己貯血及び未熟児貧血の治療、ＡＩＤＳ及び化学療法を受けている癌患者の貧血治療等が知られている。 The main treatments for these diseases include anemia treatment in patients with chronic kidney disease (CKD) using genetically modified human EPO preparation (hereinafter referred to as EPO preparation), treatment of self-accumulation and premature infant anemia, AIDS and chemistry. Treatment of anemia for cancer patients undergoing therapy is known.
　また、貧血以外の疾患、すなわち、虚血性心疾患（狭心症、心筋梗塞など）、虚血性脳血管障害（脳塞栓症、脳梗塞など）、虚血性腎疾患（虚血性腎不全など）、下肢虚血（閉塞性動脈硬化症、バージャー病、糖尿病性壊疽など）、虚血性腸炎（虚血性大腸炎など）などの虚血性疾患及び脂肪肝などの代謝性疾患も対象臓器或いは組織においては低酸素環境下にあり、ＰＨＤ阻害に基づくＨＩＦの安定化はこれらの疾患に対して、予防又は治療効果をもたらすことが期待される（非特許文献７、８）。 In addition, diseases other than anemia, such as ischemic heart disease (such as angina pectoris, myocardial infarction), ischemic cerebrovascular disorder (cerebral embolism, cerebral infarction, etc.), ischemic kidney disease (such as ischemic renal failure) Ischemic diseases such as lower limb ischemia (obstructive arteriosclerosis, Buerger's disease, diabetic gangrene, etc.), ischemic enteritis (such as ischemic colitis), and metabolic diseases such as fatty liver are also low in the target organ or tissue. Under the oxygen environment, stabilization of HIF based on PHD inhibition is expected to have a preventive or therapeutic effect on these diseases (Non-patent Documents 7 and 8).
　上記ＥＰＯ製剤は定期的な輸血を必要とする患者を激減させ、貧血に伴う諸症状を改善し、貧血患者のＱＯＬ（Ｑｕａｌｉｔｙ　ｏｆ　ｌｉｆｅ）の改善に大きく貢献してきた。しかしながら、ＥＰＯ製剤は糖タンパク質のため、ＥＰＯ表面に結合した糖鎖の構造は複雑であり、そのグリコシル化は広範かつ多様であることから、サイズの不均一性を示し、遺伝子組換えヒトＥＰＯではヒト血清ＥＰＯを再現性よく作製することが困難であった。また、生物製剤であるため高価格であり、医療費の面からも患者の負担となっている。更に、投与経路が注射であるため、医療事故防止や患者負担軽減の観点からも、経口投与可能な内因性ＥＰＯを増加させる方法及び／又は化合物が切望されている。 The above-mentioned EPO preparation has drastically reduced the number of patients who require regular blood transfusion, has improved various symptoms associated with anemia, and has greatly contributed to the improvement of QOL (Quality of life) of anemia patients. However, since the EPO preparation is a glycoprotein, the structure of the sugar chain attached to the EPO surface is complex, and its glycosylation is extensive and diverse. It was difficult to produce human serum EPO with good reproducibility. Moreover, since it is a biologic, it is expensive, and it is a burden on the patient from the viewpoint of medical costs. Furthermore, since the route of administration is injection, a method and / or compound for increasing endogenous EPO that can be administered orally is also desired from the viewpoint of preventing medical accidents and reducing patient burden.
　上記、低分子化合物のＥＰＯ産生促進剤として、トリアゾロピリジン誘導体（特許文献１）、ピリミジン誘導体（特許文献４、５）、イソキノリン誘導体（特許文献３、６）、二環ピリジン誘導体（特許文献７）、二環式複素芳香族Ｎ置換グリシン誘導体（特許文献８）等が開発されている。 As the above EPO production promoter for low molecular weight compounds, triazolopyridine derivatives (Patent Document 1), pyrimidine derivatives (Patent Documents 4 and 5), isoquinoline derivatives (Patent Documents 3 and 6), bicyclic pyridine derivatives (Patent Document 7) ), Bicyclic heteroaromatic N-substituted glycine derivatives (Patent Document 8) and the like have been developed.
特開２０１１－３７８４１JP 2011-37841 A 特開２００６－１３７７６３JP 2006-137763 A 特表２００８－５４６６４４Special table 2008-546644 特開２０１１－８８８４０JP2011-88840 特表２００９－５４１３５１Special table 2009-541351 特開２０１１－１４８８１０JP2011-148810A 特表２００９－５４１４８６Special table 2009-541486 特表２００９－５３７５５８Special table 2009-537558
　本発明の目的は、ＥＰＯ産生促進作用を有する、新規な化合物を提供することを課題とし、対象臓器或いは組織において低酸素環境が生じる疾患の症状の予防又は治療、特に貧血の予防又は治療に有用な医薬を提供することである。 An object of the present invention is to provide a novel compound having an EPO production promoting action, and is useful for the prevention or treatment of a symptom of a disease in which a hypoxic environment occurs in a target organ or tissue, particularly for the prevention or treatment of anemia. Providing a good medicine.
　本発明者らは鋭意研究した結果、ＰＨＤを阻害し、特許文献１記載の化合物に比べて強力なＥＰＯ産生促進作用を示す新規な化合物を見出した。 As a result of intensive studies, the present inventors have found a novel compound that inhibits PHD and exhibits a stronger EPO production promoting action than the compound described in Patent Document 1.
　すなわち、本発明は、次の〔１〕～〔１０〕を提供するものである。 That is, the present invention provides the following [1] to [10].
〔１〕下記一般式（１）
Figure JPOXMLDOC01-appb-C000002
 [1] The following general formula (1)
Figure JPOXMLDOC01-appb-C000002
［上記式中、
Ｘは酸素原子、イミノ基、硫黄原子、スルフィニル又はスルホニルを示し、
Ｒ1、Ｒ2及びＲ3はそれぞれ独立に、水素原子又はＣ1－Ｃ6のアルキル基を示し、
Ｒ4は水素原子、Ｃ1－Ｃ6のアルキル基又はアリールアルキル基を示し、
Ｒ5は置換基群から選択される基で置換されていても良いアルキル基、置換基群から選択される基で置換されていても良いアルケニル基、置換基群から選択される基で置換されていても良いアルキニル基、置換基群から選択される基で独立に１乃至７個置換基を有してもよいアリール基、置換基群から選択される基で独立に１乃至７個置換基を有してもよいヘテロアリール基を示す。置換基群は、１乃至７個置換基を有してもよいアリール基（当該アリール基上の置換基としてはＣ1－Ｃ6のアルキル基、トリフルオロメチル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基又はフェニル基を示す）、１乃至７個置換基を有してもよいヘテロアリール基（当該ヘテロアリール基上の置換基としてはＣ1－Ｃ6のアルキル基、トリフルオロメチル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基又はフェニル基を示す）、Ｃ1－Ｃ6のアルキル基（Ｃ3－Ｃ6アルキル基の場合は、炭素原子同士が結合して３乃至６員飽和環を形成しても良い）、Ｃ2－Ｃ6のアルケニル基、Ｃ2－Ｃ6のアルキニル基、アリールアルキル基、Ｃ2－Ｃ8のアルコキシカルボニル基、ハロゲン原子、Ｃ1－Ｃ6のハロゲン化アルキル基、ヒドロキシ基、Ｃ1－Ｃ6のアルコキシ基、Ｃ1－Ｃ6のハロゲン化アルコキシ基、アリールオキシ基、カルバモイル基、Ｃ2－Ｃ6のアルキルカルボニル基、シアノ基、カルボキシル基、ホルミル基、ニトロ基、アミノ基、Ｃ1－Ｃ6のアルキルアミノ基、Ｃ1－Ｃ6のアルキルアミノカルボニル基、Ｃ1－Ｃ6のアルキルカルボニルアミノ基、アリールアミノ基、アミノスルホニル基、Ｃ1－Ｃ6のアルキルスルホニル基、Ｃ1－Ｃ6のハロゲン化アルキルスルホニル基、アリールスルホニル基、Ｃ1－Ｃ6のアルキルスルファニル基、Ｃ1－Ｃ6のハロゲン化アルキルスルファニル基及びアリールスルファニル基からなる群を示す。］を有する化合物又はその薬学上許容される塩。
〔２〕前記〔１〕記載の化合物又はその薬学上許容される塩、及び薬学上許容される担体を含有する医薬組成物。
〔３〕前記〔１〕記載の化合物又はその薬学上許容される塩を有効成分とする医薬。
〔４〕前記〔１〕記載の化合物又はその薬学上許容される塩を有効成分とするＥＰＯ産生促進薬。
〔５〕ＥＰＯ産生促進するための前記〔１〕記載の化合物又はその薬学上許容される塩。
〔６〕慢性腎不全患者における貧血、自己貯血、未熟児貧血、ＡＩＤＳ又は化学療法を受けている癌患者の貧血、慢性貧血、鉄欠乏性貧血、再生不良性貧血、溶血性貧血及び巨赤芽球性貧血から選ばれる貧血を予防及び／又は治療するための、前記〔１〕記載の化合物又はその薬学上許容される塩。
〔７〕ＥＰＯ産生促進薬製造のための、前記〔１〕記載の化合物又はその薬学上許容される塩の使用。
〔８〕慢性腎不全患者における貧血、自己貯血、未熟児貧血、ＡＩＤＳ又は化学療法を受けている癌患者の貧血、慢性貧血、鉄欠乏性貧血、再生不良性貧血、溶血性貧血及び巨赤芽球性貧血から選ばれる貧血を予防及び／又は治療薬製造のための、前記〔１〕記載の化合物又はその薬学上許容される塩の使用。
〔９〕前記〔１〕記載の化合物又はその薬学上許容される塩を投与することを特徴とするＥＰＯ産生促進方法。
〔10〕前記〔１〕記載の化合物又はその薬学上許容される塩を投与することを特徴とする、慢性腎不全患者における貧血、自己貯血、未熟児貧血、ＡＩＤＳ又は化学療法を受けている癌患者の貧血、慢性貧血、鉄欠乏性貧血、再生不良性貧血、溶血性貧血及び巨赤芽球性貧血から選ばれる貧血の予防及び／又は治療方法。 [In the above formula,
X represents an oxygen atom, an imino group, a sulfur atom, sulfinyl or sulfonyl,
R 1 , R 2 and R 3 each independently represents a hydrogen atom or a C 1 -C 6 alkyl group,
R 4 represents a hydrogen atom, a C 1 -C 6 alkyl group or an arylalkyl group,
R 5 is an alkyl group which may be substituted with a group selected from the substituent group, an alkenyl group which may be substituted with a group selected from the substituent group, or a group selected from the substituent group. An alkynyl group optionally selected from a substituent group, an aryl group optionally having 1 to 7 substituents, and a group selected from substituent groups independently having 1 to 7 substituents The heteroaryl group which may have is shown. The substituent group includes an aryl group which may have 1 to 7 substituents (the substituent on the aryl group includes a C 1 -C 6 alkyl group, a trifluoromethyl group, a halogen atom, a methoxy group, A heteromethoxy group which may have 1 to 7 substituents (the substituent on the heteroaryl group includes a C 1 -C 6 alkyl group, trifluoro; Methyl group, halogen atom, methoxy group, trifluoromethoxy group, cyano group or phenyl group), C 1 -C 6 alkyl group (in the case of C 3 -C 6 alkyl group, carbon atoms are bonded to each other) A 3- to 6-membered saturated ring may be formed), a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, an arylalkyl group, a C 2 -C 8 alkoxycarbonyl group, a halogen atom, 1 -C 6 Halogenated alkyl group, hydroxy group, C 1 -C 6 alkoxy group, C 1 -C 6 halogenated alkoxy group, aryloxy group, carbamoyl group, C 2 -C 6 alkylcarbonyl group, cyano group, carboxyl Group, formyl group, nitro group, amino group, C 1 -C 6 alkylamino group, C 1 -C 6 alkylaminocarbonyl group, C 1 -C 6 alkylcarbonylamino group, arylamino group, aminosulfonyl group C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, arylsulfonyl group, C 1 -C 6 alkylsulfanyl group, C 1 -C 6 halogenated alkylsulfanyl group and aryl A group consisting of a sulfanyl group is shown. Or a pharmaceutically acceptable salt thereof.
[2] A pharmaceutical composition comprising the compound according to [1] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[3] A medicament comprising the compound according to [1] above or a pharmaceutically acceptable salt thereof as an active ingredient.
[4] An EPO production promoter comprising the compound according to [1] or a pharmaceutically acceptable salt thereof as an active ingredient.
[5] The compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof for promoting EPO production.
[6] Anemia in patients with chronic renal failure, self-accumulation, premature infant anemia, anemia in cancer patients undergoing AIDS or chemotherapy, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, and giant red bud The compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof for preventing and / or treating anemia selected from spherical anemia.
[7] Use of the compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof for producing an EPO production promoter.
[8] Anemia in patients with chronic renal failure, self-accumulation, premature infant anemia, anemia in cancer patients undergoing AIDS or chemotherapy, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, and giant red bud Use of the compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and / or treating anemia selected from spherical anemia.
[9] A method for promoting EPO production, comprising administering the compound according to [1] or a pharmaceutically acceptable salt thereof.
[10] An anemia, self-blood storage, premature infant anemia, AIDS or cancer receiving chemotherapy in a patient with chronic renal failure, characterized by administering the compound according to [1] or a pharmaceutically acceptable salt thereof A method for preventing and / or treating anemia selected from patient anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia and megaloblastic anemia.
　本発明の化合物は、特許文献１記載の化合物よりも持続的且つ優れたＥＰＯ産生促進作用を有することから、慢性腎不全患者における貧血、自己貯血及び未熟児貧血、ＡＩＤＳ及び化学療法を受けている癌患者の貧血、慢性貧血、鉄欠乏性貧血、再生不良性貧血、溶血性貧血、巨赤芽球性貧血などの貧血の予防薬及び／又は治療薬として有用である。 Since the compound of the present invention has a sustained and superior EPO production promoting effect than the compound described in Patent Document 1, it has undergone anemia, self-accumulation and premature infant anemia, AIDS and chemotherapy in patients with chronic renal failure. It is useful as a prophylactic and / or therapeutic agent for anemia such as anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, megaloblastic anemia in cancer patients.
　以下、本発明を具体的に説明する。 Hereinafter, the present invention will be specifically described.
　本明細書記載の「置換されていてもよい」とは、無置換、若しくは置換基を１～５個有していることを意味し、複数個の置換基を有する場合、それらの置換基は同一であっても、互いに異なっていてもよい。 The term “which may be substituted” in the present specification means unsubstituted or having 1 to 5 substituents, and when having a plurality of substituents, these substituents are They may be the same or different from each other.
　本明細書記載の「アルキル基」とは、直鎖状、分岐鎖状、環状、又はそれらの組み合わせのいずれであってもよい飽和炭化水素鎖を意味する。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、ｓ－ブチル、ｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、s－ペンチル、２－メチルブチル、１，２－ジメチルプロピル、ｎ－ヘキシル、イソヘキシル、ネオヘキシル、３－メチルペンチル、 ２，２－ジメチルブチル、１，３－ジメチルブチル、２，３－ジメチルブチル、２－エチルブチル、ｎ－へプチル、１，４－ジメチルヘプチル、３－エチルペンチル、２－プロピルペンチル、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、アダマンチル、メチルシクロプロピル、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、メチルアダマンチル、エチルシクロプロピル、エチルシクロブチル、エチルシクロペンチル、エチルシクロヘキシル、エチルアダマンチル、エチルビシクロ［2.2.1］ヘプチル等が挙げられる。このうち、Ｃ1－Ｃ18の直鎖又は分岐鎖アルキル基、Ｃ3－Ｃ18の環状アルキル基、又はそれらの組み合わせが好ましく、Ｃ1－Ｃ4の直鎖又は分岐鎖アルキル基、Ｃ3－Ｃ12環状アルキル基、又はそれらの組み合わせがより好ましい。 The “alkyl group” described in the present specification means a saturated hydrocarbon chain that may be linear, branched, cyclic, or a combination thereof. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, s-pentyl, 2-methylbutyl, 1,2-dimethylpropyl, n -Hexyl, isohexyl, neohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 1,4-dimethylheptyl, 3 -Ethylpentyl, 2-propylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methyladamantyl, ethylcyclopropyl, ethylcyclobutyl, ethyl Ropenchiru, ethyl cyclohexyl, ethyl adamantyl, ethylbicyclo [2.2.1] heptyl and the like. Of these, a C 1 -C 18 linear or branched alkyl group, a C 3 -C 18 cyclic alkyl group, or a combination thereof is preferred, and a C 1 -C 4 linear or branched alkyl group, C 3 A —C 12 cyclic alkyl group or a combination thereof is more preferred.
　本明細書記載の「アルケニル基」とは、直鎖状、分岐鎖状、環状、又はそれらの組み合わせのいずれであってもよい二重結合を有する不飽和炭化水素鎖を意味する。例えば、ｎ－プロペニル、ｎ－ブテニル、ｎ－ペンテニル、ｎ－ヘキセニル、ｎ－ヘプテニル、ｎ－オクテニル等が挙げられる。このうち、Ｃ2－Ｃ18の直鎖又は分岐鎖アルケニル基が好ましく、Ｃ2－Ｃ14の直鎖又は分岐鎖アルケニル基がより好ましい。 The “alkenyl group” described in the present specification means an unsaturated hydrocarbon chain having a double bond, which may be linear, branched, cyclic, or a combination thereof. For example, n-propenyl, n-butenyl, n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl and the like can be mentioned. Of these, a C 2 -C 18 linear or branched alkenyl group is preferable, and a C 2 -C 14 linear or branched alkenyl group is more preferable.
　本明細書記載の「アルキニル基」とは、直鎖状、分岐鎖状、環状、又はそれらの組み合わせのいずれであってもよい三重結合を有する不飽和炭化水素鎖を意味する。例えば、ｎ－ペンチニル、ｎ－ヘキシニル等が挙げられる。このうち、Ｃ2－Ｃ8の直鎖又は分岐鎖アルキニル基が好ましい。 The “alkynyl group” described in the present specification means an unsaturated hydrocarbon chain having a triple bond which may be linear, branched, cyclic, or a combination thereof. For example, n-pentynyl, n-hexynyl and the like can be mentioned. Of these, a C 2 -C 8 linear or branched alkynyl group is preferred.
　本明細書記載の「アリール基」とは、単環、二環又は三環式アリール基であり、一部の環が芳香環を有しているアリール基も含まれる。好ましくは、炭素数６～１４の単環、二環又は三環式アリール基が挙げられる。具体例としては、フェニル基、ナフチル基、テトラヒドロナフチル基、インデニル基、インダニル基、フェナントレニル基、フルオレニル基等が挙げられる。 The “aryl group” described in the present specification is a monocyclic, bicyclic or tricyclic aryl group, and includes an aryl group in which some of the rings have an aromatic ring. Preferably, a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms is used. Specific examples include phenyl group, naphthyl group, tetrahydronaphthyl group, indenyl group, indanyl group, phenanthrenyl group, fluorenyl group and the like.
　本明細書記載の「ヘテロアリール基」とは、単環、二環又は三環式ヘテロアリール基であり、例えば１～４個のヘテロ原子（窒素原子、酸素原子又は硫黄原子）を有する単環、二環又は三環のヘテロアリール基が挙げられる。具体例としては、ピロリル基、フラニル基、チエニル基、ピリジル基、イミダゾリル基、ピラゾリル基、オキサゾリル基、チアゾリル基、ピラジル基、キノリル基、イソキノリル基、キナゾリル基、インドリル基、ベンゾチオフェニル基、ベンゾフラニル基、ベンゾイミダゾリル基、ベンゾオキサゾリル基、ベンゾチアゾリル基、ベンゾジオキサニル基，ジベンゾチオフェニル基、ジベンゾフラニル基、カルバゾリル基等が挙げられる。 The “heteroaryl group” described herein is a monocyclic, bicyclic or tricyclic heteroaryl group, for example, a monocyclic ring having 1 to 4 heteroatoms (nitrogen atom, oxygen atom or sulfur atom) , Bicyclic or tricyclic heteroaryl groups. Specific examples include pyrrolyl, furanyl, thienyl, pyridyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazyl, quinolyl, isoquinolyl, quinazolyl, indolyl, benzothiophenyl, benzofuranyl. Group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzodioxanyl group, dibenzothiophenyl group, dibenzofuranyl group, carbazolyl group and the like.
　本明細書において、置換基群は、１乃至７個置換基を有してもよいアリール基（当該アリール基上の置換基としてはＣ1－Ｃ6のアルキル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基又はフェニル基を示す）、１乃至７個置換基を有してもよいヘテロアリール基（当該ヘテロアリール基上の置換基としてはＣ1－Ｃ6のアルキル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基及びフェニル基を示す）、Ｃ1－Ｃ6のアルキル基（Ｃ3－Ｃ6アルキル基の場合は、炭素原子同士が結合して３乃至６員飽和環を形成しても良い）、Ｃ2－Ｃ6のアルケニル基、Ｃ2－Ｃ6のアルキニル基、アリールアルキル基、Ｃ2－Ｃ6のアルコキシカルボニル基、ハロゲン原子、Ｃ1－Ｃ6のハロゲン化アルキル基、ヒドロキシ基、Ｃ1－Ｃ6のアルコキシ基、Ｃ1－Ｃ6のハロゲン化アルコキシ基、アリールオキシ基、カルバモイル基、Ｃ2－Ｃ6のアルキルカルボニル基、シアノ基、カルボキシル基、ホルミル基、ニトロ基、アミノ基、Ｃ1－Ｃ6のアルキルアミノ基、Ｃ1－Ｃ6のアルキルアミノカルボニル基、Ｃ1－Ｃ6のアルキルカルボニルアミノ基、アリールアミノ基、アミノスルホニル基、Ｃ1－Ｃ6のアルキルスルホニル基、Ｃ1－Ｃ6のハロゲン化アルキルスルホニル基、アリールスルホニル基、Ｃ1－Ｃ6のアルキルスルファニル基、Ｃ1－Ｃ6のハロゲン化アルキルスルファニル基及びアリールスルファニル基からなる群を示す。 In this specification, the substituent group includes an aryl group which may have 1 to 7 substituents (the substituent on the aryl group includes a C 1 -C 6 alkyl group, a halogen atom, a methoxy group, A heteromethoxy group optionally having 1 to 7 substituents (a substituent on the heteroaryl group includes a C 1 -C 6 alkyl group, a halogen atom) , A methoxy group, a trifluoromethoxy group, a cyano group and a phenyl group), a C 1 -C 6 alkyl group (in the case of a C 3 -C 6 alkyl group, carbon atoms are bonded to each other to form a 3- to 6-membered saturated group) A C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, an arylalkyl group, a C 2 -C 6 alkoxycarbonyl group, a halogen atom, a C 1 -C 6 Halogenated alkyl group, H Droxy group, C 1 -C 6 alkoxy group, C 1 -C 6 halogenated alkoxy group, aryloxy group, carbamoyl group, C 2 -C 6 alkylcarbonyl group, cyano group, carboxyl group, formyl group, nitro Group, amino group, C 1 -C 6 alkylamino group, C 1 -C 6 alkylaminocarbonyl group, C 1 -C 6 alkylcarbonylamino group, arylamino group, aminosulfonyl group, C 1 -C 6 A group consisting of an alkylsulfonyl group, a C 1 -C 6 halogenated alkylsulfonyl group, an arylsulfonyl group, a C 1 -C 6 alkylsulfanyl group, a C 1 -C 6 halogenated alkylsulfanyl group, and an arylsulfanyl group. Show.
　一般式（１）中、Ｘとしては酸素原子、硫黄原子、スルフィニル又はスルホニルが好ましく、酸素原子又は硫黄原子がより好ましい。 In the general formula (1), X is preferably an oxygen atom, a sulfur atom, sulfinyl or sulfonyl, more preferably an oxygen atom or a sulfur atom.
　Ｒ1、Ｒ2及びＲ3は、それぞれ独立して、水素原子又はＣ1－Ｃ6のアルキル基を示すが、このうち水素原子がより好ましい。
　「Ｃ1－Ｃ6アルキル基」とは、直鎖状、分岐鎖状、環状又はそれらの組み合わせのいずれかであってもよい飽和炭化水素鎖を意味する。好ましくは、Ｃ1－Ｃ6の直鎖又は分岐鎖アルキル基、Ｃ3－Ｃ6の環状のアルキル基である。具体例としては、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、ｓ－ブチル、ｔ－ブチル、ｎ－ペンチル、ｎ－ヘキシル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等が挙げられる。 R 1 , R 2 and R 3 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group, and among these, a hydrogen atom is more preferred.
“C 1 -C 6 alkyl group” means a saturated hydrocarbon chain that may be linear, branched, cyclic, or a combination thereof. Preferably, it is a C 1 -C 6 linear or branched alkyl group or a C 3 -C 6 cyclic alkyl group. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
　Ｒ4は水素原子、Ｃ1－Ｃ6アルキル基又はアリールアルキル基を示すが、水素原子がより好ましい。
　「アリールアルキル基」とは、前記アリール基にＣ1－Ｃ6アルキル基が結合した基であり、例えばＣ6－Ｃ14アリール－Ｃ1－Ｃ6アルキル基が挙げられる。具体的には、フェニル－Ｃ1－Ｃ6アルキル基が好ましく、ベンジル基、フェネチル基がより好ましい。 R 4 represents a hydrogen atom, a C 1 -C 6 alkyl group or an arylalkyl group, and more preferably a hydrogen atom.
The “arylalkyl group” is a group in which a C 1 -C 6 alkyl group is bonded to the aryl group, and examples thereof include a C 6 -C 14 aryl-C 1 -C 6 alkyl group. Specifically, a phenyl-C 1 -C 6 alkyl group is preferable, and a benzyl group and a phenethyl group are more preferable.
　Ｒ5で示されるアルキル基、アルケニル基、アリール基又はヘテロアリール基としては、例えば、Ｃ1－Ｃ18の直鎖又は分岐鎖アルキル基、Ｃ3－Ｃ8の環状アルキル基又はそれらの組み合わせ、Ｃ2－Ｃ18の直鎖又は分岐鎖アルケニル基、Ｃ2－Ｃ8の直鎖又は分岐鎖のアルキニル基、炭素数６～１４の単環、二環又は三環式アリール基、１～４個のヘテロ原子（窒素原子、酸素原子又は硫黄原子）を有する単環、二環又は三環のヘテロアリール基が好ましい。さらにはＣ1－Ｃ14の直鎖又は分岐鎖アルキル基、Ｃ3－Ｃ12環状アルキル基又はそれらの組み合わせ、Ｃ2－Ｃ14の直鎖又は分岐鎖のアルケニル基、Ｃ2－Ｃ8の直鎖又は分岐鎖アルキニル基、フェニル基、ナフチル基、テトラヒドロナフチル基、インデニル基、インダニル基、フェナントレニル基、フルオレニル基、ピロリル基、フラニル基、チエニル基、ピリジル基、イミダゾリル基、ピラゾリル基、オキサゾリル基、チアゾリル基、ピラジル基、キノリル基、イソキノリル基、キナゾリル基、インドリル基、ベンゾチオフェニル基、ベンゾフラニル基、ベンゾイミダゾリル基、ベンゾオキサゾリル基、ジベンゾチオフェニル基、ジベンゾフラニル基、カルバゾリル基がより好ましい。 Examples of the alkyl group, alkenyl group, aryl group or heteroaryl group represented by R 5 include a C 1 -C 18 linear or branched alkyl group, a C 3 -C 8 cyclic alkyl group, or a combination thereof. C 2 -C 18 linear or branched alkenyl group, C 2 -C 8 linear or branched alkynyl group, monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms, 1 to 4 Monocyclic, bicyclic or tricyclic heteroaryl groups having 1 heteroatom (nitrogen atom, oxygen atom or sulfur atom) are preferred. Further, a C 1 -C 14 linear or branched alkyl group, a C 3 -C 12 cyclic alkyl group or a combination thereof, a C 2 -C 14 linear or branched alkenyl group, a C 2 -C 8 Linear or branched alkynyl group, phenyl group, naphthyl group, tetrahydronaphthyl group, indenyl group, indanyl group, phenanthrenyl group, fluorenyl group, pyrrolyl group, furanyl group, thienyl group, pyridyl group, imidazolyl group, pyrazolyl group, oxazolyl group , Thiazolyl group, pyrazyl group, quinolyl group, isoquinolyl group, quinazolyl group, indolyl group, benzothiophenyl group, benzofuranyl group, benzoimidazolyl group, benzoxazolyl group, dibenzothiophenyl group, dibenzofuranyl group, carbazolyl group and more preferable.
　Ｒ5に１～７個置換し得る置換群としては、１～７個置換を有してもよい炭素数６～１４の単環、二環又は三環性のアリール基（当該アリール基上の置換基としてはＣ1－Ｃ6のアルキル基、トリフルオロメチル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基又はフェニル基を示す）、１乃至７個置換基を有してもよい、１～４個のヘテロ原子（窒素原子、酸素原子又は硫黄原子）を有する単環、二環又は三環性のヘテロアリール基（当該ヘテロアリール基上の置換基としてはＣ1－Ｃ6のアルキル基、トリフルオロメチル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基又はフェニル基を示す）、Ｃ1－Ｃ6のアルキル基（Ｃ3－Ｃ6アルキル基の場合は、炭素原子同士が結合して３乃至６員飽和環を形成しても良い）、Ｃ2－Ｃ6のアルケニル基、Ｃ2－Ｃ6のアルキニル基、Ｃ6－Ｃ14アリール－Ｃ1－Ｃ6アルキル基、Ｃ2－Ｃ8のアルコキシカルボニル基、ハロゲン原子、Ｃ1－Ｃ6のハロゲン化アルキル基、ヒドロキシ基、Ｃ1－Ｃ6のアルコキシ基、Ｃ1－Ｃ6のハロゲン化アルコキシ基、Ｃ6－Ｃ14アリールオキシ基、カルバモイル基、Ｃ2－Ｃ6のアルキルカルボニル基、シアノ基、カルボキシル基、ホルミル基、ニトロ基、アミノ基、Ｃ1－Ｃ6のアルキルアミノ基、Ｃ1－Ｃ6のアルキルアミノカルボニル基、Ｃ1－Ｃ6のアルキルカルボニルアミノ基、アリールアミノ基、アミノスルホニル基、Ｃ1－Ｃ6のアルキルスルホニル基、Ｃ1－Ｃ6のハロゲン化アルキルスルホニル基、Ｃ6－Ｃ14アリールスルホニル基、Ｃ1－Ｃ6のアルキルスルファニル基、Ｃ1－Ｃ6のハロゲン化アルキルスルファニル基及びアリールスルファニル基からなる群が好ましい。 The substituent group which can be substituted with 1 to 7 substituents for R 5 includes a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms which may have 1 to 7 substitutions (on the aryl group). (The substituent is a C 1 -C 6 alkyl group, a trifluoromethyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group or a phenyl group) and may have 1 to 7 substituents. A monocyclic, bicyclic or tricyclic heteroaryl group having 1 to 4 heteroatoms (nitrogen atom, oxygen atom or sulfur atom) (substituents on the heteroaryl group include C 1 -C 6 An alkyl group, a trifluoromethyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group or a phenyl group), a C 1 -C 6 alkyl group (in the case of a C 3 -C 6 alkyl group, a carbon atom) Join together to form a 3-6 membered saturated ring C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 6 -C 14 aryl-C 1 -C 6 alkyl group, C 2 -C 8 alkoxycarbonyl group, Halogen atom, C 1 -C 6 halogenated alkyl group, hydroxy group, C 1 -C 6 alkoxy group, C 1 -C 6 halogenated alkoxy group, C 6 -C 14 aryloxy group, carbamoyl group, C 2- C 6 alkylcarbonyl group, cyano group, carboxyl group, formyl group, nitro group, amino group, C 1 -C 6 alkylamino group, C 1 -C 6 alkylaminocarbonyl group, C 1 -C 6 Alkylcarbonylamino group, arylamino group, aminosulfonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 6 -C 14 arylsulfonyl group, C 1 -C 6 And the group consisting of a C 1 -C 6 halogenated alkylsulfanyl group and an arylsulfanyl group.
　「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。「アリール基」としては、例えば、フェニル、ナフチル、テトラヒドロナフチル、インダニル、フェナントレニル、フルオレニル等が挙げられる。「Ｃ1－Ｃ6のアルキル基」としては、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、ｓ－ブチル、ｔ－ブチル、ｎ－ペンチル、ｎ－ヘキシル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等が挙げられる。「ヘテロアリール基」としては、ピロリル、フラニル、チオフェニル、ピリジル、キノリル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、ベンゾチアゾリル、ピラジル、ベンゾジオキサニル等が挙げられる。「アルケニル基」としては、ビニル、プロペニル、ブテニル等が挙げられる。「Ｃ2－Ｃ6のアルキニル基」としては、エチニル、プロピニル、ペンチニル等が挙げられる。「アリールアルキル基」としては、ベンジルが挙げられる。「Ｃ2－Ｃ6のアルコキシカルボニル基」としては、メトキシカルボニル、エトキシカルボニル、ｔ－ブトキシカルボニル等が挙げられる。「Ｃ1－Ｃ6のハロゲン化アルキル基」としては、トリフルオロメチル、トリフルオロエチル等が挙げられる。「Ｃ1－Ｃ6のアルコキシ基」としては、メトキシ、エトキシ、イソプロポキシ、ｔ－ブトキシ等が挙げられる。「Ｃ1－Ｃ6のハロゲン化アルコキシ基」としては、トリフルオロメトキシ、トリフルオロエトキシ等が挙げられる。「アリールオキシ基、カルバモイル基」としては、フェノキシ、ｔ－ブトキシカルバモイル、ベンジルカルバモイル等が挙げられる。「Ｃ2－Ｃ6のアルキルカルボニル基」としては、メチルカルボニル等が挙げられる。「Ｃ1－Ｃ6のアルキルアミノ基」としては、ジメチルアミノ、ベンジルアミノ等が挙げられる。「Ｃ1－Ｃ6のアルキルアミノカルボニル基」としては、ジメチルアミノカルボニル等が挙げられる。「Ｃ1－Ｃ6のアルキルカルボニルアミノ基」としては、アセチルアミノ等が挙げられる。「アリールアミノ基」としては、フェニルアミノ、ジフェニルアミノ等が挙げられる。「Ｃ1－Ｃ6のアルキルスルホニル基」としては、メタンスルホニル等が挙げられる。「Ｃ1－Ｃ6のハロゲン化アルキルスルホニル基」としては、トリフルオロメタンスルホニル等が挙げられる。「アリールスルホニル基」としては、フェニルスルホニル等が挙げられる。「Ｃ1－Ｃ6のアルキルスルファニル基」としては、メチルスルファニル、イソプロピルスルファニル等が挙げられる。「Ｃ1－Ｃ6のハロゲン化アルキルスルファニル基」としては、トリフルオロメタンスルファニル等が挙げられる。「アリールスルファニル基」としては、フェニルスルファニル等が挙げられる。 Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the “aryl group” include phenyl, naphthyl, tetrahydronaphthyl, indanyl, phenanthrenyl, fluorenyl and the like. Examples of the “C 1 -C 6 alkyl group” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, And cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of the “heteroaryl group” include pyrrolyl, furanyl, thiophenyl, pyridyl, quinolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzothiazolyl, pyrazyl, benzodioxanyl and the like. Examples of the “alkenyl group” include vinyl, propenyl, butenyl and the like. Examples of the “C 2 -C 6 alkynyl group” include ethynyl, propynyl, pentynyl and the like. Examples of the “arylalkyl group” include benzyl. Examples of the “C 2 -C 6 alkoxycarbonyl group” include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and the like. Examples of the “C 1 -C 6 halogenated alkyl group” include trifluoromethyl, trifluoroethyl and the like. Examples of the “C 1 -C 6 alkoxy group” include methoxy, ethoxy, isopropoxy, t-butoxy and the like. Examples of the “C 1 -C 6 halogenated alkoxy group” include trifluoromethoxy, trifluoroethoxy and the like. Examples of the “aryloxy group, carbamoyl group” include phenoxy, t-butoxycarbamoyl, benzylcarbamoyl and the like. Examples of the “C 2 -C 6 alkylcarbonyl group” include methylcarbonyl and the like. Examples of the “C 1 -C 6 alkylamino group” include dimethylamino, benzylamino and the like. Examples of the “C 1 -C 6 alkylaminocarbonyl group” include dimethylaminocarbonyl and the like. Examples of the “C 1 -C 6 alkylcarbonylamino group” include acetylamino and the like. Examples of the “arylamino group” include phenylamino, diphenylamino and the like. Examples of the “C 1 -C 6 alkylsulfonyl group” include methanesulfonyl and the like. Examples of the “C 1 -C 6 halogenated alkylsulfonyl group” include trifluoromethanesulfonyl and the like. Examples of the “arylsulfonyl group” include phenylsulfonyl and the like. Examples of the “C 1 -C 6 alkylsulfanyl group” include methylsulfanyl, isopropylsulfanyl and the like. Examples of the “C 1 -C 6 halogenated alkylsulfanyl group” include trifluoromethanesulfanyl and the like. Examples of the “arylsulfanyl group” include phenylsulfanyl and the like.
　一般式（１）の好ましい態様としては、上記記載の各好ましい基の組み合わせからなる化合物であるが、例えば、実施例記載の化合物、それら医薬上許容される塩、又はそれら水和物、若しくは溶媒和物などが挙げられる。 A preferred embodiment of the general formula (1) is a compound comprising a combination of each of the above-mentioned preferred groups. For example, the compounds described in the examples, their pharmaceutically acceptable salts, or their hydrates, or solvents Japanese products are listed.
　一般式（１）で表される、本発明の化合物又はその医薬上許容される塩、水和物、溶媒和物は、置換基の種類により二重結合に基づく幾何異性体や互変異性体が存在する場合、あるいは不斉炭素原子の存在により光学異性体やジアステレオマーが存在しうる場合がある。本発明においては、これら異性体を単離したもの、あるいは混合物をすべて包含する。 The compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a geometric isomer or tautomer based on a double bond depending on the type of substituent. In some cases, optical isomers and diastereomers may exist due to the presence of an asymmetric carbon atom. In the present invention, all isolated isomers or mixtures thereof are included.
　本発明の化合物及び医薬上許容される塩、水和物、溶媒和物の製造方法は、種々の公知技術により製造することが可能である。その際、官能基の種類によっては、当該官能基を原料若しくは中間体の段階で適当な保護基に置換することにより、製造技術上効果的な場合がある。このような官能基としてはアミノ基、ヒドロキシ基、カルボキシ基等が挙げられる。当該官能基に保護基を導入して製造を行った場合、各製造段階において適時保護基を除去することにより、所望の化合物を得ることができる。このような保護基の種類、脱着方法としては、例えばＰｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ：Ｔｈｉｒｄ Ｅｄｉｔｉｏｎ（Ｇｒｅｅｎｅ、Ｗｕｔｓ著）に記載の方法などが挙げられる。以下に本発明の化合物（１）の代表的な製造方法について説明する。 The production method of the compound of the present invention and pharmaceutically acceptable salts, hydrates and solvates can be produced by various known techniques. At that time, depending on the type of the functional group, there are cases where the functional group is replaced with an appropriate protective group at the stage of the raw material or intermediate, which is effective in terms of production technology. Examples of such functional groups include amino groups, hydroxy groups, and carboxy groups. When the production is carried out by introducing a protecting group into the functional group, the desired compound can be obtained by removing the protecting group at the appropriate time in each production stage. Examples of such protective group types and desorption methods include the methods described in Protective Groups In Organic Synthesis: Third Edition (by Greene, Wuts). Hereinafter, representative production methods of the compound (1) of the present invention will be described.
　本発明の化合物の製造方法は特に限定されないが、例えば下記の製造方法に従って製造することができる。 The production method of the compound of the present invention is not particularly limited, and can be produced, for example, according to the following production method.
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
（式中、Ｙは、メチル基、ｔｅｒｔ－ブチル基等のカルボキシル基の保護基であり、他の記号は前記と同義である。） (In the formula, Y represents a protecting group for a carboxyl group such as a methyl group or a tert-butyl group, and other symbols are as defined above.)
　第１工程：特許文献１に準じて製造した化合物（２）に、置換基もしくはその前駆体を常法に従い導入することにより、化合物（３）を得ることができる。例えばＸがＳの場合、化合物（２）を加温条件下、酢酸パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム等のパラジウム触媒、キサントホス、１，１－ビス（ジ－ｔｅｒｔ－ブチルホスフィノ）フェロセン、ビス［２－（ジフェニルホスフィノ）フェニル］エーテル等のリガンド及びジイソプロピルエチルアミン、炭酸カリウム、炭酸セシウム、炭酸ナトリウム、リン酸カリウム、カリウムｔ－ブトキシド等の塩基の存在下、１，４－ジオキサン、Ｎ，Ｎ－ジメチルホルムアミド、トルエン、シクロペンチルメチルエーテル等の溶媒中、チオール（Ｒ5ＳＨ）と反応させることにより、化合物（３）を得ることができる。また、ＸがＯの場合、化合物（２）を低温乃至加温条件下、ヨウ化銅、臭化銅、塩化銅、酸化銅等の銅触媒、２－シクロヘキサノンカルボン酸エチル、１，１０－フェナントロリン、（２－ピリジル）アセトン、ピコリン酸等のリガンド及び炭酸カリウム、炭酸セシウム、リン酸カリウム等の塩基の存在下、ジメチルスルホキシド、Ｎ，Ｎ－ジメチルホルムアミド、アセトニトリル、１，４－ジオキサン、トルエン等の溶媒中、フェノール（Ｒ5ＯＨ）と反応させることにより、化合物（３）を得ることができる。 1st process: A compound (3) can be obtained by introduce | transducing a substituent or its precursor into the compound (2) manufactured according to patent document 1 according to a conventional method. For example, when X is S, the compound (2) is heated under a palladium catalyst such as palladium acetate, tris (dibenzylideneacetone) dipalladium, xanthophos, 1,1-bis (di-tert-butylphosphino) ferrocene under heating conditions. 1,4-dioxane in the presence of a ligand such as bis [2- (diphenylphosphino) phenyl] ether and a base such as diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, potassium t-butoxide, Compound (3) can be obtained by reacting with thiol (R 5 SH) in a solvent such as N, N-dimethylformamide, toluene, cyclopentyl methyl ether and the like. When X is O, the compound (2) is subjected to a copper catalyst such as copper iodide, copper bromide, copper chloride, copper oxide, ethyl 2-cyclohexanone carboxylate, 1,10-phenanthroline under low temperature to warming conditions. , Dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, 1,4-dioxane, toluene, etc. in the presence of a ligand such as (2-pyridyl) acetone and picolinic acid and a base such as potassium carbonate, cesium carbonate and potassium phosphate The compound (3) can be obtained by reacting with phenol (R 5 OH) in the solvent.
　第２工程：化合物（３）のｔ－ブトキシカルボニル基を常法に従い、脱保護することにより、化合物（４）を得ることができる。例えば、化合物（３）を低温乃至加温条件下、ヘキサン、クロロホルム、塩化メチレン、酢酸エチル、トルエン、１，２－ジメトキシエタン、１，４－ジオキサン、テトラヒドロフラン、メタノール、エタノール、２－プロパノール、ジメチルスルホキシド、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、アセトニトリル、水等の単独又は混合溶媒中、ｐ－トルエンスルホン酸、メタンスルホン酸、三フッ化ホウ素、三塩化ホウ素、三臭化ホウ素、三塩化アルミニウム、塩化水素、臭化水素、リン酸、硫酸、酢酸、トリフルオロ酢酸等の酸と反応させることにより、化合物（４）を得ることができる。また、化合物（３）を加温条件下、メタノール、エタノール、２－プロパノール、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、Ｎ，Ｎ－ジメチルホルムアミド、アセトニトリル等の溶媒と水との混合溶媒中、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等の塩基と反応させることにより、化合物（４）を得ることができる。 Second step: Compound (4) can be obtained by deprotecting the t-butoxycarbonyl group of compound (3) according to a conventional method. For example, the compound (3) is hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, dimethyl under low temperature to warming conditions. P-Toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trichloride, boron tribromide in a single or mixed solvent such as sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, water, etc. Compound (4) can be obtained by reacting with an acid such as aluminum trichloride, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid or trifluoroacetic acid. Further, the compound (3) is heated under a heating condition between methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, acetonitrile and water. Compound (4) can be obtained by reacting with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide in a mixed solvent.
　第３工程：化合物（４）に常法に従い、Ｈ2ＮＣＨ2ＣＯＯＹで表されるグリシン誘導体を縮合することにより、化合物（５）を得ることができる。例えば、化合物（４）を低温乃至加温条件下、Ｎ，Ｎ－ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、クロロホルム、酢酸エチル、塩化メチレン、トルエン等の溶媒中、ジシクロヘキシルカルボジイミド、１，１´－カルボニルジイミダゾール、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド又はその塩、ジフェニルホスホリルアジド等の縮合剤及び必要に応じてＮ－ヒドロキシスクシンイミド、１－ヒドロキシベンゾトリアゾール、ジメチルアミノピリジン等の存在下、必要に応じて炭酸カリウム、炭酸水素ナトリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、モルホリン、ピリジン等の塩基を加えて、Ｈ2ＮＣＨ2ＣＯＯＹで表されるグリシン誘導体と反応させることにより、化合物（５）を得ることができる。 Third step: Compound (5) can be obtained by condensing compound (4) with a glycine derivative represented by H 2 NCH 2 COOY according to a conventional method. For example, the compound (4) is subjected to dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole in a solvent such as N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene and the like under low temperature to warming conditions. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or a salt thereof, a condensing agent such as diphenylphosphoryl azide and optionally N-hydroxysuccinimide, 1-hydroxybenzotriazole, dimethylaminopyridine and the like, potassium carbonate if desired, sodium bicarbonate, cesium carbonate, in addition triethylamine, diisopropylethylamine, morpholine, a base such as pyridine, to be reacted with the glycine derivative represented by H 2 NCH 2 COOY , To give compound (5).
　第４工程：化合物（５）のベンジル基及びカルボキシル基の保護基を常法に従い、脱保護することにより、化合物（１）を得ることができる。例えば、Ｙがメチル基の場合、化合物（５）を加温条件下、トリフルオロ酢酸等の酸溶媒中、必要に応じてアニソール、チオアニソール、ジメチルスルフィド等の存在下、反応させることにより、ベンジル基を脱保護することができる。又は、化合物（５）を室温乃至加温条件下、水素雰囲気下、常圧乃至加圧条件下、ヘキサン、メタノール、エタノール、２－プロパノール、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、酢酸エチル、酢酸、水等の単独又は混合溶媒中、パラジウム炭素、水酸化パラジウム、酸化白金、白金炭素、ラネーニッケル等の触媒の存在下、水素化することにより、ベンジル基を脱保護することができる。続いて、低温乃至加温条件下、メタノール、エタノール、２－プロパノール、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、Ｎ，Ｎ－ジメチルホルムアミド、アセトニトリル等の溶媒と水との混合溶媒中、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等の塩基と反応させることにより、化合物（１）を得ることができる。例えば、Ｙがｔｅｒｔ－ブチル基の場合、化合物（５）を加温条件下、トリフルオロ酢酸等の酸溶媒中、必要に応じてアニソール、チオアニソール、ジメチルスルフィド等の存在下、反応させることにより、化合物（１）を得ることができる。 Fourth step: Compound (1) can be obtained by deprotecting the protecting group for the benzyl group and carboxyl group of compound (5) according to a conventional method. For example, when Y is a methyl group, the compound (5) is reacted in an acid solvent such as trifluoroacetic acid under heating conditions in the presence of anisole, thioanisole, dimethyl sulfide, etc. The group can be deprotected. Alternatively, the compound (5) is heated at room temperature to warming, in a hydrogen atmosphere, at normal pressure to under pressure, hexane, methanol, ethanol, 2-propanol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethyl. Deprotection of the benzyl group by hydrogenation in the presence of a catalyst such as palladium carbon, palladium hydroxide, platinum oxide, platinum carbon, Raney nickel in a single or mixed solvent such as acetamide, ethyl acetate, acetic acid, water, etc. Can do. Subsequently, a mixed solvent of water and a solvent such as methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, acetonitrile under low temperature to warming conditions The compound (1) can be obtained by reacting with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide. For example, when Y is a tert-butyl group, the compound (5) is reacted in an acid solvent such as trifluoroacetic acid under heating conditions in the presence of anisole, thioanisole, dimethyl sulfide, etc. as necessary. Compound (1) can be obtained.
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
（式中、Ｒ5及びＸは、前記と同義である。） (Wherein R 5 and X are as defined above.)
　第１工程：ＸがＳの場合、化合物（２）を低温乃至加温条件下、Ｎ，Ｎ－ジメチルホルムアミド等の溶媒中、硫化ナトリウム等と反応させることにより、化合物（６）を得ることができる。ＸがＯの場合、化合物（２）を低温乃至加温条件下、ジエチレングリコールモノエチルエーテル等の溶媒中、水酸化ナトリウム水溶液、水酸化カリウム水溶液等と反応させることにより、化合物（６）を得ることができる。
　第２工程：ＸがＳ及びＯの場合、化合物（６）をテトラヒドロフラン、トルエンなどの溶媒中、アゾジカルボン酸ジエチルやアゾジカルボン酸ジイソプロピルなどのアゾジカルボン酸エステルとトリフェニルホスフィン、アルコール（Ｒ5ＯＨ）を反応させることにより、化合物（３）を得ることができる。また、ＸがＳ及びＯの場合、化合物（６）を低温乃至加温条件下、トリエチルアミン、ジイソプロピルエチルアミン、炭酸カリウム、炭酸セシウム、炭酸ナトリウム、リン酸カリウム、カリウムｔ－ブトキシド、水素化ナトリウム等の塩基の存在下、１，４－ジオキサン、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、トルエン、シクロペンチルメチルエーテル等の溶媒中、Ｒ5Ｌ（ＬはＯＭｓ、ＯＴｓ、Ｂｒ、Ｃｌ、Ｉなどの脱離基）と反応させることにより、化合物（３）を得ることができる。 First step: When X is S, compound (2) can be reacted with sodium sulfide or the like in a solvent such as N, N-dimethylformamide under low temperature to warming conditions to obtain compound (6). it can. When X is O, the compound (2) is reacted with a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution or the like in a solvent such as diethylene glycol monoethyl ether under low temperature to warming conditions to obtain the compound (6). Can do.
Second Step: When X is S and O, compound (6) is mixed with azodicarboxylic acid ester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, triphenylphosphine, alcohol (R 5 OH) in a solvent such as tetrahydrofuran or toluene. ) Can be reacted to give compound (3). When X is S or O, the compound (6) is subjected to low temperature to warming conditions such as triethylamine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, potassium t-butoxide, sodium hydride and the like. In the presence of a base, in a solvent such as 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, toluene, cyclopentylmethyl ether, R 5 L (L is OMs, OTs, Br, Cl, I Etc.) can be reacted to give compound (3).
　一般式（１）の化合物は、塩として用いる場合、塩の種類は薬学上許容される塩であれば特に限定されないが、例えば塩酸、硫酸、硝酸、臭化水素酸、酢酸、シュウ酸、フマール酸、マレイン酸、クエン酸、コハク酸、酒石酸、安息香酸、メタンスルホン酸、p－トルエンスルホン酸、乳酸、酪酸、アミノ酸、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化カルシウム、ナトリウムアルコキサイド、メグルミン、トロメタミン、オラミン、ジオラミン等と処理をすることにより、塩とすることができる。 When the compound of the general formula (1) is used as a salt, the type of the salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, acetic acid, oxalic acid, fumar Acid, maleic acid, citric acid, succinic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, lactic acid, butyric acid, amino acid, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium al A salt can be obtained by treating with coloxide, meglumine, tromethamine, olamine, diolamine and the like.
　一般式（１）の化合物の薬学上許容しうる水和物としては、１／２水和物、１水和物、２水和物などが例として挙げられる。また、一般式（１）の化合物は溶媒和物として存在することもあるので、溶媒和物も包含される。 Examples of the pharmaceutically acceptable hydrate of the compound of the general formula (1) include 1/2 hydrate, monohydrate, dihydrate and the like. Moreover, since the compound of General formula (1) may exist as a solvate, a solvate is also included.
　上記のように製造された本発明の一般式（１）である化合物は、遊離のまま、あるいはその塩として、通常の化学操作である抽出、濃縮、留去、結晶化、濾過、再結晶、各種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。化合物（１）が、光学異性体、立体異性体、位置異性体を含有する場合は、分別再結晶法、キラルカラム法、ジアステレオマー法などにより、それぞれを単離できる。 The compound represented by the general formula (1) of the present invention produced as described above is in a free state or as a salt thereof, which is extraction, concentration, distillation, crystallization, filtration, recrystallization, which is a normal chemical operation. It can be isolated and purified by various chromatographies. When compound (1) contains an optical isomer, a stereoisomer, or a regioisomer, each can be isolated by a fractional recrystallization method, a chiral column method, a diastereomer method, or the like.
　本発明の化合物は、後記実施例に示すように、特許文献１記載の化合物に比べて持続的且つ優れたＥＰＯ産生促進作用を有することから、慢性腎不全患者における貧血、自己貯血、未熟児貧血、ＡＩＤＳ、化学療法を受けている癌患者の貧血、慢性貧血、鉄欠乏性貧血、再生不良性貧血、溶血性貧血、巨赤芽球性貧血などの貧血の予防薬及び／又は治療薬として有用である。 Since the compound of the present invention has a sustained and excellent EPO production promoting action as compared with the compound described in Patent Document 1, as shown in the Examples below, anemia, self-blood storage, premature infant anemia in patients with chronic renal failure , Useful as a preventive and / or therapeutic agent for anemia such as anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, megaloblastic anemia, etc. in cancer patients undergoing chemotherapy It is.
　一般式（１）で示される化合物又はその薬学上許容される塩、水和物、溶媒和物を含んでなる医薬組成物の投与は、錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。 Administration of a pharmaceutical composition comprising a compound represented by the general formula (1) or a pharmaceutically acceptable salt, hydrate or solvate thereof is carried out in the form of tablets, pills, capsules, granules, powders, liquids Oral administration, etc., or intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalation Any form of parenteral administration by an agent or the like may be used.
　一般式（１）で示される化合物又はその薬学上許容される塩、水和物、溶媒和物を含んでなる医薬組成物を前記医薬製剤として用いる場合、製剤用添加物の種類は薬学上許容される担体であれば特に限定されないが、基剤、賦形剤、滑沢剤、コーティング剤、糖衣剤、湿潤剤、結合剤、崩壊剤、溶剤、可溶化剤、溶解剤、溶解補助剤、懸濁化剤、分散剤、乳化剤、界面活性剤、等張化剤、緩衝剤、ｐＨ調節剤、無痛化剤、防腐剤、保存剤、安定化剤、抗酸化剤、着色剤、甘味剤等単独で又は適宜組み合わせて用いることができる。 When a pharmaceutical composition comprising a compound represented by the general formula (1) or a pharmaceutically acceptable salt, hydrate or solvate thereof is used as the pharmaceutical preparation, the kind of additive for the preparation is pharmaceutically acceptable The carrier is not particularly limited as long as it is a carrier, excipient, lubricant, coating agent, sugar coating, wetting agent, binder, disintegrant, solvent, solubilizer, solubilizer, solubilizer, Suspending agents, dispersing agents, emulsifiers, surfactants, tonicity agents, buffers, pH regulators, soothing agents, preservatives, preservatives, stabilizers, antioxidants, coloring agents, sweeteners, etc. It can be used alone or in appropriate combination.
　本発明の化合物又は該化合物を含有する医薬組成物の投与量及び投与回数は症状、年齢、性別、剤形、併用薬剤の種類などによって適時選択できるが、通常０．１～１０００ｍｇ／ｄａｙ／人、好ましくは１～５００ｍｇ／ｄａｙ／人の範囲で、１日１回あるいは数回に分けて投与することができる。また、本発明の医薬組成物は、単独投与のみならず、同じ薬効を有する他の医薬及び／又は別の薬効を有する他の医薬と併用してもよい。 The dose and frequency of administration of the compound of the present invention or the pharmaceutical composition containing the compound can be appropriately selected according to symptoms, age, sex, dosage form, type of concomitant drug, etc., but usually 0.1 to 1000 mg / day / person Preferably, the dose can be administered in the range of 1 to 500 mg / day / person once a day or divided into several times. In addition, the pharmaceutical composition of the present invention may be used not only alone but also in combination with other drugs having the same drug effect and / or other drugs having another drug effect.
　以下、実施例および参考例を挙げて本発明を具体的に説明するが、本発明は下記実施例により限定されることはない。 Hereinafter, the present invention will be specifically described with reference to examples and reference examples, but the present invention is not limited to the following examples.
　実施例、参考例における略号の意味は以下の通りである。ＴＨＦ：テトラヒドロフラン、ＤＭＳＯ：ジメチルスルホキシド、ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド、ＨＭＰＡ：ヘキサメチルリン酸トリアミド、Ｐｄ－Ｃ：パラジウム炭素、1Ｈ－ＮＭＲ：プロトン核磁気共鳴スペクトル、ＣＤＣｌ3：重水素化クロロホルム、Ｈｚ：ヘルツ、Ｊ：カップリング定数、ｍ：マルチプレット、ｑｕｉｎｔ：クインテット、ｑ：クワルテット、ｄｔ：ダブルトリプレット、ｔ：トリプレット、ｄ：ダブレット、ｓ：シングレット、ｂｒ：ブロード、Ｍ：モル濃度。尚、ＮＭＲは２７０ＭＨｚ核磁気共鳴スペクトルを示し、内部標準物質としてＴＭＳ（テトラメチルシラン）を用いた。ＭＳは質量分析を示し、イオン化法としてはＥＳＩ（エレクトロスプレーイオン化法）を用いた。 The meanings of the abbreviations in Examples and Reference Examples are as follows. THF: Tetrahydrofuran, DMSO: Dimethylsulfoxide, DMF: N, N-dimethylformamide, HMPA: Hexamethylphosphoric triamide, Pd-C: Palladium carbon, 1 H-NMR: Proton nuclear magnetic resonance spectrum, CDCl 3 : Deuteration Chloroform, Hz: Hertz, J: coupling constant, m: multiplet, quintet, q: quartet, dt: double triplet, t: triplet, d: doublet, s: singlet, br: broad, M: molar concentration . NMR showed a 270 MHz nuclear magnetic resonance spectrum, and TMS (tetramethylsilane) was used as an internal standard substance. MS showed mass spectrometry, and ESI (electrospray ionization method) was used as an ionization method.
　参考例１：７－ベンジルオキシ－５－フェニルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル
　ベンゼンチオール（５４ｍｇ）、７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（１０ｍｇ）、キサントホス（１３ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（１２０ｍｇ）をジオキサン溶媒（２．０ｍＬ）中混合し、アルゴン雰囲気下、１００℃で０．５時間加熱撹拌した。反応終了後、不溶物をろ去し、溶媒を減圧留去した。残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２／１）にて精製し、表題化合物（１４７ｍｇ、７７％）を得た。
1H-NMR(CDCl3)δ:1.57(9H,s),4.92(2H,s),5.96(1H,s),7.08-7.18(2H,m),7.24-7.35(3H,m),7.47-7.65(5H,m),8.33(1H,s) Reference Example 1: 7-benzyloxy-5-phenylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester benzenethiol (54 mg), 7-benzyloxy-5 -Iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg), tris (dibenzylideneacetone) dipalladium (10 mg), xanthophos (13 mg), N, N-diisopropylethylamine (120 mg) was mixed in a dioxane solvent (2.0 mL), and heated and stirred at 100 ° C. for 0.5 hours under an argon atmosphere. After completion of the reaction, insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 2/1) to obtain the title compound (147 mg, 77%).
1 H-NMR (CDCl 3 ) δ: 1.57 (9H, s), 4.92 (2H, s), 5.96 (1H, s), 7.08-7.18 (2H, m), 7.24-7.35 (3H, m), 7.47 -7.65 (5H, m), 8.33 (1H, s)
　参考例２：７－ベンジルオキシ－５－フェニルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸
　参考例１で得られた化合物（４８４ｍｇ）をトルエン（３．８ｍＬ）、酢酸エチル（１．２ｍＬ）に溶解し、室温下、酢酸エチル（０．５ｍＬ）に溶解させたメタンスルホン酸（４２９ｍｇ）を１０分以上かけて加えた。 室温にて３時間撹拌した後、析出した結晶をろ取した。得られた結晶をＤＭＦ（７．０ｍＬ）及びＤＭＳＯ（２．０ｍＬ）に溶解させ、０℃にて水（２０ｍＬ）を１０分以上かけて滴下した。析出した結晶をろ取し、表題化合物（３１１ｍｇ、７４％）を得た。
1H-NMR(DMSO-d6)δ:5.09(2H,s),6.27(1H,s),7.07-7.20(2H,m),7.26-7.41(3H,m),7.53-7.75(5H,m),8.48(1H,s),13.31(1H,brs). Reference Example 2: 7-Benzyloxy-5-phenylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid The compound (484 mg) obtained in Reference Example 1 was dissolved in toluene (3. 8 mL) and ethyl acetate (1.2 mL) were dissolved, and methanesulfonic acid (429 mg) dissolved in ethyl acetate (0.5 mL) was added over 10 minutes at room temperature. After stirring at room temperature for 3 hours, the precipitated crystals were collected by filtration. The obtained crystals were dissolved in DMF (7.0 mL) and DMSO (2.0 mL), and water (20 mL) was added dropwise at 0 ° C. over 10 minutes. The precipitated crystals were collected by filtration to give the title compound (311 mg, 74%).
1 H-NMR (DMSO-d 6 ) δ: 5.09 (2H, s), 6.27 (1H, s), 7.07-7.20 (2H, m), 7.26-7.41 (3H, m), 7.53-7.75 (5H, m), 8.48 (1H, s), 13.31 (1H, brs).
　実施例１：［（７－ベンジルオキシ－５－フェニルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ］酢酸メチル
　参考例２で得られた化合物（３０９ｍｇ）をＤＭＦ（３．０ｍＬ）に溶解させ、グリシンメチルエステル塩酸塩（１１３ｍｇ）、１－ヒドロキシベンゾトリアゾール（１３８ｍｇ）及びトリエチルアミン（９９ｍｇ）を室温にて加えた。この混合物に１－エチル－３－(３－ジメチルアミノプロピル) カルボジイミド塩酸塩（１７３ｍｇ）を加え、室温下一晩撹拌した。反応液に水（６．０ｍＬ）、飽和炭酸水素ナトリウム水溶液（３．０ｍＬ）を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。ろ過後、溶媒を減圧留去し、表題化合物（３２２ｍｇ）を得た。 Example 1: Methyl [(7-benzyloxy-5-phenylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetate Compound (309 mg) obtained in Reference Example 2 ) Was dissolved in DMF (3.0 mL), and glycine methyl ester hydrochloride (113 mg), 1-hydroxybenzotriazole (138 mg) and triethylamine (99 mg) were added at room temperature. To this mixture was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (173 mg), and the mixture was stirred overnight at room temperature. Water (6.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound (322 mg).
　実施例２：［（７－ヒドロキシ－５－フェニルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ］酢酸メチル
　実施例１で得られた化合物（３１３ｍｇ）をトリフルオロ酢酸（３．０ｍＬ）に溶解し、８０℃で５時間撹拌した。反応終了後、反応液を減圧濃縮し、得られた残渣にメタノール（０．６ｍＬ）及び水（３．０ｍＬ）を加え、室温にて０．５時間撹拌し、析出した結晶をろ取した。これをカラムクロマトグラフィー（クロロホルム／酢酸エチル＝１０／１）で精製し、表題化合物（２１６ｍｇ）を得た。 Example 2: Methyl [(7-hydroxy-5-phenylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetate Compound obtained in Example 1 (313 mg) Was dissolved in trifluoroacetic acid (3.0 mL) and stirred at 80 ° C. for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, methanol (0.6 mL) and water (3.0 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 0.5 hour, and the precipitated crystals were collected by filtration. This was purified by column chromatography (chloroform / ethyl acetate = 10/1) to obtain the title compound (216 mg).
　実施例３：［（７－ヒドロキシ－５－フェニルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ］酢酸
　実施例２で得られた化合物（２１０ｍｇ）をイソプロピルアルコール（４．０ｍＬ）中に懸濁させ、４Ｍ水酸化リチウム水溶液（０．６ｍＬ）を加えて７０℃で２時間加熱撹拌した。反応終了後、反応液を６Ｍ塩酸（０．４ｍＬ）で中和し、徐冷しながら撹拌した。結晶が析出してきたら水（２．０ｍＬ）を加え、ろ取し、表題化合物（１８９ｍｇ）を得た。 Example 3: [(7-Hydroxy-5-phenylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid The compound (210 mg) obtained in Example 2 was obtained. The suspension was suspended in isopropyl alcohol (4.0 mL), 4 M aqueous lithium hydroxide solution (0.6 mL) was added, and the mixture was heated with stirring at 70 ° C. for 2 hours. After completion of the reaction, the reaction solution was neutralized with 6M hydrochloric acid (0.4 mL) and stirred while gradually cooling. When crystals began to precipitate, water (2.0 mL) was added and collected by filtration to obtain the title compound (189 mg).
　参考例３：｛［７－ベンジルオキシ－５－（３，４－ジクロロフェノキシ)［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸t－ブチルエステル
　臭化銅（１４ｍｇ）、２－シクロヘキサノンカルボン酸エチル（３６ｍｇ）、炭酸セシウム（６８４ｍｇ）をＤＭＳＯ（３ｍＬ）中で混合し、室温下３０分間攪拌した。３，４－ジクロロフェノール（９９ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４５２ｍｇ）をＤＭＳＯ（５ｍＬ）に溶解して反応溶液中に加え、 室温下４８時間撹拌した。反応溶液に酢酸エチルを加え、不溶物を濾去したのち、ろ液を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、カラムクロマトグラフィー（ヘキサン／酢酸エチル＝３／１）にて精製し、表題化合物（３７７ｍｇ）を得た。
1H-NMR (CDCl3)δ:1.56(9H,s),5.16(2H,s),6.02(1H,s),6.96(1H,dd,J=3.0,8.9Hz),7.20-7.45(6H,m),7.51(1H,d,J=8.9Hz),8.31(1H,s). Reference example 3: {[7-benzyloxy-5- (3,4-dichlorophenoxy) [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester copper bromide ( 14 mg), ethyl 2-cyclohexanonecarboxylate (36 mg) and cesium carbonate (684 mg) were mixed in DMSO (3 mL) and stirred at room temperature for 30 minutes. 3,4-Dichlorophenol (99 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (452 mg) were added to DMSO (5 mL). And dissolved in the reaction solution and stirred at room temperature for 48 hours. Ethyl acetate was added to the reaction solution, the insoluble material was filtered off, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate = 3/1) to obtain the title compound (377 mg).
1 H-NMR (CDCl 3 ) δ: 1.56 (9H, s), 5.16 (2H, s), 6.02 (1H, s), 6.96 (1H, dd, J = 3.0, 8.9Hz), 7.20-7.45 (6H , m), 7.51 (1H, d, J = 8.9Hz), 8.31 (1H, s).
実施例４：｛［７－ベンジルオキシ－５－（３，４－ジクロロフェノキシ)［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸t－ブチルエステル
　参考例３で得られた化合物（３７７ｍｇ）を参考例２と同様にしてカルボン酸としたのち、グリシンt－ブチルエステル塩酸塩を用い、実施例１と同様にして、表題化合物（１８３ｍｇ）を得た。 Example 4: {[7-Benzyloxy-5- (3,4-dichlorophenoxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid t-butyl ester Reference The compound (377 mg) obtained in Example 3 was converted to a carboxylic acid in the same manner as in Reference Example 2, and then the title compound (183 mg) was obtained in the same manner as in Example 1 using glycine t-butyl ester hydrochloride. .
　実施例５：｛［５－（３，４－ジクロロフェノキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　実施例４で得られた化合物（１８３ｍｇ）をトリフルオロ酢酸（２ｍＬ)に溶解し、チオアニソール（８３ｍｇ）を加え、８０℃で２時間撹拌した。溶媒を減圧留去し、メタノール（０．５ｍＬ）、水（２ｍＬ）を加えた。析出した結晶をろ取し、ジエチルエーテル／ヘキサン＝１／１で洗浄し、表題化合物（７５ｍｇ）を得た。 Example 5: {[5- (3,4-Dichlorophenoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid obtained in Example 4 The compound (183 mg) was dissolved in trifluoroacetic acid (2 mL), thioanisole (83 mg) was added, and the mixture was stirred at 80 ° C. for 2 hr. The solvent was distilled off under reduced pressure, and methanol (0.5 mL) and water (2 mL) were added. The precipitated crystals were collected by filtration and washed with diethyl ether / hexane = 1/1 to obtain the title compound (75 mg).
　実施例６：｛［５－（３，５－ジメチルフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，５－ジメチルベンゼンチオール（１８２ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（５００ｍｇ）を参考例１、実施例４、５と同様にして、表題化合物（１６０ｍｇ）を得た。 Example 6: {[5- (3,5-Dimethylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,5-dimethyl Benzenethiol (182 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (500 mg) were used in Reference Example 1 and Example 4. In the same manner as in 5, the title compound (160 mg) was obtained.
　実施例７：｛［５－（２，３－ジメチルフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，３－ジメチルベンゼンチオール（１３８ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２２６ｍｇ）を参考例１、実施例４、５と同様にして、表題化合物（５５ｍｇ）を得た。 Example 7: {[5- (2,3-Dimethylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,3-dimethyl Benzenethiol (138 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (226 mg) were used in Reference Example 1 and Example 4. In the same manner as in 5, the title compound (55 mg) was obtained.
　実施例８：｛［５－（３－フルオロフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－フルオロベンゼンチオール（６２ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸t－ブチルエステル（２００ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（１６０ｍｇ）を得た。 Example 8: {[5- (3-Fluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-fluorobenzenethiol (62 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg), Reference Examples 1, 2, and Examples 1-3 In the same manner as the above, the title compound (160 mg) was obtained.
　実施例９：｛［５－（３，５－ジフルオロフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，５－ジフルオロベンゼンチオール（６５ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（８５ｍｇ）を得た。 Example 9: {[5- (3,5-Difluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,5-difluoro Reference Examples 1 and 2 were carried out using benzenethiol (65 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg). In the same manner as in Examples 1 to 3, the title compound (85 mg) was obtained.
　実施例１０：｛［５－（３，４－ジフルオロフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，４－ジフルオロベンゼンチオール（７７ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を参考例１、実施例４、５と同様にして、表題化合物（５５ｍｇ）を得た。 Example 10: {[5- (3,4-Difluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,4-difluoro Benzenethiol (77 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) were used in Reference Example 1 and Example 4. In the same manner as in 5, the title compound (55 mg) was obtained.
　実施例１１：｛［５－（３，５－ジクロロフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，５－ジクロロベンゼンチオール（８３ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（１９９ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（１１２ｍｇ）を得た。 Example 11: {[5- (3,5-Dichlorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,5-dichlorobenzene Thiol (83 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (199 mg) were used as Reference Examples 1, 2, and Examples. The title compound (112 mg) was obtained in the same manner as in 1-3.
　実施例１２：｛［７－ヒドロキシ－５－（４－トリフルオロメトキシフェニルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　４－トリフルオロメトキシベンゼンチオール（８６ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（１０７ｍｇ）を得た。 Example 12: {[7-Hydroxy-5- (4-trifluoromethoxyphenylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4-trifluoromethoxy Reference Examples 1, 2 were carried out using benzenethiol (86 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg). In the same manner as in Examples 1 to 3, the title compound (107 mg) was obtained.
　実施例１３：｛［５－（ビフェニル－３－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－フェニルベンゼンチオール（１０４ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（９９ｍｇ）を得た。 Example 13: {[5- (biphenyl-3-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-phenylbenzenethiol ( 104 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg). In the same manner as in 3, the title compound (99 mg) was obtained.
　実施例１４：｛［５－（２－クロロ－５－フルオロフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－クロロ－５－フルオロベンゼンチオール（９３ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２２６ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（７２ｍｇ）を得た。 Example 14: {[5- (2-Chloro-5-fluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-chloro Reference Example 1 was prepared using -5-fluorobenzenethiol (93 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (226 mg). 2, In the same manner as in Examples 1 to 3, the title compound (72 mg) was obtained.
　実施例１５：｛［５－（３－クロロ－５－フルオロフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－クロロ－５－フルオロベンゼンチオール（８５ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（３０ｍｇ）を得た。 Example 15: {[5- (3-Chloro-5-fluorophenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-chloro Reference Example 1 -5-fluorobenzenethiol (85 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) 2. In the same manner as in Examples 1 to 3, the title compound (30 mg) was obtained.
　実施例１６：｛［５－（３－クロロ－５－メチルフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－クロロ－５－メチルベンゼンチオール（８５ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（１０４ｍｇ）を得た。 Example 16: {[5- (3-Chloro-5-methylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-chloro Reference Example 1 -5-methylbenzenethiol (85 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) 2. In the same manner as in Examples 1 to 3, the title compound (104 mg) was obtained.
　実施例１７：｛［５－（３－フルオロ－５－メチルフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－フルオロ－５－メチルベンゼンチオール（７１ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２０１ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（１０３ｍｇ）を得た。 Example 17: {[5- (3-Fluoro-5-methylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-fluoro Reference Example 1 using -5-methylbenzenethiol (71 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (201 mg) 2, In the same manner as in Examples 1 to 3, the title compound (103 mg) was obtained.
　実施例１８：｛［５－（３－フルオロ－５－トリフルオロメチルフェニルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－フルオロ－５－（トリフルオロメチル）ベンゼンチオール（７２ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（１６６ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（８７ｍｇ）を得た。 Example 18: {[5- (3-Fluoro-5-trifluoromethylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3 -Fluoro-5- (trifluoromethyl) benzenethiol (72 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester ( 166 mg) in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3, to obtain the title compound (87 mg).
　参考例４：３－クロロ－５－トリフルオロメチルベンゼンチオール
　３－クロロ－５－トリフルオロメチルフェノール（３６２ｍｇ）をピリジン（２ｍＬ）と混合し、氷冷下トリフルオロメタンスルホン酸無水物（７７７ｍｇ）を滴下した。氷冷下１時間撹拌した後、２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥した。ろ過後、溶媒を減圧留去して、３－クロロ－５－トリフルオロメチルフェニルトリフルオロメタンスルホネートを得た。このものと３－メルカプトプロピオン酸２－エチルヘキシル（２０３ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（２１ｍｇ）、キサントホス（２７ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．４９ｍＬ）をジオキサン溶媒（２．０ｍＬ）中混合し、アルゴン雰囲気下、１００℃で２０分間加熱撹拌した。反応終了後、不溶物をろ去し、溶媒を減圧留去した。残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１０／１）にて精製し、３－（３－クロロ－５－トリフルオロメチルフェニルスルファニル）－プロピオン酸２－エチルヘキシルエステルを得た。このものをＴＨＦ（６ｍＬ）に溶解し、氷冷下、カリウムｔ－ブトキシドのＴＨＦ溶液（１．０Ｍ、２ｍＬ）を加え、同温で３０分間撹拌した。反応終了後、氷冷下１Ｍ塩酸を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥した。ろ過後、溶媒を減圧留去し、得られた残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１０／１）にて精製し、３－クロロ－５－トリフルオロメチルベンゼンチオール（１３６ｍｇ、３工程、収率３５％）を得た。
1H-NMR(DMSO-d6)δ:3.65(1H,s),7.39(2H,s),7.43(1H,s). Reference Example 4: 3-Chloro-5-trifluoromethylbenzenethiol 3-Chloro-5-trifluoromethylphenol (362 mg) was mixed with pyridine (2 mL), and trifluoromethanesulfonic anhydride (777 mg) was added under ice cooling. It was dripped. After stirring for 1 hour under ice cooling, 2M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 3-chloro-5-trifluoromethylphenyl trifluoromethanesulfonate. This product and 2-ethylhexyl 3-mercaptopropionate (203 mg), tris (dibenzylideneacetone) dipalladium (21 mg), xanthophos (27 mg), N, N-diisopropylethylamine (0.49 mL) were added to a dioxane solvent (2.0 mL). ) And stirred under heating at 100 ° C. for 20 minutes under an argon atmosphere. After completion of the reaction, insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 10/1) to obtain 3- (3-chloro-5-trifluoromethylphenylsulfanyl) -propionic acid 2-ethylhexyl ester. This was dissolved in THF (6 mL), and a solution of potassium t-butoxide in THF (1.0 M, 2 mL) was added under ice cooling, followed by stirring at the same temperature for 30 minutes. After completion of the reaction, 1M hydrochloric acid was added under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane / ethyl acetate = 10/1) to give 3-chloro-5-trifluoromethylbenzenethiol (136 mg, 3 steps, Yield 35%).
1 H-NMR (DMSO-d 6 ) δ: 3.65 (1H, s), 7.39 (2H, s), 7.43 (1H, s).
　実施例１９：（｛５－［３－クロロ－５－（トリフルオロメチル）フェニルスルファニル］－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル｝アミノ）酢酸
　参考例４で得られた化合物（１３６ｍｇ）及び７－ベンジルオキシ－５－ヨード［１,２,４］トリアゾロ「１，５－α］ピリジン－８－カルボン酸t－ブチルエステル（２８８ｍｇ）を参考例１、実施例４、５と同様にして、表題化合物（４８ｍｇ）を得た。 Example 19: ({5- [3-Chloro-5- (trifluoromethyl) phenylsulfanyl] -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl} amino) Acetic acid The compound (136 mg) obtained in Reference Example 4 and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (288 mg) In the same manner as in Reference Example 1 and Examples 4 and 5, the title compound (48 mg) was obtained.
　実施例２０：｛［５－（２，３－ジメチルフェノキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，３－ジメチルフェノール（１１９ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（１２５ｍｇ）を得た。 Example 20: {[5- (2,3-Dimethylphenoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,3-dimethylphenol (119 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (400 mg), Reference Example 3, Example 4 In the same manner as in 5, the title compound (125 mg) was obtained.
　実施例２１：｛［５－（３，５－ジクロロフェノキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，５－ジクロロフェノール（７２ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２３８ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（４２ｍｇ）を得た。 Example 21: {[5- (3,5-dichlorophenoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,5-dichlorophenol Reference Example 3, Example 4 using (72 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (238 mg). In the same manner as in 5, the title compound (42 mg) was obtained.
　実施例２２：｛［５－（ビフェニル－３－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－フェニルフェノール（１３５ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を参考例３、実施例４、５と同様にして、表題化合物（７５ｍｇ）を得た。 Example 22: {[5- (biphenyl-3-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-phenylphenol (135 mg) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) as in Reference Example 3, Examples 4 and 5. To give the title compound (75 mg).
　実施例２３：｛［５－（３－クロロ－４－フルオロフェノキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－クロロ－４－フルオロフェノール（１１０ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２２６ｍｇ）を参考例３、実施例４、５と同様にして、表題化合物（９０ｍｇ）を得た。 Example 23: {[5- (3-Chloro-4-fluorophenoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-chloro- Reference Example 3 was carried out using 4-fluorophenol (110 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (226 mg). In the same manner as in Examples 4 and 5, the title compound (90 mg) was obtained.
　実施例２４：｛［５－（４－クロロ－２－メチルフェノキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　４－クロロ－２－メチルフェノール（１１３ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（３０ｍｇ）を得た。 Example 24: {[5- (4-Chloro-2-methylphenoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4-chloro- Reference Example 3 using 2-methylphenol (113 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Examples 4 and 5, the title compound (30 mg) was obtained.
　実施例２５：｛［５－（４－フルオロ－３－トリフルオロメチルフェノキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　４－フルオロ－３－トリフルオロメチルフェノール（１４４ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（８６ｍｇ）を得た。 Example 25: {[5- (4-Fluoro-3-trifluoromethylphenoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4- Using fluoro-3-trifluoromethylphenol (144 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Reference Example 3 and Examples 4 and 5, the title compound (86 mg) was obtained.
　実施例２６：｛［７－ヒドロキシ－５－（ナフタレン－１－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　１－ナフタレンチオール（９９ｍｇ）及び７－ベンジルオキシ－５－ヨード［１,２,４］トリアゾロ「１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（３１ｍｇ）を得た。 Example 26: {[7-hydroxy-5- (naphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 1-naphthalenethiol (99 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg), Reference Examples 1, 2, and Examples 1-3 In the same manner as the above, the title compound (31 mg) was obtained.
　実施例２７：｛［５－（４－クロロナフタレン－１－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　４－クロロ－１－ナフトール（７３０ｍｇ）及び７－ベンジルオキシ－５－ヨード［１,２,４］トリアゾロ「１，５－α］ピリジン－８－カルボン酸t－ブチルエステル（３０４ｍｇ）を参考例４、実施例１９と同様にして、表題化合物（５０ｍｇ）を得た。 Example 27: {[5- (4-Chloronaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4-chloro Reference Example 4 was conducted using 1-naphthol (730 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (304 mg). In the same manner as in Example 19, the title compound (50 mg) was obtained.
　実施例２８：｛［７－ヒドロキシ－５－（ナフタレン－１－イルオキシ）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　１－ナフトール（１９２ｍｇ）及び７－ベンジルオキシ－５－ヨード［１,２,４］トリアゾロ「１，５－α］ピリジン－８－カルボン酸t－ブチルエステル（２００ｍｇ）を参考例３、実施例４、５と同様にして、表題化合物（８６ｍｇ）を得た。 Example 28: {[7-Hydroxy-5- (naphthalen-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 1-naphthol (192 mg) and 7-Benzyloxy-5-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) was prepared in the same manner as in Reference Example 3 and Examples 4 and 5. To give the title compound (86 mg).
　実施例２９：｛［７－ヒドロキシ－５－（５，６，７，８－テトラヒドロナフタレン－１－イルスルファニル）［１，２，４］－トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　５，６，７，８－テトラヒドロナフタレン－１－チオール（２２０ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（５００ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（２１５ｍｇ）を得た。 Example 29: {[7-Hydroxy-5- (5,6,7,8-tetrahydronaphthalen-1-ylsulfanyl) [1,2,4] -triazolo [1,5-α] pyridine-8-carbonyl Amino} acetic acid 5,6,7,8-tetrahydronaphthalene-1-thiol (220 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carvone The title compound (215 mg) was obtained using acid t-butyl ester (500 mg) in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
　実施例３０：｛［７－ヒドロキシ－５－（インダン－４－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　参考例７と同様に合成したインダン－４－チオール（１００ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２５０ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（７４ｍｇ）を得た。 Example 30: {[7-Hydroxy-5- (indan-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid As in Reference Example 7 Reference example of synthesized indan-4-thiol (100 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg) 1, 2 In the same manner as in Examples 1 to 3, the title compound (74 mg) was obtained.
　実施例３１：｛［７－ヒドロキシ－５－（７－トリフルオロメチルキノリン－４－イルスルファニル)［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　７－トリフルオロメチルキノリン－４－チオフェノール（１８３ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を用い、参考例１、実施例４と同様にして、表題化合物（５９ｍｇ）を得た。 Example 31: {[7-Hydroxy-5- (7-trifluoromethylquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridin-8-carbonyl] amino} acetic acid 7 -Trifluoromethylquinoline-4-thiophenol (183 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Reference Example 1 and Example 4, the title compound (59 mg) was obtained.
　参考例５：ビス（４－イソキノリン）ジスルフィド
　４－ブロモイソキノリン（５０４ｍｇ）、３－メルカプトプロピオン酸２－エチルヘキシル（５３２ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（４３ｍｇ）、キサントホス（５５ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．８５ｍＬ）をジオキサン溶媒（２．５ｍＬ）中混合し、アルゴン雰囲気下１００℃で３．５時間加熱撹拌した。反応終了後、不溶物をろ去し、溶媒を減圧留去した。残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝４／１）にて精製し、３－（イソキノリン－４－イルスルファニル）－プロピオン酸２－エチルヘキシルを得た。このものをＴＨＦ（８．０ｍＬ）に溶解し、－７０℃にてカリウムｔ－ブトキシドのＴＨＦ溶液（１．０Ｍ、４．８ｍＬ）を加え、同温で１時間撹拌した。反応終了後、酢酸（０．３５ｍＬ）及び水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥した。ろ過後、溶媒を減圧留去して、得られた残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／４）にて精製し、表題化合物（２９０ｍｇ、２工程、収率７５％）を得た。
1H-NMR(CDCl3)δ:7.61-7.82(2H,m),8.00(1H,dd,J=2.2,7.0Hz),8.17(1H,dd,J=1.1,7.0Hz), 8.44(1H,s),9.21(1H,s). Reference Example 5: Bis (4-isoquinoline) disulfide 4-bromoisoquinoline (504 mg), 2-ethylhexyl 3-mercaptopropionate (532 mg), tris (dibenzylideneacetone) dipalladium (43 mg), xanthophos (55 mg), N, N-diisopropylethylamine (0.85 mL) was mixed in a dioxane solvent (2.5 mL), and heated and stirred at 100 ° C. for 3.5 hours under an argon atmosphere. After completion of the reaction, insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 4/1) to obtain 2- (ethylquinyl 3- (isoquinolin-4-ylsulfanyl) -propionate. This was dissolved in THF (8.0 mL), potassium t-butoxide in THF (1.0 M, 4.8 mL) was added at −70 ° C., and the mixture was stirred at the same temperature for 1 hr. After completion of the reaction, acetic acid (0.35 mL) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane / ethyl acetate = 1/4) to obtain the title compound (290 mg, 2 steps, yield 75%). .
1 H-NMR (CDCl 3 ) δ: 7.61-7.82 (2H, m), 8.00 (1H, dd, J = 2.2,7.0Hz), 8.17 (1H, dd, J = 1.1,7.0Hz), 8.44 (1H , s), 9.21 (1H, s).
　参考例６：７－ベンジルオキシ－５－（イソキノリン－４－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル
　参考例５で得られた化合物（７８ｍｇ）、７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２０２ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（１１ｍｇ）、キサントホス（１３ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（１５６μＬ）、ヒドロキシメタンスルフィン酸ナトリウム二水和物（７６ｍｇ）をジオキサン溶媒（１ｍＬ）中混合し、アルゴン雰囲気下１００℃で１時間加熱撹拌した。反応終了後、不溶物をろ去し、溶媒を減圧留去した。残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／２）にて精製し、表題化合物（１８２ｍｇ、８４％）を得た。
1H-NMR(CDCl3)δ:1.56(9H,s),4.66(2H,s),5.68(1H,s),6.80-6.89(2H,m),7.07-7.23(3H, m), 7.74-7.86(2H,m),8.08-8.20(2H,m),8.40(1H,s),8.88(1H,s),9.48(1H,s). Reference Example 6: 7-Benzyloxy-5- (isoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester obtained in Reference Example 5 Compound (78 mg), 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (202 mg), tris (dibenzylideneacetone) di Palladium (11 mg), xanthophos (13 mg), N, N-diisopropylethylamine (156 μL), sodium hydroxymethanesulfinate dihydrate (76 mg) were mixed in a dioxane solvent (1 mL), and the mixture was stirred at 100 ° C. for 1 hour under an argon atmosphere. Stir with heating. After completion of the reaction, insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 1/2) to give the title compound (182 mg, 84%).
1 H-NMR (CDCl 3 ) δ: 1.56 (9H, s), 4.66 (2H, s), 5.68 (1H, s), 6.80-6.89 (2H, m), 7.07-7.23 (3H, m), 7.74 -7.86 (2H, m), 8.08-8.20 (2H, m), 8.40 (1H, s), 8.88 (1H, s), 9.48 (1H, s).
　実施例３２：｛［７－ヒドロキシ－５－（イソキノリン－４－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　参考例６で得られた化合物（２９７ｍｇ）を参考例２、実施例１～３と同様にして、表題化合物（１６８ｍｇ）を得た。 Example 32: {[7-Hydroxy-5- (isoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid obtained in Reference Example 6 The title compound (168 mg) was obtained in the same manner as in Reference Example 2 and Examples 1 to 3 using the compound (297 mg).
参考例７：７－ブロモ－５－フルオロ－２，３－ジメチル－１Ｈ－インドール
　２－ブロモ－４－フルオロ－１－ニトロベンゼン（８２０ｍｇ）をテトラヒドロフラン（８ｍＬ）に溶解し、－６０℃にて１－メチル－１－プロペニルマグネシウムブロミドのＴＨＦ溶液（０．５Ｍ、２４ｍＬ）を滴下し、同温で１．５時間撹拌した。反応終了後、飽和塩化アンモニウム水溶液を加え、室温下１時間撹拌後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥した。ろ過後、溶媒を減圧留去して、得られた残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１５／１）にて精製し、表題化合物（４３９ｍｇ、収率４９％）を得た。
1H-NMR(CDCl3)δ:2.16(3H,s),2.38(3H,s),7.02-7.14(2H,m),7.81(1H,brs). Reference Example 7: 7-Bromo-5-fluoro-2,3-dimethyl-1H-indole 2-Bromo-4-fluoro-1-nitrobenzene (820 mg) was dissolved in tetrahydrofuran (8 mL) and 1 at −60 ° C. -A solution of methyl-1-propenylmagnesium bromide in THF (0.5 M, 24 mL) was added dropwise and stirred at the same temperature for 1.5 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane / ethyl acetate = 15/1) to obtain the title compound (439 mg, yield 49%).
1 H-NMR (CDCl 3 ) δ: 2.16 (3H, s), 2.38 (3H, s), 7.02-7.14 (2H, m), 7.81 (1H, brs).
　参考例８：ビス（５－フルオロ－１，２，３－トリメチル－１Ｈ－インドール－７－イル）ジスルフィド
　参考例７で得られた化合物（３１０ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（３ｍＬ）に溶解し、氷冷下、水素化ナトリウム（６０％、７７ｍｇ）、ヨウ化メチル（９６μＬ）を加え、室温で２時間撹拌した。反応終了後、水を加えて酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄して、無水硫酸ナトリウムで乾燥した。ろ過後、溶媒を減圧留去して、得られた残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝５０／１）にて精製し、７－ブロモ－５－フルオロ－１，２，３－トリメチル－１Ｈ－インドールを得た。このものを参考例５と同様にして、表題化合物（３０９ｍｇ、３工程、収率１１５％）を得た。
1H-NMR(CDCl3)δ:2.13(3H,s),2.18(3H,s),3.40(3H,s),6.94(1H,dd,J=2.7,8.9Hz),7.13(1H,dd,J=2.7,8.9Hz). Reference Example 8: Bis (5-fluoro-1,2,3-trimethyl-1H-indol-7-yl) disulfide Dissolve the compound (310 mg) obtained in Reference Example 7 in N, N-dimethylformamide (3 mL) Under ice-cooling, sodium hydride (60%, 77 mg) and methyl iodide (96 μL) were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (hexane / ethyl acetate = 50/1) to give 7-bromo-5-fluoro-1,2,3-trimethyl- 1H-indole was obtained. This was treated in the same manner as in Reference Example 5 to give the title compound (309 mg, 3 steps, yield 115%).
1 H-NMR (CDCl 3 ) δ: 2.13 (3H, s), 2.18 (3H, s), 3.40 (3H, s), 6.94 (1H, dd, J = 2.7, 8.9Hz), 7.13 (1H, dd , J = 2.7, 8.9Hz).
　実施例３３：｛［５－（５－フルオロ－１，２，３－トリメチル－１Ｈ－インドール－７－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　参考例８で得られた化合物（４３６ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（５２１ｍｇ）を参考例６、実施例３２と同様にして、表題化合物（２３０ｍｇ）を得た。 Example 33: {[5- (5-Fluoro-1,2,3-trimethyl-1H-indol-7-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine -8-Carbonyl] amino} acetic acid The compound (436 mg) obtained in Reference Example 8 and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t -Butyl ester (521 mg) was obtained in the same manner as in Reference Example 6 and Example 32 to obtain the title compound (230 mg).
　実施例３４：｛［７－ヒドロキシ－５－（チオフェン－２－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－チオフェンチオール（１１６ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４２１ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（１９４ｍｇ）を得た。 Example 34: {[7-Hydroxy-5- (thiophen-2-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-thiophenethiol (116 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (421 mg), Reference Examples 1, 2, and Examples 1-3 In the same manner as the above, the title compound (194 mg) was obtained.
　実施例３５：｛［５－（５－クロロチオフェン－２－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　５－クロロチオフェン－２－チオール（１１７ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（１８１ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（７９ｍｇ）を得た。 Example 35: {[5- (5-chlorothiophen-2-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-chloro Thiophene-2-thiol (117 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (181 mg) were used in Reference Example 1, 2. The title compound (79 mg) was obtained in the same manner as in Examples 1 to 3.
　実施例３６：｛［５－（ベンゾ［ｂ］チオフェン－３－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ベンゾ［ｂ］チオフェン－３－チオール（８９ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２０１ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（１０９ｍｇ）を得た。 Example 36: {[5- (Benzo [b] thiophen-3-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Benzo [ b] Thiophene-3-thiol (89 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (201 mg) 1, 2 In the same manner as in Examples 1 to 3, the title compound (109 mg) was obtained.
　実施例３７：｛［５－（ベンゾ［ｂ］チオフェン－４－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ベンゾ［ｂ］チオフェン－４－チオール（７６ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（１８８ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（９０ｍｇ）を得た。 Example 37: {[5- (Benzo [b] thiophen-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Benzo [ b] Thiophene-4-thiol (76 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (188 mg) 1, 2 In the same manner as in Examples 1 to 3, the title compound (90 mg) was obtained.
　実施例３８：｛［７－ヒドロキシ－５－（２－メチルフラン－３－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－メチルフラン－３－チオール（７５ｍｇ）及び７－ベンジルオキシ－５－ヨード［１,２,４］トリアゾロ「１，５－α］ピリジン－８－カルボン酸t－ブチルエステル（２００ｍｇ）を参考例１、２、実施例１～３と同様にして、表題化合物（４８ｍｇ）を得た。 Example 38: {[7-hydroxy-5- (2-methylfuran-3-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-methyl Furan-3-thiol (75 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) were used in Reference Example 1, 2. In the same manner as in Examples 1 to 3, the title compound (48 mg) was obtained.
　実施例３９：｛［５－（５－クロロナフタレン－１－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　５－クロロ－１－ナフトール（１６８ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(２５０ｍｇ)を参考例４、実施例１９と同様にして、表題化合物（１２８ｍｇ）を得た。 Example 39: {[5- (5-Chloronaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-chloro Reference Example 4 was carried out using 1-naphthol (168 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg). In the same manner as in Example 19, the title compound (128 mg) was obtained.
　実施例４０：｛［５－（６－クロロナフタレン－１－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　６－クロロ－１－ナフトール（１２０ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(２５０ｍｇ)を参考例４、実施例１９と同様にして、表題化合物（１０９ｍｇ）を得た。 Example 40: {[5- (6-Chloronaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 6-chloro Reference Example 4 was carried out using 1-naphthol (120 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg). In the same manner as in Example 19, the title compound (109 mg) was obtained.
　実施例４１：｛［５－（５－クロロナフタレン－１－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　５－クロロ－１－ナフトール（３８８ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(４００ｍｇ)を参考例３、実施例４、５と同様にして、表題化合物（７５ｍｇ）を得た。 Example 41: {[5- (5-Chloronaphthalen-1-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-chloro- Reference Example 3, Example 1-naphthol (388 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (400 mg) In the same manner as in 4 and 5, the title compound (75 mg) was obtained.
　実施例４２：｛［７－ヒドロキシ－５－(８－トリフルオロメチルキノリン－４－イルスルファニル)[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　４－ヒドロキシ－８－トリフルオロメチルキノリン(７３９ｍｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(１８０ｍｇ)を参考例４、実施例１９と同様にして、表題化合物(１４０ｍｇ)を得た。 Example 42: {[7-Hydroxy-5- (8-trifluoromethylquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4 -Hydroxy-8-trifluoromethylquinoline (739 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (180 mg) In the same manner as in Reference Example 4 and Example 19, the title compound (140 mg) was obtained.
　実施例４３：｛［５－（ジベンゾチオフェン－４－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ジベンゾチオフェン－４－オール（１６５ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(３７９ｍｇ)を参考例４、実施例１９と同様にして、表題化合物（７３ｍｇ）を得た。 Example 43: {[5- (Dibenzothiophen-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid dibenzothiophene-4- All (165 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (379 mg) were used as Reference Example 4, Example 19 and In the same manner, the title compound (73 mg) was obtained.
　実施例４４：｛［５－ヒドロキシ－５－(１－トリフルオロメチルイソキノリン－５－イルオキシ)[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　１－トリフルオロメチル－５－ヒドロキシイソキノリン（１８３ｍｇ）及び ７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（５８ｍｇ）を得た。 Example 44: {[5-hydroxy-5- (1-trifluoromethylisoquinolin-5-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 1 Using trifluoromethyl-5-hydroxyisoquinoline (183 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Reference Example 3 and Examples 4 and 5, the title compound (58 mg) was obtained.
　実施例４５：［７－ヒドロキシ－５－(５－トリフルオロメチルナフタレン－１－イルスルファニル)［１，２，４］トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　５－トリフルオロメチルナフタレン－1－チオール(２１９ｍｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(４３３ｍｇ) を参考例１、２、実施例４、５と同様にして、表題化合物(１９５ｍｇ)を得た。 Example 45: [7-Hydroxy-5- (5-trifluoromethylnaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5- See trifluoromethylnaphthalene-1-thiol (219 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (433 mg) In the same manner as in Examples 1, 2, and Examples 4, 5, the title compound (195 mg) was obtained.
　実施例４６：[７－ヒドロキシ－５－（５－メチルナフタレン－１－イルスルファニル）［１，２，４］トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　５－メチルナフタレン－１－チオール(０．５８ｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(１．６ｇ) を参考例１、２、実施例４、５と同様にして、表題化合物(１４１ｍｇ)を得た。 Example 46: [7-hydroxy-5- (5-methylnaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-methylnaphthalene See 1-thiol (0.58 g) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (1.6 g) In the same manner as in Examples 1 and 2, and Examples 4 and 5, the title compound (141 mg) was obtained.
　実施例４７：[[５－(５－シアノナフタレン－１－イルスルファニル)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　５－シアノナフタレン－１－オール(２ｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(１．２ｇ)を参考例４、実施例１９と同様にして、表題化合物(１９９ｍｇ)を得た。 Example 47: [[5- (5-Cyanonaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-cyano Reference examples: naphthalen-1-ol (2 g) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (1.2 g) 4. In the same manner as in Example 19, the title compound (199 mg) was obtained.
　実施例４８：｛［７－ヒドロキシ－５－（６－トリフルオロメチルナフタレン－１－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　６－トリフルオロメチルナフタレン－１－チオール（６０３ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ「１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を参考例１、実施例４、５と同様にして、表題化合物（１５０ｍｇ）を得た。 Example 48: {[7-Hydroxy-5- (6-trifluoromethylnaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 6 -Trifluoromethylnaphthalene-1-thiol (603 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Reference Example 1 and Examples 4 and 5, the title compound (150 mg) was obtained.
　実施例４９：｛［７－ヒドロキシ－５－(７－トリフルオロメチルナフタレン－１－イルスルファニル) [１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　７－トリフルオロメチルナフタレン－１－チオール（６０３．６ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ「１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を参考例１、実施例４、５と同様にして、表題化合物（１９８ｍｇ）を得た。 Example 49: {[7-Hydroxy-5- (7-trifluoromethylnaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 7 -Trifluoromethylnaphthalene-1-thiol (603.6 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) The title compound (198 mg) was obtained in the same manner as in Reference Example 1, Examples 4 and 5.
　実施例５０：｛[７－ヒドロキシ－５－(５－トリフルオロメチルナフタレン－１－イルオキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　５－トリフルオロメチルナフタレン－１－オール（８０ｍｇ）および７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２０８ｍｇ）を参考例９、実施例４、５と同様にして、表題化合物(６８ｍｇ)を得た。 Example 50: {[7-Hydroxy-5- (5-trifluoromethylnaphthalen-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5- See trifluoromethylnaphthalen-1-ol (80 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (208 mg) In the same manner as in Example 9 and Examples 4 and 5, the title compound (68 mg) was obtained.
　実施例５１：｛[７－ヒドロキシ－５－(５－メトキシナフタレン－１－イルオキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　５－メトキシナフタレン－１－オール(１０６ｍｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(３２９ｍｇ)を参考例９、実施例４、５と同様にして、表題化合物(４５ｍｇ)を得た。 Example 51: {[7-Hydroxy-5- (5-methoxynaphthalen-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-methoxynaphthalene Reference Example 9 was carried out using 1-ol (106 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (329 mg). In the same manner as in Examples 4 and 5, the title compound (45 mg) was obtained.
　実施例５２：｛[７－ヒドロキシ－５－(５－メチルナフタレン－１－イルオキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　５－メチルナフタレン－１－オール(１４６ｍｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(４８７ｍｇ)を参考例９、実施例４、５と同様にして、表題化合物(５０ｍｇ)を得た。 Example 52: {[7-hydroxy-5- (5-methylnaphthalen-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-methylnaphthalene Reference Example 9 was carried out using 1-ol (146 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (487 mg). In the same manner as in Examples 4 and 5, the title compound (50 mg) was obtained.
　実施例５３：｛[７－ヒドロキシ－５－(６－メチルナフタレン－１－イルオキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　６－メチルナフタレン－１－オール(１００ｍｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(３１６ｍｇ)を参考例９、実施例４、５と同様にして、表題化合物(９７ｍｇ)を得た。 Example 53: {[7-hydroxy-5- (6-methylnaphthalen-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 6-methylnaphthalene Reference Example 9 was carried out using 1-ol (100 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (316 mg). In the same manner as in Examples 4 and 5, the title compound (97 mg) was obtained.
　実施例５４：｛［７－ヒドロキシ－５－（６－トリフルオロメチルナフタレン－１－イルオキシ）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　６－トリフルオロメチルナフタレン－１－オール（１８９ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（９８ｍｇ）を得た。 Example 54: {[7-hydroxy-5- (6-trifluoromethylnaphthalen-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 6- Using trifluoromethylnaphthalen-1-ol (189 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (400 mg) In the same manner as in Reference Example 3 and Examples 4 and 5, the title compound (98 mg) was obtained.
　実施例５５：｛［５－（６－クロロナフタレン－１－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　６－クロロナフタレン－１－オール（１２１ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（７３ｍｇ）を得た。 Example 55: {[5- (6-Chloronaphthalen-1-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 6-chloronaphthalene Reference Example 3 using 1-ol (121 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in Examples 4 and 5, the title compound (73 mg) was obtained.
　実施例５６：｛［７－ヒドロキシ－５－（８－トリフルオロメチルイソキノリン－４－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　８－トリフルオロメチルイソキノリン－４－チオール（３０７ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２５２ｍｇ）を用い、参考例２、３、実施例１～３と同様にして、表題化合物（１５９ｍｇ）を得た。 Example 56: {[7-Hydroxy-5- (8-trifluoromethylisoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 8 Trifluoromethylisoquinoline-4-thiol (307 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (252 mg) The title compound (159 mg) was obtained in the same manner as in Reference Examples 2 and 3 and Examples 1 to 3.
実施例５７：｛［７－ヒドロキシ－５－（８－メチルイソキノリン－４－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　８－メチルイソキノリン－４－チオール（６４ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（１５０ｍｇ）を用い、参考例１、２、実施例１～３と同様にして、表題化合物（７９ｍｇ）を得た。 Example 57: {[7-Hydroxy-5- (8-methylisoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 8-methyl Reference example using isoquinoline-4-thiol (64 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (150 mg) 1, 2 In the same manner as in Examples 1 to 3, the title compound (79 mg) was obtained.
　実施例５８：｛［５－（８－フルオロイソキノリン－４－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　８－フルオロイソキノリン－４－チオール（７０ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２０２ｍｇ）を用い、参考例１、実施例４、５と同様にして、表題化合物（２４ｍｇ）を得た。 Example 58: {[5- (8-Fluoroisoquinolin-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 8-fluoro Reference example using isoquinoline-4-thiol (70 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (202 mg) 1, In the same manner as in Examples 4 and 5, the title compound (24 mg) was obtained.
　実施例５９：｛［５－（８－クロロイソキノリン－４－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　８－クロロイソキノリン－４－チオール（１５２ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４０４ｍｇ）を用い、参考例１、実施例４、５と同様にして、表題化合物（１２５ｍｇ）を得た。 Example 59: {[5- (8-chloroisoquinolin-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 8-chloro Reference example using isoquinoline-4-thiol (152 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (404 mg) 1, In the same manner as in Examples 4 and 5, the title compound (125 mg) was obtained.
　実施例６０：｛［７－ヒドロキシ－５－（７－トリフルオロメチルイソキノリン－４－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　７－トリフルオロメチルイソキノリン－４－チオール（６４２ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(３３９ｍｇ)を参考例１、実施例４、５と同様にして、表題化合物（４０ｍｇ）を得た。 Example 60: {[7-Hydroxy-5- (7-trifluoromethylisoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridin-8-carbonyl] amino} acetic acid 7 -Trifluoromethylisoquinoline-4-thiol (642 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (339 mg) In the same manner as in Reference Example 1 and Examples 4 and 5, the title compound (40 mg) was obtained.
　実施例６１：｛［７－ヒドロキシ－５－（８－メチルイソキノリン－４－イルオキシ）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　８－メチルイソキノリン－４－オール（７８ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、参考例２、３、実施例１～３と同様にして、表題化合物（２５ｍｇ）を得た。 Example 61: {[7-Hydroxy-5- (8-methylisoquinolin-4-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 8-methylisoquinoline Reference Example 2 using -4-ol (78 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) 3. In the same manner as in Examples 1 to 3, the title compound (25 mg) was obtained.
　実施例６２：｛［５－（８－フルオロイソキノリン－４－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　８－フルオロイソキノリン－４－オール（１５２ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４２０ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（４６ｍｇ）を得た。 Example 62: {[5- (8-Fluoroisoquinolin-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 8-fluoroisoquinoline Reference Example 3 using -4-ol (152 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (420 mg) In the same manner as in Examples 4 and 5, the title compound (46 mg) was obtained.
　実施例６３：｛［５－（８－クロロイソキノリン－４－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　８－クロロイソキノリン－４－オール（２５０ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（６９０ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（９０ｍｇ）を得た。 Example 63: {[5- (8-Chloroisoquinolin-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 8-chloroisoquinoline Reference Example 3 using 4-ol (250 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (690 mg) In the same manner as in Examples 4 and 5, the title compound (90 mg) was obtained.
　実施例６４：｛［５－（７－クロロキノリン－４－イルスルファニル)－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　７－クロロキノリン－４－チオール（１２０ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（５５ｍｇ）を得た。 Example 64: {[5- (7-chloroquinolin-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 7-chloro Reference example using quinoline-4-thiol (120 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) 3. In the same manner as in Examples 4 and 5, the title compound (55 mg) was obtained.
　実施例６５：｛［７－ヒドロキシ－５－（２－トリフルオロメチルキナゾリン－５－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－トリフルオロメチルキナゾリン－５－チオール（１５５ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３３４ｍｇ）を用い、参考例１、実施例４、５と同様にして、表題化合物（１３５ｍｇ）を得た。 Example 65: {[7-hydroxy-5- (2-trifluoromethylquinazolin-5-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2 -Trifluoromethylquinazoline-5-thiol (155 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (334 mg) And the title compound (135 mg) was obtained in the same manner as in Reference Example 1, Examples 4 and 5.
　実施例６６：｛［５－（２－クロロベンゾ［ｂ］チオフェン－４－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－クロロベンゾ［ｂ］チオフェン－４－チオール（８７ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（１８０ｍｇ）を用い、参考例１、２、実施例１～３と同様にして、表題化合物（９２ｍｇ）を得た。 Example 66: {[5- (2-Chlorobenzo [b] thiophen-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-chlorobenzo [b] thiophene-4-thiol (87 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (180 mg) The title compound (92 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
実施例６７：｛［７－ヒドロキシ－５－（２－トリフルオロメチルベンゾ［ｂ］チオフェン－４－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－トリフルオロメチルベンゾ［ｂ］チオフェン－４－チオール（１８６ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２４９ｍｇ）を用い、参考例１、２、実施例１～３と同様にして、表題化合物（１９０ｍｇ）を得た。 Example 67: {[7-Hydroxy-5- (2-trifluoromethylbenzo [b] thiophen-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] Amino} acetic acid 2-trifluoromethylbenzo [b] thiophene-4-thiol (186 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid The title compound (190 mg) was obtained using t-butyl ester (249 mg) in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
　参考例９：５－（ベンゾ［ｂ］チオフェン－４－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル
　ベンゾ［ｂ］チオフェン－４－オール（１３０ｍｇ）、７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２８９ｍｇ）、ヨウ化銅（１４７ｍｇ）、１，１０－フェナントロリン（１５２ｍｇ）、炭酸セシウム（４２３ｍｇ）をトルエン溶媒（３．０ｍＬ）中混合し、アルゴン雰囲気下、１００℃で１時間撹拌した。反応終了後、不溶物をろ去し、溶媒を減圧留去した。残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３／２）にて精製し、表題化合物（２２０ｍｇ，７３％）を得た。
1H-NMR(CDCl3)δ:1.58(9H,s),4.92(2H,s),5.83(1H,s),7.07-7.20(4H,m),7.22-7.28(3H,m),7.41(1H,t,J=8.1Hz),7.46(1H,d,J=5.7Hz),7.89(1H,d,J=8.1Hz),8.36(1H,s). Reference Example 9: 5- (Benzo [b] thiophen-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester Benzo [b] Thiophen-4-ol (130 mg), 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (289 mg), copper iodide ( 147 mg), 1,10-phenanthroline (152 mg) and cesium carbonate (423 mg) were mixed in a toluene solvent (3.0 mL), and the mixture was stirred at 100 ° C. for 1 hour under an argon atmosphere. After completion of the reaction, insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 3/2) to obtain the title compound (220 mg, 73%).
1 H-NMR (CDCl 3 ) δ: 1.58 (9H, s), 4.92 (2H, s), 5.83 (1H, s), 7.07-7.20 (4H, m), 7.22-7.28 (3H, m), 7.41 (1H, t, J = 8.1Hz), 7.46 (1H, d, J = 5.7Hz), 7.89 (1H, d, J = 8.1Hz), 8.36 (1H, s).
　実施例６８：｛［５－（ベンゾ［ｂ］チオフェン－４－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　参考例９で得られた化合物（２２０ｍｇ）を参考例２、実施例１～３と同様にして、表題化合物（１４６ｍｇ）を得た。 Example 68: {[5- (Benzo [b] thiophen-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Reference Example 9 The title compound (146 mg) was obtained in the same manner as in Reference Example 2 and Examples 1 to 3 using the compound obtained in step (220 mg).
　実施例６９：｛［７－ヒドロキシ－５－（３－メチルベンゾ［ｂ］チオフェン－７－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－メチルベンゾ［ｂ］チオフェン－７－チオール（１０８ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２１３ｍｇ）を用い、参考例１、２、実施例１～３と同様にして、表題化合物（１５５ｍｇ）を得た。 Example 69: {[7-Hydroxy-5- (3-methylbenzo [b] thiophen-7-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-methylbenzo [b] thiophene-7-thiol (108 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (213 mg) The title compound (155 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
　実施例７０：｛［７－ヒドロキシ－５－（３－トリフルオロメチルベンゾ［ｂ］チオフェン－７－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－トリフルオロメチルベンゾ［ｂ］チオフェン－７－チオール（４０４ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２３１ｍｇ）を用い、参考例１、２、実施例１～３と同様にして、表題化合物（１５５ｍｇ）を得た。 Example 70: {[7-hydroxy-5- (3-trifluoromethylbenzo [b] thiophen-7-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] Amino} acetic acid 3-trifluoromethylbenzo [b] thiophene-7-thiol (404 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid The title compound (155 mg) was obtained using t-butyl ester (231 mg) in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
　実施例７１：｛［５－（ベンゾ［ｂ］チオフェン－７－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ベンゾ［ｂ］チオフェン－７－オール（１１０ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２５５ｍｇ）を用い、参考例９、２、実施例１～３と同様にして、表題化合物（９１ｍｇ）を得た。 Example 71: {[5- (Benzo [b] thiophen-7-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Benzo [b ] Using thiophen-7-ol (110 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (255 mg) In the same manner as in Examples 9 and 2 and Examples 1 to 3, the title compound (91 mg) was obtained.
　実施例７２：｛［７－ヒドロキシ－５－（３－メチルベンゾ［ｂ］チオフェン－７－イルオキシ）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－メチルベンゾ［ｂ］チオフェン－７－オール（１１７ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２４７ｍｇ）を用い、参考例９、２、実施例１～３と同様にして、表題化合物（１０５ｍｇ）を得た。 Example 72: {[7-hydroxy-5- (3-methylbenzo [b] thiophen-7-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3 -Methylbenzo [b] thiophen-7-ol (117 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (247 mg) In the same manner as in Reference Examples 9 and 2 and Examples 1 to 3, the title compound (105 mg) was obtained.
　実施例７３：｛［７－ヒドロキシ－５－（３－トリフルオロメチルベンゾ［ｂ］チオフェン－７－イルオキシ）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－トリフルオロメチルベンゾ［ｂ］チオフェン－７－オール（２２７ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２４６ｍｇ）を用い、参考例９、２、実施例１～３と同様にして、表題化合物（８８ｍｇ）を得た。 Example 73: {[7-Hydroxy-5- (3-trifluoromethylbenzo [b] thiophen-7-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino } Acetic acid 3-trifluoromethylbenzo [b] thiophen-7-ol (227 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t Using butyl ester (246 mg), the title compound (88 mg) was obtained in the same manner as in Reference Examples 9 and 2 and Examples 1 to 3.
　実施例７４：｛［５－（４－クロロベンゾ［ｂ］チオフェン－７－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　４－クロロベンゾ［ｂ］チオフェン－７－オール（１２３ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２５２ｍｇ）を用い、参考例９、２、実施例１～３と同様にして、表題化合物（１１４ｍｇ）を得た。 Example 74: {[5- (4-Chlorobenzo [b] thiophen-7-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4 -Chlorobenzo [b] thiophen-7-ol (123 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (252 mg) In the same manner as in Reference Examples 9 and 2 and Examples 1 to 3, the title compound (114 mg) was obtained.
　実施例７５：｛［７－ヒドロキシ－５－（７－トリフルオロメチルベンゾ［ｂ］チオフェン－３－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　７－トリフルオロメチルベンゾ［ｂ］チオフェン－３－チオール（２０１ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３０１ｍｇ）を用い、参考例１、２、実施例１～３と同様にして、表題化合物（２１４ｍｇ）を得た。 Example 75: {[7-hydroxy-5- (7-trifluoromethylbenzo [b] thiophen-3-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] Amino} acetic acid 7-trifluoromethylbenzo [b] thiophene-3-thiol (201 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid Using the t-butyl ester (301 mg), the title compound (214 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3.
　実施例７６：｛［５－（ベンゾ［ｂ］チオフェン－３－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ベンゾ［ｂ］チオフェン－３－オン（５５４ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（９８７ｍｇ）を用い、参考例９、実施例４、５と同様にして、表題化合物（７６ｍｇ）を得た。 Example 76: {[5- (Benzo [b] thiophen-3-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Benzo [b ] Using thiophen-3-one (554 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (987 mg) In the same manner as in Example 9 and Examples 4 and 5, the title compound (76 mg) was obtained.
　実施例７７：｛［５－（６－クロロベンゾフラン－３－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　６－クロロベンゾフラン－３－チオール（１１３ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２１４ｍｇ）を用い、参考例１、実施例４、５と同様にして、表題化合物（１３６ｍｇ）を得た。 Example 77: {[5- (6-Chlorobenzofuran-3-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 6-chloro Reference example using benzofuran-3-thiol (113 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (214 mg) 1, In the same manner as in Examples 4 and 5, the title compound (136 mg) was obtained.
　実施例７８：｛［７－ヒドロキシ－５－（１，２，３－トリメチル－１Ｈ－インドール－７－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　１，２，３－トリメチル－１Ｈ－インドール－７－チオール（１３８ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２８８ｍｇ）を用い、参考例１、２、実施例１～３と同様にして、表題化合物（１１１ｍｇ）を得た。 Example 78: {[7-Hydroxy-5- (1,2,3-trimethyl-1H-indol-7-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl Amino} acetic acid 1,2,3-trimethyl-1H-indole-7-thiol (138 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8- The title compound (111 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3, using carboxylic acid t-butyl ester (288 mg).
　実施例７９：｛［５－（３－クロロ－１－メチル－１Ｈ－インドール－７－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－クロロ－１－メチル－１Ｈ－インドール－７－チオール（１９８ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、参考例１、実施例４、５と同様にして、表題化合物（９０ｍｇ）を得た。 Example 79: {[5- (3-Chloro-1-methyl-1H-indol-7-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl Amino} acetic acid 3-chloro-1-methyl-1H-indole-7-thiol (198 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8- The title compound (90 mg) was obtained in the same manner as in Reference Example 1, Example 4, and 5 using carboxylic acid t-butyl ester (200 mg).
　実施例８０：｛［７－ヒドロキシ－５－（１，２，３－トリメチル－１Ｈ－インドール－４－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　１，２，３－トリメチル－１Ｈ－インドール－４－チオール（１３２ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２７９ｍｇ）を用い、参考例１、２、実施例１～３と同様にして、表題化合物（１５９ｍｇ）を得た。 Example 80: {[7-Hydroxy-5- (1,2,3-trimethyl-1H-indol-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl Amino} acetic acid 1,2,3-trimethyl-1H-indole-4-thiol (132 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8- The title compound (159 mg) was obtained in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3, using carboxylic acid t-butyl ester (279 mg).
　実施例８１：｛［７－ヒドロキシ－５－（１，２，３－トリメチル－１Ｈ－インドール－４－イルオキシ）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　１，２，３－トリメチル－１Ｈ－インドール－４－オール（２５４ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（５５０ｍｇ）を用い、参考例２、３、実施例１～３と同様にして、表題化合物（４１ｍｇ）を得た。 Example 81: {[7-Hydroxy-5- (1,2,3-trimethyl-1H-indol-4-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] Amino} acetic acid 1,2,3-trimethyl-1H-indole-4-ol (254 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carvone The title compound (41 mg) was obtained in the same manner as in Reference Examples 2 and 3, and Examples 1 to 3, using acid t-butyl ester (550 mg).
　実施例８２：｛[５－(９Ｈ－フルオレン－１－イルオキシ)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　９Ｈ－フルオレン－１－オール(１６５ｍｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(４７４ｍｇ)を参考例９、実施例４、５と同様にして、表題化合物(３１ｍｇ)を得た。 Example 82: {[5- (9H-fluoren-1-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 9H-fluorene-1 -Ol (165 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (474 mg) were used in Reference Example 9 and Example 4. In the same manner as in 5, the title compound (31 mg) was obtained.
　実施例８３：｛［５－（ジベンゾフラン－４－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ジベンゾフラン－４－オール（１６４ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（１７７ｍｇ）を得た。 Example 83: {[5- (Dibenzofuran-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid dibenzofuran-4-ol (164 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (400 mg), Reference Example 3, Examples 4, 5 In the same manner as the above, the title compound (177 mg) was obtained.
　実施例８４：｛［５－（ジベンゾチオフェン－４－イルオキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ジベンゾチオフェン－４－オール（１７８ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（７８ｍｇ）を得た。 Example 84: {[5- (Dibenzothiophen-4-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid dibenzothiophen-4-ol (178 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (400 mg), Reference Example 3, Example 4 In the same manner as in 5, the title compound (78 mg) was obtained.
　実施例８５：｛［５－（ジベンゾフラン－４－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ジベンゾフラン－４－チオール（６０３ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ「１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を参考例１、実施例４、５と同様にして、表題化合物（７８ｍｇ）を得た。 Example 85: {[5- (dibenzofuran-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid dibenzofuran-4-thiol ( 603 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner, the title compound (78 mg) was obtained.
　実施例８６：｛［７－ヒドロキシ－５－（フェナントレン－１－イルオキシ）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　フェナントレン－１－オール（１７３ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４００ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（１２５ｍｇ）を得た。 Example 86: {[7-hydroxy-5- (phenanthren-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid phenanthren-1-ol (173 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (400 mg), Reference Example 3, Examples 4, 5 In the same manner as the above, the title compound (125 mg) was obtained.
　実施例８７：｛[７－ヒドロキシ－５－(５，６，７，８－テトラヒドロナフタレン－１－イルオキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　５，６，７，８－テトラヒドロナフタレン－１－オール(１ｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(２ｇ)を参考例９、実施例４、５と同様にして、表題化合物(６６７ｍｇ)を得た。 Example 87: {[7-Hydroxy-5- (5,6,7,8-tetrahydronaphthalen-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino } Acetic acid 5,6,7,8-tetrahydronaphthalen-1-ol (1 g) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t -The title compound (667 mg) was obtained by treating the butyl ester (2 g) in the same manner as in Reference Example 9, Examples 4 and 5.
　実施例８８：｛[７－ヒドロキシ－５－(５－メチル－５，６，７，８－テトラヒドロナフタレン－１－イルオキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ｝酢酸
　５－メチル－５，６，７，８－テトラヒドロナフタレン－１－オール(１００ｍｇ)および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(３１６ｍｇ)を参考例９、実施例４、５と同様にして、表題化合物(９７ｍｇ)を得た。 Example 88: {[7-hydroxy-5- (5-methyl-5,6,7,8-tetrahydronaphthalen-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8 -Carbonyl] amino} acetic acid 5-methyl-5,6,7,8-tetrahydronaphthalen-1-ol (100 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α ] Pyridine-8-carboxylic acid t-butyl ester (316 mg) was treated in the same manner as in Reference Example 9, Examples 4 and 5 to give the title compound (97 mg).
　実施例８９：｛［７－ヒドロキシ－５－（インダン－４－イルオキシ）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　インダン－４－オール（１２０ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３５０ｍｇ）を用い、参考例３、実施例４、５と同様にして、表題化合物（１４９ｍｇ）を得た。 Example 89: {[7-hydroxy-5- (indan-4-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid indan-4-ol (120 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (350 mg), and Reference Example 3, Examples 4, 5 In the same manner as described above, the title compound (149 mg) was obtained.
　実施例９０：｛［５－（３，５－ジメチルフェノキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，５－ジメチルフェノール（８１ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２５０ｍｇ）を用い、参考例２、３、実施例１～３と同様にして、表題化合物（７０ｍｇ）を得た。 Example 90: {[5- (3,5-dimethylphenoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,5-dimethylphenol (81 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg) were used. In the same manner as in Examples 1 to 3, the title compound (70 mg) was obtained.
　実施例９１：｛［５－（５－フルオロビフェニル－３－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　５－フルオロビフェニル－３－チオール（１３５ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を参考例１、実施例４、５と同様にして、表題化合物（５５ｍｇ）を得た。 Example 91: {[5- (5-Fluorobiphenyl-3-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-fluoro Biphenyl-3-thiol (135 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) were used in Reference Example 1, In the same manner as in Examples 4 and 5, the title compound (55 mg) was obtained.
　参考例１０：７－ベンジルオキシ－５－ヒドロキシ－[１,２,４]トリアゾロ[１,５－ａ]ピリジン－８－カルボン酸t－ブチルエステル
　７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（１.０ｇ）をジエチレングリコールモノエチルエーテル（７．０ｍＬ）に溶解させ０℃で３０分撹拌した。その後、８Ｎ水酸化ナトリウム(２．５ｍＬ)を加え、室温に昇温し３．５時間撹拌した。クエン酸水を加えた。析出した結晶をろ取し、水で洗浄した。表題化合物(７５６ｍｇ、８０％)を得た。
1H-NMR(DMSO-d6)δ：1.43(9H,s),5.13(2H,s),5.73(1H,s),7.30-7.57(5H,m),8.67(1H,s). Reference Example 10: 7-benzyloxy-5-hydroxy- [1,2,4] triazolo [1,5-a] pyridine-8-carboxylic acid t-butyl ester 7-benzyloxy-5-iodo [1,2 , 4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (1.0 g) was dissolved in diethylene glycol monoethyl ether (7.0 mL) and stirred at 0 ° C. for 30 minutes. Thereafter, 8N sodium hydroxide (2.5 mL) was added, and the mixture was warmed to room temperature and stirred for 3.5 hours. Citric acid water was added. The precipitated crystals were collected by filtration and washed with water. The title compound (756 mg, 80%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 1.43 (9H, s), 5.13 (2H, s), 5.73 (1H, s), 7.30-7.57 (5H, m), 8.67 (1H, s).
　参考例１１：７－ベンジルオキシ－５－(２－シクロペンチルエトキシ)［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル
　参考例１０で得られた化合物（２００ｍｇ)をテトラヒドロフラン（１０ｍＬ）と混合し、氷冷下２－シクロペンタンエタノール（１１４μｌ）、アゾジカルボン酸ジイソプロピル（２３５μｌ）、トリフェニルホスフィン（３１５ｍｇ）を順次加えた。室温で2時間撹拌した後、溶媒を減圧蒸留した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２／1～1／1）にて精製し、表題化合物（１４８ｍｇ、５７％）を得た。
1H-NMR(CDCl3)δ:1.13-1.26(3H,m),1.49-1.68(11H,m),1.81-2.04(6H,m),4.29(2H,t,J=6.5Hz),5.26(1H,s),6.08(1H,s),7.35-7.47(5H,m),8.26（1H,s）. Reference Example 11: 7-Benzyloxy-5- (2-cyclopentylethoxy) [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester Compound obtained in Reference Example 10 (200 mg) was mixed with tetrahydrofuran (10 mL), and 2-cyclopentaneethanol (114 μl), diisopropyl azodicarboxylate (235 μl), and triphenylphosphine (315 mg) were sequentially added under ice cooling. After stirring at room temperature for 2 hours, the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 to 1/1) to give the title compound (148 mg, 57%).
1 H-NMR (CDCl 3 ) δ: 1.13-1.26 (3H, m), 1.49-1.68 (11H, m), 1.81-2.04 (6H, m), 4.29 (2H, t, J = 6.5Hz), 5.26 (1H, s), 6.08 (1H, s), 7.35-7.47 (5H, m), 8.26 (1H, s).
　実施例９２：[[７－ヒドロキシ－５－（２－メチルブチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　２－メチルブタンチオール（６３ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(２５０ｍｇ)を用い、実施例８と同様にして、表題化合物（７１ｍｇ）を得た。 Example 92: [[7-Hydroxy-5- (2-methylbutylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-methylbutanethiol (63 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg) in the same manner as in Example 8, Compound (71 mg) was obtained.
　実施例９３：（Ｓ）－[[７－ヒドロキシ－５－(２－メチルブチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　（Ｓ）－２－メチルブタノール（７１ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、参考例１１、実施例２と同様にしたのち，得られた残渣をイソプロピルアルコール（１．５ｍL）中に懸濁させ、４Ｍ水酸化リチウム水溶液（０．５ｍL）を加えて室温下4時間撹拌し，反応終了後、反応液を２Ｍ塩酸で中和し、酢酸エチルで抽出した有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、溶媒を減圧留去して、表題化合物（３５ｍｇ）を得た。 Example 93: (S)-[[7-hydroxy-5- (2-methylbutylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid (S) After using -2-methylbutanol (71 mg) and the compound (200 mg) obtained in Reference Example 15 in the same manner as in Reference Example 11 and Example 2, the resulting residue was placed in isopropyl alcohol (1.5 mL). Suspended, 4M aqueous lithium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was neutralized with 2M hydrochloric acid, and the organic layer extracted with ethyl acetate was washed with water and saturated brine. After washing with water, drying over anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure to obtain the title compound (35 mg).
　実施例９４：[[７－ヒドロキシ－５－メチルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　メタノール（１ｍＬ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、参考例１１、実施例２、３と同様にして、表題化合物（４２ｍｇ）を得た。 Example 94: [[7-Hydroxy-5-methylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid obtained in methanol (1 mL) and Reference Example 15 Using the compound (200 mg), the title compound (42 mg) was obtained in the same manner as in Reference Example 11, Examples 2 and 3.
　実施例９５：［（７－ヒドロキシ－５－プロピルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ］酢酸
　プロパンチオール（４０ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして、表題化合物（２８ｍｇ）を得た。 Example 95: [(7-hydroxy-5-propylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid propanethiol (40 mg) and 7-benzyloxy-5 Using the iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg), the title compound (28 mg) was obtained in the same manner as in Example 8.
　実施例９６：｛［７－ヒドロキシ－５－（３，３，３－トリフルオロプロピルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，３，３－トリフルオロプロパンチオール（１７３ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル（２０１ｍｇ）を用い、実施例８と同様にして、表題化合物（７４ｍｇ）を得た。 Example 96: {[7-hydroxy-5- (3,3,3-trifluoropropylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3, Using 3,3-trifluoropropanethiol (173 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (201 mg) In the same manner as in Example 8, the title compound (74 mg) was obtained.
　実施例９７：[（７－ヒドロキシ－５－ブチルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ]酢酸
　ブタノール（８０ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例９４と同様にして、表題化合物（１１７ｍｇ）を得た。 Example 97: [(7-hydroxy-5-butylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid obtained in butanol (80 mg) and Reference Example 15 The title compound (117 mg) was obtained in the same manner as in Example 94, using the compound (200 mg).
　実施例９８：[[７－ヒドロキシ－５－(３－メチルブチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　３－メチルブタンチオール（５５ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして、表題化合物（４０ｍｇ）を得た。 Example 98: [[7-Hydroxy-5- (3-methylbutylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 3-methylbutanethiol (55 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, Compound (40 mg) was obtained.
　実施例９９：｛［５－（３，３－ジメチルブチルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，３－ジメチルブチル－４－メチルベンゼンスルホネート（９５ｍｇ）及び参考例１５で得られた化合物（１２５ｍｇ）を用い、実施例１５２と同様にして表題化合物（３９ｍｇ）を得た。 Example 99: {[5- (3,3-dimethylbutylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,3-dimethyl The title compound (39 mg) was obtained in the same manner as in Example 152, using butyl-4-methylbenzenesulfonate (95 mg) and the compound (125 mg) obtained in Reference Example 15.
　実施例１００：[[７－ヒドロキシ－５－（２，２－ジメチルブチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　２，２－ジメチルブタノール（１１０ｍｇ）及び参考例１３で得られた化合物（２００ｍｇ）を用い、参考例１１、実施例５と同様にして、表題化合物（９５ｍｇ）を得た。 Example 100: [[7-Hydroxy-5- (2,2-dimethylbutylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2,2-dimethyl The title compound (95 mg) was obtained in the same manner as in Reference Example 11 and Example 5, using butanol (110 mg) and the compound (200 mg) obtained in Reference Example 13.
　参考例１２：３－[７－ベンジルオキシ－８－(t－ブトキシカルボニルメチルカルバモイル)－[１，２，４]トリアゾロ[１，５－α]ピリジン－５－イルスルファニル]プロピオン酸３－エチルヘキシルエステル
　３－メルカプトプロピオン酸－３－エチルヘキシルエステル（４．７４ｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸t－ブチルエステル（９．０４ｇ）を参考例１、および実施例４と同様にして、表題化合物（９．８５ｇ）を得た。
1H-NMR (CDCl3)δ：0.81-0.97(6H,m),1.19-1.66(17H,m),2.65(2H,t,J=7.4Hz),3.31 (2H,t,J=7.2Hz),4.06(2H,dd,J=5.7,6.0Hz),4.24(2H,d,J=4.9Hz),5.43(2H,s),6.70(1H,s),7.25-7.59(5H,m),8.02(1H,s),8.31(1H s),9.57(1H,brs). Reference Example 12: 3-ethylhexyl 3- [7-benzyloxy-8- (t-butoxycarbonylmethylcarbamoyl)-[1,2,4] triazolo [1,5-α] pyridin-5-ylsulfanyl] propionate Esters 3-mercaptopropionic acid-3-ethylhexyl ester (4.74 g) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (9.04 g) was treated in the same manner as in Reference Example 1 and Example 4 to obtain the title compound (9.85 g).
1 H-NMR (CDCl 3 ) δ: 0.81-0.97 (6H, m), 1.19-1.66 (17H, m), 2.65 (2H, t, J = 7.4Hz), 3.31 (2H, t, J = 7.2Hz ), 4.06 (2H, dd, J = 5.7,6.0Hz), 4.24 (2H, d, J = 4.9Hz), 5.43 (2H, s), 6.70 (1H, s), 7.25-7.59 (5H, m) , 8.02 (1H, s), 8.31 (1H s), 9.57 (1H, brs).
　参考例１３：[(７－ベンジルオキシ－５－メルカプト[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸t－ブチルエステル
参考例１２で得られた化合物（１５．７ｇ）をメタノール（６０ｍＬ）に溶解させ０℃で３０分撹拌した。その後、ナトリウムメトキシド(２．６ｇ)を加え、さらに３０分撹拌し、クエン酸水を加えた。析出した結晶をろ取し、水で洗浄して表題化合物(８．０ｇ)を得た。
1H-NMR(DMSO-d6)δ：1.42(9H,s),4.00(2H,d,J=5.9Hz),5.54(2H,s),6.99(1H,s),7.31-7.58(5H,m),8.46(1H,brs),8.90(1H,s),13.77(1H,brs). Reference Example 13: [(7-Benzyloxy-5-mercapto [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid t-butyl ester Compound obtained in Reference Example 12 (15.7 g) was dissolved in methanol (60 mL) and stirred at 0 ° C. for 30 minutes. Thereafter, sodium methoxide (2.6 g) was added, the mixture was further stirred for 30 minutes, and aqueous citric acid was added. The precipitated crystals were collected by filtration and washed with water to give the title compound (8.0 g).
1 H-NMR (DMSO-d 6 ) δ: 1.42 (9H, s), 4.00 (2H, d, J = 5.9 Hz), 5.54 (2H, s), 6.99 (1H, s), 7.31-7.58 (5H , m), 8.46 (1H, brs), 8.90 (1H, s), 13.77 (1H, brs).
　参考例１４：３－[７－ベンジルオキシ－８－(メトキシカルボニルメチルカルバモイル)－[１，２，４]トリアゾロ[１，５－α]ピリジン－５－イルスルファニル]プロピオン酸３－エチルヘキシルエステル
　３－メルカプトプロピオン酸３－エチルヘキシルエステル（２.７ｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸t－ブチルエステル（５.０ｇ）を参考例１、２および実施例１と同様にして、表題化合物（３.８５ｇ）を得た。
1H-NMR(CDCl3)δ:0.81-0.99(6H,m),1.22-1.49(8H,m),2.66(2H,t,J=7.3Hz),3.31(2H,t,J=7.2Hz),3.80(3H,s),4.05(2H,dd,J=1.6,5.9Hz),4.33(2H,d,J=5.1Hz),5.44(2H,s),6.71(1H,s),7.25-7.59(5H,m),8.30(1H,s),9.68(1H,brs). Reference Example 14: 3- [7-Benzyloxy-8- (methoxycarbonylmethylcarbamoyl)-[1,2,4] triazolo [1,5-α] pyridin-5-ylsulfanyl] propionic acid 3-ethylhexyl ester 3 -Mercaptopropionic acid 3-ethylhexyl ester (2.7 g) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (5. The title compound (3.85 g) was obtained in the same manner as in Reference Examples 1 and 2 and Example 1.
1 H-NMR (CDCl3) δ: 0.81-0.99 (6H, m), 1.22-1.49 (8H, m), 2.66 (2H, t, J = 7.3Hz), 3.31 (2H, t, J = 7.2Hz) , 3.80 (3H, s), 4.05 (2H, dd, J = 1.6,5.9Hz), 4.33 (2H, d, J = 5.1Hz), 5.44 (2H, s), 6.71 (1H, s), 7.25- 7.59 (5H, m), 8.30 (1H, s), 9.68 (1H, brs).
　参考例１５：[(７－ベンジルオキシ－５－メルカプト－[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸メチルエステル
　参考例１４で得られた化合物（３．５ｇ）を参考例１３と同様にして表題化合物(２．２４ｇ)を得た。
1H-NMR(DMSO-d6)δ：3.66(3H,s),4.11(2H,d,J=5.7Hz),5.55(2H,s),6.99(1H,s),7.28-7.57(5H,m),8.55(1H,brs),8.90(1H,s),13.76(1H,brs). Reference Example 15: [(7-Benzyloxy-5-mercapto- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid methyl ester Compound obtained in Reference Example 14 ( 3.5 g) was obtained in the same manner as in Reference Example 13 to obtain the title compound (2.24 g).
1 H-NMR (DMSO-d 6 ) δ: 3.66 (3H, s), 4.11 (2H, d, J = 5.7 Hz), 5.55 (2H, s), 6.99 (1H, s), 7.28-7.57 (5H , m), 8.55 (1H, brs), 8.90 (1H, s), 13.76 (1H, brs).
　実施例１０１：[[５－（２－エチルブチルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　２－エチルブタノール（８７ｍｇ）および参考例１５で得られた化合物（２５０ｍｇ）を用い、実施例９３と同様にして、表題化合物（４８ｍｇ）を得た。 Example 101: [[5- (2-Ethylbutylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-ethylbutanol (87 mg) The title compound (48 mg) was obtained in the same manner as in Example 93, using the compound (250 mg) obtained in Reference Example 15.
　実施例１０２：[[５－(１，３－ジメチルブチルスルファニル)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　４－メチル－２－ペンタノール（１０５ｍｇ）及び参考例１３で得られた化合物（２００ｍｇ）を用い、実施例１００と同様にして、表題化合物（３０ｍｇ）を得た。 Example 102: [[5- (1,3-Dimethylbutylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 4-methyl-2 -The title compound (30 mg) was obtained in the same manner as in Example 100 using pentanol (105 mg) and the compound (200 mg) obtained in Reference Example 13.
　実施例１０３：[[７－ヒドロキシ－５－(４，４，４－トリフルオロブチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　メタンスルホン酸４，４，４－トリフルオロ－ブチルエステル（３０９ｍｇ）及び参考例１５で得られた化合物（２７９ｍｇ）を用い、実施例１５２と同様にして、表題化合物（１０４ｍｇ）を得た。 Example 103: [[7-hydroxy-5- (4,4,4-trifluorobutylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid methanesulfone Using the acid 4,4,4-trifluoro-butyl ester (309 mg) and the compound (279 mg) obtained in Reference Example 15, the title compound (104 mg) was obtained in the same manner as in Example 152.
　実施例１０４：[(７－ヒドロキシ－５－ペンチルスルファニル[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　ペンタンチオール(１２５ｍｇ)及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル（４５１ｍｇ）を用い、実施例６と同様にして、表題化合物（４８ｍｇ）を得た。 Example 104: [(7-Hydroxy-5-pentylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid pentanethiol (125 mg) and 7-benzyloxy-5 Using iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (451 mg), the title compound (48 mg) was obtained in the same manner as in Example 6.
　実施例１０５：[(７－ヒドロキシ－５－(４－メチルペンチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　４－メチルペンタノール（１００ｍｇ）及び参考例１３で得られた化合物（２００ｍｇ）を用い、実施例１００と同様にして、表題化合物（１００ｍｇ）を得た。 Example 105: [(7-hydroxy-5- (4-methylpentylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 4-methylpentanol (100 mg ) And the compound (200 mg) obtained in Reference Example 13 were used in the same manner as in Example 100 to obtain the title compound (100 mg).
　実施例１０６：[(７－ヒドロキシ－５－(３－メチルペンチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　３－メチルペンタノール（１００ｍｇ）及び参考例１３で得られた化合物（２００ｍｇ）を用い、実施例１００と同様にして、表題化合物（７０ｍｇ）を得た。 Example 106: [(7-Hydroxy-5- (3-methylpentylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 3-methylpentanol (100 mg ) And the compound (200 mg) obtained in Reference Example 13 were used in the same manner as in Example 100 to obtain the title compound (70 mg).
　実施例１０７：[[７－ヒドロキシ－５－(２－プロピルペンチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２－プロピルペンテン－1－オール（１４７ｍｇ）及び参考例１３で得られた化合物（３１１ｍｇ）を用い、実施例１００と同様にして、表題化合物（１０２ｍｇ）を得た。 Example 107: [[7-Hydroxy-5- (2-propylpentylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-propylpentene-1- The title compound (102 mg) was obtained in the same manner as in Example 100, using all (147 mg) and the compound (311 mg) obtained in Reference Example 13.
　実施例１０８：[[５－(３－エチルペンチルスルファニル)－7－ヒドロキシ－[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　３－エチルペンタン－1－オール（１３１ｍｇ）及び参考例１３で得られた化合物（３１１ｍｇ）を用い、実施例１００と同様にして、表題化合物（１３５ｍｇ）を得た。 Example 108: [[5- (3-Ethylpentylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 3-ethylpentane-1 Using the ol (131 mg) and the compound (311 mg) obtained in Reference Example 13, the title compound (135 mg) was obtained in the same manner as in Example 100.
　実施例１０９：[[７－ヒドロキシ－５－（ペンタ－３－ニルスルファニル）[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　３－ペンチン－１－オール（３２ｍｇ）及び参考例１５で得られた化合物（１３０ｍｇ）を用い、参考例１１、実施例５、３と同様にして、表題化合物（６９ｍｇ）を得た。 Example 109: [[7-Hydroxy-5- (pent-3-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 3-pentyne-1- Using all (32 mg) and the compound (130 mg) obtained in Reference Example 15, the title compound (69 mg) was obtained in the same manner as in Reference Example 11, Example 5, and 3.
　実施例１１０：[[７－ヒドロキシ－５－(４，４，５，５，５－ペンタフルオロペンチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　トルエンスルホン酸４，４，５，５，５－ペンタフルオロペンタンエステル（３３２ｍｇ）及び参考例１５で得られた化合物（２７９ｍｇ）を用い、実施例１５２と同様にして、表題化合物（２１０ｍｇ）を得た。 Example 110: [[7-Hydroxy-5- (4,4,5,5,5-pentafluoropentylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino ] Acetic acid Toluenesulfonic acid 4,4,5,5,5-pentafluoropentane ester (332 mg) and the compound obtained in Reference Example 15 (279 mg) were used in the same manner as in Example 152 to give the titled compound (210 mg) Got.
　実施例１１１：[(５－ヘキシルスルファニル－７－ヒドロキシ－[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　ヘキサンチオール（８８ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして、表題化合物（６０ｍｇ）を得た。 Example 111: [(5-Hexylsulfanyl-7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid hexanethiol (88 mg) and 7-benzyloxy- The title compound (60 mg) was obtained in the same manner as in Example 8 using 5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg). .
　実施例１１２：[(５－ヘキサ－３－イン－１－イルスルファニル－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　３－ヘキシン－１－ヒドロキシメタンスルホン酸エステル（１４３ｍｇ）及び参考例１５で得られた化合物（３５０ｍｇ）を用い、実施例１５２と同様にして、表題化合物（５７ｍｇ）を得た。 Example 112: [(5-hex-3-yn-1-ylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 3-hexyne- The title compound (57 mg) was obtained in the same manner as in Example 152, using 1-hydroxymethanesulfonic acid ester (143 mg) and the compound (350 mg) obtained in Reference Example 15.
　実施例１１３：［（７－ヒドロキシ－５－イソプロピルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ］酢酸
　２－プロパンチオール（９２ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(２５０ｍｇ)を用い、実施例８と同様にして、表題化合物（３２ｍｇ）を得た。 Example 113: [(7-Hydroxy-5-isopropylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 2-propanethiol (92 mg) and 7-benzyloxy Using -5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg), the title compound (32 mg) was obtained in the same manner as in Example 8. It was.
　実施例１１４：[(５－ｔ－ブチルスルファニル－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　２－メチルプロパン－２－チオール（４８ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして、表題化合物（６０ｍｇ）を得た。 Example 114: [(5-tert-butylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 2-methylpropane-2-thiol (48 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, Compound (60 mg) was obtained.
　実施例１１５：[(７－ヒドロキシ－５－イソブチルスルファニル[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　２－メチルプロパン－1－チオール（４８ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして、表題化合物（７３ｍｇ）を得た。 Example 115: [(7-hydroxy-5-isobutylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 2-methylpropane-1-thiol (48 mg) and Using 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, the title compound ( 73 mg) was obtained.
　実施例１１６：[[５－（１，２－ジメチルプロピルスルファニル）－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　１、２－ジメチル－１－プロパンチオール（７４ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(３００ｍｇ)を用い、実施例６と同様にして、表題化合物（４０ｍｇ）を得た。 Example 116: [[5- (1,2-Dimethylpropylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 1,2-dimethyl Examples using 1-propanethiol (74 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as in 6, the title compound (40 mg) was obtained.
　実施例１１７：[(５－アリルスルファニル－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　アリルメルカプタン（５３．８ｍｇ）と７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸メチルエステル(３００ｍｇ)を用い、参考例１、２、実施例１と同様にして、５－アリルスルファニル－７－ベンジルオキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニルアミノ酢酸メチルエステル(１０４ｍｇ)を得た。これに、トリフルオロ酢酸(１ｍＬ)、トリエチルシラン(５９ｍｇ)を加え、８０℃、６時間加熱撹拌した。減圧下留去し、ジイソプロピルエーテルを加え、析出結晶をろ取し、乾燥して表題化合物（５５ｍｇ）を得た。 Example 117: [(5-allylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid allyl mercaptan (53.8 mg) and 7-benzyloxy Using 5--5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid methyl ester (300 mg) in the same manner as in Reference Examples 1, 2, and Example 1, 5-allyl Sulfanyl-7-benzyloxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonylaminoacetic acid methyl ester (104 mg) was obtained. To this was added trifluoroacetic acid (1 mL) and triethylsilane (59 mg), and the mixture was heated and stirred at 80 ° C. for 6 hours. The residue was evaporated under reduced pressure, diisopropyl ether was added, and the precipitated crystals were collected by filtration and dried to give the title compound (55 mg).
　実施例１１８：［（５－シクロペンチルスルファニル－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ］酢酸
　シクロペンタンチオール（４５ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして、表題化合物（７２ｍｇ）を得た。 Example 118: [(5-Cyclopentylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid cyclopentanethiol (45 mg) and 7-benzyloxy- Using 5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, the title compound (72 mg) was obtained. .
　実施例１１９:［（５－シクロヘキシルスルファニル－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ］酢酸
　シクロヘキサンチオール（６１ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(２５０ｍｇ)を用い、実施例８と同様にして、表題化合物（５５ｍｇ）を得た。 Example 119: [(5-cyclohexylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid cyclohexanethiol (61 mg) and 7-benzyloxy-5 The title compound (55 mg) was obtained in the same manner as in Example 8 using iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg).
　実施例１２０：[[５－（アダマンタン－１－イルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　１－アダマンタンチオール（４００ｍｇ）および７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル(４００ｍｇ)を用い、実施例８と同様にして、表題化合物（１１０ｍｇ）を得た。 Example 120: [[5- (adamantan-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 1-adamantanethiol (400 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (400 mg) in the same manner as in Example 8, Compound (110 mg) was obtained.
　実施例１２１：｛［５－シクロプロピルメチルスルファニル－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ブロモメチルシクロプロパン（８７ｍｇ）及び参考例１５で得られた化合物（８１ｍｇ）を用い、実施例１５２と同様にして、表題化合物（５６ｍｇ）を得た。 Example 121: {[5-Cyclopropylmethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Bromomethylcyclopropane (87 mg) and Reference Example The title compound (56 mg) was obtained in the same manner as in Example 152, using the compound (81 mg) obtained in 15.
　実施例１２２：｛［５－シクロブチルメチルスルファニル－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ブロモメチルシクロブタン（３９ｍｇ）及び参考例１５で得られた化合物（７６ｍｇ）を用い、実施例１５２と同様にして、表題化合物（５０ｍｇ）を得た。 Example 122: {[5-cyclobutylmethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Bromomethylcyclobutane (39 mg) and Reference Example 15 The title compound (50 mg) was obtained in the same manner as in Example 152 using the compound obtained in (76 mg).
　実施例１２３：｛［５－シクロペンチルメチルスルファニル－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　トルエン－４－スルホン酸シクロペンチルメチルエステル（２５４ｍｇ）及び参考例１５で得られた化合物(２５０ｍｇ)を用い、実施例１５２と同様にして表題化合物（１１１ｍｇ）を得た。 Example 123: {[5-Cyclopentylmethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Toluene-4-sulfonic acid cyclopentylmethyl ester (254 mg ) And the compound (250 mg) obtained in Reference Example 15 were used to obtain the title compound (111 mg) in the same manner as in Example 152.
　実施例１２４：｛［５－シクロヘキシルメチルスルファニル－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　トルエン－４－スルホン酸シクロヘキシルメチルエステル（７５μL）及び参考例１５で得られた化合物(２００ｍｇ)を用い、実施例１５２と同様にして表題化合物（８５ｍｇ）を得た。 Example 124: {[5-cyclohexylmethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid toluene-4-sulfonic acid cyclohexylmethyl ester (75 μL ) And the compound (200 mg) obtained in Reference Example 15 were used to obtain the title compound (85 mg) in the same manner as in Example 152.
　実施例１２５：｛［５－(２－シクロヘキシルエチルスルファニル)－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　トルエン－４－スルホン酸シクロヘキシルエチルエステル（２５１ｍｇ）及び参考例１５で得られた化合物(３００ｍｇ)を用い、実施例１５２と同様にして表題化合物（１３６ｍｇ）を得た。 Example 125: {[5- (2-cyclohexylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid toluene-4-sulfonic acid cyclohexyl The title compound (136 mg) was obtained in the same manner as in Example 152, using ethyl ester (251 mg) and the compound (300 mg) obtained in Reference Example 15.
　実施例１２６：｛［５－（２－シクロヘキシルプロピルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－シクロへキシルプロパノール（１０２ｍｇ）及び参考例１３で得られた化合物（２００ｍｇ）を用い、実施例１００と同様にして、表題化合物（１１９ｍｇ）を得た。 Example 126: {[5- (2-cyclohexylpropylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-cyclohexylpropanol ( 102 mg) and the compound obtained in Reference Example 13 (200 mg) were used in the same manner as in Example 100 to obtain the title compound (119 mg).
　実施例１２７：[[５－(２－シクロプロピルエチルスルファニル)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　トルエン－４－スルホン酸２－シクロプロピルエチルエステル（１３２ｍｇ）及び参考例１５で得られた化合物（２０７ｍｇ）を用い、実施例１５２と同様にして、表題化合物（９５ｍｇ）を得た。 Example 127: [[5- (2-Cyclopropylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid Toluene-4-sulfonic acid The title compound (95 mg) was obtained in the same manner as in Example 152, using 2-cyclopropylethyl ester (132 mg) and the compound (207 mg) obtained in Reference Example 15.
　実施例１２８：｛［５－（２－シクロブチルエチルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　トルエン－４－スルホン酸－２－シクロブチルエチルエステル（１６５ｍｇ）及び参考例１５で得られた化合物(２００ｍｇ)を用い、実施例１５２と同様にして表題化合物（４０ｍｇ）を得た。 Example 128: {[5- (2-cyclobutylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Toluene-4-sulfonic acid The title compound (40 mg) was obtained in the same manner as in Example 152, using -2-cyclobutylethyl ester (165 mg) and the compound (200 mg) obtained in Reference Example 15.
　実施例１２９：｛［５－（２－シクロペンチルエチルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　トルエン－４－スルホン酸－２－シクロペンチルエチルエステル（２１７ｍｇ）及び参考例１５で得られた化合物(２００ｍｇ)を用い、実施例１５２と同様にして表題化合物（５６ｍｇ）を得た。 Example 129: {[5- (2-Cyclopentylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Toluene-4-sulfonic acid The title compound (56 mg) was obtained in the same manner as in Example 152, using 2-cyclopentylethyl ester (217 mg) and the compound (200 mg) obtained in Reference Example 15.
　実施例１３０：｛［５－（２－ビシクロ［２．２．１］ヘプト－２－イルエチルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　（２－ビシクロ［２，２，１］ヘプト－２－イルエタノール（１４４ｍｇ）とトリエチルアミン（１０１ｍｇ）の混合物をＴＨＦ(２ｍＬ)に溶解し、氷冷下メシルクロリド（１１２ｍｇ）を加え、室温で１時間撹拌した。反応終了後、水を加え、酢酸エチルで抽出し、有機相を水、飽和食塩水で洗浄して、無水硫酸マグネシウムで乾燥した。ろ過後、溶媒を減圧留去し、メタンスルホン酸２－ビシクロ[２，２，１]ヘプト－２－イル－エチルエステルを得た。この化合物（１９７ｍｇ）及び参考例１５で得られた化合物（３１１ｍｇ）を用い、実施例１５２と同様にして、表題化合物（１１６ｍｇ）を得た。 Example 130: {[5- (2-bicyclo [2.2.1] hept-2-ylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8- Carbonyl] amino} acetic acid A mixture of (2-bicyclo [2,2,1] hept-2-ylethanol (144 mg) and triethylamine (101 mg) was dissolved in THF (2 mL), and mesyl chloride (112 mg) was added under ice cooling. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. To give methanesulfonic acid 2-bicyclo [2,2,1] hept-2-yl-ethyl ester, which was obtained using this compound (197 mg) and the compound obtained in Reference Example 15 (311 mg). In the same manner as in Example 152, the title compound (116 mg) was obtained.
　実施例１３１：｛［５－（２－アダマンタン－1－イルエチル）スルファニル－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　トルエン－４－スルホン酸－２－アダマンタン－１－イルエチルエステル（２３４ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例１５２と同様にして表題化合物（７１ｍｇ）を得た。 Example 131: {[5- (2-adamantan-1-ylethyl) sulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Toluene-4- The title compound (71 mg) was obtained in the same manner as in Example 152, using sulfonic acid-2-adamantan-1-ylethyl ester (234 mg) and the compound (200 mg) obtained in Reference Example 15.
　実施例１３２：｛（７－ヒドロキシ－５－フェネチルスルファニル［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ｝酢酸
　２－フェニルエタンチオール（９２ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２５０ｍｇ）を用い、参考例３、実施例３２と同様にして表題化合物（６０ｍｇ）を得た。 Example 132: {(7-hydroxy-5-phenethylsulfanyl [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino} acetic acid 2-phenylethanethiol (92 mg) and 7-benzyl Using oxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg) in the same manner as in Reference Example 3 and Example 32, the title compound ( 60 mg) was obtained.
　実施例１３３：([５－[２－(３，４－ジクロロフェニル)エチルスルファニル]－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ)酢酸
　３，４－ジクロロフェニルエタノール（１１０ｍｇ）及び参考例１３で得られた化合物（２００ｍｇ）を用い、実施例１００と同様にして、表題化合物（１２０ｍｇ）を得た。 Example 133: ([5- [2- (3,4-Dichlorophenyl) ethylsulfanyl] -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino) acetic acid 3 , 4-Dichlorophenylethanol (110 mg) and the compound obtained in Reference Example 13 (200 mg) were used in the same manner as in Example 100 to obtain the title compound (120 mg).
　実施例１３４：([７－ヒドロキシ－５－[２－(４－メトキシフェニル)エチルスルファニル][１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ)酢酸
　２－(４－メトキシフェニル)エタノール（１５０ｍｇ）及び参考例１３で得られた化合物（２００ｍｇ）を用い、実施例１００と同様にして、表題化合物（１００ｍｇ）を得た。 Example 134: ([7-hydroxy-5- [2- (4-methoxyphenyl) ethylsulfanyl] [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino) acetic acid 2- The title compound (100 mg) was obtained in the same manner as in Example 100, using (4-methoxyphenyl) ethanol (150 mg) and the compound (200 mg) obtained in Reference Example 13.
　実施例１３５：[(７－ヒドロキシ－５－(２－フェニルプロピルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　２－フェニルプロパノール（９０ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例９４と同様にして、表題化合物（９０ｍｇ）を得た。 Example 135: [(7-hydroxy-5- (2-phenylpropylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 2-phenylpropanol (90 mg) The title compound (90 mg) was obtained in the same manner as in Example 94, using the compound (200 mg) obtained in Reference Example 15.
　実施例１３６：[(７－ヒドロキシ－５－(２－メチル－２－フェニルプロピルスルファニル)－[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　２－メチル－２－フェニルプロパノール(９０ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例９４と同様にして、表題化合物（９０ｍｇ）を得た。 Example 136: [(7-Hydroxy-5- (2-methyl-2-phenylpropylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 2- The title compound (90 mg) was obtained in the same manner as in Example 94, using methyl-2-phenylpropanol (90 mg) and the compound (200 mg) obtained in Reference Example 15.
　実施例１３７：[(７－ヒドロキシ－５－(２－チオフェン－２－イルエチルスルファニル)－[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　２－チオフェンエタノール（７１ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例９４と同様にして、表題化合物（８４ｍｇ）を得た。 Example 137: [(7-hydroxy-5- (2-thiophen-2-ylethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 2- The title compound (84 mg) was obtained in the same manner as in Example 94, using thiophene ethanol (71 mg) and the compound (200 mg) obtained in Reference Example 15.
　実施例１３８：｛［５－（３－シクロヘキシルプロピルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　トルエン－４－スルホン酸３－シクロヘキシルプロピルエステル（１１２ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例１５２と同様にして表題化合物（５０ｍｇ）を得た。 Example 138: {[5- (3-cyclohexylpropylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid toluene-4-sulfonic acid 3 -The title compound (50 mg) was obtained in the same manner as in Example 152, using cyclohexylpropyl ester (112 mg) and the compound (200 mg) obtained in Reference Example 15.
　実施例１３９：[[７－ヒドロキシ－５－（３－フェニルプロピルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　３－フェニルプロパノール（１１０ｍｇ）及び参考例１３で得られた化合物（２００ｍｇ）を用い、実施例１００と同様にして、表題化合物（８９ｍｇ）を得た。 Example 139: [[7-hydroxy-5- (3-phenylpropylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 3-phenylpropanol (110 mg) The title compound (89 mg) was obtained in the same manner as in Example 100 using the compound (200 mg) obtained in Reference Example 13.
　実施例１４０：｛［７－ヒドロキシ－５－（２－メトキシエチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　１－ブロモ－２－メトキシエタン（７６μＬ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例１５２と同様にして表題化合物（１０５ｍｇ）を得た。 Example 140: {[7-hydroxy-5- (2-methoxyethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 1-bromo-2-methoxy The title compound (105 mg) was obtained in the same manner as in Example 152, using ethane (76 μL) and the compound (200 mg) obtained in Reference Example 15.
　実施例１４１：[[７－ヒドロキシ－５－(２－イソプロポキシエチルスルファニル）[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２－イソプロポキシエタノール（７３ｍｇ）及び参考例１７で得られた化合物(２００ｍｇ)を用い、参考例１１、２、実施例１～３と同様にして、表題化合物（４４ｍｇ）を得た。 Example 141: [[7-Hydroxy-5- (2-isopropoxyethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-isopropoxyethanol ( 73 mg) and the compound obtained in Reference Example 17 (200 mg) were used in the same manner as in Reference Examples 11 and 2 and Examples 1 to 3, to obtain the title compound (44 mg).
　実施例１４２：[(７－ヒドロキシ－５－(２－フェノキシエチルスルファニル)[１,２,４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　２－フェノキシエタノール（９０ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例９４と同様にして、表題化合物（４０ｍｇ）を得た。 Example 142: [(7-hydroxy-5- (2-phenoxyethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 2-phenoxyethanol (90 mg) and The title compound (40 mg) was obtained in the same manner as in Example 94, using the compound (200 mg) obtained in Reference Example 15.
　実施例１４３：[[５－(２，３－ジヒドロベンゾ[ｂ][１，４]ジオキシン－２－イルメチルスルファニル)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２－ヒドロキシメチル－１，４－ベンゾジオキサン（１５０ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例９４と同様にして、表題化合物（２０ｍｇ）を得た。 Example 143: [[5- (2,3-dihydrobenzo [b] [1,4] dioxin-2-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] [Pyridine-8-carbonyl] amino] acetic acid 2-hydroxymethyl-1,4-benzodioxane (150 mg) and the compound obtained in Reference Example 15 (200 mg) were used in the same manner as in Example 94 to obtain the title compound (20 mg )
　実施例１４４：｛[５－(２，３－ジフェニルプロピルスルファニル)－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，３－ジフェニルプロパノール（１．０ｇ）を用い，実施例１３０と同様の方法で２，３－ジフェニルプロパノールメタンスルホネート（１．４ｇ）を得た。この化合物（１９０ｍｇ）及び参考例１７で得られた化合物（２００ｍｇ）を用い、参考例１６及び実施例３２と同様にして表題化合物（５５ｍｇ）を得た。 Example 144: {[5- (2,3-diphenylpropylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,3-diphenyl 2,3-Diphenylpropanol methanesulfonate (1.4 g) was obtained in the same manner as in Example 130, using propanol (1.0 g). Using this compound (190 mg) and the compound (200 mg) obtained in Reference Example 17, the title compound (55 mg) was obtained in the same manner as in Reference Example 16 and Example 32.
　実施例１４５：（｛５－[２－（２－エチルヘキシルオキシカルボニル）エチルスルファニル]－７－ヒドロキシ[１，２，４]トリアゾロ[１，５，α]ピリジン－８－カルボニル]アミノ）酢酸
　３－メルカプトプロパン酸２－エチルヘキシルエステル（７２ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル（１３７ｍｇ）を用い、実施例９４と同様にして、表題化合物（９０ｍｇ）を得た。 Example 145: ({5- [2- (2-ethylhexyloxycarbonyl) ethylsulfanyl] -7-hydroxy [1,2,4] triazolo [1,5, α] pyridine-8-carbonyl] amino) acetic acid 3 -Using mercaptopropanoic acid 2-ethylhexyl ester (72 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (137 mg) In the same manner as in Example 94, the title compound (90 mg) was obtained.
　実施例１４６：[（５－ベンジルスルファニル－７－ヒドロキシ－［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル）アミノ]酢酸
　ベンジルメルカプタン（４９ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（１５０ｍｇ）を用い、参考例３、参考例２、実施例１～３と同様にして表題化合物（２１ｍｇ）を得た。 Example 146: [(5-Benzylsulfanyl-7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid benzyl mercaptan (49 mg) and 7-benzyloxy- Use 5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (150 mg) in the same manner as Reference Example 3, Reference Example 2, and Examples 1 to 3. To give the title compound (21 mg).
　実施例１４７：｛［７－ヒドロキシ－５－（２－メチルベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　（２－メチルフェニル）メタンチオール（６７ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして表題化合物（４４ｍｇ）を得た。 Example 147: {[7-hydroxy-5- (2-methylbenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (2-methylphenyl) methane Using thiol (67 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) as in Example 8. To give the title compound (44 mg).
　実施例１４８：｛［７－ヒドロキシ－５－（２－トリフルオロメチルベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－（トリフルオロメチル）ベンジルブロミド（５７ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（４６ｍｇ）を得た。 Example 148: {[7-hydroxy-5- (2-trifluoromethylbenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2- (trifluoro The title compound (46 mg) was obtained in the same manner as in Example 152, using methyl) benzyl bromide (57 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１４９：｛［５－（２－フルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－フルオロベンジルブロミド（４５ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（５６ｍｇ）を得た。 Example 149: {[5- (2-Fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-fluorobenzyl bromide (45 mg ) And the compound (80 mg) obtained in Reference Example 15 were used to obtain the title compound (56 mg) in the same manner as in Example 152.
　実施例１５０：｛［５－（２－クロロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　（２－クロロフェニル）メタンチオール（７７ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして表題化合物（６６ｍｇ）を得た。 Example 150: {[5- (2-chlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (2-chlorophenyl) methanethiol (77 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) as in Example 8. The title compound (66 mg) was obtained.
　参考例１６： [[７－ベンジルオキシ－５－（２－メトキシベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸メチルエステル
　２－メトキシベンジルクロライド（１１０ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）をＴＨＦ溶媒（２ｍＬ）中混合し、ジイソプロピルエチルアミン（０．５ｍＬ）を加えて７時間加熱還流した。反応液を濃縮し、残渣をカラムクロマトグラフィー（クロロホルム／メタノール＝５０／１）にて精製し、表題化合物（１０５ｍｇ）を得た。
1H-NMR(DMSO-d6)δ3.79(3H,s),3.85(3H,s),4.32(2H,d,J=4.59Hz),4.33(2H,s),5.28(2H,s),6.73(1H),6.87-6.94(2H,m),7.26-7.50(7H,m),8.30(1H,s),9.73(1H,brs) Reference Example 16: [[7-Benzyloxy-5- (2-methoxybenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid methyl ester 2-methoxybenzyl Chloride (110 mg) and the compound obtained in Reference Example 15 (80 mg) were mixed in THF solvent (2 mL), diisopropylethylamine (0.5 mL) was added, and the mixture was heated to reflux for 7 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (chloroform / methanol = 50/1) to obtain the title compound (105 mg).
1 H-NMR (DMSO-d 6 ) δ 3.79 (3H, s), 3.85 (3H, s), 4.32 (2H, d, J = 4.59Hz), 4.33 (2H, s), 5.28 (2H, s ), 6.73 (1H), 6.87-6.94 (2H, m), 7.26-7.50 (7H, m), 8.30 (1H, s), 9.73 (1H, brs)
　実施例１５１：[[７－ヒドロキシ－５－（２－メトキシベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　参考例１６で得られた化合物（１００ｍｇ）を用い、実施例２、３と同様にして、表題化合物（４８ｍｇ）を得た。 Example 151 1: [[7-Hydroxy-5- (2-methoxybenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid obtained in Reference Example 16 The title compound (48 mg) was obtained in the same manner as in Examples 2 and 3 using the compound (100 mg).
　実施例１５２：[[７－ヒドロキシ－５－（２－トリフルオロメトキシベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　２－（トリフルオロメトキシ）ベンジルブロミド（６５ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、参考例１６、実施例１５１と同様にして、表題化合物（７０ｍｇ）を得た。 Example 152: [[7-hydroxy-5- (2-trifluoromethoxybenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2- (trifluoro The title compound (70 mg) was obtained in the same manner as in Reference Example 16 and Example 151 using (methoxy) benzyl bromide (65 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１５３：｛［７－ヒドロキシ－５－（３－メチルベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－メチルベンジルブロミド（４４ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（５１ｍｇ）を得た。 Example 153: {[7-Hydroxy-5- (3-methylbenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-methylbenzyl bromide (44 mg ) And the compound (80 mg) obtained in Reference Example 15 were used to obtain the title compound (51 mg) in the same manner as in Example 152.
　実施例１５４：｛［７－ヒドロキシ－５－（３－トリフルオロメチルベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－（トリフルオロメチル）ベンジルブロミド（５７ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（６０ｍｇ）を得た。 Example 154: {[7-hydroxy-5- (3-trifluoromethylbenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3- (trifluoro The title compound (60 mg) was obtained in the same manner as in Example 152, using (methyl) benzyl bromide (57 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１５５：｛［５－（３－フルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－フルオロベンジルブロミド（４５ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（６０ｍｇ）を得た。 Example 155: {[5- (3-Fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-fluorobenzyl bromide (45 mg ) And the compound (80 mg) obtained in Reference Example 15 were used to obtain the title compound (60 mg) in the same manner as in Example 152.
　実施例１５６：｛［５－（３－クロロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－クロロベンジルブロミド（４９ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（６０ｍｇ）を得た。 Example 156: {[5- (3-chlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-chlorobenzyl bromide (49 mg ) And the compound (80 mg) obtained in Reference Example 15 were used to obtain the title compound (60 mg) in the same manner as in Example 152.
　実施例１５７：[[７－ヒドロキシ－５－（４－メチルベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　４－メチルベンジルメルカプタン（６６ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして、表題化合物（６６ｍｇ）を得た。 Example 157: [[7-hydroxy-5- (4-methylbenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 4-methylbenzyl mercaptan (66 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) in the same manner as in Example 8, Compound (66 mg) was obtained.
　実施例１５８：｛［７－ヒドロキシ－５－（４－トリフルオロメチルベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　［４－（トリフルオロメチル）フェニル］メタンチオール（１０８ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２３０ｍｇ）を用い、実施例８と同様にして表題化合物（８９ｍｇ）を得た。 Example 158: {[7-hydroxy-5- (4-trifluoromethylbenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid [4- (tri Fluoromethyl) phenyl] methanethiol (108 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (230 mg) In the same manner as in Example 8, the title compound (89 mg) was obtained.
　実施例１５９：｛［５－（４－フルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　（４－フルオロフェニル）メタンチオール（６９ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして表題化合物（８８ｍｇ）を得た。 Example 159: {[5- (4-Fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (4-fluorophenyl) methane Using thiol (69 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) as in Example 8. To give the title compound (88 mg).
　実施例１６０：[[５－（４－クロロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　４－クロロベンジルメルカプタン（１６８ｍｇ）及び７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（４００ｍｇ）を用い、実施例６と同様にして、表題化合物（４８ｍｇ）を得た。 Example 160: [[5- (4-Chlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 4-chlorobenzyl mercaptan (168 mg ) And 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (400 mg) in the same manner as in Example 6, Compound (48 mg) was obtained.
　参考例１７：７－ベンジルオキシ－５－メルカプト［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル
　７－ベンジルオキシ－５－ヨード［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２０ｇ）をＮ，Ｎ－ジメチルホルムアミド（１００ｍｌ）に溶解し、室温下硫化ナトリウム無水物（６．９ｇ）を加えた。室温下３０分間撹拌し、飽和クエン酸水溶液を加えて酸性とし、水（４００ｍＬ）加えて析出した結晶をろ取し、表題化合物（１４．７ｇ）を得た。
1H-NMR(DMSO-d6)1.46(9H,s),5.25(2H,s),7.01(1H,s),7.31-7.57(5H,m),8.90(1H,s) Reference Example 17: 7-benzyloxy-5-mercapto [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester 7-benzyloxy-5-iodo [1,2, 4] Triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (20 g) is dissolved in N, N-dimethylformamide (100 ml), and anhydrous sodium sulfide (6.9 g) is added at room temperature. It was. The mixture was stirred at room temperature for 30 minutes, acidified with saturated aqueous citric acid solution, water (400 mL) was added, and the precipitated crystals were collected by filtration to give the title compound (14.7 g).
1 H-NMR (DMSO-d 6 ) 1.46 (9H, s), 5.25 (2H, s), 7.01 (1H, s), 7.31-7.57 (5H, m), 8.90 (1H, s)
　実施例１６１：｛［５－（４－シアノベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　４－（メルカプトメチル）ベンゾニトリル（７３ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例６と同様にして表題化合物（９７ｍｇ）を得た。 Example 161: {[5- (4-Cyanobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4- (mercaptomethyl) benzo Similar to Example 6 using nitrile (73 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg). To give the title compound (97 mg).
　実施例１６２：｛［５－（４－ｔ－ブチルベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　（４－ｔ－ブチルフェニル）メタンチオール（１４４ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（３００ｍｇ）を用い、実施例１４６と同様にして表題化合物（２４ｍｇ）を得た。 Example 162: {[5- (4-t-butylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (4-t- Examples using butylphenyl) methanethiol (144 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) In the same manner as 146, the title compound (24 mg) was obtained.
　実施例１６３：｛［５－（ビフェニル－４－イルメチルスルファニル）－７－ヒドロキシ－［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ビフェニル－４－イルメタンチオール（１１７ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２２０ｍｇ）を用い、実施例１４６と同様にして表題化合物（４２ｍｇ）を得た。 Example 163: {[5- (biphenyl-4-ylmethylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid biphenyl-4- Example 146 with ylmethanethiol (117 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (220 mg) In the same manner, the title compound (42 mg) was obtained.
　実施例１６４：｛［７－ヒドロキシ－５－（４－メトキシベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　４－メトキシベンジルアルコール（１３４ｍｇ）及び参考例１５で得られた化合物（３００ｍｇ）を用い、参考例１１、実施例２、３と同様にして表題化合物（５３ｍｇ）を得た。 Example 164: {[7-hydroxy-5- (4-methoxybenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4-methoxybenzyl alcohol (134 mg ) And the compound (300 mg) obtained in Reference Example 15 were used to obtain the title compound (53 mg) in the same manner as in Reference Example 11, Examples 2 and 3.
　実施例１６５：｛［５－（２－フルオロ－３－メチルベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－フルオロ－３－メチルベンジルブロミド（４８ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（４７ｍｇ）を得た。 Example 165: {[5- (2-Fluoro-3-methylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-fluoro The title compound (47 mg) was obtained in the same manner as in Example 152, using -3-methylbenzyl bromide (48 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１６６：｛［５－（２，３－ジフルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，３－ジフルオロベンジルブロミド（４９ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（５６ｍｇ）を得た。 Example 166: {[5- (2,3-difluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,3-difluoro The title compound (56 mg) was obtained in the same manner as in Example 152, using benzyl bromide (49 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１６７：｛［５－（２，４－ジクロロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　（２，４－ジクロロフェニル）メタンチオール（９４ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして表題化合物（６５ｍｇ）を得た。 Example 167: {[5- (2,4-dichlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (2,4- Example 8 using dichlorophenyl) methanethiol (94 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) To give the title compound (65 mg).
　実施例１６８：｛［５－（２，４－ジメチルベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，４－ジメチルベンジルアルコール（５０ｍｇ）とテトラヒドロフラン（２．０ｍＬ）を混合し、氷冷下、トリエチルアミン（４５ｍｇ）及びメタンスルホニルクロリド（４２ｍｇ）を順次加えた。同温にて２時間攪拌し反応終了を確認した後、トリエチルアミン（４５ｍｇ）及び参考例１３で得られた化合物（１５２ｍｇ）を更に加えた。室温にて１時間攪拌した後、反応終了を確認した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、ろ過後、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝２／３）で精製し、｛[７－ベンジルオキシ－５－（２，４－ジメチルベンジルスルファニル）－［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸ｔ－ブチルエステルを得た。この得られた化合物を実施例５と同様にして表題化合物（５０ｍｇ）を得た。 Example 168: {[5- (2,4-dimethylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,4-dimethyl Benzyl alcohol (50 mg) and tetrahydrofuran (2.0 mL) were mixed, and triethylamine (45 mg) and methanesulfonyl chloride (42 mg) were sequentially added under ice cooling. After stirring at the same temperature for 2 hours and confirming the completion of the reaction, triethylamine (45 mg) and the compound obtained in Reference Example 13 (152 mg) were further added. After stirring for 1 hour at room temperature, the completion of the reaction was confirmed. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate = 2/3), and {[7-benzyloxy-5- (2,4-dimethylbenzylsulfanyl)-[1,2,4] triazolo [ 1,5-α] pyridine-8-carbonyl] amino} acetic acid t-butyl ester was obtained. The obtained compound was treated in the same manner as in Example 5 to obtain the title compound (50 mg).
　実施例１６９：｛［５－（２，５－ジメチルベンジルスルファニル）－７－ヒドロキシ－［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，５－ジメチルフェニルメチル　メタンスルホネート（５７ｍｇ）及び参考例１５で得られた化合物（９０ｍｇ）を用い、実施例１５２と同様にして表題化合物（７１ｍｇ）を得た。 Example 169: {[5- (2,5-dimethylbenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,5- The title compound (71 mg) was obtained in the same manner as in Example 152, using dimethylphenylmethyl methanesulfonate (57 mg) and the compound (90 mg) obtained in Reference Example 15.
　実施例１７０：｛［５－（２，５－ジフルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，５－ジフルオロベンジルブロミド（４３ｍｇ）及び参考例１５で得られた化合物（７０ｍｇ）を用い、実施例１５２と同様にして表題化合物（５０ｍｇ）を得た。 Example 170: {[5- (2,5-difluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,5-difluoro The title compound (50 mg) was obtained in the same manner as in Example 152, using benzyl bromide (43 mg) and the compound (70 mg) obtained in Reference Example 15.
　実施例１７１：｛［５－（２，５－ジクロロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，５－ジクロロベンジルブロミド（５７ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（５２ｍｇ）を得た。 Example 171: {[5- (2,5-dichlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,5-dichloro The title compound (52 mg) was obtained in the same manner as in Example 152, using benzyl bromide (57 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１７２：｛［５－（５－クロロ－２－フルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　５－クロロ－２－フルオロベンジルブロミド（５３ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（５７ｍｇ）を得た。 Example 172: {[5- (5-chloro-2-fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-chloro The title compound (57 mg) was obtained in the same manner as in Example 152, using -2-fluorobenzyl bromide (53 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１７３：｛［５－（２－クロロ－５－フルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－クロロ－５－フルオロベンジルブロミド（５３ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（５１ｍｇ）を得た。 Example 173: {[5- (2-chloro-5-fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-chloro The title compound (51 mg) was obtained in the same manner as in Example 152, using -5-fluorobenzyl bromide (53 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１７４：｛［５－（２－フルオロ－５－メチルベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－フルオロ－５－メチルベンジルアルコール（８０ｍｇ）及び参考例１５で得られた化合物（９０ｍｇ）を用い、実施例１３０と同様にして表題化合物（７０ｍｇ）を得た。 Example 174: {[5- (2-Fluoro-5-methylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-fluoro The title compound (70 mg) was obtained in the same manner as in Example 130, using -5-methylbenzyl alcohol (80 mg) and the compound (90 mg) obtained in Reference Example 15.
　実施例１７５：｛［５－（２－クロロ－３，６－ジフルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－クロロ－３，６－ジフルオロベンジルブロミド（５７ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（６３ｍｇ）を得た。 Example 175: {[5- (2-Chloro-3,6-difluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2 The title compound (63 mg) was obtained in the same manner as in Example 152, using -chloro-3,6-difluorobenzyl bromide (57 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１７６：｛［５－（２，６－ジクロロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，６－ジクロロベンジルブロミド（５０ｍｇ）及び参考例１５で得られた化合物（７０ｍｇ）を用い、実施例１５２と同様にして表題化合物（５６ｍｇ）を得た。 Example 176: {[5- (2,6-dichlorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,6-dichloro The title compound (56 mg) was obtained in the same manner as in Example 152, using benzyl bromide (50 mg) and the compound (70 mg) obtained in Reference Example 15.
　実施例１７７：｛［５－（３－クロロ－４－フルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－クロロ－４－フルオロベンジルブロミド（５３ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（６８ｍｇ）を得た。 Example 177: {[5- (3-Chloro-4-fluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-chloro The title compound (68 mg) was obtained in the same manner as in Example 152, using -4-fluorobenzyl bromide (53 mg) and the compound obtained in Reference Example 15 (80 mg).
　実施例１７８：｛［５－（３，５－ビストリフルオロメチルベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，５－ビス（トリフルオロメチル）ベンジルブロミド（９５ｍｇ）及び参考例１７で得られた化合物（９２ｍｇ）を用い、実施例３２と同様にして表題化合物（６７ｍｇ）を得た。 Example 178: {[5- (3,5-bistrifluoromethylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,5 Using the bis (trifluoromethyl) benzyl bromide (95 mg) and the compound (92 mg) obtained in Reference Example 17, the title compound (67 mg) was obtained in the same manner as in Example 32.
　実施例１７９：[[５－（２，６－ジメチルベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　２，６－ジメチルベンジルヨージド（１５９ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例１５２と同様にして、表題化合物（７５ｍｇ）を得た。 Example 179: [[5- (2,6-dimethylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2,6-dimethyl The title compound (75 mg) was obtained in the same manner as in Example 152, using benzyl iodide (159 mg) and the compound (200 mg) obtained in Reference Example 15.
　実施例１８０：｛［７－ヒドロキシ－５－（２，４，６－トリメチルベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　（２，４，６－トリメチルフェニル）メタンチオール（８１ｍｇ）及び７－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ［１，５－α］ピリジン－８－カルボン酸ｔ－ブチルエステル（２００ｍｇ）を用い、実施例８と同様にして表題化合物（６４ｍｇ）を得た。 Example 180: {[7-hydroxy-5- (2,4,6-trimethylbenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (2, 4,6-trimethylphenyl) methanethiol (81 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg). And the title compound (64 mg) was obtained as in Example 8.
　実施例１８１：｛［７－ヒドロキシ－５－（２，３，６－トリフルオロベンジルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，３，６－トリフルオロベンジルブロミド（５３ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（４８ｍｇ）を得た。 Example 181: {[7-hydroxy-5- (2,3,6-trifluorobenzylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2, The title compound (48 mg) was obtained in the same manner as in Example 152, using 3,6-trifluorobenzyl bromide (53 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１８２：｛［７－ヒドロキシ－５－（２，３，４，５，６－ペンタフルオロベンジルスルファニル）－［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２，３，４，５，６－ペンタフルオロベンジルブロミド（４６ｍｇ）及び参考例１５で得られた化合物（６０ｍｇ）を用い、実施例１５２と同様にして表題化合物（３３ｍｇ）を得た。 Example 182: {[7-hydroxy-5- (2,3,4,5,6-pentafluorobenzylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] Amino} acetic acid 2,3,4,5,6-pentafluorobenzyl bromide (46 mg) and the compound obtained in Reference Example 15 (60 mg) were used in the same manner as in Example 152 to obtain the title compound (33 mg). .
　実施例１８３：｛［５－（３，６－ジフルオロ－２－メチルベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　１，４－ジフルオロ－２，３－ジメチルベンゼン（１００ｍｇ）とモノクロロベンゼン（１．０ｍＬ）を混合し、混合液にN－ブロモスクシンイミド（１５０ｍｇ）及びアゾビスイソブチロニトリル（６ｍｇ）を加え、９０℃で４時間攪拌した。反応終了後、不溶物をセライトろ過し、溶媒を減圧濃縮した。得られた２－ブロモメチル－１，４－ジフルオロ－３－メチルベンゼン及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（７３ｍｇ）を得た。 Example 183: {[5- (3,6-difluoro-2-methylbenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 1 , 4-Difluoro-2,3-dimethylbenzene (100 mg) and monochlorobenzene (1.0 mL) were added, and N-bromosuccinimide (150 mg) and azobisisobutyronitrile (6 mg) were added to the mixture. Stir at 4 ° C. for 4 hours. After completion of the reaction, the insoluble material was filtered through Celite, and the solvent was concentrated under reduced pressure. The title compound (73 mg) was obtained in the same manner as in Example 152, using the obtained 2-bromomethyl-1,4-difluoro-3-methylbenzene and the compound (80 mg) obtained in Reference Example 15.
　実施例１８４：｛［５－（２，６－ジフルオロベンジルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２,６－ジフルオロベンジルアルコール（１１０ｍｇ）及び参考例１３で得られた化合物（２００ｍｇ）を用い、実施例１００と同様にして、表題化合物（３０ｍｇ）を得た。 Example 184: {[5- (2,6-difluorobenzylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,6-difluoro The title compound (30 mg) was obtained in the same manner as in Example 100 using benzyl alcohol (110 mg) and the compound (200 mg) obtained in Reference Example 13.
　実施例１８５：(±)－[[７－ヒドロキシ－５－（１－フェニルエチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　(±)－１－フェニルエチルクロリド（１０６ｍｇ）及び参考例１５で得られた化合物（１４０ｍｇ）を用い、実施例１５２と同様にして、表題化合物（１１３ｍｇ）を得た。 Example 185: (±)-[[7-hydroxy-5- (1-phenylethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid (±) The title compound (113 mg) was obtained in the same manner as in Example 152, using 1-phenylethyl chloride (106 mg) and the compound (140 mg) obtained in Reference Example 15.
　実施例１８６：[[７－ヒドロキシ－５－（１，２，３，４－テトラヒドロナフタレン－１－イルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　１－クロロ－１，２，３，４－テトラヒドロナフタレン（８０ｍｇ）及び参考例１５で得られた化合物（９４ｍｇ）を用い、実施例１５２と同様にして、表題化合物（４０ｍｇ）を得た。 Example 186: [[7-hydroxy-5- (1,2,3,4-tetrahydronaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] Amino] acetic acid 1-chloro-1,2,3,4-tetrahydronaphthalene (80 mg) and the compound obtained in Reference Example 15 (94 mg) were used in the same manner as in Example 152 to obtain the title compound (40 mg). It was.
　実施例１８７：｛［７－ヒドロキシ－５－（５，６，７，８－テトラヒドロナフタレン－２－イルメチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　５，６，７，８－テトラヒドロナフタレン－２－イルメタノール（２７４ｍｇ）参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１３０と同様にして表題化合物（６５ｍｇ）を得た。 Example 187: {[7-Hydroxy-5- (5,6,7,8-tetrahydronaphthalen-2-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl Amino} acetic acid 5,6,7,8-tetrahydronaphthalen-2-ylmethanol (274 mg) The title compound (65 mg) was obtained in the same manner as in Example 130, using the compound (80 mg) obtained in Reference Example 15. It was.
　実施例１８８：｛［５－（ベンゾチアゾール－２－イルメチルスルファニル）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－ベンゾチアゾールメタノール　２－メタンスルホネート（５７ｍｇ）及び参考例１５で得られた化合物（８０ｍｇ）を用い、実施例１５２と同様にして表題化合物（６２ｍｇ）を得た。 Example 188: {[5- (benzothiazol-2-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-benzothiazole The title compound (62 mg) was obtained in the same manner as in Example 152, using methanol 2-methanesulfonate (57 mg) and the compound (80 mg) obtained in Reference Example 15.
　実施例１８９：｛［７－ヒドロキシ－５－（ピリジン－２－イルメチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－ブロモメチルピリジン臭素酸塩（１１２ｍｇ）及び参考例１５で得られた化合物（１５０ｍｇ）を用い、実施例１５２と同様にして表題化合物（５３ｍｇ）を得た。 Example 189: {[7-hydroxy-5- (pyridin-2-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-bromomethylpyridine The title compound (53 mg) was obtained in the same manner as in Example 152, using bromate (112 mg) and the compound (150 mg) obtained in Reference Example 15.
　実施例１９０：｛［７－ヒドロキシ－５－（ピリジン－３－イルメチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　ピリジン－３－イルメチルメタンスルホネート（８３ｍｇ）及び参考例１５で得られた化合物（１５０ｍｇ）を用い、実施例１５２と同様にして表題化合物（３５ｍｇ）を得た。 Example 190: {[7-Hydroxy-5- (pyridin-3-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Pyridin-3-yl The title compound (35 mg) was obtained in the same manner as in Example 152, using methylmethanesulfonate (83 mg) and the compound (150 mg) obtained in Reference Example 15.
　実施例１９１：｛［７－ヒドロキシ－５－（ピリジン－４－イルメチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　４－ブロモメチルピリジン臭素酸塩（１３６ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例１５２と同様にして表題化合物（１０１ｍｇ）を得た。 Example 191 1: {[7-Hydroxy-5- (pyridin-4-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4-Bromomethylpyridine The title compound (101 mg) was obtained in the same manner as in Example 152, using bromate (136 mg) and the compound (200 mg) obtained in Reference Example 15.
　実施例１９２：｛［７－ヒドロキシ－５－（６－メチルピリジン－２－イルメチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　６－メチル－２－ピリジンメタノール（４９ｍｇ）と参考例１５で得られた化合物（１３５ｍｇ）を用い、実施例１６８と同様にして｛［７－ベンジルオキシ－５－（６－メチルピリジン－２－イルメチルスルファニル）－［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸メチルエステルを得た。この得られた化合物を実施例２及び３と同様にして表題化合物（７０ｍｇ）を得た。 Example 192: {[7-hydroxy-5- (6-methylpyridin-2-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 6- {[7-Benzyloxy-5- (6-methylpyridin-2-ylmethyl) was prepared in the same manner as in Example 168 using methyl-2-pyridinemethanol (49 mg) and the compound obtained in Reference Example 15 (135 mg). Sulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid methyl ester was obtained. The title compound (70 mg) was obtained from the obtained compound in the same manner as in Examples 2 and 3.
　実施例１９３：[[７－ヒドロキシ－５－(６－トリフルオロメチルピリジン－３－イルメチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　６－トリフルオロメチルピリジン－３－イルメタノール（２５５ｍｇ）及び参考例１５で得られた化合物（３１１ｍｇ）を用い、実施例１３０と同様にして、表題化合物（１０９ｍｇ）を得た。 Example 193: [[7-hydroxy-5- (6-trifluoromethylpyridin-3-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid The title compound (109 mg) was obtained in the same manner as in Example 130, using 6-trifluoromethylpyridin-3-ylmethanol (255 mg) and the compound (311 mg) obtained in Reference Example 15.
　実施例１９４：[[５－(２，６－ジクロロピリジン－３－イルメチルスルファニル)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　メタンスルホン酸２，６－ジクロロピリジン－３－イルメチルエステル（２５６ｍｇ）及び参考例１５で得られた化合物（３１１ｍｇ）を用い、実施例１５２と同様にして、表題化合物（１８５ｍｇ）を得た。 Example 194: [[5- (2,6-dichloropyridin-3-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid The title compound (185 mg) was obtained in the same manner as in Example 152, using methanesulfonic acid 2,6-dichloropyridin-3-ylmethyl ester (256 mg) and the compound (311 mg) obtained in Reference Example 15.
　実施例１９５：[[７－ヒドロキシ－５－(２－トリフルオロメチルピリジン－４－イルメチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　(２－トリフルオロメチルピリジン－４－イル)メタノール（１７７ｍｇ）及び参考例１５で得られた化合物（３１１ｍｇ）を用い、実施例１３０と同様にして、表題化合物（１６０ｍｇ）を得た。 Example 195: [[7-hydroxy-5- (2-trifluoromethylpyridin-4-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid The title compound (160 mg) was obtained in the same manner as in Example 130, using (2-trifluoromethylpyridin-4-yl) methanol (177 mg) and the compound (311 mg) obtained in Reference Example 15.
　実施例１９６：[[５－(２,６－ジメチルピリジン－４－イルメチルスルファニル)－ ７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　メタンスルホン酸２，６－ジメチルピリジン－４－イルメチルエステル（１６１ｍｇ）及び参考例１５で得られた化合物（２５０ｍｇ）を用い、実施例１５２と同様にして、表題化合物（１２０ｍｇ）を得た。 Example 196: [[5- (2,6-Dimethylpyridin-4-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid Using the methanesulfonic acid 2,6-dimethylpyridin-4-ylmethyl ester (161 mg) and the compound obtained in Reference Example 15 (250 mg), the title compound (120 mg) was obtained in the same manner as in Example 152.
　実施例１９７：[[５－(２，６－ジクロロピリジン－４－イルメチルスルファニル)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　メタンスルホン酸２、６－ジクロロピリジン－４－イルメチルエステル(２５６ｍｇ）及び参考例１５で得られた化合物（３１１ｍｇ）を用い、実施例１５２と同様にして、表題化合物（１８０ｍｇ）を得た。 Example 197: [[5- (2,6-dichloropyridin-4-ylmethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid The title compound (180 mg) was obtained in the same manner as in Example 152, using methanesulfonic acid 2,6-dichloropyridin-4-ylmethyl ester (256 mg) and the compound (311 mg) obtained in Reference Example 15.
　実施例１９８：｛［７－ヒドロキシ－５－（キノリン－４－イルメチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　キノリン－４－イルメタノール（９４ｍｇ）及び参考例１５で得られた化合物（２００ｍｇ）を用い、実施例１９２と同様にして表題化合物（７０ｍｇ）を得た。 Example 198: {[7-Hydroxy-5- (quinolin-4-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridin-8-carbonyl] amino} acetic acid quinolin-4-yl The title compound (70 mg) was obtained in the same manner as Example 192 using methanol (94 mg) and the compound (200 mg) obtained in Reference Example 15.
　実施例１９９：[[７－ヒドロキシ－５－(８－トリフルオロメチルキノリン－４－イルメチルスルファニル)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　８－トリフルオロメチルキノリン－４－カルボアルデヒド（３４１ｍｇ）のメタノール溶液(４ｍＬ)にナトリウムボロハイドライド(８６ｍｇ)を加え、室温で1時間撹拌した。反応終了後、酢酸エチルで抽出し、有機相を水、飽和食塩水で洗浄して、無水硫酸マグネシウムで乾燥した。ろ過後、溶媒を減圧留去し、８－トリフルオロメチル－キノリン－４－イルメタノールを得た。上記で得たアルコールとトリエチルアミン（１０１ｍｇ）の混合物をＴＨＦ(２ｍＬ)に溶解し、氷冷下、メシルクロリド（１１２ｍｇ）を加え、室温で１時間撹拌した。反応終了後、酢酸エチルで抽出し、有機相を水、飽和食塩水で洗浄して、無水硫酸マグネシウムで乾燥した。ろ過後、溶媒を減圧留去し、メタンスルホン酸８－トリフルオロメチルキノリン－４－イルメチルエステルを得た。このようにして得た化合物（２２８ｍｇ）及び参考例１５で得られた化合物（２５０ｍｇ）を用い、実施例１５２と同様にして、表題化合物（１８６ｍｇ）を得た。 Example 199: [[7-Hydroxy-5- (8-trifluoromethylquinolin-4-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid Sodium borohydride (86 mg) was added to a methanol solution (4 mL) of 8-trifluoromethylquinoline-4-carbaldehyde (341 mg), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 8-trifluoromethyl-quinolin-4-ylmethanol. A mixture of the alcohol and triethylamine (101 mg) obtained above was dissolved in THF (2 mL), mesyl chloride (112 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain methanesulfonic acid 8-trifluoromethylquinolin-4-ylmethyl ester. The title compound (186 mg) was obtained in the same manner as in Example 152, using the compound (228 mg) thus obtained and the compound (250 mg) obtained in Reference Example 15.
　実施例２００：[[７－ヒドロキシ－５－（キノリン－２－イルメチルスルファニル）［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル]アミノ]酢酸
　２－キノリンメタノール（２３０ｍｇ）及び参考例１５で得られた化合物（３００ｍｇ）を用い、実施例９４と同様にして、表題化合物（１３０ｍｇ）を得た。 Example 200: [[7-Hydroxy-5- (quinolin-2-ylmethylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-quinoline methanol ( 230 mg) and the compound obtained in Reference Example 15 (300 mg) were used in the same manner as in Example 94 to obtain the title compound (130 mg).
　実施例２０１：[[７－ヒドロキシ－５－（２－メチルブトキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２－メチルブタノール（２２ｍｇ）及び、参考例１０で得られた化合物（９３．７ｍｇ）を用い参考例１１、実施例４、５と同様にして、表題化合物（５０ｍｇ）を得た。 Example 201: [[7-Hydroxy-5- (2-methylbutoxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-methylbutanol (22 mg) and The title compound (50 mg) was obtained in the same manner as in Reference Example 11, Example 4 and 5, using the compound (93.7 mg) obtained in Reference Example 10.
　実施例２０２：（Ｓ）－[(７－ヒドロキシ－５－(２－メチルブトキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　（Ｓ）－２－メチルブタノール（２２ｍｇ）及び、参考例１０で得られた化合物（９４ｍｇ）を用い、実施例２０１と同様にして、表題化合物（３５ｍｇ）を得た。 Example 202: (S)-[(7-hydroxy-5- (2-methylbutoxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid (S)- The title compound (35 mg) was obtained in the same manner as in Example 201, using 2-methylbutanol (22 mg) and the compound (94 mg) obtained in Reference Example 10.
　実施例２０３：[(５－ブトキシ－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル)アミノ]酢酸
　ｎ－ブタノール（１０８ｍｇ）及び参考例１０で得られた化合物（２５０ｍｇ）を用い、実施例２０１と同様にして、表題化合物（１２３ｍｇ）を得た。 Example 203: [(5-butoxy-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid obtained in n-butanol (108 mg) and Reference Example 10 The title compound (123 mg) was obtained in the same manner as in Example 201 using the obtained compound (250 mg).
　実施例２０４：｛［５－（３，３－ジメチルブトキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３，３－ジメチルブタノール（７２ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、参考例１１、参考例２及び実施例１と同様にして｛［７－ベンジルオキシ－５－（３，３－ジメチルブトキシ）－［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸メチルエステルを得た。この得られた化合物（１１５ｍｇ）とテトラヒドロフラン（１ｍＬ）及びメタノール（０．６ｍｌ）を混合し、５％パラジウム炭素（１２ｍｇ）を加えた。混合液を水素雰囲気下常圧で２時間攪拌し、反応終了を確認した。反応液をセライトろ過し、濃縮することにより、｛［５－（３，３－ジメチルブトキシ）－７－ヒドロキシ－［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸メチルを得た。この得られた化合物（９３ｍｇ）を実施例３と同様にして、表題化合物（６８ｍｇ）を得た。 Example 204: {[5- (3,3-dimethylbutoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,3-dimethylbutanol (72 mg) and the compound obtained in Reference Example 10 (200 mg) were used in the same manner as Reference Example 11, Reference Example 2 and Example 1, {[7-benzyloxy-5- (3,3-dimethylbutoxy) -[1,2,4] Triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid methyl ester was obtained. The obtained compound (115 mg), tetrahydrofuran (1 mL) and methanol (0.6 ml) were mixed, and 5% palladium carbon (12 mg) was added. The mixture was stirred at normal pressure under a hydrogen atmosphere for 2 hours to confirm the completion of the reaction. The reaction solution was filtered through Celite and concentrated to obtain {[5- (3,3-dimethylbutoxy) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl]. Amino} methyl acetate was obtained. The obtained compound (93 mg) was treated in the same manner as in Example 3 to obtain the title compound (68 mg).
　実施例２０５：[[５－(２－エチルブトキシ)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２－エチルブタノール（９０ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（９０ｍｇ）を得た。 Example 205: [[5- (2-Ethylbutoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-ethylbutanol (90 mg) and The title compound (90 mg) was obtained in the same manner as in Example 201 using the compound (200 mg) obtained in Reference Example 10.
　実施例２０６：[[５－（２，３－ジメチルブトキシ)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２，３－ジメチルブタン－１－オール（７７ｍｇ）及び、参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（３５ｍｇ）を得た。 Example 206: [[5- (2,3-Dimethylbutoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2,3-dimethylbutane The title compound (35 mg) was obtained in the same manner as in Example 201, using -1-ol (77 mg) and the compound (200 mg) obtained in Reference Example 10.
　実施例２０７：[[５－（１，２－ジメチルブトキシ)－７－ヒドロキシ[１，２，４]トリアゾロ[１,５－α]ピリジン－８－カルボニル]アミノ]酢酸
　１，２－ジメチルブタノール（１８５ｍｇ）及び、参考例１０で得られた化合物（５００ｍｇ）を用い、参考例１１と同様に実施し、エーテル体（２１６ｍｇ）を得た。次いで、酢酸エチル（２．５ｍＬ）、トルエン（２．５ｍＬ）に溶解し、メタンスルホン酸（２８３ｍｇ）を加え、室温で終夜撹拌した。減圧下留去し、酢酸エチルで抽出、飽和食塩水で洗浄して、無水硫酸マグネシウムで乾燥後、溶媒を留去してカルボン酸（２１６ｍｇ）を得た。次いで、グリシンメチルエステルを用い、実施例１と同様にして、アミド体（１９３ｍｇ）を得た。この化合物を酢酸エチル（３ｍＬ）、メタノール（３ｍＬ）に溶解し、５％Ｐｄ－Ｃ(３０ｍｇ)を加え、水素気流中、常圧下、２時間撹拌し、濾去した後、溶媒を留去して、目的物（１４０ｍｇ）を得た．次いで実施例３と同様にして表題化合物（４０ｍｇ）を得た。 Example 207: [[5- (1,2-dimethylbutoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 1,2-dimethylbutanol (185 mg) and the compound (500 mg) obtained in Reference Example 10 were used in the same manner as in Reference Example 11 to obtain an ether form (216 mg). Subsequently, it melt | dissolved in ethyl acetate (2.5 mL) and toluene (2.5 mL), methanesulfonic acid (283 mg) was added, and it stirred at room temperature all night. After evaporation under reduced pressure, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain carboxylic acid (216 mg). Subsequently, the amide body (193 mg) was obtained like Example 1 using glycine methyl ester. This compound was dissolved in ethyl acetate (3 mL) and methanol (3 mL), 5% Pd—C (30 mg) was added, and the mixture was stirred in a hydrogen stream under normal pressure for 2 hours. After filtration, the solvent was distilled off. To obtain the desired product (140 mg). Then, the title compound (40 mg) was obtained in the same manner as Example 3.
　実施例２０８：[[７－ヒドロキシ－５－(４－メチルペンチルオキシ）[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　４－メチルペンタノール（７２ｍｇ）及び、参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（８３ｍｇ）を得た。 Example 208: [[7-Hydroxy-5- (4-methylpentyloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 4-methylpentanol (72 mg ) And the compound (200 mg) obtained in Reference Example 10 were used in the same manner as in Example 201 to obtain the title compound (83 mg).
　実施例２０９：[[７－ヒドロキシ－５－（３－メチルペンチルオキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸－メチルペンタン－１－オール（７２ｍｇ）及び、参考例１０で得られた化合物（２００ｍｇ）用い、実施例２０１と同様にして、表題化合物（７５ｍｇ）を得た。 Example 209: [[7-Hydroxy-5- (3-methylpentyloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid-methylpentan-1-ol (72 mg) and the compound (200 mg) obtained in Reference Example 10 were used, and the title compound (75 mg) was obtained in the same manner as in Example 201.
　実施例２１０：[(７－ヒドロキシ－５－（ペンタ－３－イニルオキシ）[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　３－ペンチン－１－オール（５９ｍｇ）及び、参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（３６ｍｇ）を得た。 Example 210: [(7-Hydroxy-5- (pent-3-ynyloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 3-pentyn-1-ol (59 mg) and the compound (200 mg) obtained in Reference Example 10 were used, and the title compound (36 mg) was obtained in the same manner as in Example 201.
　実施例２１１：[[５－(１，４－ジメチルペンチルオキシ)－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　１，４－ジメチル－１－ペンタノール（１１６ｍｇ）及び、参考例１０で得られた化合物（３００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（５０ｍｇ）を得た。 Example 211: [[5- (1,4-Dimethylpentyloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 1,4-dimethyl The title compound (50 mg) was obtained in the same manner as in Example 201, using -1-pentanol (116 mg) and the compound (300 mg) obtained in Reference Example 10.
　実施例２１２：[(５－ヘキシルオキシ－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　１－ヘキサノール（８５ｍｇ）及び、参考例１０で得られた化合物（１２２ｍｇ）を用い、実施例２０１と同様にして、表題化合物（２５ｍｇ）を得た。 Example 212: [(5-Hexyloxy-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 1-hexanol (85 mg) and Reference Example 10 The title compound (25 mg) was obtained in the same manner as in Example 201 using the obtained compound (122 mg).
　実施例２１３：[[５－(ヘキサ－４－エン－１－イルオキシ)－７－ヒドロキシ－[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　シス－４－ヘキセン－１－オール（７０．３ｍｇ）及び、参考例１０で得られた化合物（２００ｍｇ）用い、実施例２０１と同様にして、表題化合物（５７ｍｇ）を得た。 Example 213: [[5- (Hex-4-en-1-yloxy) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid cis- Using 4-hexen-1-ol (70.3 mg) and the compound obtained in Reference Example 10 (200 mg), the title compound (57 mg) was obtained in the same manner as in Example 201.
　実施例２１４：[[７－ヒドロキシ－５－（オクタ－３－エン－１－イルオキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　シス－３－オクテン－１－オール（９０ｍｇ）及び、参考例１０で得られた化合物（２５０ｍｇ）用い、実施例２０１と同様にして、表題化合物（３１０ｍｇ）を得た。 Example 214: [[7-Hydroxy-5- (oct-3-en-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid cis-3 Using the -octen-1-ol (90 mg) and the compound (250 mg) obtained in Reference Example 10, the title compound (310 mg) was obtained in the same manner as in Example 201.
　実施例２１５：[[７－ヒドロキシ－５－（ノナ－３－イン－１－イルオキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　３－ノニン－１－オール（９８．５ｍｇ）及び、参考例１０で得られた化合物（２００ｍｇ）用い、実施例２０１と同様にして、表題化合物（３５ｍｇ）を得た。 Example 215: [[7-hydroxy-5- (non-3-yn-1-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 3-nonine The title compound (35 mg) was obtained in the same manner as in Example 201, using -1-ol (98.5 mg) and the compound (200 mg) obtained in Reference Example 10.
　実施例２１６：([５－[２－(２－エトキシエトキシ)エトキシ]－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ)酢酸
　ジエチレングリコールモノエチルエーテル（１００ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（４０ｍｇ）を得た。 Example 216: ([5- [2- (2-ethoxyethoxy) ethoxy] -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino) acetic acid diethylene glycol monoethyl The title compound (40 mg) was obtained in the same manner as in Example 201 using ether (100 mg) and the compound (200 mg) obtained in Reference Example 10.
　実施例２１７：[[５－(２－シクロヘキシルエトキシ）－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２－シクロヘキサン－１－エタノール（４６ｍｇ）及び、参考例１０で得られた化合物（１０２ｍｇ）を用い、実施例２０１と同様にして、表題化合物（４４ｍｇ）を得た。 Example 217: [[5- (2-cyclohexylethoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-cyclohexane-1-ethanol ( The title compound (44 mg) was obtained in the same manner as in Example 201 using 46 mg) and the compound (102 mg) obtained in Reference Example 10.
　実施例２１８：｛［５－（２－シクロブチルエトキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－シクロブチルエタノール（６０ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（２５ｍｇ）を得た。 Example 218: {[5- (2-cyclobutylethoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-cyclobutylethanol (60 mg ) And the compound (200 mg) obtained in Reference Example 10 were used in the same manner as in Example 201 to obtain the title compound (25 mg).
　実施例２１９：｛［５－（２－シクロペンチルエトキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－シクロペンチルエタノール（１１４ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（６６ｍｇ）を得た。 Example 219: {[5- (2-Cyclopentylethoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-cyclopentylethanol (114 mg) and The title compound (66 mg) was obtained in the same manner as in Example 201 using the compound (200 mg) obtained in Reference Example 10.
　実施例２２０：[［５－（２－ビシクロ[２．２．１]ヘプト－２－イルエトキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－ビシクロ［２，２，１］ヘプト－２－イルエタノール（１６４ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（４０ｍｇ）を得た。 Example 220: [[5- (2-bicyclo [2.2.1] hept-2-ylethoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] Amino} acetic acid 2-bicyclo [2,2,1] hept-2-ylethanol (164 mg) and the compound obtained in Reference Example 10 (200 mg) were used in the same manner as in Example 201 to give the title compound (40 mg). Got.
　実施例２２１：[［５－（２－アダマンタン－１－イルエトキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　２－アダマンタン－１－イルエタノール（１２８ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（６７ｍｇ）を得た。 Example 221: [[5- (2-adamantan-1-ylethoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-adamantane-1 -The title compound (67 mg) was obtained in the same manner as in Example 201 using ylethanol (128 mg) and the compound (200 mg) obtained in Reference Example 10.
　実施例２２２：[(７－ヒドロキシ－５－フェネチロキシ [１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル)アミノ]酢酸
　２－フェニルエタノール（９０ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（７０ｍｇ）を得た。 Example 222: [(7-hydroxy-5-phenethyloxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid obtained in 2-phenylethanol (90 mg) and Reference Example 10 Using the obtained compound (200 mg), the title compound (70 mg) was obtained in the same manner as in Example 201.
　実施例２２３：([５－[２－(２－フルオロフェニル)エトキシ]－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ)酢酸
　２－（２－フルオフェニル）－１－エタノール（１３９ｍｇ）及び、参考例１０で得られた化合物（３００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（７３ｍｇ）を得た。 Example 223: ([5- [2- (2-Fluorophenyl) ethoxy] -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino) acetic acid 2- ( Using 2-fluorophenyl) -1-ethanol (139 mg) and the compound (300 mg) obtained in Reference Example 10, the title compound (73 mg) was obtained in the same manner as in Example 201.
　実施例２２４：[[７－ヒドロキシ－５－(２－チオフェン－２－イルエトキシ)[１,２,４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２－チオフェンエタノール（８１ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（３５ｍｇ）を得た。 Example 224: [[7-hydroxy-5- (2-thiophen-2-ylethoxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-thiophene ethanol ( 81 mg) and the compound (200 mg) obtained in Reference Example 10 were used, and the title compound (35 mg) was obtained in the same manner as in Example 201.
　実施例２２５：｛［５－（３－シクロヘキシルプロポキシ）－７－ヒドロキシ［１，２，４］トリアゾロ［１，５－α］ピリジン－８－カルボニル］アミノ｝酢酸
　３－シクロヘキシルプロパノール（１３９μＬ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、参考例１１、実施例４及び実施例５と同様にして、表題化合物（６０ｍｇ）を得た。 Example 225: {[5- (3-cyclohexylpropoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-cyclohexylpropanol (139 μL) and Using the compound (200 mg) obtained in Reference Example 10, the title compound (60 mg) was obtained in the same manner as in Reference Example 11, Example 4 and Example 5.
　実施例２２６：[[７－ヒドロキシ－５－(２－フェノキシエトキシ)[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２－フェノキシエタノール（９０ｍｇ）及び参考例１０で得られた化合物（２００ｍｇ）を用い、実施例２０１と同様にして、表題化合物（７０ｍｇ）を得た。 Example 226: [[7-Hydroxy-5- (2-phenoxyethoxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-phenoxyethanol (90 mg) and reference Using the compound (200 mg) obtained in Example 10, the title compound (70 mg) was obtained in the same manner as in Example 201.
　実施例２２７：[[５－(２，６－ジメチルベンジルオキシ）－７－ヒドロキシ[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸
　２－フルオロ－５－メチルベンジルアルコール（３．３４ｇ）をＨＭＰＡ（３５ｍＬ）に溶解し、氷浴撹拌下、ＮａＨ(８６６ｍｇ)を加え、６５℃で２時間撹拌し、氷浴で冷却撹拌下、7－ベンジルオキシ－５－ヨード[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸ｔ－ブチルエステル（３．２６ｇ）を加え、１５℃以下で２時間撹拌した。クエン酸水を加え、酸性にして析出結晶をろ取し、水洗してエーテル体（１．１ｇ）を得た。次いで参考例２、実施例１と同様にしてアミド体（７３５ｍｇ）を得た。このアミド体にＤＭＦ(１２ｍＬ)を加え溶解し、５％Ｐｄ－Ｃ(１００ｍｇ)を加え、常温常圧下、水素添加を行い、不溶物をセライト濾去し、ろ液を減圧留去し、得られた残差に少量の水を加え、濾過して５，７－ジヒドロオキシ [１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボン酸メチルエステル（４４３ｍｇ）を得た。このジオール体（１００ｍｇ）と２，６－ジメチルベンジルアルコール(６２ｍｇ)を用い参考例１１と同様ににして、[[５－(２，６－ジメチルベンジルオキシ）－７－ヒドロキシ－[１，２，４]トリアゾロ[１，５－α]ピリジン－８－カルボニル]アミノ]酢酸メチルエステル(４２ｍｇ)を得た。これを実施例３と同様にして表題化合物（２３ｍｇ）を得た。 Example 227: [[5- (2,6-Dimethylbenzyloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid 2-fluoro-5 -Methylbenzyl alcohol (3.34 g) was dissolved in HMPA (35 mL), NaH (866 mg) was added with stirring in an ice bath, stirred at 65 ° C. for 2 hours, and cooled in an ice bath with cooling and stirring. 5-Iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (3.26 g) was added, and the mixture was stirred at 15 ° C. or lower for 2 hours. Citric acid water was added to make it acidic, and the precipitated crystals were collected by filtration and washed with water to obtain an ether form (1.1 g). Subsequently, an amide compound (735 mg) was obtained in the same manner as in Reference Example 2 and Example 1. DMF (12 mL) was added to this amide and dissolved, 5% Pd—C (100 mg) was added, hydrogenation was performed at room temperature and normal pressure, insoluble material was filtered off through Celite, and the filtrate was distilled off under reduced pressure. A small amount of water was added to the resulting residue, followed by filtration to obtain 5,7-dihydrooxy [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid methyl ester (443 mg). Using this diol (100 mg) and 2,6-dimethylbenzyl alcohol (62 mg), in the same manner as in Reference Example 11, [[5- (2,6-dimethylbenzyloxy) -7-hydroxy- [1,2 , 4] triazolo [1,5-α] pyridine-8-carbonyl] amino] acetic acid methyl ester (42 mg) was obtained. This was treated in the same manner as in Example 3 to obtain the title compound (23 mg).
　下記表１～３５は、一般式（１）で示される化合物につき、上記各実施例における化学構造式及び物性データを一覧表としたものである。 Tables 1 to 35 below list the chemical structural formulas and physical property data in the above examples for the compounds represented by the general formula (1).
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
試験例　Ｈｅｐ３Ｂ細胞におけるＥＰＯ産生促進作用
　１０％ウシ胎仔血清（ＦＢＳ）添加ＭＥＭ培地で培養したＨｅｐ３Ｂ細胞を２４ウェルプレートに蒔き込み、３７℃で一晩培養した後、被験物質１μＭ又は媒体（０．５％ジメチルスルホキシド）を添加した１０％ＦＢＳ添加ＭＥＭ培地に交換した。更に、４８時間培養した後に上清を回収し、上清中のＥＰＯ濃度をＥＬＩＳＡキット（ｅＢｉｏｓｃｉｅｎｃｅ社製）で測定した。媒体添加時のＥＰＯ濃度に対する被験物質添加時のＥＰＯ濃度の増加の割合、すなわち、ＥＰＯ増加率（％）を下式に従って求め、表３６に示す。
ＥＰＯ増加率（％）＝（被験物質添加時のＥＰＯ濃度／媒体添加時のＥＰＯ濃度―１）×１００ Test Example Promoting EPO Production in Hep3B Cells Hep3B cells cultured in a MEM medium supplemented with 10% fetal bovine serum (FBS) were seeded in a 24-well plate and cultured at 37 ° C. overnight. The medium was replaced with MEM medium supplemented with 10% FBS supplemented with 5% dimethyl sulfoxide. Furthermore, after culturing for 48 hours, the supernatant was collected, and the EPO concentration in the supernatant was measured with an ELISA kit (manufactured by eBioscience). The rate of increase in EPO concentration at the time of test substance addition relative to EPO concentration at the time of medium addition, that is, the EPO increase rate (%) was determined according to the following formula and is shown in Table 36.
EPO increase rate (%) = (EPO concentration when test substance is added / EPO concentration when medium is added−1) × 100
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
　表３６から明らかなように、本発明化合物は１μＭの濃度で持続的かつ強力なＥＰＯ産生促進作用を有し、特許文献１記載の化合物に比べて顕著に優れていることがわかる。 As is clear from Table 36, it can be seen that the compound of the present invention has a sustained and strong EPO production promoting action at a concentration of 1 μM, and is significantly superior to the compound described in Patent Document 1.
製剤例（錠剤の製法）
１）実施例１１　　　　　　　　　　　５．０ｍｇ
２）乳糖　　　　　　　　　　　　　９４．０ｍｇ
３）コーンスターチ　　　　　　　　２０．０ｍｇ
４）ヒドロキシプロピルセルロース　　４．０ｍｇ
５）ステアリン酸マグネシウム　　　　０．５ｍｇ
６）カルボキシメチルセルロース　　　６．５ｍｇ
計（１錠）　　　            　　１３０．０ｍｇ
　攪拌造粒機により、上記１）、２）、３）を分散させ、この粉末に４）の水溶液を添加し、練合、乾燥、整粒し、５）及び６）を加え混合し、打錠機により打錠する。 Formulation example (tablet manufacturing method)
1) Example 11 5.0 mg
2) Lactose 94.0mg
3) Corn starch 20.0mg
4) Hydroxypropylcellulose 4.0mg
5) Magnesium stearate 0.5mg
6) Carboxymethylcellulose 6.5mg
Total (1 tablet) 130.0mg
The above 1), 2) and 3) are dispersed with a stirring granulator, the aqueous solution of 4) is added to this powder, kneaded, dried and sized, and 5) and 6) are added and mixed. Tablet using a tablet machine.
　本発明の化合物は、持続的且つ優れたＥＰＯ産生促進作用を有し、対象臓器或いは組織において低酸素環境が生じる疾患の予防又は治療、特に貧血の予防又は治療に有用である。 The compound of the present invention has a sustained and excellent EPO production-promoting action, and is useful for the prevention or treatment of diseases in which a hypoxic environment occurs in a target organ or tissue, particularly for the prevention or treatment of anemia.

Claims (12)

  1. 　一般式（１）
    Figure JPOXMLDOC01-appb-C000001
     ［上記式中、
    Ｘは酸素原子、イミノ基、硫黄原子、スルフィニル又はスルホニルを示し、
    Ｒ１、Ｒ２及びＲ３はそれぞれ独立に、水素原子又はＣ１－Ｃ６のアルキル基を示し、
    Ｒ４は水素原子、Ｃ１－Ｃ６のアルキル基又はアリールアルキル基を示し、
    Ｒ５は置換基群から選択される基で置換されていても良いアルキル基、置換基群から選択される基で置換されていても良いアルケニル基、置換基群から選択される基で置換されていても良いアルキニル基、置換基群から選択される基で独立に１乃至７個置換基を有してもよいアリール基は置換基群から選択される基で独立に１乃至７個置換基を有してもよいヘテロアリール基を示す。置換基群は、１乃至７個置換基を有してもよいアリール基（当該アリール基上の置換基としてはＣ１－Ｃ６のアルキル基、トリフルオロメチル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基又はフェニル基を示す）、１乃至７個置換基を有してもよいヘテロアリール基（当該ヘテロアリール基上の置換基としてはＣ１－Ｃ６のアルキル基、トリフルオロメチル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基又はフェニル基を示す）、Ｃ１－Ｃ６のアルキル基（Ｃ３－Ｃ６アルキル基の場合は、炭素原子同士が結合して３乃至６員飽和環を形成しても良い）、Ｃ２－Ｃ６のアルケニル基、Ｃ２－Ｃ６のアルキニル基、アリールアルキル基、Ｃ２－Ｃ8のアルコキシカルボニル基、ハロゲン原子、Ｃ１－Ｃ６のハロゲン化アルキル基、ヒドロキシ基、Ｃ1－Ｃ６のアルコキシ基、Ｃ１－Ｃ６のハロゲン化アルコキシ基、アリールオキシ基、カルバモイル基、Ｃ２－Ｃ６のアルキルカルボニル基、シアノ基、カルボキシル基、ホルミル基、ニトロ基、アミノ基、Ｃ１－Ｃ６のアルキルアミノ基、Ｃ１－Ｃ６のアルキルアミノカルボニル基、Ｃ１－Ｃ６のアルキルカルボニルアミノ基、アリールアミノ基、アミノスルホニル基、Ｃ１－Ｃ６のアルキルスルホニル基、Ｃ１－Ｃ６のハロゲン化アルキルスルホニル基、アリールスルホニル基、Ｃ１－Ｃ６のアルキルスルファニル基、Ｃ１－Ｃ６のハロゲン化アルキルスルファニル基及びアリールスルファニル基からなる群を示す。］を有する化合物又はその薬学上許容される塩。     General formula (1)
    Figure JPOXMLDOC01-appb-C000001
     [In the above formula,
    X represents an oxygen atom, an imino group, a sulfur atom, sulfinyl or sulfonyl,
    R 1 , R 2 and R 3 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group,
    R 4 represents a hydrogen atom, a C 1 -C 6 alkyl group or an arylalkyl group,
    R 5 is an alkyl group which may be substituted with a group selected from the substituent group, an alkenyl group which may be substituted with a group selected from the substituent group, or a group selected from the substituent group. An alkynyl group optionally selected from a group of substituents and an aryl group optionally having 1 to 7 substituents independently selected from a group of substituents and 1 to 7 substituents independently The heteroaryl group which may have is shown. The substituent group includes an aryl group which may have 1 to 7 substituents (the substituent on the aryl group includes a C 1 -C 6 alkyl group, a trifluoromethyl group, a halogen atom, a methoxy group, A heteromethoxy group which may have 1 to 7 substituents (a substituent on the heteroaryl group includes a C 1 -C 6 alkyl group, trifluoro; a fluoromethoxy group, a cyano group or a phenyl group) A methyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group or a phenyl group), a C 1 -C 6 alkyl group (in the case of a C 3 -C 6 alkyl group, the carbon atoms are bonded to each other) A 3- to 6-membered saturated ring may be formed), C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, arylalkyl group, C 2 -C 8 alkoxycarbonyl group, halogen Atoms, C 1 -C 6 halogenated alkyl groups, hydroxy groups, C 1 -C 6 alkoxy groups, C 1 -C 6 halogenated alkoxy groups, aryloxy groups, carbamoyl groups, C 2 -C 6 Alkylcarbonyl group, cyano group, carboxyl group, formyl group, nitro group, amino group, C 1 -C 6 alkylamino group, C 1 -C 6 alkylaminocarbonyl group, C 1 -C 6 alkylcarbonylamino group , Arylamino group, aminosulfonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, arylsulfonyl group, C 1 -C 6 alkylsulfanyl group, C 1 -C 6 A group consisting of a halogenated alkylsulfanyl group and an arylsulfanyl group. Or a pharmaceutically acceptable salt thereof.
  2. 　一般式（１）中、
    Ｘが、酸素原子又は硫黄原子であり、
    Ｒ1、Ｒ2、Ｒ3及びＲ4が水素原子である請求項１記載の化合物又はその薬学上許容される塩。     In general formula (1),
    X is an oxygen atom or a sulfur atom,
    The compound according to claim 1 , wherein R 1 , R 2 , R 3 and R 4 are hydrogen atoms, or a pharmaceutically acceptable salt thereof.
  3. 　一般式（１）中、
    Ｒ5が置換基群から選択される基で置換されていてもよいＣ1－Ｃ18の直鎖又は分岐鎖アルキル基、Ｃ3－Ｃ18の環状アルキル基又はそのらの組み合わせ；置換基群から選択される基で置換されていてもよいＣ2－Ｃ18の直鎖又は分岐鎖アルケニル基；置換基群から選択される基で置換されていてもよいＣ2－Ｃ8の直鎖又は分岐鎖のアルキニル基；置換基群から選択される基で置換されていてもよい炭素数６～１４の単環、二環又は三環式アリール基；又は置換基群から選択される基で置換されていてもよい１～４個のヘテロ原子（窒素原子、酸素原子又は硫黄原子）を有する単環、二環又は三環性のヘテロアリール基であり、
    　置換基群が、１～７個置換を有してもよい炭素数６～１４の単環、二環又は三環性のアリール基（当該アリール基上の置換基としてはＣ１－Ｃ６のアルキル基、トリフルオロメチル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基又はフェニル基を示す）、１乃至７個置換基を有してもよい１～４個のヘテロ原子（窒素原子、酸素原子又は硫黄原子）を有する単環、二環又は三環性のヘテロアリール基、（当該ヘテロアリール基上の置換基としてはＣ１－Ｃ６のアルキル基、トリフルオロメチル基、ハロゲン原子、メトキシ基、トリフルオロメトキシ基、シアノ基又はフェニル基を示す）、Ｃ１－Ｃ６のアルキル基（Ｃ３－Ｃ６アルキル基の場合は、炭素原子同士が結合して３乃至６員飽和環を形成しても良い）、Ｃ２－Ｃ６のアルケニル基、Ｃ２－Ｃ６のアルキニル基、Ｃ６－Ｃ１４アリール－Ｃ１－Ｃ６アルキル基、Ｃ２－Ｃ8のアルコキシカルボニル基、ハロゲン原子、Ｃ１－Ｃ６のハロゲン化アルキル基、ヒドロキシ基、Ｃ1－Ｃ６のアルコキシ基、Ｃ１－Ｃ６のハロゲン化アルコキシ基、Ｃ６－Ｃ１４アリールオキシ基、カルバモイル基、Ｃ２－Ｃ６のアルキルカルボニル基、シアノ基、カルボキシル基、ホルミル基、ニトロ基、アミノ基、Ｃ１－Ｃ６のアルキルアミノ基、Ｃ１－Ｃ６のアルキルアミノカルボニル基、Ｃ１－Ｃ６のアルキルカルボニルアミノ基、アリールアミノ基、アミノスルホニル基、Ｃ１－Ｃ６のアルキルスルホニル基、Ｃ１－Ｃ６のハロゲン化アルキルスルホニル基、Ｃ６－Ｃ１４アリールスルホニル基、Ｃ１－Ｃ６のアルキルスルファニル基、Ｃ１－Ｃ６のハロゲン化アルキルスルファニル基及びＣ６－Ｃ１４アリールスルファニル基からなる群である請求項１又は２記載の化合物又はその薬学上許容される塩。     In general formula (1),
    R 5 may be a C 1 -C 18 linear or branched alkyl group, C 3 -C 18 cyclic alkyl group or a combination thereof optionally substituted with a group selected from the substituent group; A C 2 -C 18 linear or branched alkenyl group optionally substituted with a group selected from: a C 2 -C 8 straight chain optionally substituted with a group selected from the substituent group A branched alkynyl group; a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms which may be substituted with a group selected from the substituent group; or substituted with a group selected from the substituent group A monocyclic, bicyclic or tricyclic heteroaryl group having 1 to 4 heteroatoms (nitrogen atom, oxygen atom or sulfur atom),
    The substituent group is a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms which may have 1 to 7 substituents (the substituent on the aryl group includes C 1 -C 6 An alkyl group, a trifluoromethyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group, or a phenyl group) 1 to 4 heteroatoms (nitrogen atoms) optionally having 1 to 7 substituents A monocyclic, bicyclic or tricyclic heteroaryl group having an oxygen atom or a sulfur atom) (as a substituent on the heteroaryl group, a C 1 -C 6 alkyl group, a trifluoromethyl group, a halogen atom) , A methoxy group, a trifluoromethoxy group, a cyano group or a phenyl group), a C 1 -C 6 alkyl group (in the case of a C 3 -C 6 alkyl group, 3 to 6-membered saturated carbon atoms are bonded to each other) A ring may be formed) C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, C 6 -C 14 aryl -C 1 -C 6 alkyl group, an alkoxycarbonyl group having C 2 -C 8, halogen atom, C 1 -C 6 halogenated alkyl groups, hydroxy groups, C 1 -C 6 alkoxy groups, C 1 -C 6 halogenated alkoxy groups, C 6 -C 14 aryloxy groups, carbamoyl groups, C 2 -C 6 alkylcarbonyls Group, cyano group, carboxyl group, formyl group, nitro group, amino group, C 1 -C 6 alkylamino group, C 1 -C 6 alkylaminocarbonyl group, C 1 -C 6 alkylcarbonylamino group, aryl Amino group, aminosulfonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 halogenated alkylsulfonyl group, C 6 -C 14 ali The compound according to claim 1 or 2, which is a group consisting of an arylsulfonyl group, a C 1 -C 6 alkylsulfanyl group, a C 1 -C 6 halogenated alkylsulfanyl group, and a C 6 -C 14 arylsulfanyl group Acceptable salt.
  4. 　請求項１～３のいずれか１項記載の化合物又はその薬学上許容される塩、及び薬学上許容される担体を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  5. 　請求項１～３のいずれか１項記載の化合物又はその薬学上許容される塩を有効成分とする医薬。 A pharmaceutical 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１～３のいずれか１項記載の化合物又はその薬学上許容される塩を有効成分とするＥＰＯ産生促進薬。 An EPO production promoter comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  7. 　ＥＰＯ産生促進するための請求項１～３のいずれか１項記載の化合物又はその薬学上許容される塩。 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for promoting EPO production.
  8. 　慢性腎不全患者における貧血、自己貯血、未熟児貧血、ＡＩＤＳ又は化学療法を受けている癌患者の貧血、慢性貧血、鉄欠乏性貧血、再生不良性貧血、溶血性貧血及び巨赤芽球性貧血から選ばれる貧血を予防及び／又は治療するための、請求項１～３のいずれか１項記載の化合物又はその薬学上許容される塩の使用。 Anemia in patients with chronic renal failure, self-accumulation, premature infant anemia, anemia in cancer patients undergoing AIDS or chemotherapy, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia and megaloblastic anemia Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of anemia selected from:
  9. 　ＥＰＯ産生促進薬製造のための、請求項１～３のいずれか１項記載の化合物又はその薬学上許容される塩の使用。 Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for producing an EPO production promoter.
  10. 　慢性腎不全患者における貧血、自己貯血、未熟児貧血、ＡＩＤＳ又は化学療法を受けている癌患者の貧血、慢性貧血、鉄欠乏性貧血、再生不良性貧血、溶血性貧血及び巨赤芽球性貧血から選ばれる貧血の予防薬及び／又は治療薬製造のための、請求項１～３のいずれか１項記載の化合物又はその薬学上許容される塩を投与することを特徴とする塩の使用。 Anemia in patients with chronic renal failure, self-accumulation, premature infant anemia, anemia in cancer patients undergoing AIDS or chemotherapy, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia and megaloblastic anemia Use of a salt characterized by administering the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of a prophylactic and / or therapeutic agent for anemia selected from
  11. 　請求項１～３のいずれか１項記載の化合物又はその薬学上許容される塩を投与することを特徴とするＥＰＯ産生促進方法。 A method for promoting EPO production, comprising administering the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  12. 　請求項１～３のいずれか１項記載の化合物又はその薬学上許容される塩を投与することを特徴とする、慢性腎不全患者における貧血、自己貯血、未熟児貧血、ＡＩＤＳ又は化学療法を受けている癌患者の貧血、慢性貧血、鉄欠乏性貧血、再生不良性貧血、溶血性貧血及び巨赤芽球性貧血から選ばれる貧血の予防及び／又は治療方法。 4. An anemia, self-accumulation, premature infant anemia, AIDS or chemotherapy in a patient with chronic renal failure, characterized by administering the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. A method for preventing and / or treating anemia selected from anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia and megaloblastic anemia in cancer patients.
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