TW201625614A - Novel heterocyclic derivatives - Google Patents

Abstract

The present invention relates to the compound represented by the following formula (1) [in the formula, X represents an oxygen atom, an imino group, a sulfur atom, sulfinyl, or sulfonyl, R1, R2 and R3 each independently represent a hydrogen atom or a C1-C6 alkyl group, R4 represents a hydrogen atom, a C1-C6 alkyl group, or an arylalkyl group, and R5 represents an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or a heteroaryl group]. By having an excellent activity of promoting EPO production, the compound is useful as a pharmaceutical agent.

Description

Novel heterocyclic derivatives

The present invention relates to a novel heterocyclic derivative having the promoting action of erythropoietin (EPO, Erythropoietin).

EPO is a glycoprotein hormone containing 165 amino acids mainly produced in the kidney and a part of the liver, and promotes differentiation induction of red blood cell germ cell line stem cells (precursor cells) to produce mature red blood cells. There is a positive correlation between the EPO concentration in the blood and the production of red blood cells, and the increase in the number of red blood cells suggests the importance of the continuous concentration of EPO (Non-Patent Document 1).

The production of EPO is controlled by a hypoxia inducible factor (HIF) as a transcription factor. The HIF contains an alpha subunit (HIF-α) and a beta subunit (HIF-β), and exhibits different responses depending on the oxygen concentration in the tissue. Under normal oxygen pressure, HIF-α is catalyzed by amidoxime hydroxylase (PHD) and is decomposed by the ubiquitin-proteasome system.

It is reported that there are one to three isoforms in the PHD, and the intracellular localization, the oxygen partial pressure response, and the reactivity with respect to the HIF isoform are different (Non-Patent Documents 2 and 3). Further, a number of isoforms are also present in HIF-α, and although HIF-1α and HIF-2α are structurally similar, the amount of expression and orientation are different (Non-Patent Document 3). Regarding HIF, it also suggests effects on hypoxia-inducible factors other than EPO (glucose transporters 1 and 3, lactate dehydrogenase, hepcidin, etc.) (Non-Patent Documents 3 and 4), but it is not fully explained. Its physiological function.

On the other hand, under low oxygen, HIF-α is less stable from decomposition caused by PHD, and is transferred from the cytoplasm to the nucleus to form a dimer with HIF-β. The heterodimer of HIF-α and β binds to the hypoxia responsible element sequence of the EPO gene to promote transcription, thereby promoting EPO production. It has been confirmed in mammals such as rodents, monkeys or humans that stabilization of HIF based on PHD inhibition promotes EPO production, an increase in red blood cells with an increase in EPO concentration, and an EPO production promoter using PHD inhibition shows Usefulness as an anemia therapeutic agent (Patent Documents 1, 2, 3 and Non-Patent Documents 5 and 6).

For example, if the occurrence of EPO occurs in the kidney due to a kidney disorder or the like, the concentration of EPO in the blood is lowered, and the generation of red blood cells is suppressed, and anemia (renal anemia) is generated. Regarding acute kidney diseases such as renal failure, it is known that renal anemia is caused by a high probability. Further, anemia caused by a decrease in EPO production irrespective of a renal disorder or the like is also known.

As a main treatment method for such diseases, anemia treatment, self-storage, and anemia of premature infants in patients with chronic kidney disease (CKD) using genetically recombinant human EPO preparation (hereinafter referred to as EPO preparation) are known ( Anemia of prematurity), AIDS (Acquired Immune Deficiency Syndrome), and anemia treatment for cancer patients undergoing chemotherapy.

In addition, diseases other than anemia, that is, ischemic heart disease (angina pectoris, myocardial infarction, etc.), ischemic cerebrovascular disease (cerebral embolism, cerebral infarction, etc.), ischemic kidney disease (ischemic renal failure) Etc., ischemia of the lower extremities (obstructive atherosclerosis, Buerger's disease, diabetic gangrene, etc.), ischemic enteritis (ischemic colitis, etc.) and other ischemic diseases and fatty liver metabolism The disease is also located in a hypoxic environment in a target organ or tissue, and stabilization of HIF based on PHD inhibition is expected to bring about a preventive or therapeutic effect on these diseases (Non-Patent Documents 7 and 8).

The above EPO preparations reduce the number of patients requiring regular blood transfusion, improve the symptoms associated with anemia, and improve the QOL (Quality of Life) improvement of anemia patients. contribution. However, since the EPO preparation is a glycoprotein, the structure of the sugar chain bound to the surface of the EPO is complicated, and its glycosylation is broad and diverse, thus exhibiting size heterogeneity and being difficult to reproduce by genetic recombination of human EPO. Human serum EPO is produced well. Moreover, since it is a biological preparation, the price is high, and it is also a burden on the patient in terms of medical expenses. Further, since the route of administration is injection, it is also highly desirable to increase the method and/or compound of endogenous EPO which can be administered orally in view of preventing medical accidents or reducing the burden on the patient.

As an EPO production promoter of the above-mentioned low molecular weight compound, triazolopyridine derivatives (Patent Document 1), pyrimidine derivatives (Patent Documents 4 and 5), and isoquinoline derivatives (Patent Documents 3 and 6) have been developed. A bicyclic pyridine derivative (Patent Document 7), a bicyclic heteroaromatic N-substituted glycine derivative (Patent Document 8), and the like.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Special Opening 2011-37841

[Patent Document 2] Japanese Patent Laid-Open No. 2006-137763

[Patent Document 3] Japanese Patent Special Table 2008-546644

[Patent Document 4] Japanese Patent Special Open 2011-88840

[Patent Document 5] Japanese Patent Special Table 2009-541351

[Patent Document 6] Japanese Patent Special Open 2011-148810

[Patent Document 7] Japanese Patent Special Table 2009-541486

[Patent Document 8] Japanese Patent Special Table 2009-537558

[Non-patent literature]

[Non-Patent Document 1] Elliott S et al, Erythropoietins: A common mechanism of action, Exp Hematol, 2008; 36: 1573 - 84

[Non-Patent Document 2] Metzen E et al. Intracellular localisation of human HIF-1α hydroxylases. J Cell Sci. 116: 1319 - 26, 2002.

[Non-Patent Document 3] Muchnik E and Kaplan J. HIF prolyl hydroxylase inhibitors for anemia. Expert Opin Investig Drugs. 20 (5): 645 - 56, 2011.

[Non-Patent Document 4] Calvert JW et al. Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1α and its downstream target genes. J Appl Physiol (1985). 101 (3): 853 - 65, 2006.

[Non-Patent Document 5] Matthew MM et al, HIF-prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques, blood, 2007; 110: 2140 - 7

[Non-Patent Document 6] Flamme I et al, Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85 - 3934 (Molidustat) stimulates erythropoietin production without hypertensive effects, PLoS One. 2014; 9 (11): e111838. doi: 10. 1371/journal. pone. 0111838.

[Non-Patent Document 7] Nakayama Hiroshi, a hypoxic response system that acts on diverse life phenomena, Experimental Medicine 2012; 30: 1246 - 51

[Non-Patent Document 8] Hetian Yiren et al., Energy Metabolism Controlled by HIF, Experimental Medicine 2012; 30: 1252 - 57

An object of the present invention is to provide a novel compound having an EPO production promoting action as a subject, and to provide a method for preventing or treating a symptom of a disease caused by a hypoxic environment in a target organ or tissue, particularly anemia prevention or treatment. Useful drugs.

The inventors of the present invention conducted an effort to study and found that inhibition of PHD, and Patent Document 1 A novel compound exhibiting a stronger EPO production-promoting effect than the compound described in the above.

That is, the present invention provides the following [1] to [10].

[1] A compound or a pharmaceutically acceptable salt thereof, which has the following formula (1),

[In the above formula, X represents an oxygen atom, an imine group, a sulfur atom, a sulfinyl group or a sulfonyl group, and 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 aralkyl group, and R ⁵ represents an alkyl group which may be substituted with a group selected from the group of substituents, and an alkenyl group which may be substituted with a group selected from the group of substituents. An alkynyl group substituted with a group selected from the group of substituents, an aryl group selected from the group of substituents and independently having 1 to 7 substituents, selected from the group of substituents and independently having 1 to 7 The heteroaryl group of the substituent; the substituent group represents a group consisting of a group: an aryl group which may have 1 to 7 substituents (as a substituent on the aryl group, exemplified by a C ₁ -C ₆ alkyl group) , a trifluoromethyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group or a phenyl group), a heteroaryl group which may have 1 to 7 substituents (as a substituent on the heteroaryl group, exemplified : C ₁ -C ₆ alkyl, trifluoromethyl, halogen atom, methoxy, trifluoromethoxy, cyano or phenyl), C ₁ -C ₆ alkyl (in C ₃ -C ₆ In the case of an alkyl group, carbon atoms can be bonded to each other to form 3 6-membered saturated ring), C ₂ -C ₆ alkenyl group of, C ₂ -C ₆ alkynyl group, the aralkyl, C alkoxycarbonyl of ₂ -C ₈ group, a halogen atom, C ₁ -C ₆ alkyl halide of a hydroxy group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ halogenated alkoxy group, an aryloxy group, an amine carbaryl group, a C ₂ -C ₆ alkylcarbonyl group, a cyano group, a carboxyl group, a group Mercapto, nitro, amine, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkylcarbonylamino, arylamine, amine Alkylsulfonyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, arylsulfonyl, C ₁ -C ₆ alkylthio, C ₁ - a halogenated alkylthio group of C ₆ and an arylthio group].

[2] A pharmaceutical composition comprising the compound according to the above [1] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[3] A drug according to the above [1], or a pharmaceutically acceptable salt thereof, as an active ingredient.

[4] An EPO production-promoting drug comprising the compound according to the above [1] or a pharmaceutically acceptable salt thereof as an active ingredient.

[5] The compound according to the above [1], or a pharmaceutically acceptable salt thereof, for promoting the production of EPO.

[6] The compound according to the above [1], or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of anemia selected from a patient with chronic renal failure, self-storage, anemia of premature infant, AIDS or Anemia in patients with chemotherapy, anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, and anemia in giant embryo erythrocyte anemia.

[7] The use of the compound according to the above [1] or a pharmaceutically acceptable salt thereof for producing an EPO production promoting drug.

[8] The use of a compound according to the above [1] or a pharmaceutically acceptable salt thereof for producing anemia, self-storage, anemia of premature infant, AIDS or acceptance selected from patients with chronic renal failure A preventive and/or therapeutic agent for anemia in cancer patients with anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, and giant embryo erythrocyte anemia.

[9] A method for promoting EPO production, which comprises administering the compound according to the above [1] or a pharmaceutically acceptable salt thereof.

[10] Anemia selected from patients with chronic renal failure, self-storage, premature infants Prevention and/or treatment of anemia in blood, AIDS or chemotherapy patients with anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia and giant embryo erythrocyte anemia, characterized by: The compound according to the above [1] or a pharmaceutically acceptable salt thereof.

Since the compound of the present invention has a sustained and excellent EPO-promoting action as compared with the compound described in Patent Document 1, it is an anemia, self-storage and premature infant anemia, AIDS, and chemotherapy-induced cancer in patients with chronic renal failure. Patients with anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, giant embryo red blood cell anemia and other anemia preventive drugs and / or therapeutic drugs are more useful.

Hereinafter, the present invention will be specifically described.

The term "substitutable" as used in the specification means unsubstituted or has 1 to 5 substituents, and when a plurality of substituents are present, the substituents may be the same or different.

The term "alkyl group" as used in the specification means a saturated hydrocarbon chain which may be linear, branched, cyclic, or a combination of the above. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, second 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, B Cyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, ethyladamantyl, ethylbicyclo[2.2.1]heptyl and the like. Of these, a C ₁ -C ₁₈ linear or branched alkyl group, a C ₃ -C ₁₈ cyclic alkyl group, or a combination thereof, more preferably a C ₁ -C ₄ linear or branched chain is preferred. An alkyl group, a C ₃ -C ₁₂ cyclic alkyl group, or a combination thereof.

The "alkenyl group" described in the present specification means an unsaturated hydrocarbon chain having a double bond which may be linear, branched, cyclic, or a combination of the above. For example, n-propenyl group, n-butenyl group, n-pentenyl group, n-hexenyl group, n-heptenyl group, n-octenyl group, etc. are mentioned. Among them, a linear or branched alkenyl group of C ₂ - C _{18 is} preferred, and a linear or branched alkenyl group of C ₂ - C _{14 is more} preferred.

The "alkynyl group" described in the present specification means an unsaturated hydrocarbon chain having a triple bond which may be linear, branched, cyclic, or a combination of the above. For example, an n-pentynyl group, an n-hexynyl group, etc. are mentioned. Among them, a linear or branched alkynyl group of C ₂ - C _{8 is} preferred.

The "aryl group" described in the present specification is a monocyclic, bicyclic or tricyclic aryl group, and also includes an aryl group in which a part of the ring has an aromatic ring. A monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms is preferably exemplified. Specific examples thereof include a phenyl group, a naphthyl group, a tetrahydronaphthyl group, an anthracenyl group, a dihydroindenyl group, a phenanthryl group, and an anthracenyl group.

The "heteroaryl group" described in the present specification is a monocyclic, bicyclic or tricyclic heteroaryl group, and examples thereof include a single ring having 1 to 4 hetero atoms (nitrogen atom, oxygen atom or sulfur atom). , bicyclic or tricyclic heteroaryl. Specific examples thereof include a pyrrolyl group, a furyl group, a thienyl group, a pyridyl group, an imidazolyl group, and a pyrazolyl group. Azyl, thiazolyl, pyridyl , quinolyl, isoquinolyl, quinazolinyl, fluorenyl, benzothienyl, benzofuranyl, benzimidazolyl, benzo Azolyl, benzothiazolyl, benzodioxanyl, dibenzothiophenyl, dibenzofuranyl, oxazolyl and the like.

In the present specification, the substituent group means an aryl group which may have 1 to 7 substituents (as a substituent on the aryl group, exemplified by an alkyl group of C ₁ -C ₆ , a halogen atom, a methoxy group, and three a fluoromethoxy group, a cyano group or a phenyl group, a heteroaryl group having 1 to 7 substituents (as a substituent on the heteroaryl group, exemplified by a C ₁ -C ₆ alkyl group, a halogen atom, A Oxyl, trifluoromethoxy, cyano and phenyl), C ₁ -C ₆ alkyl (in the case of a C ₃ -C ₆ alkyl group, the carbon atoms can be bonded to each other to form a 3 to 6 member saturation Ring), C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, aralkyl group, C ₂ -C ₆ alkoxycarbonyl group, halogen atom, C ₁ -C ₆ halogenated alkyl group, hydroxyl group a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ halogenated alkoxy group, an aryloxy group, an amine carbenyl group, a C ₂ -C ₆ alkylcarbonyl group, a cyano group, a carboxyl group, a methyl group, Nitro, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkylcarbonylamino, arylamino, aminosulfonate group, C alkylsulfonyl group of ₁ -C _6, C sulfo halogenated alkyl of ₁ -C ₆ acyl, aryl acyl group sulfo, C ₁ -C ₆ alkyl of thio, C ₁ -C ₆ Halogenated alkylthio and arylthio group consisting of the group.

In the formula (1), as X, an oxygen atom, a sulfur atom, a sulfinylene group or a sulfonyl group is preferred, and an oxygen atom or a sulfur atom is more preferred.

R ¹ , R ² and R ³ each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group, more preferably a hydrogen atom.

The "C ₁ -C ₆ alkyl group" means a saturated hydrocarbon chain which may be linear, branched, cyclic or a combination of the above. Preferred is a C ₁ -C ₆ linear or branched alkyl group or a C ₃ -C ₆ cyclic alkyl group. Specific examples thereof include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, second butyl group, tert-butyl group, n-pentyl group, n-hexyl group, and cyclopropyl group. Cyclobutyl, cyclopentyl, cyclohexyl and the like.

R ⁴ represents a hydrogen atom, a C ₁ -C ₆ alkyl group or an aralkyl group, more preferably a hydrogen atom.

The "aralkyl group" is a group having a C ₁ -C ₆ alkyl group bonded to the above aryl group, and examples thereof include a C ₁ -C ₁₄ aryl-C ₁ -C ₆ alkyl group. Specifically, a phenyl-C ₁ -C ₆ alkyl group is preferred, and a benzyl group or a phenethyl group is more preferred.

The alkyl group, the alkenyl group, the aryl group or the heteroaryl group represented by R ⁵ is, for example, a C ₁ -C ₁₈ linear or branched alkyl group, a C ₃ -C ₈ cyclic alkyl group or the like. a combination of such a C ₂ -C ₁₈ linear or branched alkenyl group, a linear or branched alkynyl group of C ₂ -C ₈ , a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms; A monocyclic, bicyclic or tricyclic heteroaryl group having 1 to 4 hetero atoms (nitrogen atom, oxygen atom or sulfur atom). More preferably, it is a C ₁ -C ₁₄ linear or branched alkyl group, a C ₃ -C ₁₂ cyclic alkyl group or a combination thereof, a C ₂ -C ₁₄ linear or branched alkenyl group, C ₂ -C ₈ linear or branched alkynyl, phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, indanyl, phenanthryl, anthracenyl, pyrrolyl, furyl, thienyl, pyridyl, imidazole Base, pyrazolyl, Azyl, thiazolyl, pyridyl , quinolyl, isoquinolyl, quinazolinyl, fluorenyl, benzothienyl, benzofuranyl, benzimidazolyl, benzo Azolyl, dibenzothiophenyl, dibenzofuranyl, oxazolyl.

The substituted group which may be substituted with 1 to 7 of R ^{5 is} preferably a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms which may have 1 to 7 substitutions (as the aryl group) a substituent, exemplified by a C ₁ -C ₆ alkyl group, a trifluoromethyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group or a phenyl group), which may have 1 to 7 substituents a monocyclic, bicyclic or tricyclic heteroaryl group of 1 to 4 hetero atoms (nitrogen atom, oxygen atom or sulfur atom) (as a substituent on the heteroaryl group, exemplified by a C ₁ -C ₆ alkane a group, a trifluoromethyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group or a phenyl group), a C ₁ -C ₆ alkyl group (in the case of a C ₃ -C ₆ alkyl group, a carbon atom) Bonded to each other to form a 3 to 6 membered saturated ring), C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₆ -C ₁₄ aryl-C ₁ -C ₆ alkyl group, C ₂ -C ₈ alkoxycarbonyl group, halogen atom, C ₁ -C ₆ halogenated alkyl group, hydroxyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ halogenated alkoxy group, C ₆ -C ₁₄ Aryloxy, aminemethanyl, C ₂ -C ₆ alkylcarbonyl, cyano, carboxyl, methionyl, nitro, amine, C ₁ -C ₆ alkylamino, C ₁ -C ₆ Alkane Aminocarbonyl, C alkylcarbonyl group of ₁ -C _6, aryl group, acyl group sulfo, C alkylsulfonyl group of ₁ -C _6, C ₁ -C ₆ alkylsulfonyl halide of a group consisting of a C ₆ -C ₁₄ arylsulfonyl group, a C ₁ -C ₆ alkylthio group, a C ₁ -C ₆ halogenated alkylthio group, and an arylthio group.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the "aryl group" include a phenyl group, a naphthyl group, a tetrahydronaphthyl group, a dihydroindenyl group, a phenanthryl group, and an anthracenyl group. Examples of the "C ₁ -C ₆ alkyl group" include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a second butyl group, a tert-butyl group, and a n-pentyl group. Base, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of the "heteroaryl group" include a pyrrolyl group, a furyl group, a thienyl group, a pyridyl group, a quinolyl group, an imidazolyl group, and a pyrazolyl group. Azyl, thiazolyl, benzothiazolyl, pyridyl , benzodioxanyl and the like. Examples of the "alkenyl group" include a vinyl group, a propenyl group, and a butenyl group. Examples of the "alkynyl group of C ₂ -C ₆ " include an ethynyl group, a propynyl group, a pentynyl group and the like. The "aralkyl group" is exemplified by a benzyl group. Examples of the "C ₂ -C ₆ alkoxycarbonyl group" include a methoxycarbonyl group, an ethoxycarbonyl group, and a third butoxycarbonyl group. Examples of the "C ₁ -C ₆ halogenated alkyl group" include a trifluoromethyl group and a trifluoroethyl group. Examples of the "alkoxy group of C ₁ -C ₆ " include a methoxy group, an ethoxy group, an isopropoxy group, and a third butoxy group. Examples of the "C ₁ -C ₆ halogenated alkoxy group" include a trifluoromethoxy group and a trifluoroethoxy group. Examples of the "aryloxy group and the amine carbenyl group" include a phenoxy group, a tert-butoxyamine-methyl group, and a benzylamine-methyl group. Examples of the "C ₂ -C ₆ alkylcarbonyl group" include a methylcarbonyl group and the like. Examples of the "alkyl group of C ₁ -C ₆ " include a dimethylamino group and a benzylamino group. Examples of the "alkylaminocarbonyl group of C ₁ -C ₆ " include a dimethylaminocarbonyl group and the like. Examples of the "C ₁ -C ₆ alkylcarbonylamino group" include an acetamino group and the like. Examples of the "arylamino group" include a phenylamino group and a diphenylamino group. Examples of the "C ₁ -C ₆ alkylsulfonyl group" include a methylsulfonyl group and the like. Examples of the "C ₁ -C ₆ halogenated alkylsulfonyl group" include a trifluoromethanesulfonyl group and the like. Examples of the "arylsulfonyl group" include a phenylsulfonyl group and the like. Examples of the "alkylthio group of C ₁ -C ₆ " include a methylthio group and an isopropylthio group. Examples of the "C ₁ -C ₆ halogenated alkylthio group" include a trifluoromethanethio group and the like. Examples of the "arylthio group" include a phenylthio group and the like.

The preferred embodiment of the formula (1) is a compound containing a combination of the above-described preferred groups, and examples thereof include the compounds described in the examples, the pharmaceutically acceptable salts, or the like. An hydrate or a solvate or the like.

The compound of the present invention represented by the formula (1) or a pharmaceutically acceptable salt, hydrate or solvate thereof may have a geometrical isomer or a tautomer based on a double bond depending on the kind of the substituent. Or may exist optical isomers based on the presence of asymmetric carbon atoms or The case of non-mirrored isomers. In the present invention, all of the isomers are separated or all of the mixture is included.

The compound of the present invention and a method for producing a salt, a hydrate or a solvate which are pharmaceutically acceptable can be produced by various known techniques. In this case, depending on the kind of the functional group, there is a case where the functional group is substituted with an appropriate protecting group based on the stage of the raw material or the intermediate, which is effective in terms of manufacturing technology. Examples of such a functional group include an amine group, a hydroxyl group, and a carboxyl group. In the case where the protective group is introduced into the functional group and produced, the desired compound can be obtained by removing the protective group at appropriate intervals in each production stage. Examples of the type and removal method of such a protective group include a protective group in organic synthesis, a method described in 3rd edition (Protective Groups in Organic Synthesis: Third Edition) (Greene, Wuts), and the like. A representative production method of the compound (1) of the present invention will be described below.

The method for producing the compound of the present invention is not particularly limited, and for example, it can be produced according to the following production method.

(wherein, Y is a protecting group for a carboxyl group such as a methyl group or a tert-butyl group, and the other symbols have the same meanings as described above)

First step: A compound (3) can be obtained by introducing a substituent or a precursor thereof to the compound (2) produced according to Patent Document 1 by a usual method. For example, when X is S, the compound (2) is heated under conditions of a palladium catalyst such as palladium acetate or tris(dibenzylideneacetone)dipalladium, 4,5-bisdiphenylphosphino-9, Ligands such as 9-dimethyloxaxan, 1,1-bis(di-t-butylphosphino)ferrocene, bis[2-(diphenylphosphino)phenyl]ether, and diisopropyl In the presence of a base such as ethyl ethylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate or potassium butoxide, in the presence of 1,4-two The compound (3) can be obtained by reacting with a mercaptan (R ⁵ SH) in a solvent such as an alkane, N,N-dimethylformamide, toluene or cyclopentyl methyl ether. Further, when X is O, the compound (2) is subjected to a copper catalyst such as copper iodide, copper bromide, copper chloride or copper oxide or a 2-cyclohexanonecarboxylic acid B under low temperature or heating. a ligand such as ester, 1,10-morpholine, (2-pyridyl)acetone or picolinic acid, and a base such as potassium carbonate, cesium carbonate or potassium phosphate, in the presence of a dimethyl sulfoxide, N, N-dimethyl Carbenamide, acetonitrile, 1,4-two The compound (3) can be obtained by reacting with a phenol (R ⁵ OH) in a solvent such as an alkane or toluene.

Second step: The third butoxycarbonyl group of the compound (3) is deprotected according to a usual method, whereby the compound (4) can be obtained. For example, the compound (3) is subjected to low temperature or heating under hexane, chloroform, dichloromethane, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-di Alkane, tetrahydrofuran, methanol, ethanol, 2-propanol, dimethyl hydrazine, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, water, etc., alone or in a mixed solvent Reacting with acids such as p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid Thereby, the compound (4) can be obtained. Further, the compound (3) is heated under the conditions of methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-two In a mixed solvent of a solvent such as an alkane, 1,2-dimethoxyethane, N,N-dimethylformamide or acetonitrile and water, reacting with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide Thereby, the compound (4) can be obtained.

Third step: Compound (5) can be obtained by condensing compound (4) with a glycine derivative represented by H ₂ NCH ₂ COOY according to a usual method. For example, the compound (4) is dissolved in a solvent such as N,N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, dichloromethane or toluene at a low temperature or under heating in dicyclohexyl carbon. Diquinone imine, 1,1'-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or a salt thereof, diphenyl azide phosphate, etc. In the presence of a condensing agent and, if necessary, N-hydroxybutanediamine, 1-hydroxybenzotriazole, dimethylaminopyridine, etc., if necessary, potassium carbonate, sodium hydrogencarbonate, cesium carbonate, triethyl carbonate is added. Amine, diisopropylethylamine, A base such as a porphyrin or a pyridine is reacted with a glycine derivative represented by H ₂ NCH ₂ COOY, whereby the compound (5) can be obtained.

Step 4: Deprotection of the protecting group of the benzyl group and the carboxyl group of the compound (5) according to a usual method, whereby the compound (1) can be obtained. For example, when Y is a methyl group, the compound (5) is allowed to exist in an acid solvent such as trifluoroacetic acid under heating, if necessary, in the presence of anisole, thioanisole, dimethyl sulfide, or the like. The reaction is carried out, whereby the benzyl group can be deprotected. Alternatively, the compound (5) is allowed to react under hexane, methanol, ethanol, 2-propanol, tetrahydrofuran, N, N-dimethyl at room temperature or under heating under a hydrogen atmosphere under normal pressure or under pressure. Basementamide, N,N-dimethylacetamide, ethyl acetate, acetic acid, water, etc., alone or in a mixed solvent, in palladium on carbon, palladium hydroxide, platinum oxide, platinum carbon, nickel ray, etc. Hydrogenation is carried out in the presence of, whereby the benzyl group can be deprotected. Then, under low temperature or heating conditions, in methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-two In a mixed solvent of a solvent such as an alkane, 1,2-dimethoxyethane, N,N-dimethylformamide or acetonitrile and water, reacting with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide Thereby, the compound (1) can be obtained. For example, when Y is a third butyl group, the compound (5) is heated under an elevated temperature in an acid solvent such as trifluoroacetic acid, if necessary, in anisole, thioanisole, dimethyl sulfide, or the like. The reaction is carried out in the presence of the compound, whereby Compound (1) can be obtained.

(wherein R ⁵ and X have the same meaning as above)

Step 1: When X is S, the compound (2) can be reacted with a sodium sulfide or the like in a solvent such as N,N-dimethylformamide under a low temperature or a heating condition. Compound (6). When X is O, the compound (2) can be 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 a low temperature or a heating condition, whereby a compound can be obtained. (6).

Step 2: When X is S and O, compound (6) is added to a solvent such as tetrahydrofuran or toluene, and azodicarboxylic acid such as diethyl azodicarboxylate or diisopropyl azodicarboxylate. The ester is reacted with triphenylphosphine and an alcohol (R ⁵ OH), whereby Compound (3) can be obtained. Further, when X is S and O, the compound (6) is subjected to low temperature or heating under triethylamine, diisopropylethylamine, potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, In the presence of a base such as potassium butoxide or sodium hydride, in the presence of 1,4-two In a solvent such as alkane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene or cyclopentyl methyl ether, and R ⁵ L (L is OMs, OTs, Br, Cl, The reaction is carried out by I, and the like, and the compound (3) can be obtained.

When the compound of the formula (1) is used in the form of a salt, the type of the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and for example, it can be used with hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, Acetic acid, oxalic acid, fumaric acid, maleic acid, citric acid, succinic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, lactic acid, butyric acid, amino acid, sodium hydroxide, hydrogen Potassium oxide, lithium hydroxide, calcium hydroxide, sodium alkoxide, meglumine, tromethamine, ethanolamine, diethanolamine or the like is treated to form a salt.

Examples of the pharmaceutically acceptable hydrate of the compound of the formula (1) include a half hydrate, a monohydrate, a dihydrate and the like. Further, since the compound of the formula (1) is also present in the form of a solvate, a solvate is also included.

The compound of the formula (1) of the present invention produced as described above can be extracted, concentrated, and distilled as a usual chemical operation in a state of being free or in the form of a salt thereof. Removal, crystallization, filtration, recrystallization, various chromatography methods, etc. are separated and purified. When the compound (1) contains an optical isomer, a stereoisomer or a positional isomer, it may be separated by a fractional recrystallization method, a chiral column method, a non-image isomer method, or the like.

As shown in the following examples, the compound of the present invention has a sustained and excellent EPO-promoting action as compared with the compound described in Patent Document 1, and therefore, as an anemia, self-storage, anemia of premature infants, and chronic anemia in a patient with chronic renal failure, AIDS, anemia of cancer patients receiving chemotherapy, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, giant embryo erythrocyte anemia, and other anemia preventives and / or therapeutic drugs are more useful.

The pharmaceutical composition comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt, hydrate or solvate thereof can be administered by using a tablet, a pill, a capsule, a granule, a powder, Oral administration of a liquid preparation, or an injection, a suppository, an eye drop, an ophthalmic ointment, a transdermal solution, an ointment, a transdermal patch, a transmucosal solution, or the like for intravenous or intramuscular injection, Any form that is administered orally by a mucosa patch, an inhalant, or the like.

When a pharmaceutical composition comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt, hydrate or solvate thereof is used as the pharmaceutical preparation, the type of the additive for the preparation is only pharmaceutically acceptable. The carrier which is permissible is not particularly limited, and the base, excipient, lubricant, coating agent, sugar coating agent, wetting agent, binding agent, disintegrating agent, solvent, and solubilizing agent may be used singly or in combination. , dissolving agents, dissolving aids, suspending agents, dispersing agents, emulsifiers, surfactants, isotonic agents, buffers, pH adjusters, soothing agents, preservatives, preservatives, stabilizers, antioxidants, colorants , sweeteners, etc.

The dose of the compound of the present invention or the pharmaceutical composition containing the compound and the number of administrations thereof can be appropriately selected depending on the symptoms, age, sex, dosage form, type of the combination, and the like, and can usually be 0.1 to 1000 mg/day/person. Preferably, it is in the range of 1 to 500 mg/day/person, once a day or divided into several doses. Further, the pharmaceutical composition of the present invention can be administered not only alone, but also other drugs having the same pharmacological effects and/or other drugs having different pharmacological effects. And use it.

[Examples]

Hereinafter, the present invention will be specifically described by way of examples and reference examples, but the present invention is not limited by the following examples.

The meanings of the abbreviations in the examples and reference examples are as follows. THF: tetrahydrofuran, DMSO: dimethyl hydrazine, DMF: N, N-dimethylformamide, HMPA: trimethylamine hexamethylphosphate, Pd-C: palladium carbon, ¹ H-NMR: proton nuclear magnetic resonance Spectroscopy, CDCl ₃ : deuterated chloroform, Hz: Hertz, J: coupling constant, m: multiplet, quint: quintuple, q: quartet, dt: double triplet, t: triplet, d: doublet , s: single peak, br: broad peak, M: molar concentration. Further, NMR indicates a 270 MHz nuclear magnetic resonance spectrum, and TMS (tetramethylnonane) was used as an internal standard substance. MS indicates mass spectrometry using ESI (electrospray ionization) as the ionization method.

Reference Example 1: 7-Benzyloxy-5-phenylthio[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester

Benzene mercaptan (54 mg), 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg), three ( Dibenzylideneacetone) dipalladium (10 mg), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (13 mg), N,N-diisopropylethylamine (120 mg) Mix to two The alkane solvent (2.0 mL) was heated and stirred at 100 ° C for 0.5 hour under an argon atmosphere. After completion of the reaction, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate)

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-phenylthio[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), ethyl acetate (1.2 mL), and dissolved in ethyl acetate at room temperature over 10 minutes. Methanesulfonic acid (429 mg) in (0.5 mL). After stirring at room temperature for 3 hours, the precipitated crystals were filtered. The obtained crystal was dissolved in DMF (7.0 mL) and DMSO (2.0 mL), and water (20 mL) was added dropwise at 0 ° C for 10 minutes or more. The crystals which precipitated were filtered 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: [(7-Benzyloxy-5-phenylthio[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetate methyl acetate

The compound (309 mg) obtained in Reference Example 2 was dissolved in DMF (3.0 mL), and methyl glycinate (113 mg), 1-hydroxybenzotriazole (138 mg) and three were added at room temperature. Ethylamine (99 mg). To the mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (173 mg), and stirred at room temperature overnight. Water (6.0 mL) and a saturated aqueous sodium hydrogencarbonate solution (3.0 mL) were added to the mixture, 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 evaporated under reduced pressure to give the title compound (322mg).

Example 2: [(7-Hydroxy-5-phenylthio[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetate methyl acetate

The compound obtained in Example 1 (313 mg) was dissolved in trifluoroacetic acid (3.0 mL), and stirred at 80 ° C for 5 hr. After the 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 obtained residue, and the mixture was stirred at room temperature for 0.5 hour, and the precipitated crystals were filtered. The title compound (216 mg) was obtained.

Example 3: [(7-Hydroxy-5-phenylthio[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

The compound obtained in Example 2 (210 mg) was suspended in isopropyl alcohol (4.0 mL). A 4 M aqueous lithium hydroxide solution (0.6 mL) was added and heated and stirred at 70 ° C for 2 hours. After completion of the reaction, the reaction liquid was neutralized with 6 M hydrochloric acid (0.4 mL), and stirred while stirring slowly. After the crystals were crystallized, water (2OmL) was obtained.

Reference Example 3: {[7-Benzyloxy-5-(3,4-dichlorophenoxy)[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid III 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 tert-butyl ester (452 mg) It was dissolved in DMSO (5 mL) and added to the reaction solution, and stirred at room temperature for 48 hours. Ethyl acetate was added to the reaction solution, and the insoluble matter was filtered off, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified to purified crystals eluted elute

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 (6H) , m), 7.51 (1H, d, J = 8.9 Hz), 8.31 (1H, s).

Example 4: {[7-Benzyloxy-5-(3,4-dichlorophenoxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino }T-butyl acetate

The title compound was obtained in the same manner as in Example 1 except that the compound obtained in Reference Example 3 (377 mg) was obtained in the same manner as in Reference Example 2, using the butyl succinate hydrochloride. (183 mg).

Example 5: {[5-(3,4-Dichlorophenoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The compound (183 mg) obtained in Example 4 was dissolved in trifluoroacetic acid (2 mL), thioanisole (83 mg) was added, and the mixture was stirred at 80 ° C for 2 hours. Decompressing the solvent It was distilled off, and methanol (0.5 mL) and water (2 mL) were added. The crystals thus precipitated were filtered, washed with diethyl ether /hexane = 1 / 1 to give the title compound (75 mg).

Example 6: {[5-(3,5-Dimethylphenylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

3,5-Dimethylbenzenethiol (182 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tributyl The ester (500 mg) was treated in the same manners as the title compound (1), and the title compound (160 mg).

Example 7: {[5-(2,3-Dimethylphenylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

2,3-Dimethylbenzenethiol (138 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tertidine The ester (226 mg) was treated in the same manners as the title compound (1), and the title compound (55 mg).

Example 8: {[5-(3-Fluorophenylthio)-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 tert-butyl ester (200 mg) The treatment was carried out in the same manners as in Reference Example 1 and 2, to give the title compound (160 mg).

Example 9: {[5-(3,5-Difluorophenylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

3,5-difluorobenzenethiol (65 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg) was treated in the same manners as in Reference Example 1, 2, and Example 1-3 to give the title compound (85 mg).

Example 10: {[5-(3,4-Difluorophenylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

3,4-difluorobenzenethiol (77 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg) in the same manner as Reference Example 1, Example 4, and 5 The title compound (55 mg) was obtained.

Example 11: {[5-(3,5-Dichlorophenylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

3,5-dichlorobenzenethiol (83 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (199 mg) The title compound (112 mg) was obtained from

Example 12: {[7-Hydroxy-5-(4-trifluoromethoxyphenylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

4-Trifluoromethoxybenzenethiol (86 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl The ester (200 mg) was treated in the same manners as the title compound (1, 2), and the title compound (107 mg).

Example 13: {[5-(Biphenyl-3-ylthio)-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 tert-butyl ester (200 mg) The title compound (99 mg) was obtained.

Example 14: {[5-(2-Chloro-5-fluorophenylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

2-Chloro-5-fluorobenzenethiol (93 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tributyl The ester (226 mg) was treated in the same manners as the title compound (1), and the title compound (72 mg).

Example 15: {[5-(3-Chloro-5-fluorophenylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

3-Chloro-5-fluorobenzenethiol (85 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tributyl The ester (200 mg) was treated in the same manners as the title compound (1), and the title compound (30 mg).

Example 16: {[5-(3-Chloro-5-methylphenylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

3-Chloro-5-methylbenzenethiol (85 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The butyl ester (200 mg) was treated in the same manner as in the the the

Example 17: {[5-(3-Fluoro-5-methylphenylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

3-Fluoro-5-methylbenzenethiol (71 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The butyl ester (201 mg) was treated in the same manners as in the same.

Example 18: {[5-(3-Fluoro-5-trifluoromethylphenylthio)-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- The carboxylic acid tert-butyl ester (166 mg) was treated in the same manners as the title compound (1, 2), and 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 dropwise under ice-cooling. After stirring for 1 hour under ice cooling, 2M hydrochloric acid was added 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 to give 3-chloro-5-trifluoromethylphenyl trifluoromethanesulfonate. 3-Chloro-5-trifluoromethylphenyl trifluoromethanesulfonate and 2-ethylhexyl 3-mercaptopropionate (203 mg), tris(dibenzylideneacetone) dipalladium (21 mg), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (27 mg), N,N-diisopropylethylamine (0.49 mL) mixed to two The mixture was heated and stirred at 100 ° C for 20 minutes in an alkane solvent (2.0 mL) under an argon atmosphere. After completion of the reaction, the insoluble matter was 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 give 3-(3-chloro-5-trifluoromethylphenylthio)-propionic acid 2-B Hexyl hexyl ester. The 3-(3-chloro-5-trifluoromethylphenylthio)-propionic acid 2-ethylhexyl ester was dissolved in THF (6 mL). The solution (1.0 M, 2 mL) was stirred at the same temperature for 30 min. After completion of the reaction, 1 M hydrochloric acid was added thereto 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 obtained residue was purified by column chromatography (hexane/ethyl acetate = 10/1) to obtain 3-chloro-5-trifluoromethyl. Phenyl mercaptan (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-(trifluoromethyl)phenylthio]-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8 -carbonyl}amino)acetic acid

The compound obtained in Reference Example 4 (136 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( 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 (119 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( The title compound (125 mg) was obtained in the same manner as the compound of the title compound (3).

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 tert-butyl ester (238 mg) The title compound (42 mg) was obtained in the same manner as the the the the

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 tert-butyl ester (300 mg) The title compound (75 mg) was obtained in the same manner as the the the the

Example 23: {[5-(3-Chloro-4-fluorophenoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

3-Chloro-4-fluorophenol (110 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( 226 mg) was treated in the same manners as the title compound (3).

Example 24: {[5-(4-Chloro-2-methylphenoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

4-Chloro-2-methylphenol (113 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (300 mg), the title compound (30 mg).

Example 25: {[5-(4-Fluoro-3-trifluoromethylphenoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl] Amino-acetic acid

4-Fluoro-3-trifluoromethylphenol (144 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The title compound (86 mg) was obtained from the title compound (m.

Example 26: {[7-Hydroxy-5-(naphthalen-1-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

1-naphthylthiol (99 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg) The treatment was carried out in the same manners as in Reference Example 1 and 2, and the title compound (31 mg) was obtained.

Example 27: {[5-(4-Chloronaphthalen-1-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

4-Chloro-1-naphthol (730 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine- The title compound (50 mg) was obtained.

Example 28: {[7-Hydroxy-5-(naphthalen-1-yloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

1-naphthol (192 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg) The title compound (86 mg) was obtained.

Example 29: {[7-Hydroxy-5-(5,6,7,8-tetrahydronaphthalen-1-ylthio)[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 The carboxylic acid tert-butyl ester (500 mg) was treated in the same manners as in the the the

Example 30: {[7-Hydroxy-5-(indan-4-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Indane-4-thiol (100 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8- synthesized in the same manner as in Reference Example 7. The carboxylic acid tert-butyl ester (250 mg) was treated in the same manners as the the the the

Example 31: {[7-Hydroxy-5-(7-trifluoromethylquinolin-4-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl Amino}acetic acid

Using 7-trifluoromethylquinoline-4-benzenethiol (183 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylate 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), 4,5-bisdiphenylphosphine- 9,9-Dimethyloxaxan (55 mg), N,N-diisopropylethylamine (0.85 mL) mixed to two The alkane solvent (2.5 mL) was heated and stirred at 100 ° C for 3.5 hours under an argon atmosphere. After completion of the reaction, the insoluble matter was 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 give 3-(isoquinolin-4-ylthio)-propionic acid 2-ethylhexyl ester. The 3-(isoquinolin-4-ylthio)-propionic acid 2-ethylhexyl ester was dissolved in THF (8.0 mL), and a solution of potassium tert-butoxide in THF (1.0 M) was added at -70 °C. 4.8 mL) and stirred at the same temperature for 1 hour. 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 evaporated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate = 1/4) to give the title compound (290 mg, Rate 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: 7-Benzyloxy-5-(isoquinolin-4-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester

The compound obtained in Reference Example 5 (78 mg), 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( 202 mg), tris(dibenzylideneacetone)dipalladium (11 mg), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (13 mg), N,N-diisopropyl Base amine (156 μL), sodium hydroxymethanesulfinate dihydrate (76 mg) mixed to two The alkane solvent (1 mL) was heated and stirred at 100 ° C for 1 hour under an argon atmosphere. After completion of the reaction, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate)

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-ylthio)[1,2,4]triazolo[1,5-α]pyrr Pyridin-8-carbonyl]amino}acetic acid

The compound (297 mg) obtained in the title compound (yield: 297 mg) was obtained to give the title compound (168 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-methyl-1-propenylmagnesium bromide in THF (0.5 M) was added dropwise at -60 °C. , 24 mL), and stirred at the same temperature for 1.5 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added thereto, and the mixture was stirred at room temperature for 1 hour, and then 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 evaporated under reduced pressure, and the residue obtained was purified by column chromatography (hexane/ethyl acetate = 15/1) to give 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

The compound (310 mg) obtained in Reference Example 7 was dissolved in N,N-dimethylformamide (3 mL), and sodium hydride (60%, 77 mg) It was stirred at room temperature for 2 hours. After completion of the reaction, water was added 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 obtained residue was purified by column chromatography (hexane/ethyl acetate = 50/1) to give 7-bromo-5-fluoro-1. , 2,3-trimethyl-1H-indole. The 7-bromo-5-fluoro-1,2,3-trimethyl-1H-indole was treated in the same manner as in the the the the

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-ylthio)-7-hydroxy[1,2,4]triazolo[1 ,5-α]pyridine-8-carbonyl]amino}acetic acid

The compound obtained in Reference Example 8 (436 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( The title compound (230 mg) was obtained.

Example 34: {[7-Hydroxy-5-(thiophen-2-ylthio)[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 tert-butyl ester (421 mg) The title compound (194 mg) was obtained.

Example 35: {[5-(5-Chlorothiophen-2-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

5-Chlorothiophene-2-thiol (117 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (181 mg) The title compound (m.

Example 36: {[5-(Benzo[b]thiophen-3-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine 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 third The butyl ester (201 mg) was treated in the same manner as in the the the

Example 37: {[5-(Benzo[b]thiophen-4-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine 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 The butyl ester (188 mg) was treated in the same manners as in the the the

Example 38: {[7-Hydroxy-5-(2-methylfuran-3-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

2-methylfuran-3-thiol (75 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α] The pyridine-8-carboxylic acid tert-butyl ester (200 mg) was treated in the same manners as the title compound (1, 2), and the title compound (48 mg).

Example 39: {[5-(5-Chloronaphthalen-1-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

5-Chloro-1-naphthol (168 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( The title compound (128 mg) was obtained.

Example 40: {[5-(6-Chloronaphthalen-1-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

6-Chloro-1-naphthol (120 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( The title compound (109 mg) was obtained from m.

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) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( The title compound (75 mg) was obtained in the same manner as the title compound (3).

Example 42: {[7-Hydroxy-5-(8-trifluoromethylquinolin-4-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl Amino}acetic acid

4-hydroxy-8-trifluoromethylquinoline (739 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid Tributyl ester (180 mg) was treated in the same manners as the title compound (m.

Example 43: {[5-(Dibenzothiophen-4-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

Dibenzothiophene-4-ol (165 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( 379 mg) in the same manner as in Reference Example 4 and Example 19 The title compound (73 mg) was obtained.

Example 44: {[5-Hydroxy-5-(1-trifluoromethylisoquinolin-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 The title compound (58 mg) was obtained from the title compound (m.

Example 45: [7-Hydroxy-5-(5-trifluoromethylnaphthalen-1-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

5-Trifluoromethylnaphthalene-1-thiol (219 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The tributyl ester (433 mg) was treated in the same manners as the the the the

Example 46: [7-Hydroxy-5-(5-methylnaphthalen-1-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

5-methylnaphthalene-1-thiol (0.58g) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid third The butyl ester (1.6 g) was treated in the same manners as the title compound (1, 2), and the title compound (141 mg).

Example 47: {[5-(5-Cyanophthalen-1-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

5-Cyanonaphthalen-1-ol (2g) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (1.2 g) The title compound (199 mg) was obtained.

Example 48: {[7-Hydroxy-5-(6-trifluoromethylnaphthalen-1-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl] Amino-acetic acid

6-Trifluoromethylnaphthalene-1-thiol (603 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid Tributyl ester (300 mg) was treated in the same manners as the title compound (1), to afford the title compound (150 mg).

Example 49: {[7-Hydroxy-5-(7-trifluoromethylnaphthalen-1-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl] Amino-acetic acid

7-Trifluoromethylnaphthalene-1-thiol (603.6 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The third butyl ester (300 mg) was treated in the same manners as the title compound (1), and the title compound (198 mg).

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 The butyl ester (208 mg) was treated in the same manner as the the the the

Example 51: {[7-Hydroxy-5-(5-methoxynaphthalen-1-yloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

5-methoxynaphthalen-1-ol (106 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl The ester (329 mg) was treated in the same manners as the title compound (yield of

Example 52: {[7-Hydroxy-5-(5-methylnaphthalen-1-yloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino }acetic acid

5-Methylnaphthalen-1-ol (146 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (487 mg) 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-Methylnaphthalen-1-ol (100 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (316 mg) The title compound (97 mg) was obtained.

Example 54: {[7-Hydroxy-5-(6-trifluoromethylnaphthalen-1-yloxy)[1,2,4]triazole [1,5-α]pyridine-8-carbonyl]amino}acetic acid

6-Trifluoromethylnaphthalen-1-ol (189 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid third The title compound (98 mg) was obtained from the title compound (400 mg).

Example 55: {[5-(6-Chloronaphthalen-1-yloxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

6-Chloronaphthyl-1-ol (121 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( 300 mg) The title compound (73 mg) was obtained from

Example 56: {[7-Hydroxy-5-(8-trifluoromethylisoquinolin-4-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8- Carbonyl]amino}acetic acid

Using 8-trifluoromethylisoquinoline-4-thiol (307 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylate The title compound (159 mg) was obtained in the same manner as in the the the

Example 57: {[7-Hydroxy-5-(8-methylisoquinolin-4-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl] Amino-acetic acid

Using 8-methylisoquinoline-4-thiol (64 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The title compound (79 mg) was obtained in the same manners as the title compound (1, 2).

Example 58: {[5-(8-Fluoroisoquinolin-4-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

Using 8-fluoroisoquinoline-4-thiol (70 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid third The title compound (24 mg) was obtained from the title compound (m.

Example 59: {[5-(8-chloroisoquinolin-4-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

Using 8-chloroisoquinoline-4-thiol (152 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid third The title compound (125 mg) was obtained from the title compound (m.

Example 60: {[7-Hydroxy-5-(7-trifluoromethylisoquinolin-4-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8- Carbonyl]amino}acetic acid

7-Trifluoromethylisoquinoline-4-thiol (642 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylate The acid tert-butyl ester (339 mg) was treated in the same manner as the the the the

Example 61: {[7-Hydroxy-5-(8-methylisoquinolin-4-yloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl] Amino-acetic acid

Using 8-methylisoquinolin-4-ol (78 mg) and 7-benzyloxy-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg) The title compound (25 mg) was obtained from

Example 62: {[5-(8-Fluoroisoquinolin-4-yloxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

8-fluoroisoquinolin-4-ol (152 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl The title compound (46 mg) was obtained from m.

Example 63: {[5-(8-chloroisoquinolin-4-yloxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

8-chloroisoquinolin-4-ol (250 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tributyl The title compound (90 mg) was obtained from the title compound (m.

Example 64: {[5-(7-Chloroquinolin-4-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

Using 7-chloroquinolin-4-thiol (120 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5- The title compound (55 mg) was obtained in the same manners as the title compound (3).

Example 65: {[7-Hydroxy-5-(2-trifluoromethylquinazolin-5-ylthio)[1,2,4]triazolo[1,5-α]pyridine-8- Carbonyl]amino}acetic acid

2-Trifluoromethylquinazolin-5-thiol (155 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylate The title compound (135 mg) was obtained.

Example 66: {[5-(2-Chlorobenzo[b]thiophen-4-ylthio)-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-carboxylate The title compound (92 mg) was obtained in the same manners as the title compound (1, 2).

Example 67: {[7-Hydroxy-5-(2-trifluoromethylbenzo[b]thiophen-4-ylthio)[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- The title compound (190 mg) was obtained in the same manners as the title compound (1, 2).

Reference Example 9: 5-(Benzo[b]thiophen-4-yloxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tertidine ester

Benzo[b]thiophen-4-ol (130 mg), 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl The ester (289 mg), copper iodide (147 mg), 1,10-morpholine (152 mg), cesium carbonate (423 mg) were mixed in toluene solvent (3.0 mL), and stirred at 100 ° C for 1 hour under an argon atmosphere. . After completion of the reaction, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj

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]amine Acetic acid

The compound (220 mg) obtained in Reference Example 9 was obtained to give the title compound (146 mg).

Example 69: {[7-Hydroxy-5-(3-methylbenzo[b]thiophen-7-ylthio)[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- The title compound (155 mg) was obtained in the same manners as the title compound (1, 2).

Example 70: {[7-Hydroxy-5-(3-trifluoromethylbenzo[b]thiophen-7-ylthio)[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- The title compound (155 mg) was obtained in the same manner as the the the the

Example 71: {[5-(Benzo[b]thiophen-7-yloxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

Use of benzo[b]thiophen-7-ol (110 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tertidine The title compound (91 mg) was obtained from m.

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-carboxylate The title compound (105 mg) was obtained in the same manner as the the the the

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 The title compound (88 mg) was obtained in the same manner as the the the the

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 The title compound (114 mg) was obtained from m.

Example 75: {[7-Hydroxy-5-(7-trifluoromethylbenzo[b]thiophen-3-ylthio)[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- The title compound (214 mg) was obtained in the same manner as the the the the

Example 76: {[5-(Benzo[b]thiophen-3-yloxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

Use of benzo[b]thiophene-3-one (554 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tertidine The title compound (76 mg) was obtained.

Example 77: {[5-(6-Chlorobenzofuran-3-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

6-chlorobenzofuran-3-thiol (113 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The title compound (136 mg) was obtained from the title compound ( 141 mg).

Example 78: {[7-Hydroxy-5-(1,2,3-trimethyl-1H-indol-7-ylthio)[1,2,4] Triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Using 1,2,3-trimethyl-1H-indole-7-thiol (138 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α] Pyridine-8-carboxylic acid tert-butyl ester (288 mg) was obtained from the title compound (111 mg).

Example 79: {[5-(3-Chloro-1-methyl-1H-indol-7-ylthio)-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 The title compound (90 mg) was obtained in the same manners as the title compound (1, 4, 5).

Example 80: {[7-Hydroxy-5-(1,2,3-trimethyl-1H-indol-4-ylthio)[1,2,4]triazolo[1,5-α Pyridine-8-carbonyl]amino}acetic acid

Using 1,2,3-trimethyl-1H-indole-4-thiol (132 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α] Pyridine-8-carboxylic acid tert-butyl ester (279 mg) was obtained from the title compound (159 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-indol-4-ol (254 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine The title compound (41 mg) was obtained in the same manners as the the the the

Example 82: {[5-{9H-Indol-1-yloxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

9H-indol-1-ol (165 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (474 mg) 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 tert-butyl ester ( The title compound (177 mg) was obtained in the same manners as the title compound (3).

Example 84: {[5-(Dibenzothiophen-4-yloxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

Dibenzothiophene-4-ol (178 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester ( The title compound (78 mg) was obtained from m.

Example 85: {[5-(Dibenzofuran-4-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

Dibenzofuran-4-thiol (603 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (300 mg) was treated in the same manners as the title compound (1), and the title compound (78 mg).

Example 86: {[7-Hydroxy-5-(phenanthr-1-yloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Using phenanthrene-1-ol (173 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (400 mg), The title compound (125 mg) was obtained in the same manner as the the the the the

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- The carboxylic acid tert-butyl ester (2 g) was treated in the same manner as in the the the

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] The oxazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (316 mg) was treated in the same manners as the the the the

Example 89: {[7-Hydroxy-5-(indan-4-yloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Indane-4-ol (120 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (350 mg) 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 tert-butyl ester ( 250 mg) The title compound (70 mg) was obtained.

Example 91: {[5-(5-Fluorobiphenyl-3-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

5-fluorobiphenyl-3-thiol (135 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The butyl ester (200 mg) was treated in the same manners as the title compound (1), and the title compound (55 mg).

Reference Example 10: 7-Benzyloxy-5-hydroxy-[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester

Dissolving 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (1.0 g) in diethylene glycol monoethyl ether ( In 7.0 mL), and stirred at 0 ° C for 30 minutes. Thereafter, 8N sodium hydroxide (2.5 mL) was added, and the mixture was warmed to room temperature and stirred for 3.5 hours. Add citric acid water. The precipitated crystals were filtered off and washed with water. The title compound was obtained (756 mg, 80%).

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 tert-butyl ester

The compound (200 mg) obtained in Reference Example 10 was mixed with tetrahydrofuran (10 mL), and 2-cyclopentaneethanol (114 μl), diisopropyl azodicarboxylate (235 μl), and three were sequentially added thereto under ice-cooling. Phenylphosphine (315 mg). After stirring at room temperature for 2 hours, the solvent was distilled under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (CDCl ₃ ) δ: 1.13-1.26 (3H, m), 1.49-1.68 (11H, m), 1.81-2.04 (6H, m), 4.29 (2H, t, J = 6.5 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-methylbutylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

2-methylbutyl mercaptan (63 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (250 mg) The title compound (71 mg) was obtained in the same manner as in Example 8.

Example 93: (S)-{[7-Hydroxy-5-(2-methylbutylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

(S)-2-methylbutanol (71 mg) and the compound (200 mg) obtained in Reference Example 15 were carried out in the same manner as in Reference Example 11 and Example 2, and the obtained residue was suspended in isopropanol. (1.5 mL), a 4 M aqueous lithium hydroxide solution (0.5 mL) was added and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was neutralized with 2M hydrochloric acid, and washed with water and saturated brine and extracted with ethyl acetate. After the organic layer was obtained, dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated to give the title compound (35 mg).

Example 94: {[7-Hydroxy-5-methylthio[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Using methanol (1 mL) and the compound obtained in Reference Example 15 (200 mg), The title compound (42 mg) was obtained in the same manner as in the the

Example 95: [(7-Hydroxy-5-propylthio[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

Using propanethiol (40 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg), The title compound (28 mg) was obtained.

Example 96: {[7-Hydroxy-5-(3,3,3-trifluoropropylsulfanyl)[1,2,4]triazolo[1,5-alpha]pyridine-8-carbonyl]amine Acetic acid

Using 3,3,3-trifluoropropanethiol (173 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The title compound (74 mg) was obtained.

Example 97: [(7-Hydroxy-5-butylthio[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

The title compound (117 mg) was obtained from the title compound (yield: 129 mg).

Example 98: {[7-Hydroxy-5-{3-methylbutylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

3-methylbutyl mercaptan (55 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg) The title compound (40 mg) was obtained in the same manner as in Example 8.

Example 99: {[5-(3,3-Dimethylbutylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

The title compound (39 mg) was obtained from m. m.

Example 100: {[7-Hydroxy-5-(2,2-dimethylbutylthio)[1,2,4]triazolo[1,5- ]]pyridine-8-carbonyl]amino}acetic acid

The title compound (95 mg) was obtained in the same manners as the compound of the title compound (m.).

Reference Example 12: 3-[7-Benzyloxy-8-(t-butoxycarbonylmethylaminecarbamyl)-[1,2,4]triazolo[1,5-α]pyridine-5 -ylthio]propionic acid 3-ethylhexyl ester

3-mercaptopropionic acid-3-ethylhexyl ester (4.74g) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The third butyl ester (9.04 g) was treated in the same manner as in the the the

¹ H-NMR (CDCl ₃ ) δ: 0.81-0.97 (6H, m), 1.19-1.66 (17H, m), 2.65 (2H, t, J = 7.4 Hz), 3.31 (2H, t, J = 7.2 Hz) ), 4.06 (2H, dd, J = 5.7, 6.0 Hz), 4.24 (2H, d, J = 4.9 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, brs).

Reference Example 13: [(7-Benzyloxy-5-fluorenyl[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid tert-butyl ester

The compound (15.7 g) obtained in Reference Example 12 was dissolved in methanol (60 mL) and stirred at 0 ° C for 30 min. Thereafter, sodium methoxide (2.6 g) was added, and the mixture was further stirred for 30 minutes, and citric acid water was added. The precipitated crystals were filtered and washed with water to give the title compound (8.0 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.42 (9H, s), 4.00 (2H, d, J = 5.9 Hz), 5.54 (2H, s), 6.99 (1H, s), 7.31-7.58 (5H , m), 8.46 (1H, brs), 8.90 (1H, s), 13.77 (1H, brs).

Reference Example 14: 3-[7-Benzyloxy-8-(methoxycarbonylmethylaminecarbamyl)-[1,2,4]triazolo[1,5-α]pyridin-5-yl Thio]diethylhexyl propionate

3-ethylhexyl 3-mercaptopropionate (2.7 g) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid Tributyl ester (5.0 g) was treated in the same manner as in the the the

¹ H-NMR (CDCl ₃ ) δ: 0.81 - 0.99 (6H, m), 1.22-1.49 (8H, m), 2.66 (2H, t, J = 7.3 Hz), 3.31 (2H, t, J = 7.2 Hz) ), 3.80 (3H, s), 4.05 (2H, dd, J = 1.6, 5.9 Hz), 4.33 (2H, d, J = 5.1 Hz), 5.44 (2H, s), 6.71 (1H, s), 7.25 -7.59 (5H, m), 8.30 (1H, s), 9.68 (1H, brs).

Reference Example 15: [(7-Benzyloxy-5-fluorenyl-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetate methyl acetate

The compound (3.5 g) obtained in the title compound (m.

¹ H-NMR (DMSO-d ₆ ) δ: 3.66 (3H, s), 4.11 (2H, d, J = 5.7 Hz), 5.55 (2H, s), 6.99 (1H, s), 7.28-7.57 (5H , m), 8.55 (1H, brs), 8.90 (1H, s), 13.76 (1H, brs).

Example 101: {[5-(2-ethylbutylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (48 mg) was obtained from m.

Example 102: {[5-(1,3-Dimethylbutylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

The title compound (30 mg) was obtained in the same manner as in the Example 100, using 4-methyl-2-pentanol (105 mg).

Example 103: {[7-Hydroxy-5-(4,4,4-trifluorobutylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

The title compound (104 mg) was obtained from m. m.

Example 104: [(7-Hydroxy-5-pentylthio[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

Using pentyl mercaptan (125 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8- The title compound (48 mg) was obtained.

Example 105: {(7-Hydroxy-5-(4-methylpentylthio}[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl}amino)acetic acid

The title compound (100 mg) was obtained in the same manner as in the Example 100, using 4-methylpentanol (100 mg) and the compound (200 mg).

Example 106: {(7-Hydroxy-5-(3-methylpentylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl}amino)acetic acid

The title compound (70 mg) was obtained.

Example 107: {[7-Hydroxy-5-(2-propylpentylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (102 mg) was obtained.

Example 108: {[5-(3-Ethylpentylthio)-7-hydroxy-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (135 mg) was obtained in the same manner as in Example 100, using 3-ethylpentane-1-ol (131 mg).

Example 109: {[7-Hydroxy-5-(pent-3-ynylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (69 mg) was obtained in the same manners as the compound of the title compound (yield).

Example 110: {[7-Hydroxy-5-(4,4,5,5,5-pentafluoropentylthio)[1,2,4]triazolo[1,5-α]pyridine-8 -carbonyl]amino}acetic acid

4,4,5,5,5-pentafluoropentane toluenesulfonate (332 mg) and obtained in Reference Example 15 The title compound (210 mg) was obtained.

Example 111: [(5-Hexylthio-7-hydroxy-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

Using hexyl mercaptan (88 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg), The title compound (60 mg) was obtained.

Example 112: [(5-Hex-3-yn-1-ylthio-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

The title compound (57 mg) was obtained from m. m.

Example 113: [(7-Hydroxy-5-isopropylthio[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

2-propanethiol (92 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (250 mg), The title compound (32 mg) was obtained in the same manner as in Example 8.

Example 114: [(5-Tertiarybutylthio-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 tributyl The title compound (60 mg) was obtained.

Example 115: [(7-Hydroxy-5-isobutylthio[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 tributyl The title compound (73 mg) was obtained.

Example 116: {[5-(1,2-Dimethylpropylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino }acetic acid

Using 1,2-dimethyl-1-propanethiol (74 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The title compound (40 mg) was obtained.

Example 117: [(5-allylthio-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

Allyl mercaptan (53.8 mg) and methyl 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylate (300 mg) were used. 5-Allylthio-7-benzyloxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonylamine was obtained in the same manner as in Reference Examples 1 and 2 Methyl acetate (104 mg). Trifluoroacetic acid (1 mL) and triethyldecane (59 mg) were added thereto, and the mixture was stirred under heating at 80 ° C for 6 hours. Distillation and removal were carried out under reduced pressure, and diisopropyl ether was added, and the precipitated crystals were filtered and dried to give the title compound (55 mg).

Example 118: [(5-Cyclopentylthio-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

Using cyclopentanethiol (45 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (200 mg), The title compound (72 mg) was obtained.

Example 119: [(5-Cyclohexylthio-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

Using cyclohexyl mercaptan (61 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (250 mg), The title compound (55 mg) was obtained in the same manner as in Example 8.

Example 120: {(5-(Adamantyl-1-ylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

1-adamantanethiol (400 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α] 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

The title compound (56 mg) was obtained from m. m.

Example 122: {[5-Cyclobutylmethylthio-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (50 mg) was obtained from m. m.

Example 123: {[5-Cyclopentylmethylthio-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (111 mg) was obtained from m. m.

Example 124: {[5-Cyclohexylmethylthio-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (85 mg) was obtained from the title compound (m.

Example 125: {[5-(2-Cyclohexylethylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (136 mg) was obtained from m. m.

Example 126: {[5-(2-Cyclohexylpropylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (119 mg) was obtained.

Example 127: {[5-(2-Cyclopropylethylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (95 mg) was obtained from m. m.

Example 128: {[5-(2-Cyclobutylethylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (40 mg) was obtained from the title compound (m.

Example 129: {[5-(2-Cyclopentylethylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (56 mg) was obtained from m. m.

Example 130: {[5-(2-Bicyclo[2.2.1]hept-2-ylethylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine- 8-carbonyl]amino}acetic acid

A mixture of (2-bicyclo[2,2,1]heptan-2-ylethanol (144 mg) and triethylamine (101 mg) was dissolved in THF (2 mL). 112 mg), the mixture was stirred at room temperature for 1 hour. After the completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The mixture was removed by pressure distillation to obtain 2-bicyclo[2,2,1]hept-2-yl-ethyl methanesulfonate. The compound (197 mg) and the compound obtained in Reference Example 15 (311 mg) were used to carry out The title compound (116 mg) was obtained.

Example 131: {[5-(2-adamantan-1-ylethyl)thio-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

Using toluene-4-sulfonic acid-2-adamantan-1-ylethyl ester (234 mg) and obtained in Reference Example 15. The title compound (71 mg) was obtained.

Example 132: {(7-Hydroxy-5-phenethylthio[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino}acetic acid

2-Phenylethanethiol (92 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (250 mg) The title compound (60 mg) was obtained in the same manner to

Example 133: ({5-[2-(3,4-Dichlorophenyl)ethylthio]-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8 -carbonyl}amino)acetic acid

The title compound (120 mg) was obtained in the same manner as in Example 100, using 3,4-dichlorophenylethanol (110 mg).

Example 134: ({7-Hydroxy-5-[2-(4-methoxyphenyl)ethylthio][1,2,4]triazolo[1,5-α]pyridine-8- Carbonyl}amino)acetic acid

The title compound (100 mg) was obtained from m.

Example 135: {(7-Hydroxy-5-(2-phenylpropylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino}acetic acid

The title compound (90 mg) was obtained from the title compound (yield: EtOAc)

Example 136: {(7-Hydroxy-5-(2-methyl-2-phenylpropylthio)-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl Amino}acetic acid

The title compound (90 mg) was obtained.

Example 137: {(7-Hydroxy-5-(2-thien-2-ylethylthio)-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amine Acetic acid

Using 2-thiopheneethanol (71 mg) and the compound obtained in Reference Example 15 (200 mg), The title compound (84 mg) was obtained.

Example 138: {[5-(3-Cyclohexylpropylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (50 mg) was obtained from m. m.

Example 139: {[7-Hydroxy-5-(3-phenylpropylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (89 mg) was obtained in the same manner as in Example 100, using 3-phenylpropanol (110 mg).

Example 140: {[7-Hydroxy-5-(2-methoxyethylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (105 mg) was obtained from the title compound (m.).

Example 141: {[7-Hydroxy-5-(2-isopropoxyethylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (44 mg) was obtained in the same manners as the compound of the title compound (1, 2).

Example 142: {(7-Hydroxy-5-(2-phenoxyethylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl}amino)acetic acid

The title compound (40 mg) was obtained.

Example 143: {[5-(2,3-Dihydrobenzo[b][1,4]dioxine-2-ylmethylthio)-7-hydroxy[1,2,4 Triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Using 2-hydroxymethyl-1,4-benzoic acid The title compound (20 mg) was obtained from m.

Example 144: {[5-(2,3-Diphenylpropylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

2,3-Diphenylpropanol mesylate (1.4 g) was obtained by the same method as Example 130 using 2,3-diphenylpropanol (1.0 g). The title compound (55 mg) was obtained from the title compound (m.

Example 145: ({5-[2-(2-ethylhexyloxycarbonyl)ethylthio]-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8 -carbonyl}amino)acetic acid

2-ethylhexyl 3-mercaptopropionate (72 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The title compound (90 mg) was obtained.

Example 146: [(5-Benzylthio-7-hydroxy-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

Benzyl mercaptan (49 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (150 mg) were used. The title compound (21 mg) was obtained.

Example 147: {[7-Hydroxy-5-(2-methylbenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Using (2-methylphenyl)methyl mercaptan (67 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid third The title compound (44 mg) was obtained.

Example 148: {[7-Hydroxy-5-(2-trifluoromethylbenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (46 mg) was obtained from m. m.

Example 149: {[5-(2-Fluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine- 8-carbonyl]amino}acetic acid

The title compound (56 mg) was obtained from m. m.

Example 150: {[5-(2-chlorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Using (2-chlorophenyl)methyl mercaptan (77 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tertidine The title compound (66 mg) was obtained.

Reference Example 16: {[7-Benzyloxy-5-(2-methoxybenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }methyl acetate

2-methoxybenzyl chloride (110 mg) and the compound obtained in Reference 15 (80 mg) were mixed in THF solvent (2 mL), and diisopropylethylamine (0.5 mL) was added and heated for 7 hours. Reflux. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal crystal

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: {[7-Hydroxy-5-(2-methoxybenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (48 mg) was obtained.

Example 152: {[7-Hydroxy-5-(2-trifluoromethoxybenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino }acetic acid

The title compound (70 mg) was obtained from the title compound (yield: EtOAc)

Example 153: {[7-Hydroxy-5-(3-methylbenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (51 mg) was obtained from m. m.

Example 154: {[7-Hydroxy-5-(3-trifluoromethylbenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (60 mg) was obtained from m. m.

Example 155: {[5-(3-Fluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (60 mg) was obtained from m.

Example 156: {[5-(3-Chlorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (60 mg) was obtained from m. m.

Example 157: {[7-Hydroxy-5-(4-methylbenzylthio)[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 tert-butyl ester ( The title compound (66 mg) was obtained.

Example 158: {[7-Hydroxy-5-(4-trifluoromethylbenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

[4-(Trifluoromethyl)phenyl]methyl mercaptan (108 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8- The title compound (89 mg) was obtained.

Example 159: {[5-(4-Fluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Using (4-fluorophenyl)methyl mercaptan (69 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tertidine The title compound (88 mg) was obtained.

Example 160: {[5-(4-Chlorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

4-Chlorobenzyl mercaptan (168 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (400 mg) The title compound (48 mg) was obtained.

Reference Example 17: 7-Benzyloxy-5-mercapto[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester

Dissolving 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (20 g) in N,N-dimethylmethyl Anhydrous sodium sulfide (6.9 g) was added to guanamine (100 ml) at room temperature. After stirring at room temperature for 30 minutes, a saturated aqueous solution of citric acid was added and the mixture was acidified, and the crystals thus precipitated were filtered with water (400 mL) 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-Cyanobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

4-(Mercaptomethyl)benzonitrile (73 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl The title compound (97 mg) was obtained.

Example 162: {[5-(4-Terbutylbenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

Using (4-t-butylphenyl)methyl mercaptan (144 mg) and 7-benzyloxy-5-iodo [1,2,4] three The title compound (24 mg) was obtained in the same manner as Example 146.

Example 163: {[5-(Biphenyl-4-ylmethylthio)-7-hydroxy-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

Use of biphenyl-4-ylmethyl mercaptan (117 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester The title compound (42 mg) was obtained.

Example 164: {[7-Hydroxy-5-(4-methoxybenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

Using 4-methoxybenzyl alcohol (134 mg) and the compound obtained in Reference 15 (300 mg), the title compound (53 mg).

Example 165: {[5-(2-Fluoro-3-methylbenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

The title compound (47 mg) was obtained from m. m.

Example 166: {[5-(2,3-Difluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (56 mg) was obtained from m. m.

Example 167: {[5-(2,4-Dichlorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

Using (2,4-dichlorophenyl)methyl mercaptan (94 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid The title compound (65 mg) was obtained.

Example 168: {[5-(2,4-Dimethylbenzylthio)-7-hydroxy[1,2,4]triazolo[1,5- ]]pyridine-8-carbonyl]amino}acetic acid

2,4-Dimethylbenzyl alcohol (50 mg) was mixed with tetrahydrofuran (2.0 mL), and triethylamine (45 mg) and methanesulfonyl chloride (42 mg) were added sequentially under ice-cooling. After stirring at the same temperature for 2 hours, it was confirmed that the reaction was completed, and further, triethylamine (45 mg) and the compound (152 mg) obtained in Reference Example 13 were added. After stirring at room temperature for 1 hour, it was confirmed that the reaction was completed. Water was added to the reaction liquid, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue obtained was purified by silica gel chromatography (hexane/ethyl acetate = 2/3) to give {[7-benzyloxy-5-(2,4-dimethylbenzylthio). )-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid tert-butyl ester. The obtained compound was treated in the same manner as in Example 5 to give the title compound (50 mg).

Example 169: {[5-(2,5-Dimethylbenzylthio)-7-hydroxy-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

The title compound (71 mg) was obtained from m. m.

Example 170: {[5-(2,5-Difluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (50 mg) was obtained from m. m.

Example 171: {[5-(2,5-Dichlorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (52 mg) was obtained from m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m

Example 172: {[5-(5-Chloro-2-fluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

5-Chloro-2-fluorobenzyl bromide (53 mg) and the compound obtained in Reference Example 15 (80) The title compound (57 mg) was obtained from m.

Example 173: {[5-(2-Chloro-5-fluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

The title compound (51 mg) was obtained from m. m.

Example 174: {[5-(2-Fluoro-5-methylbenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

The title compound (70 mg) was obtained.

Example 175: {[5-(2-Chloro-3,6-difluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl Amino}acetic acid

The title compound (63 mg) was obtained from m. m.

Example 176: {[5-(2,6-Dichlorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (56 mg) was obtained from m. m.

Example 177: {[5-(3-Chloro-4-fluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino }acetic acid

The title compound (68 mg) was obtained from m. m.

Example 178: {[5-(3,5-Bis-Trifluoromethylbenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl Amino}acetic acid

The title compound (67 mg) was obtained from m. m.

Example 179: {[5-(2,6-Dimethylbenzylthio)-7-hydroxy[1,2,4]triazolo[1,5- ]]pyridine-8-carbonyl]amino}acetic acid

The title compound (75 mg) was obtained from m. m.

Example 180: {[7-Hydroxy-5-(2,4,6-trimethylbenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl] Amino-acetic acid

Using (2,4,6-trimethylphenyl)methyl mercaptan (81 mg) and 7-benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8 The title compound (64 mg) was obtained in the same manner as in Example 8 to the title compound.

Example 181: {[7-Hydroxy-5-(2,3,6-trifluorobenzylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

The title compound (48 mg) was obtained from m. m.

Example 182: {[7-Hydroxy-5-(2,3,4,5,6-pentafluorobenzylthio)-[1,2,4]triazolo[1,5-α]pyridine- 8-carbonyl]amino}acetic acid

The title compound (33 mg) was obtained from m. m.

Example 183: {[5-(3,6-Difluoro-2-methylbenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8- Carbonyl]amino}acetic acid

1,4-Difluoro-2,3-dimethylbenzene (100 mg) was mixed with monochlorobenzene (1.0 mL), and N-bromosuccinimide (150 mg) and azobissin were added to the mixture. Nitrile (6 mg) was stirred 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. Using the obtained 2-bromomethyl-1,4-difluoro-3-methylbenzene and the compound obtained in the title compound (80 mg), the title compound (73 mg).

Example 184: {[5-(2,6-Difluorobenzylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

2,6-difluorobenzyl alcohol (110 mg) and the compound obtained in Reference Example 13 (200) The title compound (30 mg) was obtained in the same manner as in Example 100.

Example 185: (±)-{[7-Hydroxy-5-(1-phenylethylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

The title compound (113 mg) was obtained from m.

Example 186: {[7-Hydroxy-5-(1,2,3,4-tetrahydronaphthalen-1-ylthio)[1,2,4]triazolo[1,5-α]pyridine- 8-carbonyl]amino}acetic acid

The title compound (40 mg) was obtained from m. m.

Example 187: {[7-Hydroxy-5-(5,6,7,8-tetrahydronaphthalen-2-ylmethylthio)[1,2,4]triazolo[1,5-α] Pyridine-8-carbonyl]amino}acetic acid

The title compound (65 mg) was obtained from the title compound (m.

Example 188: {[5-(Benzothiazol-2-ylmethylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino }acetic acid

The title compound (62 mg) was obtained from m. m.

Example 189: {[7-Hydroxy-5-(pyridin-2-ylmethylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (53 mg) was obtained from m. m.

Example 190: {[7-Hydroxy-5-(pyridin-3-ylmethylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (35 mg) was obtained in the same manner as in the the the the the the

Example 191: {[7-Hydroxy-5-(pyridin-4-ylmethylthio)[1,2,4]triazolo[1,5-α] Pyridine-8-carbonyl]amino}acetic acid

The title compound (101 mg) was obtained in the same manner as in the the the the the

Example 192: {[7-Hydroxy-5-(6-methylpyridin-2-ylmethylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl] Amino-acetic acid

Using [6-benzyloxy-5-(6-methyl) in the same manner as in Example 168, using 6-methyl-2-pyridinemethanol (49 mg) Methyl pyridin-2-ylmethylthio)-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetate. The obtained compound was treated in the same manners as in the the

Example 193: {[7-Hydroxy-5-(6-trifluoromethylpyridin-3-ylmethylthio)[1,2,4]triazolo[1,5-α]pyridine-8- Carbonyl]amino}acetic acid

The title compound (109 mg) was obtained.

Example 194: {[5-(2,6-Dichloropyridin-3-ylmethylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8- Carbonyl]amino}acetic acid

The title compound (185 mg) was obtained from m. m.

Example 195: {[7-Hydroxy-5-(2-trifluoromethylpyridin-4-ylmethylsulfanyl)[1,2,4]triazolo[1,5-alpha]pyridine-8- Carbonyl]amino}acetic acid

The title compound (160 mg) was obtained from m.

Example 196: {[5-(2,6-Dimethylpyridin-4-ylmethylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8 -carbonyl]amino}acetic acid

The title compound (120 mg) was obtained from m. m.

Example 197: {[5-(2,6-Dichloropyridin-4-ylmethylthio)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8- Carbonyl]amino}acetic acid

The title compound (180 mg) was obtained from m.

Example 198: {[7-Hydroxy-5-(quinolin-4-ylmethylthio)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (70 mg) was obtained from m. m.

Example 199: {[7-Hydroxy-5-(8-trifluoromethylquinolin-4-ylmethylthio)[1,2,4]triazolo[1,5-α]pyridine-8 -carbonyl]amino}acetic acid

Sodium borohydride (86 mg) was added to a solution of 7-trifluoromethylquinoline-4-carbaldehyde (341 mg) in methanol (4 mL). 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 give 8-trifluoromethyl-quinolin-4-ylmethanol. The mixture of the above-obtained alcohol and triethylamine (101 mg) was dissolved in THF (2 mL), and methanesulfonium 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 8-trifluoromethylquinolin-4-ylmethyl methanesulfonate. The title compound (186 mg) was obtained.

Example 200: {[7-Hydroxy-5-(quinolin-2-ylmethylthio)[1,2,4]triazolo[1,5-α] Pyridine-8-carbonyl]amino}acetic acid

The title compound (130 mg) was obtained from m.

Example 201: {[7-Hydroxy-5-(2-methylbutoxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (50 mg) was obtained in the same manner as the compound of the title compound (yield).

Example 202: (S)-{(7-Hydroxy-5-(2-methylbutoxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amine }acetic acid

The title compound (35 mg) was obtained from m.

Example 203: [(5-Butoxy-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

The title compound (123 mg) was obtained.

Example 204: {[5-(3,3-Dimethylbutoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

Using [3-7-benzyloxy group], 3,3-dimethylbutanol (72 mg) and the compound (200 mg) obtained in Reference Example 10 were obtained in the same manner as Reference Example 11, Reference Example 2 and Example 1. Methyl 5-5-(3,3-dimethylbutoxy)-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetate. The obtained compound (115 mg) was mixed with tetrahydrofuran (1 mL) and methanol (0.6 ml), and 5% palladium carbon (12 mg) was added. The mixture was stirred under a hydrogen atmosphere at normal pressure for 2 hours to confirm the completion of the reaction. The reaction solution was filtered through Celite and concentrated to give {[5-(3,3-dimethylbutoxy)-7-hydroxy-[1,2,4]triazolo[1, Methyl 5-α]pyridine-8-carbonyl]amino}acetate. The obtained compound (93 mg) was obtained in the same manner as in Example 3. The title compound (68 mg) was obtained.

Example 205: {[5-(2-Ethylbutoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (90 mg) was obtained from m.

Example 206: {[5-(2,3-Dimethylbutoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (35 mg) was obtained from m.

Example 207: {[5-(1,2-Dimethylbutoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

Using 1,2-dimethylbutanol (185 mg) and the compound (500 mg) obtained in Reference Example 10 were carried out in the same manner as in Reference Example 11 to give an ether (216 mg). Then, it was dissolved in ethyl acetate (2.5 mL) and toluene (2.5 mL), and methanesulfonic acid (283 mg) was added, and stirred at room temperature overnight. The mixture was evaporated under reduced pressure, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give carboxylic acid (216 mg). Then, a guanamine body (193 mg) was obtained in the same manner as in Example 1 using methyl glycinate. The compound was dissolved in ethyl acetate (3 mL), methanol (3 mL), and 5% Pd-C (30 mg) was added, and the mixture was stirred under a normal pressure for 2 hours under a hydrogen stream, and filtered, and then the solvent was distilled. The target was obtained (140 mg). The title compound (40 mg) was obtained in the same manner as in Example 3.

Example 208: {[7-Hydroxy-5-(4-methylpentyloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (83 mg) was obtained.

Example 209: {[7-Hydroxy-5-(3-methylpentyloxy)[1,2,4]triazolo[1,5-α]pyridine- 8-carbonyl]amino}acetic acid

The title compound (75 mg) was obtained from m.

Example 210: [(7-Hydroxy-5-(pent-3-ynyloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

The title compound (36 mg) was obtained.

Example 211: {[5-(1,4-Dimethylpentyloxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (50 mg) was obtained in the same manner as in Example 201 using 1,4-dimethyl-1-pentanol (116 mg).

Example 212: [(5-Hexyloxy-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl)amino]acetic acid

The title compound (25 mg) was obtained.

Example 213: {[5-(Hex-4-en-1-yloxy)-7-hydroxy-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amine Acetic acid

The title compound (57 mg) was obtained.

Example 214: {[7-Hydroxy-5-(oct-3-en-1-yloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino }acetic acid

The title compound (310 mg) was obtained in the same manner as in Example 201, using cis-3-octene-1-ol (90 mg) and the compound (250 mg).

Example 215: {[7-Hydroxy-5-(indol-3-yn-1-yloxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino }acetic acid

3-decen-1-ol (98.5 mg) and the compound obtained in Reference Example 10 (200) The title compound (35 mg) was obtained from m.

Example 216: ({5-[2-(2-ethoxyethoxy)ethoxy]-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8- Carbonyl}amino)acetic acid

The title compound (40 mg) was obtained from m.

Example 217: {[5-(2-Cyclohexylethoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (44 mg) was obtained from m.

Example 218: {[5-(2-Cyclobutylethoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (25 mg) was obtained.

Example 219: {[5-(2-Cyclopentylethoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (66 mg) was obtained.

Example 220: {[5-(2-Bicyclo[2.2.1]hept-2-ylethoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8 -carbonyl]amino}acetic acid

The title compound (40 mg) was obtained in the same manner as in Example 201, using 2-bis-bi[2,2,1]heptan-2-ylethanol (164 mg)

Example 221: {[5-(2-adamantan-1-ylethoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino group }acetic acid

The title compound (67 mg) was obtained from m.

Example 222: [(7-Hydroxy-5-phenoxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl) Amino]acetic acid

The title compound (70 mg) was obtained.

Example 223: ({5-[2-(2-Fluorophenyl)ethoxy]-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl}amine Acetate

The title compound (73 mg) was obtained from m. m.

Example 224: {[7-Hydroxy-5-(2-thien-2-ylethoxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino} Acetic acid

The title compound (35 mg) was obtained in the same manner as in Example 201, using 2- thiopheneethanol (81 mg) and the compound (200 mg).

Example 225: {[5-(3-Cyclohexylpropoxy)-7-hydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (60 mg) was obtained in the same manner as the compound of the title compound (yield).

Example 226: {[7-Hydroxy-5-(2-phenoxyethoxy)[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid

The title compound (70 mg) was obtained in the same manner as in Example 201, using 2- phenoxyethanol (90 mg) and the compound (200 mg).

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 (3.34g) was dissolved in HMPA (35mL), NaH (866mg) was added with stirring in ice bath, stirred at 65 ° C for 2 hours, and cooled in an ice bath under cooling 7-Benzyloxy-5-iodo[1,2,4]triazolo[1,5-α]pyridine-8-carboxylic acid tert-butyl ester (3.26 g) was added, and the mixture was stirred at 15 ° C or less for 2 hours. Adding citric acid water to make it acidic, and performing precipitation crystallization Filtration and washing with water gave an ether (1.1 g). Then, a guanamine body (735 mg) was obtained in the same manner as in Reference Example 2 and Example 1. To the guanamine, DMF (12 mL) was added and dissolved, and 5% Pd-C (100 mg) was added thereto, and hydrogenation was carried out at normal temperature and normal pressure, and the insoluble matter was removed by filtration through diatomaceous earth, and the filtrate was distilled off under reduced pressure. Adding a small amount of water to the obtained residue and filtering to obtain methyl 5,7-dihydroxy[1,2,4]triazolo[1,5-α]pyridine-8-carboxylate (443 mg) ). Using the diol (100 mg) and 2,6-dimethylbenzyl alcohol (62 mg), {[5-(2,6-dimethylbenzyloxy)-7- Hydroxy-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetic acid methyl ester (42 mg). {[5-(2,6-Dimethylbenzyloxy)-7-hydroxy-[1,2,4]triazolo[1,5-α]pyridine-8-carbonyl]amino}acetate The ester was treated in the same manner as in Example 3 to give the title compound (23 mg).

Tables 1 to 35 below are based on the compounds represented by the formula (1), and the chemical structure formula and physical property data in the above respective examples are summarized.

Test Example EPO production promotion in Hep3B cells

Hep3B cells cultured in MEM medium supplemented with 10% fetal bovine serum (FBS) were inoculated into a 24-well culture dish, and cultured at 37 ° C for one night, and then replaced with 1 μM or medium (0.5% of the test substance added). Methyl hydrazine was added to MEM medium supplemented with 10% FBS. Further, the supernatant was recovered after 48 hours of culture, and was subjected to an ELISA (Enzyme Linked Immunosorbent Assay) kit (eBioscience). Manufactured) The EPO concentration in the supernatant was measured. The increase ratio of the EPO concentration at the time of the addition of the test substance to the EPO concentration at the time of the medium addition, that is, the EPO increase rate (%), was obtained from the following formula, and is shown in Table 36.

EPO increase rate (%) = (EPO concentration when the test substance is added / EPO concentration at the time of medium addition - 1) × 100

As is clear from Table 36, the compound of the present invention has a sustained and strong EPO production promoting action at a concentration of 1 μM, and is remarkably superior to the compound described in Patent Document 1.

Formulation example (preparation method of tablet)

The above 1), 2), and 3) are dispersed by a stirring granulator, and an aqueous solution of 4) is added to the powder, kneaded, dried, sized, and 5) and 6) are added and mixed, and the tablet is pressed by a tablet press. .

[Industrial availability]

The compound of the present invention has a sustained and excellent EPO production promoting action, and is useful for prevention or treatment of a disease caused by a hypoxic environment in a subject organ or tissue, particularly anemia prevention or treatment.

Claims (6)

a compound or a pharmaceutically acceptable salt thereof having the formula (1), [In the above formula, X represents an oxygen atom, an imine group, a sulfur atom, a sulfinyl group or a sulfonyl group, and 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 aralkyl group, and R ⁵ represents an alkyl group which may be substituted with a group selected from the group of substituents, and an alkenyl group which may be substituted with a group selected from the group of substituents. An alkynyl group substituted with a group selected from the group of substituents, an aryl group selected from the group of substituents and independently having 1 to 7 substituents, or a group selected from the group of substituents and independently having 1 to 7 a heteroaryl group; a group of substituents represents a group consisting of a group: an aryl group having 1 to 7 substituents (as a substituent on the aryl group: C ₁ -C ₆ alkane) a heteroaryl group having 1 to 7 substituents as a substituent on the heteroaryl group, a trifluoromethyl group, a halogen atom, a methoxy group, a trifluoromethoxy group, a cyano group or a phenyl group, Illustrative: C ₁ -C ₆ alkyl, trifluoromethyl, halogen atom, methoxy, trifluoromethoxy, cyano or phenyl), C ₁ -C ₆ alkyl (in C ₃ -C _In the case of ₆ alkyl groups, carbon atoms can be bonded to each other to form 3 to 6 membered saturated ring), C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, aralkyl group, C ₂ -C ₈ alkoxycarbonyl group, halogen atom, C ₁ -C ₆ Halogenated alkyl group, hydroxyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ halogenated alkoxy group, aryloxy group, amine carbenyl group, C ₂ -C ₆ alkylcarbonyl group, cyano group, carboxyl group , mercapto, nitro, amine, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkylcarbonylamino, arylamine , Aminosulfonyl, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ halogenated alkylsulfonyl, arylsulfonyl, C ₁ -C ₆ alkylthio, C ₁ - C ₆ haloalkylthio and arylthio]. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in the formula (1), X is an oxygen atom or a sulfur atom, and R ¹ , R ² , R ³ and R ⁴ are a hydrogen atom. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in the formula (1), R ⁵ is a straight or branched chain of C ₁ -C ₁₈ which may be substituted with a group selected from the group of substituents An alkyl group, a C ₃ -C ₁₈ cyclic alkyl group or a combination thereof; a C ₂ -C ₁₈ linear or branched alkenyl group which may be substituted with a group selected from the group of substituents; a linear or branched alkynyl group substituted with a C ₂ -C ₈ group in the group; a monocyclic, bicyclic or tricyclic aromatic group having 6 to 14 carbon atoms which may be substituted with a group selected from the group of substituents a monocyclic, bicyclic or tricyclic heteroaryl group having 1 to 4 hetero atoms (nitrogen atom, oxygen atom or sulfur atom) substituted with a group selected from a substituent group, a substituent group A group consisting of 1 to 7 substituted monocyclic, bicyclic or tricyclic aryl groups having 6 to 14 carbon atoms (as a substituent on the aryl group: C ₁ - C ₆ alkyl, trifluoromethyl, halogen atom, methoxy, trifluoromethoxy, cyano or phenyl), having 1 to 7 substituents having 1 to 4 hetero atoms (nitrogen atom) a monocyclic, bicyclic or tricyclic heteroaryl group of an oxygen atom or a sulfur atom, The substituent on the heteroaryl group means: C ₁ -C ₆ alkyl group, trifluoromethyl group, halogen atom, methoxy group, trifluoromethoxy group, cyano group or phenyl group), C ₁ -C An alkyl group of ₆ (in the case of a C ₃ -C ₆ alkyl group, carbon atoms may be bonded to each other to form a 3 to 6-membered saturated ring), a C ₂ -C ₆ alkenyl group, and a C ₂ -C ₆ alkynyl group. , C ₆ -C ₁₄ aryl-C ₁ -C ₆ alkyl, C ₂ -C ₈ alkoxycarbonyl, halogen atom, C ₁ -C ₆ halogenated alkyl, hydroxy, C ₁ -C ₆ alkane An oxy group, a C ₁ -C ₆ halogenated alkoxy group, a C ₆ -C ₁₄ aryloxy group, an amine carbenyl group, a C ₂ -C ₆ alkylcarbonyl group, a cyano group, a carboxyl group, a decyl group, a nitro group, Amino group, C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkylaminocarbonyl group, C ₁ -C ₆ alkylcarbonylamino group, arylamino group, aminosulfonyl group, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ haloalkylsulfonyl, C ₆ -C ₁₄ arylsulfonyl, C ₁ -C ₆ alkylthio, C ₁ -C ₆ haloalkylthio and C ₆ -C ₁₄ arylthio. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of an EPO production promoting drug. A method of using a salt, which comprises administering a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for producing an anemia, self-storage selected from a patient suffering from chronic renal failure Preventives and/or therapeutic agents for anemia in blood, premature infant anemia, AIDS or cancer patients undergoing anemia, chronic anemia, iron deficiency anemia, aplastic anemia, hemolytic anemia, and giant embryo erythrocyte anemia.