JP2018039733A - Novel heterocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound which accelerates induction of differentiation of erythroid stem cells and has activity of accelerating production of erythropoietin, which is a glycoprotein hormone contributing to mature erythrocyte production.SOLUTION: The compound is represented by the general formula (1) in the figure. [X is O, N, S, a sulfinyl group, or a sulfonyl group; R1, R2 and R3 are each independently H or a C1-C6 alkyl group; R4 is H, a C1-C6 alkyl group, or an arylalkyl group; and R5 is a substituted/unsubstituted alkyl group, substituted/unsubstituted alkenyl group, substituted/unsubstituted aryl group, or the like.]SELECTED DRAWING: None

Description

  The present invention relates to a novel heterocyclic derivative having an erythropoietin (EPO) production promoting action.

  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).

  The production of EPO 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 has 1 to 3 isoforms, and it has been reported that localization in cells, oxygen partial pressure response, reactivity to HIF isoforms, etc. are different (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.

  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).

  For example, when EPO production decreases in the kidney due to kidney damage or the like, the EPO concentration in the blood decreases, erythrocyte 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.

  The main treatment methods for these diseases include the treatment of anemia in patients with chronic kidney disease (CKD) by means of 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.

  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).

  The 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.

  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.

JP 2011-37841 A JP 2006-137766 A Special table 2008-546644 JP2011-88840 Special table 2009-541351 JP2011-148810A Special table 2009-541486 Special table 2009-537558

S Elliott et al, Erythropoietins: Acommon mechanism of action, Exp Hematol, 2008; 36: 1573-84. Metzen E et al. Intracellular localization of human HIF-1α hydroxylases. J Cell Sci. 116: 1319-26, 2002. Muchnik E and Kaplan J.M. HIF polyhydroxylase inhibitors for anemia. Expert Opin Investig Drugs. 20 (5): 645-56, 2011. Calvert JW et al. Oxygen treatment after experimental hypoxia-ischemia in neonate rats alters the expression of HIF-1α and it's downstream stream targets. J Appl Physiol (1985). 101 (3): 853-65, 2006. Matthew MH et al, HIF-prolyl hydrolase inhibition results in endogenous erythropoietin inducion, erthrocytosis, and modest het Ingo F et al, Micking hypoxia torator anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production witness. 2014; 9 (11): e111838. doi: 10.1371 / journal. pone. 0111838. Nakayama, et al., Hypoxic response system for various life phenomena, experimental medicine 2012; 30: 1246-51 Nobuhito Goda et al., Energy Metabolism Controlled by HIF, Experimental Medicine 2012; 30: 1252-71

  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.

  As a result of intensive studies, the present inventors have found a novel compound that inhibits PHD and exhibits a potent EPO production promoting action.

［上記式中、
Ｘは酸素原子、窒素原子、硫黄原子、スルフィニル、スルホニルを示し、
Ｒ^１、Ｒ^２、Ｒ^３はそれぞれ独立に、水素原子又はＣ_１−Ｃ_６のアルキル基を示し、
Ｒ^４は水素原子、Ｃ_１−Ｃ_６のアルキル基又はアリールアルキル基を示し、
Ｒ^５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又は、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ケニル基又は、置換基群から選択される基で置換されていても良いアルキニル基又は、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単環性、二環性又は三環性芳香環又は、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単環性、二環性又は三環性芳香族複素環を示す。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（置換基としてはＣ_１−Ｃ_６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、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（置換基としてはＣ_１−Ｃ_６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、フェニル基を示す）、Ｃ_１−Ｃ_６のアルキル基（Ｃ_３−Ｃ_６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）、Ｃ_２−Ｃ_６のアルケニル基、Ｃ_２−Ｃ_６のアルキニル基、アリールアルキル基、Ｃ_２−Ｃ_８のアルコキシカルボニル基、ハロゲン原子、Ｃ_１−Ｃ_６のハロゲン化アルキル基、ヒドロキシ基、Ｃ_１−Ｃ_６のアルコキシ基、Ｃ_１−Ｃ_６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、Ｃ_２−Ｃ_６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、Ｃ_１−Ｃ_６のアルキルアミノ基、Ｃ_１−Ｃ_６のアルキルアミノカルボニル基、Ｃ_１−Ｃ_６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、Ｃ_１−Ｃ_６のアルキルスルホニル基、Ｃ_１−Ｃ_６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、Ｃ_１−Ｃ_６のアルキルスルファニル基、Ｃ_１−Ｃ_６のハロゲン化アルキルスルファニル基、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医薬上許容される塩、及びこれらを含んでなる医薬組成物が提供される。That is, according to the present invention, the following general formula (1)

[In the above formula,
X represents an oxygen atom, a nitrogen atom, a sulfur atom, sulfinyl, 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 optionally substituted alkynyl group, or a group selected from a substituent group, which may independently have 1 to 7 substituents, a monocyclic, bicyclic or tricyclic aromatic ring or substituent A monocyclic, bicyclic or tricyclic aromatic heterocycle which may independently have 1 to 7 substituents selected from the group. Substituent group, 1 to 7 as the aryl group (substituent group which may have a substituent C ₁ -C ₆ alkyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group, a phenyl group shown), indicating 1 to 7 as a heteroaryl group (the substituent may have a substituent of C ₁ -C ₆ alkyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group, a phenyl group ), A C ₁ -C ₆ alkyl group (in the case of a C ₃ -C ₆ alkyl group, carbon atoms may be bonded to form a 3- to 6-membered saturated ring), C ₂ -C ₆ alkenyl _groups, C alkynyl group 2 -C _6, arylalkyl _group, an alkoxycarbonyl group having C 2 -C _8, a halogen _atom, a halogenated alkyl group of C 1 -C _6, hydroxy _group, an alkoxy group of C 1 -C ₆ , C Halogenated alkoxy groups ₁ -C _6, an aryloxy group, a carbamoyl _group, an alkylcarbonyl group C 2 -C _6, a cyano group, a carboxyl group, a formyl group, a nitro group, an amino _group, alkylamino C 1 -C ₆ 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 halogenation It shows an alkylsulfonyl group, an arylsulfonyl group, an alkylsulfanyl group of C ₁ -C _6, halogenated alkylsulfanyl group C ₁ -C _6, a group consisting of arylsulfanyl group. Or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising these.

  Since the compound of the present invention has a sustained and excellent EPO production-promoting action, anemia in patients with chronic renal failure, self-blood storage and premature infant anemia, anemia in cancer patients undergoing AIDS and chemotherapy, chronic anemia, It is useful as prevention and / or treatment of anemia such as iron deficiency anemia, aplastic anemia, hemolytic anemia, megaloblastic anemia.

  Hereinafter, the present invention will be specifically described.

  The monocyclic aromatic ring described in the present specification is a benzene ring, and the monocyclic aromatic heterocycle includes a pyrrole ring, a furan ring, a thiophene ring, a pyridine ring, an imidazole ring, a pyrazole ring, an oxazole ring, and a thiazole. Ring, pyrazine ring and the like.

  The term “which may be substituted” in the present specification means that it is unsubstituted or has 1 to 5 substituents. When it has a plurality of substituents, these substituents are They may be the same or different from each other.

The “alkyl group” described in the present specification means a 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 and the like. Substituent group, 1 to 7 as the aryl group (substituent group which may have a substituent C ₁ -C ₆ alkyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group, a phenyl group shown), indicating 1 to 7 as a heteroaryl group (the substituent may have a substituent of C ₁ -C ₆ alkyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group, a phenyl group ), A C ₁ -C ₆ alkyl group (in the case of a C ₃ -C ₆ alkyl group, carbon atoms may be bonded to form a 3- to 6-membered saturated ring), C ₂ -C ₆ alkenyl _groups, C alkynyl group 2 -C _6, arylalkyl _group, an alkoxycarbonyl group having C 2 -C _6, a halogen _atom, a halogenated alkyl group of C 1 -C _6, hydroxy _group, an alkoxy group of C 1 -C ₆ , C Halogenated alkoxy groups ₁ -C _6, an aryloxy group, a carbamoyl _group, an alkylcarbonyl group C 2 -C _6, a cyano group, a carboxyl group, a formyl group, a nitro group, an amino _group, alkylamino C 1 -C ₆ 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 halogenation It shows an alkylsulfonyl group, an arylsulfonyl group, an alkylsulfanyl group of C ₁ -C _6, halogenated alkylsulfanyl group C ₁ -C _6, a group consisting of arylsulfanyl group.

  The “alkenyl group” described in the present specification means an unsaturated hydrocarbon chain that 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.

  The “alkynyl group” described in the present specification means an unsaturated hydrocarbon chain that may be linear, branched, cyclic, or a combination thereof. For example, n-pentynyl, n-hexynyl and the like can be mentioned.

  The bicyclic aromatic ring, tricyclic aromatic ring, bicyclic aromatic heterocycle, and tricyclic aromatic heterocycle described in this specification are saturated rings such as tetrahydronaphthalene ring, indane ring, and fluorene ring. In the case of a condensed aromatic ring, only the side chain in which the aromatic ring moiety is directly bonded to X is shown. Examples of the bicyclic aromatic ring include a naphthalene ring, a tetrahydronaphthalene ring, and an indane ring. Examples of the tricyclic aromatic ring include a phenanthrene ring and a fluorene ring. Examples of the bicyclic aromatic heterocycle include quinoline ring, isoquinoline ring, quinazoline ring, indole ring, benzothiophene ring, benzofuran ring, benzimidazole ring, benzoxazole ring, and the like, and tricyclic aromatic heterocycle Examples thereof include a dibenzothiophene ring, a dibenzofuran ring, and a carbazole ring.

Examples of the “halogen atom” in the present specification include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The “aryl group” is a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring group, and examples thereof include phenyl, naphthyl, tetrahydronaphthyl, indanyl, phenanthrenyl, fluorenyl and the like. The “C ₁ -C ₆ alkyl group” means a hydrocarbon chain that may be linear, branched, cyclic, or a combination thereof. 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. Examples of the “heteroaryl group” include pyrrole, furan, thiophene, pyridine, imidazole, pyrazole, oxazole, thiazole, pyrazine 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, phenethyl and the like. 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 and 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.

  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.

  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 these isolated isomers or mixtures thereof are included.

  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 types of protecting groups 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.

Although the manufacturing method of the compound of this invention is not specifically limited, For example, it can manufacture according to the following manufacturing method.

（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 is a protecting group for a carboxyl group such as a methyl group or a tert-butyl group, and the other symbols are as defined above.)

  First step: Compound (3) can be obtained by introducing substituent R or a precursor thereof into compound (2) produced 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 (RSH) 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 under low temperature to warming conditions, ethyl 2-cyclohexanonecarboxylate, 1,10-phenanthroline. Dimethylsulfoxide, N, N-dimethylformamide, acetonitrile, 1,4-dioxane, toluene, etc. in the presence of ligands such as (2-pyridyl) acetone and picolinic acid and bases such as potassium carbonate, cesium carbonate and potassium phosphate The compound (3) can be obtained by reacting with phenol (ROH) in the solvent.

  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 with a solvent such as methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, acetonitrile, and water under heating conditions. Compound (4) can be obtained by reacting with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide in a mixed solvent.

Third step: Compound (5) can be obtained by condensing glycine derivative represented by H ₂ NCH ₂ COOY to compound (4) 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 under low temperature to warming conditions. In the presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or a salt thereof, diphenylphosphoryl azide and optionally N-hydroxysuccinimide, 1-hydroxybenzotriazole, dimethylaminopyridine, etc. potassium carbonate if desired, sodium bicarbonate, cesium carbonate, triethylamine, diisopropylethylamine, morpholine, by adding a base such as pyridine, to be reacted with the glycine derivative represented by H ₂ NCH ₂ COOY Ri, it is possible to obtain the compound (5).

  Fourth step: Compound (1) can be obtained by deprotecting the protecting group for 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 allowed to react with hexane, methanol, ethanol, 2-propanol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethyl under room temperature to warming conditions, hydrogen atmosphere, normal pressure to pressurized conditions. 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 such as methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, acetonitrile, etc. 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.

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、ＲＬ（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 obtained by reacting compound (2) with sodium sulfide or the like in a solvent such as N, N-dimethylformamide under low to warm conditions. 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 reacted with azodicarboxylic acid ester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and triphenylphosphine in a solvent such as tetrahydrofuran and toluene. Compound (3) can be obtained. In addition, when X is S and 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, RL (L is OMs, OTs, Br, Cl, I Compound (3) can be obtained by reacting with a leaving group.

  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 medically 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.

  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 of the general formula (1) according to 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 are usual chemical operations. It can be isolated and purified by various chromatography. 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.

  Administration of the pharmaceutical composition comprising the compound represented by the general formula (1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof can be carried out by using tablets, pills, capsules, granules, powders, Oral administration by liquid etc., injections such as intravenous and intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, Any form of parenteral administration by an inhalant or the like may be used.

  When the pharmaceutical composition comprising the compound represented by the general formula (1) or a pharmaceutically acceptable salt, hydrate or solvate thereof is used as the pharmaceutical preparation, the type of additive for preparation is not particularly limited. But base, excipient, lubricant, coating agent, sugar coating, wetting agent, binder, disintegrant, solvent, solubilizer, solubilizer, solubilizer, suspending agent, dispersant, emulsifier , Surfactants, isotonic agents, buffers, pH adjusters, soothing agents, preservatives, preservatives, stabilizers, antioxidants, coloring agents, sweeteners, etc., alone or in appropriate combination. it can.

  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 once or several times a day, preferably in the range of 1 to 500 mg / day / person. 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.

  EXAMPLES Hereinafter, although an Example and a reference example are given and this invention is demonstrated concretely, this invention is not limited by the following Example.

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 on ^carbon, 1 H-NMR: Proton nuclear magnetic resonance spectrum, CDCl _3: deuterated chloroform , Hz: Hertz, J: coupling constant, m: multiplet, quint: 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.

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)

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)

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).

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).

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 The suspension was suspended in isopropyl alcohol (4.0 mL), 4 M lithium hydroxide aqueous solution (0.6 mL) was added, and the mixture was heated and stirred 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-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) , 8.9 Hz), 7.20-7.45 (6 H, m), 7.51 (1 H, d, J = 8.9 Hz), 8.31 (1 H, s)

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 obtained in Example 3 (377 mg) was converted to a carboxylic acid in the same manner as in Reference Example 2, and then the title compound (183 mg, 2 steps) was prepared in the same manner as in Example 1 using glycine t-butyl ester hydrochloride. Got.

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).

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.

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.

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) were used in 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-α] pyridine-8-carbonyl] amino} acetic acid 3,5-difluoro Reference Examples 1 and 2 and 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.

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. The title compound (55 mg) was obtained in the same manner as 5 and 5.

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 in 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-α] pyridine-8-carbonyl] amino} acetic acid 4-trifluoromethoxy Reference Examples 1 and 2 and benzenethiol (86 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 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-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.

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 -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 and Examples 1 to 3 gave the title compound (72 mg).

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 and Examples 1 to 3 gave the title compound (30 mg).

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 and Examples 1 to 3 gave the title compound (104 mg).

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 -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 and Examples 1 to 3 gave the title compound (103 mg).

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).

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 and 2-merhexyl 3-mercaptopropionate (203 mg), tris (dibenzylideneacetone) dipalladium (21 mg), xanthophos (27 mg), N, N-diisopropylethylamine (0.49 mL) in 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)

Example 19: {[5- (3-Chloro-5-trifluoromethylphenylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Reference Reference example: Compound obtained in Example 4 (136 mg) and 7-benzyloxy-7-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (288 mg) 1, In the same manner as in Examples 4 and 5, the title compound (48 mg) was obtained.

Example 20: {[5- (2,3-Dimethylphenoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,3-dimethylphenol Reference Example 3, Example 4 using (119 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (400 mg). And in the same manner as in Example 5, the title compound (125 mg) was obtained.

Example 21: {[5- (3,5-Dichlorophenoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,5-dichlorophenol (72 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (238 mg), Reference Example 3, Example 4 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-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).

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.

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 using 2-methyl-phenol (113 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 (30 mg) was obtained.

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.

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-7-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) were used in 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-α] pyridine-8-carbonyl] amino} acetic acid 4-chloro -1-Naphthol (730 mg) was treated in the same manner as in Reference Example 4 and Example 19 to obtain the title compound (50 mg, 7 steps).

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-7-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).

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 acid t-butyl ester (500 mg) was treated in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3 to obtain the title compound (215 mg).

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) In the same manner as 1 and 2 and Examples 1 to 3, the title compound (74 mg) was obtained.

Example 31: {[7-Hydroxy-5- (7-trifluoromethylquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-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.

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 mL), a solution of 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 7.0 Hz), 8.17 (1H, dd, J = 1.1, 7.0 Hz), 8.44 (1H, s), 9.21 (1H, s).

Reference Example 6: t-butyl 7-benzyloxy-5- (isoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carboxylate 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) dipalladium (11 mg), xanthophos (13 mg), N, N-diisopropylethylamine (156 μL) and sodium hydroxymethanesulfinate dihydrate (76 mg) were mixed in a dioxane solvent (1 mL) and heated at 100 ° C. under an argon atmosphere for 1 hour. Stir. 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).

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).

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).

Reference Example 8: Bis (5-fluoro-1,2,3-trimethyl-1H-indol-7-yl) disulfide Dissolve the compound obtained in Reference Example 7 (310 mg) 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) , 8.9 Hz), 7.13 (1H, dd, J = 2.7, 8.9 Hz).

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 -The title compound (230 mg) was obtained in the same manner as in Reference Example 6 and Example 32 using butyl ester (521 mg).

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). 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-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 and Examples 1 to 3 gave the title compound (79 mg).

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) In the same manner as in Examples 1 and 2, and 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-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) In the same manner as 1 and 2 and 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-α] pyridine-8-carbonyl] amino} acetic acid 2-methyl Furan-3-thiol (75 mg) and 7-benzyloxy-7-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) were used in Reference Example 1, 2 and Examples 1 to 3 were used to give the titled compound (48 mg).

Example 39: {[5- (5-Chloronaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-chloro The title compound (128 mg) was obtained by treating -1-naphthol (168 mg) in the same manner as in Reference Example 4 and Example 19.

Example 40: {[5- (6-Chloronaphthalen-1-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 6-chloro The title compound (109 mg) was obtained by treating -1-naphthol (120 mg) in the same manner as in Reference Example 4 and Example 19.

Example 41: {[5- (5-Chloronaphthalen-1-yloxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5-chloro- 1-Naphthol (388 mg) was treated in the same manner as in Reference Example 3, Examples 4 and 5 to obtain the title compound (75 mg).

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) was treated in the same manner as in Reference Example 4 and Example 19 to give the title compound (140 mg).

Example 43: {[5- (Dibenzothiophen-4-ylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid dibenzothiophene-4- The title compound (73 mg) was obtained in the same manner as in Reference Example 4 and Example 19 using thiol (182 mg).

Example 44: {[5-Hydroxy-5- (1-trifluoromethylquinolin-5-yloxy) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 1- 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) The title compound (58.7 mg) was obtained in the same manner as in Reference Example 3 and Examples 4 and 5.

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.

Example 46: [7-Hydroxy-5- (5-methylnaphthalen-1-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] -amino} acetic acid 5-methyl Naphthalene-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 Reference 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-α] pyridine-8-carbonyl] amino} acetic acid -Cyanonaphthalene-1-thiol (0.48 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (1.2 g ) In the same manner as in Reference Examples 1 and 2, and Examples 4 and 5, to give the title compound (199 mg).

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 (603.6 mg) and 7-benzyloxy-7-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) The title compound (150 mg) was obtained in the same manner as in Reference Example 1, Examples 4 and 5.

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-7-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.

Example 50: {[7-Hydroxy-5- (5-trifluoromethylnaphthalen-1-yloxy)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 5 -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 Reference 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-α] pyridine-8-carbonyl] amino} acetic acid 5-methoxy Naphthalen-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) were used in Reference Example 9, 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-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.

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.

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.

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.

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 Example 3, Reference Example 2 and Examples 1-3.

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) In the same manner as in Examples 1 and 2, and Examples 1 to 3, the title compound (79 mg) was obtained.

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) In the same manner as in Example 1, Example 4 and Example 5, the title compound (24 mg) was obtained.

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.

Example 60: {[7-Hydroxy-5- (7-trifluoromethylisoquinolin-4-ylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 7 -Trifluoromethylisoquinoline-4-thiol (642 mg) was treated in the same manner as in Reference Example 1, Examples 4 and 5, and the title compound (40 mg) was obtained.

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 3 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) In the same manner as in Reference Example 2 and 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-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.

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.

Example 64: {[5- (7-chloroquinolin-4-ylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 7- Using chloroquinoline-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) In the same manner as in Example 3 and 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-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.

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.

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.

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 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 = 8.1 Hz), 7.46 (1H, d, J = 5.7 Hz), 7.89 (1H, d , J = 8.1 Hz), 8.36 (1H, s).

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 (220 mg).

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.

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 in the same manner as in Reference Examples 1 and 2 and Examples 1 to 3 using t-butyl ester (231 mg).

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 ] Reference 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 Example 9, Reference Example 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-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) The title compound (105 mg) was obtained in the same manner as in Reference Examples 9 and 2 and Examples 1 to 3.

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 -The title compound (88 mg) was obtained in the same manner as in Reference Examples 9 and 2 and Examples 1 to 3, using butyl ester (246 mg).

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.

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 The title compound (214 mg) was obtained using t-butyl ester (301 mg) 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-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.

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.

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).

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).

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).

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 Example 3, Reference Example 2, 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-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, 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-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.

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.

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-7-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester (300 mg) as Reference Example 1, Examples 4, 5 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-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.

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 -Butyl ester (2 g) was treated in the same manner as in Reference Example 9, Examples 4 and 5 to give the title compound (667 mg).

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 ] The title compound (97 mg) was obtained by using pyridine-8-carboxylic acid t-butyl ester (316 mg) in the same manner as in Reference Example 9, Examples 4 and 5.

Example 89: {[7-Hydroxy-5- (indan-4-yloxy) [1,2,4] triazolo [1,5-α] pyridin-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), 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-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), using Reference Examples 3, 2 and 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-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.

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 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)

Reference Example 11: 7-Benzyloxy-5- (2-cyclopentylethoxy)-[1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester obtained in Reference Example 10 The compound (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 obtain the title compound (148 mg, 57%).
¹ H-NMR (CDCl ₃ ) δ: 1.13 to 1.26 (3H, m), 1.49 to 1.68 (11H, m), 1.81 to 2.04 (6H, m), 4 .29 (2H, t, J = 6.5 Hz), 5.26 (1H, s), 6.08 (1H, s), 7.35-7.47 (5H, m), 8.26 (1H , S)

Example 92: {[7-Hydroxy-5- (2-methylbutylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-methyl-1- Similar to Example 8 using butanethiol (63 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg) To give the title compound (71 mg).

Example 93: {[7-Hydroxy-5- (2-methylbutylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (S) -2-methyl The title compound (35 mg) was obtained in the same manner as in Example 94 using butanol (71 mg) and the compound (200 mg) obtained in Reference Example 15.

Example 94: {[7-hydroxy-5-methylsulfanyl- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid obtained in methanol (1000 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, Example 2, and 3.

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- 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 (28 mg) was obtained. .

Example 96: {[7-Hydroxy-5- (3,3,3-trifluoropropylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3 , 3,3-trifluoro-propanethiol (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.

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 obtained compound (200 mg).

Example 98: {[7-hydroxy-5- (3-methylbutylsulfanyl) [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3-methylbutane-1-thiol (55 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 (40 mg).

Example 99: {[5- (3,3-Dimethylbutylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,3- The title compound (39 mg) was obtained in the same manner as in Example 152, using dimethylbutyl-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-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.

Reference Example 12: 3- [7-Benzyloxy-8- (t-butoxycarbonylmethylcarbamoyl)-[1,2,4] triazolo [1,5-α] pyridin-5-ylsulfanyl] propionic acid 3-ethylhexyl 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 -d) δ: 0.81-0.97 (6H, m), 1.19-1.66 (17 H, m), 2.65 (2 H, t, J = 7.43 Hz) ), 3.31 (2H, t, J = 7.16 Hz), 4.06 (2H, dd, J = 5.67, 5.94 Hz), 4.24 (2H, d, J = 4.86 Hz) , 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, br)

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 (2.56 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 = 5.94 Hz), 5.54 (2H, s), 6.99 (1H , S), 7.31-7.58 (5H, m), 8.46 (1H, br), 8.90 (1H, s), 13.77 (1H, br)

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 (2.66 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, 2 and Example 1.
¹ H-NMR (CDCl 3 -d) δ: 0.81-0.99 (6H, m), 1.22-1.49 (8H, m), 2.66 (2H, t, J = 7.29 Hz) ), 3.31 (2H, t, J = 7.16 Hz), 3.80 (3H, s), 4.05 (2H, dd, J = 5.94, 5.94 Hz), 4.33 (2H) , D, J = 5.13 Hz), 5.44 (2H, s), 6.71 (1H, s), 7.25-7.59 (5H, m), 8.30 (1H, s), 9.68 (1H, br)

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 = 5.67 Hz), 5.55 (2H, s), 6.99 (1H , S), 7.28-7.57 (5H, m), 8.55 (1H, br), 8.90 (1H, s), 13.76 (1H, br)

Example 101: {[7-Hydroxy-5- (2-ethylbutylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid obtained in Reference Example 15 The title compound was obtained in the same manner as in Example 94 using 250 mg of the above compound.

Example 102: {[5- (1,3-Dimethylbutylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] -amino} acetic acid 4-methyl The title compound (30 mg) was obtained in the same manner as in Example 100, using -2-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-α] pyridine-8-carbonyl] -amino} acetic acid The title compound (104 mg) was obtained in the same manner as in Example 152, using methanesulfonic acid 4,4,4-trifluoro-butyl ester (309 mg) and the compound (279 mg) obtained in Reference Example 15.

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-Iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (451 mg) was used in the same manner as in Example 94 to obtain the title compound (48 mg). It was.

Example 105: {(7-hydroxy-5- (4-methylpentylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridin-8-carbonyl) amino} acetic acid 4-methyl-1- The title compound (100 mg) was obtained in the same manner as in Example 100 using pentanol (100 mg) and the compound (200 mg) obtained in Reference Example 13.

Example 106: {(7-hydroxy-5- (3-methylpentylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino} acetic acid 3-methyl-1- The title compound (70 mg) was obtained in the same manner as in Example 100, using pentanol (100 mg) and the compound (200 mg) obtained in Reference Example 13.

Example 107: {[7-Hydroxy-5- (2-propylpentylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-propylpentene-1 Using the alcohol (147 mg) and the compound (311 mg) obtained in Reference Example 13, the title compound (102 mg) was obtained in the same manner as in Example 100.

Example 108: {[5- (3-Ethylpentylsulfanyl) -hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] -amino} acetic acid 3-ethylpentane-1- Using all (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-α] pyridine-8-carbonyl) amino] acetic acid 3-pentyn-1-ol (31.6 mg) and the compound (130 mg) obtained in Reference Example 15 were used in the same manner as in Reference Example 11 and Example 5, to obtain the title compound (69 mg).

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-pentafluoro-pentane ester (332 mg) and the compound obtained in Reference Example 13 (279 mg) were used in the same manner as in Example 152 to give the title compound (210 mg )

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 -5-Iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) was used in the same manner as in Example 8 to obtain the title compound (60 mg). It was.

Example 112: [(5-Hex-3-ylsulfanyl-7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) -amino] acetic acid 3-hexyne-1- The title compound (57 mg) was obtained in the same manner as in Example 152, using 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-α] pyridine-8-carbonyl) amino] acetic acid 2-propanethiol (92.2 mg) and 7 -Benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg) was used in the same manner as in Example 8 to obtain the title compound (32 mg )

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) as in Example 8. To give the title compound (60 mg).

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 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 (73 mg) was obtained.

Example 116: {[5- (1,2-Dimethylpropylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] -amino} acetic acid -Dimethyl-1-propanethiol (73.9 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 Example 6, the title compound (40 mg) was obtained.

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-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid methyl ester (300 mg) was used in the same manner as in Reference Example 1, Reference Example 2 and Example 1. 5-Allylsulfanyl-5-benzyloxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonylaminoacetic acid methyl ester (104 mg) was obtained. To this was added trifluoroacetic acid (1.04 mL) and triethylsilane (58.5 mg), and the mixture was heated with stirring 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).

Example 118: [(7-Hydroxy-5-cyclopentylsulfanyl- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid cyclopentanethiol (45 mg) and 7-benzyloxy -5-Iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) was used in the same manner as in Example 8 to obtain the title compound (72 mg). It was.

Example 119: [(7-Hydroxy-5-cyclohexylsulfanyl- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid cyclohexanethiol (61 mg) and 7-benzyloxy- The title compound (55 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 (250 mg). .

Example 120: {[7-Hydroxy-5- (adamantan-1-ylsulfanyl)-[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), The title compound (110 mg) was obtained.

Example 121: {[5-Cyclopropylmethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Bromomethanecyclopropane (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-α] pyridine-8-carbonyl] amino} acetic acid Bromomethanecyclobutane (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-α] pyridine-8-carbonyl] amino} acetic acid toluene-4-sulfonic acid cyclopentylmethyl ester (254 .4 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-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.

Example 125: {[5- (2-cyclohexylethylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid toluene-4-cyclopentylsulfonate 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-α] pyridine-8-carbonyl] amino} acetic acid 2-cyclohexylpropanol (102 mg) The title compound (119 mg) was obtained in the same manner as in Example 100 using the compound (200 mg) obtained in Reference Example 13.

Example 127: {[5- (2-Cyclopropylethylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Toluene-4-sulfone The title compound (95 mg) was obtained in the same manner as in Example 152, using acid 2-cyclopropylethyl ester (132 mg) and the compound (207 mg) obtained in Reference Example 15.

Example 128: {[5-Cyclobutylethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Toluene-4-sulfonic acid-2-cyclo The title compound (40 mg) was obtained in the same manner as in Example 152, using butyl ethyl ester (165 mg) and the compound (200 mg) obtained in Reference Example 15.

Example 129: {[5-Cyclopentylethylsulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid toluene-4-sulfonic acid-2-cyclopentylethyl The title compound (56 mg) was obtained in the same manner as in Example 152, using the 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-α] pyridine-8 -Carbonyl] amino} acetic acid (2-bicyclo [2,2,1] hept-2-ylethanol (144 mg) and triethylamine (101 mg) dissolved in THF (2 mL), and mesyl chloride (112 mg) 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. Distilled to obtain methanesulfonic acid 2-bicyclo [2,2,1] hept-2-yl-ethyl ester, the above compound (197 mg) and the compound obtained in Reference Example 15 (311 mg). There, in the same manner as in Example 152 to give the title compound (116 mg).

Example 131: {[5- (adamantan-1-ylethyl) sulfanyl-7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid toluene-4-sulfonic acid The title compound (71 mg) was obtained in the same manner as in Example 152, using -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-α] pyridine-8-carbonyl) amino} acetic acid 2-phenylethanethiol (92 mg) and 7- Reference Example 3, Reference Example 2, and Examples 1-3 using benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (250 mg) To give the title compound (60 mg).

Example 133: ({5- [2- (3,4-dichlorophenyl) -ethylsulfanyl] -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridin-8-carbonyl} amino) The title compound (120 mg) was obtained in the same manner as in Example 100 using 3,4-dichlorophenylethanol acetate (110 mg) and the compound (200 mg) obtained in Reference Example 13.

Example 134: ({7-hydroxy-5- [2- (4-methoxyphenyl) -ethylsulfanyl]-[1,2,4] triazolo [1,5-α] pyridin-8-carbonyl} amino) The title compound (100 mg) was obtained in the same manner as in Example 100, using 2- (4-methoxyphenyl) ethanol acetate (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-α] pyridine-8-carbonyl) amino} acetic acid 3-phenylbutanol (90 mg ) And the compound (200 mg) obtained in Reference Example 15 were used to obtain the title compound (900 mg) in the same manner as in Example 94.

Example 136: {(7-hydroxy-5- (2-methyl-2-phenylpropylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridin-8-carbonyl) amino} acetic acid 2- The title compound (90 mg) was obtained in the same manner as in Example 94, using methyl-2-phenylethanol (90 mg) and the compound (200 mg) obtained in Reference Example 15.

Example 137: {(7-Hydroxy-5- (2-thiophen-2-yl-ethylsulfanyl)-[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.

Example 138: {[5- (3-cyclohexylpropylsulfanyl) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid toluene-4-sulfonic acid- The title compound (50 mg) was obtained in the same manner as in Example 152, using 3-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-α] pyridine-8-carbonyl] amino} acetic acid 3-phenylpropanol (110 mg ) And the compound (200 mg) obtained in Reference Example 13 were used in the same manner as in Example 100 and in the same manner as in Example 6, to obtain the title compound (89 mg).

Example 140: {[7-Hydroxy-5- (2-methoxyethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 1-bromomethoxyethane ( 76 μL) and the compound (200 mg) obtained in Reference Example 15 were used to obtain the title compound (105 mg) in the same manner as in Example 152.

Example 141: {[7-Hydroxy-5- (2-isopropoxyethylsulfanyl- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-isopropoxy-1 Example 11 using -ethanol (73.1 mg) and 7-benzyloxy-5-mercapto [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg) In the same manner as in Example 5, a thioether compound (176 mg) was obtained, and then in the same manner as in Example 5, the title compound (44 mg) was obtained.

Example 142: {(7-hydroxy-5- (2-phenoxyethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino} acetic acid 2-phenoxyethanol (90 mg) 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 [1,4] dioxinylmethylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridin-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-α] pyridine-8-carbonyl] amino} acetic acid 2,3- Triethylamine (0.8 mL) and methanesulfonyl chloride (0.65 g) were added to a solution of diphenylpropanol (1.0 g) in tetrahydrofuran (5 mL) under ice cooling. The reaction mixture was stirred for 1 hour under ice-cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dehydrated with anhydrous sodium sulfate, and the reduced-pressure solvent was distilled off to obtain 2,3-diphenylpropanol methanesulfonate (1.4 g). Using this compound (190 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo [1,5-α] pyridine-8-carboxylic acid t-butyl ester (200 mg), Reference Example 16 and In the same manner as in Example 32, the title compound (55 mg) was obtained.

Example 145: 3- [8- (Carboxymethylcarbamoyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridin-5-ylsulfani] propanoic acid-2-ethyl-hexyl ester 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.

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 in Reference Example 3, Reference Example 2, and Examples 1-3. To give the title compound (21 mg).

Example 147: {[7-Hydroxy-5- (2-methylbenzylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (2-methylphenyl) Similar to Example 8 with methanethiol (67 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 (44 mg).

Example 148: {[7-hydroxy-5- (2-trifluoromethylbenzylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2- (tri The title compound (46 mg) was obtained in the same manner as in Example 152, using (fluoromethyl) 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-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.

Example 150: {[5- (2-Chlorobenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (2-chlorophenyl) methane As in Example 8, using thiol (77 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 (66 mg).

Reference Example 16: {[7-Benzyloxy-5- (2-methoxybenzylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid methyl ester 2-methoxy Benzyl chloride (110 mg) and the compound obtained in Reference Example 15 (80 mg) were mixed in a 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 = 4.59 Hz), 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)

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 obtained compound (100 mg).

Example 152: {[7-hydroxy-5- (2-trifluoromethoxybenzylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2- (tri Using the fluoromethoxy) benzyl bromide (65.8 mg) and the compound obtained in Reference Example 15 (80 mg), the title compound (70 mg) was obtained in the same manner as in Reference Examples 16 and 151.

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, and the title compound (51 mg) was obtained in the same manner as in Example 152.

Example 154: {[7-hydroxy-5- (3-trifluoromethylbenzylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3- (tri The title compound (60 mg) was obtained in the same manner as in Example 152, using (fluoromethyl) 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-α] pyridine-8-carbonyl] amino} acetic acid (3-fluorobenzyl bromide (45 mg) and the compound (80 mg) obtained in Reference Example 15 were used, and the title compound (60 mg) was obtained in the same manner as in Example 152.

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, and the title compound (60 mg) was obtained in the same manner as in Example 152.

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), as in Example 8, The title compound (66 mg) was obtained.

Example 158: {[7-hydroxy-5- (4-trifluoromethylbenzylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid [4- ( Using (trifluoromethyl) 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.

Example 159: {[5- (4-Fluorobenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (4-fluorophenyl) Similar to Example 8 with methanethiol (69 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 (88 mg).

Example 160: {[7-Hydroxy-5- (4-chlorobenzylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4-chlorobenzyl mercaptan And the title compound was obtained as in Example 6.

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) was dissolved in N, N-dimethylformamide, and sodium sulfide anhydride (6.9 g) was added at room temperature. 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)

Example 161: {[5- (4-Cyanobenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4- (mercaptomethyl) Similar to Example 6 using benzonitrile (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).

Example 162: {[5- (4-tert-butylbenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (4-tert -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 in Example 146, the title compound (24 mg) was obtained.

Example 163: {[5- (biphenyl-4-ylmethylsulfanyl) -7-hydroxy- [1,2,4] and riazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid Reference Example 13 Biphenyl-4-ylmethanethiol (117 mg) and 7-benzyloxy-5-iodo [1,2,4] triazolo “1,5-α] pyridine-8-carboxylic acid t-butyl ester synthesized in the same manner as above (220 mg) was used, and the title compound (42 mg) was obtained in the same manner as in Example 146.

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, and the title compound (53 mg) was obtained 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-α] pyridine-8-carbonyl] amino} acetic acid 2- The title compound (47 mg) was obtained in the same manner as in Example 152, using fluoro-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-α] pyridine-8-carbonyl] amino} acetic acid 2,3- The title compound (56 mg) was obtained in the same manner as in Example 152, using difluorobenzyl 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-α] pyridine-8-carbonyl] amino} acetic acid (2,4 Examples 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) In the same manner as in 8, the title compound (65 mg) was obtained.

Example 168: {[7-hydroxy-5- (2,4-dimethylbenzylsulfanyl) [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).

Example 169: {[7-hydroxy-5- (2,5-dimethylbenzylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (2,5 -Dimethylphenyl) methyl methanesulfonate (57 mg) and the compound obtained in Reference Example 15 (90 mg) were used in the same manner as in Example 152 to obtain the title compound (71 mg).

Example 170: {[5- (2,5-difluorobenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (2,5 Using the difluorobenzyl bromide (43 mg) and the compound (70 mg) obtained in Reference Example 15, the title compound (50 mg) was obtained in the same manner as in Example 152.

Example 171: {[5- (2,5-dichlorobenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (2,5 -The title compound (52 mg) was obtained in the same manner as in Example 152, using dichlorobenzyl 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-α] pyridine-8-carbonyl] amino} acetic acid 5- The title compound (57 mg) was obtained in the same manner as in Example 152, using chloro-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-α] pyridine-8-carbonyl] amino} acetic acid 2- The title compound (51 mg) was obtained in the same manner as in Example 152, using chloro-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-α] pyridine-8-carbonyl] amino} acetic acid 2- Fluoro-5-methylbenzyl alcohol (80 mg) and tetrahydrofuran (1.0 mL) were mixed, and triethylamine (87 mg) and methanesulfonyl chloride (72 mg) were sequentially added under ice cooling. The mixture was stirred at the same temperature for 1 hour to confirm the completion of the reaction. 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 to give 2-fluoro-5-methylbenzyl methanesulfonate. Using the obtained compound (58 mg) and the compound (90 mg) obtained in Reference Example 15, the title compound (70 mg) was obtained in the same manner as in Example 152.

Example 175: {[5- (2-Chloro-3,6-difluorobenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid The title compound (63 mg) was obtained in the same manner as in Example 152, using 2-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-α] pyridine-8-carbonyl] amino} acetic acid (2,6 -The title compound (56 mg) was obtained in the same manner as in Example 152, using dichlorobenzyl 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-α] pyridine-8-carbonyl] amino} acetic acid (3 The title compound (68 mg) was obtained in the same manner as in Example 152, using -chloro-4-fluorobenzyl bromide (53 mg) and the compound (80 mg) obtained in Reference Example 15.

Example 178: {[5- (3,5-bistrifluoromethylbenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3, The title compound (67 mg) was obtained in the same manner as in Reference Example 2 and Examples 1 to 3, using 5-bis (trifluoromethyl) benzyl bromide (95 mg) and the compound (92 mg) obtained in Reference Example 17.

Example 179: {[7-hydroxy-5- (2,6-dimethylbenzylsulfanyl) [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.

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) In the same manner as in Example 8, the title compound (64 mg) was obtained.

Example 181: {[5- (2,3,6-trifluorobenzylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2 , 3,6-trifluorobenzyl bromide (53 mg) and the compound (80 mg) obtained in Reference Example 15 were used to give the title compound (48 mg) in the same manner as in Example 152.

Example 182: {[5- (2,3,4,5,6-pentafluorobenzylsulfanyl) -7-hydroxy- [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). .

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 mixed, and N-bromosuccinimide (150 mg) and azobisisobutyronitrile (6 mg) were added to the mixture, Stir at 90 ° 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-α] pyridine-8-carbonyl] amino} acetic acid 2,6- The title compound (30 mg) was obtained in the same manner as in Example 100, using difluorobenzyl alcohol (110 mg) and the compound (200 mg) obtained in Reference Example 13. In the same manner as in Example 6, the title compound was obtained.

Example 185: {[7-hydroxy-5- (1-phenylethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid (±) -1- The title compound (113 mg) was obtained in the same manner as in Example 152, using 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-α] pyridine-8-carbonyl] Amino} acetic acid I-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-α] pyridine-8- Carbonyl] amino} acetic acid 5,6,7,8-tetrahydronaphthalen-2-ylmethanol (274 mg) and tetrahydrofuran (3.0 mL) were mixed, and triethylamine (258 mg) and methanesulfonyl chloride (214 mg) were added under ice cooling. Added sequentially. The reaction was stirred at the same temperature for 2 hours to confirm the completion of the reaction. 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 to obtain 5,6,7,8-tetrahydronaphthalen-2-ylmethylmethanesulfonate. The title compound (65 mg) was obtained in the same manner as in Example 152, using the obtained compound (62 mg) and the compound (80 mg) obtained in Reference Example 15.

Example 188: {[5- (Benzothiazol-2-ylmethylsulfanyl) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-benzo The title compound (62 mg) was obtained in the same manner as in Example 152, using thiazolemethanol 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-α] pyridine-8-carbonyl] amino} acetic acid 2-bromomethyl The title compound (53 mg) was obtained in the same manner as in Example 152, using pyridine 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-α] pyridine-8-carbonyl] amino} acetic acid Pyridine-3- The title compound (35 mg) was obtained in the same manner as in Example 152, using ylmethylmethanesulfonate (83 mg) and the compound obtained in Reference Example 15 (150 mg).

Example 191: {[7-Hydroxy-5- (pyridin-4-ylmethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4-bromomethyl The title compound (101 mg) was obtained in the same manner as in Example 152, using pyridine 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-α] pyridine-8-carbonyl] amino} acetic acid 6 Using {-7-benzyloxy-5- (6-methylpyridin-2-yl) in the same manner as in Example 168 using -methyl-2-pyridinemethanol (49 mg) and the compound obtained in Reference Example 15 (135 mg) Methylsulfanyl)-[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.

Example 193: {[7-Hydroxy-5- (6-trifluoromethylpyridin-3-ylmethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} Acetic acid methanesulfonic acid-6-trifluoromethylpyridin-3-ylmethyl ester was obtained. The title compound (109 mg) was obtained in the same manner as in Example 152, using the compound (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-α] pyridine-8-carbonyl] amino} Acetic acid Methanesulfonic acid 2,6-dichloro-pyridin-3-ylmethyl ester (256 mg) and the compound obtained in Reference Example 15 (311 mg) were used in the same manner as in Example 152 to obtain the title compound (185 mg). It was.

Example 195: {[7-hydroxy-5- (2-trifluoromethylpyridin-4-ylmethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} A mixture of acetic acid (2-trifluoromethylpyridin-4-yl) methanol (177 mg) and triethylamine (101 mg) 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. did. 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 2-trifluoromethyl-pyridin-4-ylmethyl ester. The title compound (160 mg) was obtained in the same manner as in Example 152, using the above compound (255 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-α] pyridine-8-carbonyl] amino} Acetic acid Methanesulfonic acid 2,6-dimethylpyridin-4-ylmethyl ester (161 mg) and the compound (250 mg) obtained in Reference Example 15 were used, and 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-α] pyridine-8-carbonyl] amino} Acetic acid Methanesulfonic acid 2,6-dichloropyridin-4-ylmethyl ester (256 mg) and the compound obtained in Reference Example 15 (311 mg) were used in the same manner as in Example 152 to obtain the title compound (180 mg). .

Example 198: {[7-Hydroxy-5- (quinolin-4-ylmethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid quinoline-4- The title compound (70 mg) was obtained in the same manner as in Example 192 using ilmethanol (94 mg).

Example 199: {[7-hydroxy-5- (8-trifluoromethylquinolin-4-ylmethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} Sodium borohydride (86 mg) was added to a methanol solution (4 mL) of acetic acid 8-trifluoromethyl-quinoline-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.

Example 200: {[7-Hydroxy-5- (quinolin-2-ylmethylsulfanyl)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-quinolinemethane The title compound was obtained in the same manner as in Example 6 using thiol.

Example 201: {[7-Hydroxy-5- (2-methylbutoxy)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-methylbutanol (22. 4 mg) and the compound (93.7 mg) obtained in Reference Example 10 were used in the same manner as in Reference Example 11, Examples 4 and 5, and the title compound (50 mg) was obtained.

Example 202: {(7-Hydroxy-5- (2-methylbutoxy)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino} acetic acid 2-methyl-1-butanol In the same manner as in Example 201, the title compound was obtained.

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).

Example 204: {[5- (3,3-Dimethylbutoxy) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 3,3-dimethyl -1-Butanol (72 mg) and the compound obtained in Reference Example 10 (200 mg) were used in the same manner as in 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 (1.2 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).

Example 205: {[5- (2-Ethylbutoxy) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-ethyl-1-butanol (90 mg) and the compound (200 mg) obtained in Reference Example 10 were used, and the title compound (90 mg) was obtained in the same manner as in Example 201.

Example 206: {[5- (2,3-Dimethylbutoxy) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2,3-dimethyl The title compound (35 mg) was obtained in the same manner as in Example 201, using butane-1ol (77.3 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-α] pyridine-8-carbonyl] amino} acetic acid 1,2-dimethyl Using butane-1ol (185 mg) and the compound (500 mg) obtained in Reference Example 10 and carrying out in the same manner as in Reference Example 11, an ether form (216 mg) was obtained. 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 for 2 hours under normal pressure in a hydrogen stream, filtered off, and the solvent was evaporated. To obtain the desired product (140 mg). Then, the title compound (40 mg) was obtained in the same manner as Example 3.

Example 208: {[7-Hydroxy-5- (4-methylpentyloxy)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 4-methylpentane-1 The title compound (83 mg) was obtained in the same manner as in Example 201 using all (72 mg) and the compound (200 mg) obtained in Reference Example 10.

  Example 209: {[7-Hydroxy-5- (3-methylpentyloxy)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} vinegar 3-methylpentane-1 The title compound (75 mg) was obtained in the same manner as in Example 201 using all (71.8 mg) and the compound (200 mg) obtained in Reference Example 10.

Example 210: [(7-Hydroxy-5-pent-3-ynyloxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 3-pentyn-1ol (59 .1 mg) and the compound (200 mg) obtained in Reference Example 10 were used in the same manner as in Example 207 to obtain the title compound (36 mg).

Example 211: ({5- (1,4-Dimethylpentyloxy) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl} amino) acetic acid 1,4- The title compound was obtained in the same manner as in Example 201 using dimethyl-1-pentanol.

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 compound (122 mg) obtained in (1).

Example 213: [(5-hex-4-enyloxy) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 4-cishexen-1-ol (70.3 mg) and the compound (200 mg) obtained in Reference Example 10 were used, and the title compound (57 mg) was obtained in the same manner as in Example 201.

Example 214: [(7-Hydroxy-5-oct-3-enyloxy)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 3-cisocten-1-ol (90 mg) and the compound (250 mg) obtained in Reference Example 10 were used, and the title compound (310 mg) was obtained in the same manner as in Example 201.

Example 215: [(7-hydroxy-5-non-3-nonyloxy)-[1,2,4] triazolo [1,5-α] pyridine-8-carbonyl) amino] acetic acid 3-nonin-1-ol Using the compound (98.5 mg) and the compound (200 mg) obtained in Reference Example 10, the title compound (35 mg) was obtained in the same manner as in Example 201.

Example 216: ({5- [2- (2-Ethoxyethoxy) -ethoxy] -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl} amino) acetic acid diethylene glycol The title compound (40 mg) was obtained in the same manner as in Example 201 using monoethyl ether (100 mg) and the compound (200 mg) obtained in Reference Example 10.

Example 217: {[5- (2-cyclohexyl-ethoxy) -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-cyclohexane-1- The title compound (44 mg) was obtained in the same manner as in Example 201 using ethanol (46.1 mg) and the compound (102.4 mg) obtained in Reference Example 10.

Example 218: {[5- (2-Cyclobutyl-ethoxy) -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).

Example 219: {[5- (2-Cyclopentyl-ethoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-cyclopentylethanol (114 mg) 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-yl-ethoxy) -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 )

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.

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.

Example 223: ({5- [2- (2-Fluorophenyl) -ethoxy] -7-hydroxy- [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl} amino) acetic acid 2 -(2-Fluorophenyl) -1-ethanol (139 mg) and the compound obtained in Reference Example 10 (300 mg) were used in the same manner as in Example 201,
The title compound (73 mg) was obtained.

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.

Example 225: {[5- (2-cyclohexylpropoxy) -7-hydroxy [1,2,4] triazolo [1,5-α] pyridine-8-carbonyl] amino} acetic acid 2-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.

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 The title compound (70 mg) was obtained in the same manner as in Example 201 using the compound (200 mg) obtained in Reference Example 10.

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). Then, in the same manner as in Reference Example 2, carboxylic acid (810 mg) was obtained. Subsequently, the amide body (735 mg) was obtained like Example 1 using glycine methyl ester. 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 (61.5 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).

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).

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, and then the test substance 1 μM or vehicle (0. 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

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 by 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 press.

  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, in particular, the prevention or treatment of anemia.

Claims (2)

The following general formula (1)

[In the above formula,
X represents an oxygen atom, a nitrogen atom, a sulfur atom, sulfinyl, 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 optionally substituted alkynyl group, or a group selected from a substituent group, which may independently have 1 to 7 substituents, a monocyclic, bicyclic or tricyclic aromatic ring or substituent A monocyclic, bicyclic or tricyclic aromatic heterocycle which may independently have 1 to 7 substituents selected from the group. Substituent group, 1 to 7 as the aryl group (substituent group which may have a substituent C ₁ -C ₆ alkyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group, a phenyl group shown), indicating 1 to 7 as a heteroaryl group (the substituent may have a substituent of C ₁ -C ₆ alkyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group, a phenyl group ), A C ₁ -C ₆ alkyl group (in the case of a C ₃ -C ₆ alkyl group, carbon atoms may be bonded to form a 3- to 6-membered saturated ring), C ₂ -C ₆ alkenyl _groups, C alkynyl group 2 -C _6, arylalkyl _group, an alkoxycarbonyl group having C 2 -C _8, a halogen _atom, a halogenated alkyl group of C 1 -C _6, hydroxy _group, an alkoxy group of C 1 -C ₆ , C Halogenated alkoxy groups ₁ -C _6, an aryloxy group, a carbamoyl _group, an alkylcarbonyl group C 2 -C _6, a cyano group, a carboxyl group, a formyl group, a nitro group, an amino _group, alkylamino C 1 -C ₆ 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 halogenation It shows an alkylsulfonyl group, an arylsulfonyl group, an alkylsulfanyl group of C ₁ -C _6, halogenated alkylsulfanyl group C ₁ -C _6, a group consisting of arylsulfanyl group. Or a pharmaceutically acceptable salt thereof. The general formula (1) according to claim 1, wherein
X represents an oxygen atom or a sulfur atom,
R ¹ , R ² , R ³ and R ⁴ represent a hydrogen atom, and R ⁵ is substituted with an alkyl group which may be substituted with a group selected from the substituent group or a group selected from the substituent group An alkynyl group which may be substituted, an alkynyl group which may be substituted with a group selected from the group of substituents, or a group selected from the group of substituents may have 1 to 7 substituents independently. A monocyclic, bicyclic or tricyclic aromatic ring, or a monocyclic, bicyclic or tricyclic aromatic ring optionally having 1 to 7 substituents selected from a group of substituents A group heterocycle is shown. Alkyl C ₁ -C ₆ substituent groups as aryl group (substituent group which may have 1 to 7 substituents, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group, a phenyl group ), 1 to 7 an optionally substituted heteroaryl group (the alkyl group of C ₁ -C ₆ as substituents, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group, a phenyl group) , _(in the case of C 3 -C ₆ alkyl group, may form 3 to 6-membered saturated ring by bonding between carbon _atoms) alkyl group _C 1 -C _6, alkenyl radicals in C 2 -C ₆ C ₂ -C ₆ alkynyl group, arylalkyl 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 Halogenated alkoxy group -C _6, an aryloxy group, a carbamoyl _group, an alkylcarbonyl group C 2 -C _6, a cyano group, a carboxyl group, a formyl group, a nitro group, an amino _group, an alkylamino group of C 1 -C ₆ 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 alkyl a sulfonyl group, an arylsulfonyl group, an alkylsulfanyl group, halogenated alkylsulfanyl group C ₁ -C _6, compound or a pharmaceutically acceptable salt thereof according to claim 1 consisting of arylsulfanyl group C ₁ -C _6.