KR20210048589A - Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer - Google Patents

Abstract

The present invention provides a triazolopyridine compound having a prolyl hydroxylase inhibitory action and an ability to induce erythropoietin production. The present invention relates to a compound represented by the following formula [I] (wherein each symbol is as described in the specification) or a pharmaceutically acceptable salt or solvate thereof, as well as a prolyl hydroxylase inhibitor or erythrolyte containing the compound. It relates to an agent for inducing poietin production. The compounds of the present invention exhibit a prolyl hydroxylase inhibitory action and an ability to induce erythropoietin production, and are useful as a preventive or therapeutic agent for various diseases and conditions (disorders) resulting from a decrease in the production of erythropoietin.

Description

Triazolopyridine compound, and its action as a prolyl hydroxylase inhibitor and an agent for inducing erythropoietin production {TRIAZOLOPYRIDINE COMPOUND, AND ACTION THEREOF AS PROLYL HYDROXYLASE INHIBITOR AND ERYTHROPOIETIN PRODUCTION INDUCER}

The present invention relates to a novel triazolopyridine compound having a prolyl hydroxylase (hereinafter, referred to as "PHD") inhibitory effect and an erythropoietin (hereinafter, referred to as "EPO") production-inducing ability. In addition, the present invention relates to a prolyl hydroxylase inhibitor (hereinafter also referred to as "PHD inhibitor") and an erythropoietin production inducing agent (hereinafter also referred to as "EPO production inducing agent") each containing a triazolopyridine compound. .

EPO is a hormone that promotes the growth of red blood cells, consisting of 165 amino acids. EPO is mainly produced in the kidney and partly in the liver, and its production increases under low oxygen conditions.

Anemia refers to a condition in which the level of red blood cells and hemoglobin in the blood is low. The symptoms are derived from oxygen deficiency due to a decrease in the number of red blood cells, or a change in circulatory dynamics due to an increase in respiratory rate and heart rate to compensate for oxygen deficiency. , "Winter season", "dumbness", "dizziness", "the complexion is bad", "shoulder stiffness", "difficult to wake up in the morning", etc.

The causes of anemia are largely divided into low production of red blood cells, hyperdestruction and hypertrophy of loss, anemia due to abnormal hematopoiesis in the bone marrow, anemia due to a deficiency of iron, vitamin B ₁₂ or folic acid, bleeding during accidents or surgery, and chronic inflammation ( Anemia associated with autoimmune diseases, malignant tumors, chronic infectious diseases, plasma cell dysfunction, etc.), endocrine diseases (hypothyroidism, polysomal autoimmune syndrome, type IA diabetes, irregular uterine bleeding, etc.), chronic heart failure Concomitant anemia, anemia associated with ulcers, anemia associated with liver disease, senile anemia, drug-induced anemia, nephrotic anemia (anemia associated with renal failure), anemia associated with chemotherapy, and the like.

In 1989, the U.S. Food and Drug Administration on adaptation of the renal anemia, anemia accompanying AZT treatment in HIV patients, anemia accompanying chemotherapy in cancer patients, or reduction in blood transfusion volume in patients undergoing surgery in 1989. Approved by (FDA). Moreover, the adaptation has also spread to premature infants, such as anemia.

Nephrotic anemia is being treated with erythropoiesis stimulating agents (ESA). In nephrotic anemia, the main factor is the decrease in EPO production in interstitial cells around the renal tubules. Genetically modified human erythropoietin is an adaptation that is very often used for supplementation of EPO. Genetically modified human erythropoietin drastically reduced the number of patients requiring regular blood transfusions, improved various symptoms associated with anemia, and greatly contributed to the improvement of ADL (Activities of daily living) and QOL (Quality of Life). On the other hand, since it is a biological agent, it is expensive and requires a high medical cost. In addition, the blood half-life is short, and in hemodialysis patients, intravenous administration from the dialysis circuit 2 to 3 times a week is required. That is, it is desired to reduce the number of injections from the viewpoint of prevention of medical accidents and also the amount of medical work and waste. Moreover, for peritoneal dialysis patients and renal failure patients in the predialysis period, subcutaneous administration provided for a long period of time has been adopted, and administration once a week or once every two weeks is still required. In this case, it is often necessary to go to the hospital for the administration of genetically modified human erythropoietin only, which places a burden on the patient.

Moreover, long-acting EPO drugs have been developed with prolonged blood half-life by intravenous and subcutaneous injection by modifying EPO by adding new sugar chains or PEG chains. However, since only injections have been developed, an ESA that can be administered orally is desired to prevent medical accidents and reduce patient burden.

Moreover, ESA, which can be administered orally, is expected to broaden the range of treatment for anemia caused by various causes as well as nephrotic anemia.

As a representative molecule that promotes the transcription of EPO, a hypoxia inducible factor (Hypoxia Inducible Factor, hereinafter also referred to as "HIF") is exemplified. HIF is a protein consisting of a heterodimer having an oxygen-regulating α-subunit and a constitutively expressed β-subunit, wherein in the presence of oxygen, proline of the α-subunit is hydrated by prolyl hydroxylase (PHD). The resulting α-subunit binds to the von Hippel-Lindau (VHL) protein and becomes ubiquitinated. However, since the α-subunit is not applied to hydroxylation by PHD under low oxygen conditions, it is not ubiquitinated, but it binds to the hypoxia response element (HRE) in the nucleus and promotes the transcription of EPO present downstream of HIF. Let it. Therefore, as a result of inhibiting the activity of PHD, ubiquitination of HIF is prevented and it is stabilized. As a result, EPO production is increased.

Examples of diseases that are expected to improve by inhibiting PHD and stabilizing HIF include ischemic heart disease (angina pectoris, myocardial infarction, etc.), ischemic cerebrovascular disorder (cerebral infarction, cerebral embolism, transient cerebral ischemic attack, etc.), chronic renal failure (ischemic kidney disease, tubules Interstitial disorders), diabetes complications (diabetic wounds, etc.), cognitive disorders (dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.).

Based on the knowledge obtained from the studies so far, drugs that inhibit prolyl hydroxylase (PHD) promote the production of erythropoietin (EPO) and prevent various diseases and conditions (disorders) caused by the decrease in EPO production. Or it has become clear that it is effective for treatment, especially for the treatment of anemia.

Accordingly, the present invention aims to provide a drug having a prolyl hydroxylase (PHD) inhibitory action. In addition, the present invention aims to provide a drug having the ability to induce EPO production.

The present inventors discovered a compound having a prolyl hydroxylase (PHD) inhibitory action and an ability to induce EPO production, and completed the present invention.

More specifically, the present invention provides the following.

[1] A compound represented by the following formula [I] (hereinafter, also referred to as "the compound of the present invention"), a pharmaceutically acceptable salt thereof, or a solvate thereof:

[In the formula,

Partial structural formula:

Is the following formula:

It is a group represented by any of;

R ¹ is

(1) a hydrogen atom,

(2) C _1-6 alkyl group,

(3) C _6-14 aryl group,

(4) C _3-8 cycloalkyl group,

(5) C _6-14 aryl-C _1-6 alkyl group, or

(6) a C _3-8 cycloalkyl-C _1-6 alkyl group;

R ² is

(1) a hydrogen atom,

(2) a C _1-10 alkyl group,

_{(3) a C 6-14} aryl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B,

_{(4) a C 3-8} cycloalkyl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B,

_{(5) a C 3-8} cycloalkenyl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B,

(6) a heteroaryl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B (here, heteroaryl is 1 to 6 selected from nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms) Having a hetero atom),

(7) C _6-14 aryl-C _1-6 alkyl group (wherein C _6-14 aryl is optionally substituted with the same or different 1 to 5 substituents selected from the following group B), or,

(8) a C _3-8 cycloalkyl-C _1-6 alkyl group, wherein C _3-8 cycloalkyl is optionally substituted with the same or different 1 to 5 substituents selected from Group B below;

R ³ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) C _1-6 alkyl group,

(4) C _6-14 aryl group,

(5) C _3-8 cycloalkyl group, or

(6) a C _6-14 aryl-C _1-6 alkyl group;

R ⁴ and R ⁵ are each independently

(1) a hydrogen atom, or,

(2) It is a C _1-6 alkyl group.

Group B:

(a) a halogen atom,

(b) a C _1-6 alkyl group,

(c) a C _3-8 cycloalkyl group,

(d) a cyano group, and

(e) halo C _1-6 alkyl group].

[2] Partial structural formula:

This formula:

The group represented by the compound according to [1] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[3] Partial structural formula:

This formula:

The group represented by the compound according to [1] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[4] Partial structural formula:

This formula:

The group represented by the compound according to [1] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[5] Partial structural formula:

This formula:

The group represented by the compound according to [1] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[6] The compound according to any one of [1] to [5], wherein both of ^{R 4} and R ^{5 are hydrogen atoms, or a pharmaceutically acceptable salt thereof, or a solvate thereof.}

[7] The ^{compound according to any one of [1] to [5], wherein R 3} is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[8] The ^{compound according to any one of [1] to [5], wherein R 1} is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[9] R ² is

(1) C _1-10 alkyl group,

_{(2) a C 6-14} aryl group optionally substituted with the same or different 1 to 5 substituents selected from the group B,

(3) C _6-14 aryl-C _1-6 alkyl group (wherein C _6-14 aryl is optionally substituted with the same or different 1 to 5 substituents selected from the group B), or,

(4) a C _3-8 cycloalkyl-C _1-6 alkyl group (wherein C _3-8 cycloalkyl is optionally substituted with the same or different 1 to 5 substituents selected from the group B), the above [1] The compound according to any one of [5] to [5], a pharmaceutically acceptable salt thereof, or a solvate thereof.

[10] The ^{compound according to [2], wherein both of R 4} and R ⁵ are hydrogen atoms, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[11] The ^{compound according to [10], wherein R 3} is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[12] The ^{compound according to [11], wherein R 1} is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[13] R ² is

(1) a C _1-10 alkyl group, or

(2) C _6-14 aryl-C _1-6 alkyl group (wherein, C _6-14 aryl is optionally substituted with the same or different 1 to 5 substituents selected from the group B), as described in [12] above. A compound or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[14] A compound represented by the following formula [I-1], a pharmaceutically acceptable salt thereof, or a solvate thereof:

[In the formula, partial structural formula:

Is the following formula:

It is a group represented by any of;

R ¹¹ is

(1) a hydrogen atom,

(2) C _1-6 alkyl group,

(3) a phenyl group,

(4) C _3-8 cycloalkyl group,

(5) a phenyl-C _1-6 alkyl group, or,

(6) a C _3-8 cycloalkyl-C _1-6 alkyl group;

R ²¹ is

(1) a hydrogen atom,

(2) a C _1-10 alkyl group,

(3) a phenyl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B,

(4) C _3-8 cycloalkyl group,

(5) C _3-8 cycloalkenyl group,

(6) a thienyl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B,

(7) a phenyl-C _1-6 alkyl group (wherein phenyl is optionally substituted with the same or different 1 to 5 substituents selected from the following group B), or

(8) a C _3-8 cycloalkyl-C _1-6 alkyl group;

R ³¹ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) C _1-6 alkyl group,

(4) a phenyl group,

(5) C _3-8 cycloalkyl group, or

(6) a phenyl-C _1-6 alkyl group;

R ⁴¹ and R ⁵¹ are each independently

(1) a hydrogen atom, or

(2) It is a C _1-6 alkyl group.

Group B:

(a) a halogen atom,

(b) a C _1-6 alkyl group,

(c) a C _3-8 cycloalkyl group,

(d) a cyano group, and

(e) halo C _1-6 alkyl group].

[15] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[16] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[17] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[18] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[19] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[20] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[21] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[22] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[23] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[24] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[25] The following formula:

The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[26] A pharmaceutical composition comprising the compound according to any one of [1] to [25] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier (hereinafter, " Also referred to as "a pharmaceutical composition").

[27] A prolyl hydroxylase inhibitor comprising the compound according to any one of [1] to [25], a pharmaceutically acceptable salt thereof, or a solvate thereof.

[28] An agent for inducing erythropoietin production, comprising the compound according to any one of [1] to [25], a pharmaceutically acceptable salt thereof, or a solvate thereof.

[29] A therapeutic agent for anemia comprising the compound according to any one of [1] to [25] above, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[30] A therapeutic agent for nephrotic anemia comprising the compound according to any one of [1] to [25] above, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[31] Use of the compound according to any one of [1] to [25] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a prolyl hydroxylase inhibitor.

[32] Use of the compound according to any one of [1] to [25], or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the production of an agent for inducing erythropoietin production.

[33] Use of the compound according to any one of [1] to [25] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic agent for anemia.

[34] Use of the compound according to any one of [1] to [25] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a therapeutic agent for nephrotic anemia.

[35] A method for inhibiting prolyl hydroxylase, comprising administering to a mammal an effective amount of the compound according to any one of [1] to [25], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[36] A method for inducing erythropoietin production, comprising administering to a mammal an effective amount of the compound according to any one of [1] to [25], a pharmaceutically acceptable salt thereof, or a solvate thereof.

[37] A method for treating anemia, comprising administering to a mammal an effective amount of the compound according to any one of [1] to [25], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[38] A method for treating nephrotic anemia, comprising administering to a mammal an effective amount of the compound according to any one of [1] to [25], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[39] The pharmaceutical composition according to [26] above, and a substrate related to the pharmaceutical composition showing that the pharmaceutical composition can be used or should be used for the treatment or prevention of a disease selected from anemia and nephrotic anemia. Commercial package.

[40] The pharmaceutical composition according to [26] above, and a substrate related to the pharmaceutical composition showing that the pharmaceutical composition can or should be used for the treatment or prevention of a disease selected from anemia and nephrotic anemia. Kit.

The definitions of each substituent and each moiety used in the present specification are as follows.

"Halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"C _1-10 alkyl group" is a C 1 to C 10 linear or branched alkyl group, preferably a C 1 to C 7 linear or branched alkyl group. For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, 1-ethylpropyl group, Neopentyl group, hexyl group, 2-ethylbutyl group, 3,3-dimethylbutyl group, 3,3-dimethylpentyl group, heptyl group, octyl group, nonyl group, decyl group and the like can be mentioned.

"C _1-6 alkyl group" is a C 1 to C 6 linear or branched alkyl group, preferably a C 1 to C 3 linear or branched alkyl group. For example, _{as exemplified as the above "C 1-10} alkyl group", one having 1 to 6 carbon atoms may be mentioned.

"C _1-3 alkyl group" is a C1-C3 straight-chain or branched-chain alkyl group. For example, as exemplified as the above alkyl group, one having 1 to 3 carbon atoms may be mentioned.

"C _6-14 aryl group" is an aromatic hydrocarbon group having 6 to 14 carbon atoms. For example, a phenyl group, a naphthyl group, an anthryl group, an indenyl group, an azulenyl group, a fluorenyl group, a phenanthryl group, a pentalenyl group, and the like can be mentioned, preferably a phenyl group.

"C _3-8 cycloalkyl group" is a saturated cycloalkyl group having 3 to 8 carbon atoms, preferably 3 to 5 carbon atoms, for example a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclo Octyl group and the like can be mentioned.

"C _3-5 cycloalkyl group" is a saturated cycloalkyl group having 3 to 5 carbon atoms. For example, those having 3 to 5 carbon atoms may be mentioned as exemplified as the _{above "C 3-8 cycloalkyl group".}

“C _6-14 aryl-C _1-6 alkyl group” means that the C _6-14 aryl moiety is a “C _6-14 aryl group” as _{defined above and the C 1-6} alkyl moiety is a “C _1-6 alkyl group” as defined above It is a phosphorus C _6-14 aryl-C _1-6 alkyl group, and preferably the C _1-6 alkyl moiety is a _{C 6-14} aryl-C _1-6 alkyl group in which _{the C 1-6 alkyl group is a straight chain.} Examples of C _6-14 aryl-C _1-6 alkyl groups include phenylmethyl group, phenylethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, phenylhexyl group, naphthylmethyl group, naphthylethyl group, naphthylpropyl group, naphthyl Tylbutyl group, naphthylpentyl group, naphthylhexyl group, anthrylmethyl group, indenylmethyl group, azulenylmethyl group, fluorenylmethyl group, phenanthrylmethyl group, pentalenylmethyl group, and the like.

"C _3-8 cycloalkyl-C _1-6 alkyl group" means that the C _3-8 cycloalkyl moiety is a “C _3-8 cycloalkyl group” as _{defined above and the C 1-6} alkyl moiety is “C _1-6 Alkyl group" is a C _3-8 cycloalkyl-C _1-6 alkyl group. Examples include cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclopropylbutyl group, cyclopropylpentyl group, cyclopropylhexyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclobutylpropyl group, cyclobutylbutyl group, cyclo Butylpentyl group, cyclobutylhexyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclopentylpropyl group, cyclopentylbutyl group, cyclopentylpentyl group, cyclopentylhexyl group, cyclohexylmethyl group, cyclohexylethyl group, cyclohexylpropyl group, Cyclohexylbutyl group, cyclohexylpentyl group, cyclohexylhexyl group, cycloheptylmethyl group, cycloheptylethyl group, cycloheptylpropyl group, cycloheptylbutyl group, cycloheptylpentyl group, cycloheptylhexyl group, cyclooctylmethyl group, cyclooctylethyl group , A cyclooctylpropyl group, a cyclooctylbutyl group, a cyclooctylpentyl group, a cyclooctylhexyl group, and the like.

"C _3-8 cycloalkenyl group" is a C 3 to C 8 cycloalkenyl group, and contains at least 1, preferably 1 or 2 double bonds. For example, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl group (2,4-cyclohexadien-1-yl group, 2,5-cyclohexadiene 1-yl group, etc.), cycloheptenyl group, cyclooctenyl group, and the like can be mentioned.

"Heteroaryl group" is an aromatic heterocycle having 1 to 6 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms as ring-constituent atoms, and the number of ring-constituent atoms is 3 to 14, Includes monocyclic and condensed rings.

"Monocyclic heteroaryl group" is preferably a monocyclic heteroaryl group having 1 to 4 hetero atoms, for example thienyl group (eg, thiophen-2-yl, thiophen-3-yl ), furyl group (eg, furan-2-yl, furan-3-yl, etc.), pyrrolyl group (eg, 2-pyrrolin-1-yl group, 3-pyrrolin-3-yl, etc.), oxazolyl group ( Example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, etc.), isoxazolyl group (e.g., isoxazol-3-yl, isoxazol-4-yl, isoxazol-5 -Yl, etc.), thiazolyl group (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, etc.), isothiazolyl group (e.g., isothiazol-3-yl, iso Thiazol-4-yl, isothiazol-5-yl, etc.), imidazolyl group (e.g., imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, etc.) , Pyrazolyl group (eg, pyrazol-1-yl, 1H-pyrazol-3-yl, 2H-pyrazol-3-yl, 1H-pyrazol-4-yl, etc.), oxadiazolyl group (eg, 1,3,4-oxadiazol-2-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadia Zol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, etc.), thiadiazolyl group (e.g., 1,3,4-thia Diazol-2-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, etc.), triazolyl group (e.g., 1,2,4-triazol-3-yl, 1, 2,4-triazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,3,4-triazol-1-yl, etc. ), tetrazolyl group (e.g., tetrazol-1-yl, tetrazol-2-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, etc.), pyridyl group (e.g., pyridin-2 -Yl, pyridin-3-yl, pyridin-4-yl, etc.), pyrimidinyl group (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, etc.), pyridazinyl group (Eg, pyridazin-3-yl, pyridazin-4-yl, etc.), pyrazinyl group (eg, pyrazin-2-yl, etc.), triazinyl group (eg, 1,3,5-triazine-2- To mention things etc.) I can.

Examples of "condensed heteroaryl group" include quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalyl group, phthalazinyl group, cinnolinyl group, naphthyridinyl group, indolyl group, benzimidazolyl group, indoli Nyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzothiazolyl group, benzodioxynyl group, benzothiazolyl group, tetrahydroquinolyl group, dihydrobenzofuranyl group, dihydrobenzothienyl group, dihydro Benzodioxynyl group, indenothiazolyl group, tetrahydrobenzothiazolyl group, 5,7-dihydropyrrolo[3,4-d]pyrimidinyl group, 6,7-dihydro-5H-cyclopentapyrimidi A nil group, an imidazo[2,1-b]thiazolyl group, a pteridinyl group, a purinyl group, etc. are included.

"Halo C _{1-6 alkyl group" is a "C 1-6} alkyl group" as defined above, substituted with 1 to 5 halogen atoms identical or different, for example, chloromethyl, fluoromethyl, difluoromethyl, tri Fluoromethyl, bromomethyl, chloroethyl, fluoroethyl, bromoethyl, chloropropyl, fluoropropyl, bromopropyl and the like may be mentioned.

"Group B" includes the following groups of substituents (a) to (e).

(a) "halogen atom" as defined above,

(b) "C _1-6 alkyl group" as defined above,

(c) "C _3-8 cycloalkyl group" as defined above,

(d) a cyano group, and

(e) "Halo C _1-6 alkyl group" as defined above.

_{"C 6-14} aryl group optionally substituted with the same or different 1 to 5 substituents selected from group B" means that "C _6-14 aryl group" as defined above is optionally substituted with the same or different 1 to 5 substituents And an unsubstituted C _6-14 aryl group. The substituents are the same or different and are selected from "Group B" as defined above.

_{"C 3-8} cycloalkyl group optionally substituted with the same or different 1 to 5 substituents selected from group B" means that "C _3-8 cycloalkyl group" as defined above is optionally substituted with the same or different 1 to 5 substituents And an unsubstituted C _3-8 cycloalkyl group. The substituents are the same or different and are selected from "Group B" as defined above.

_{"C 3-8} cycloalkenyl group optionally substituted with the same or different 1 to 5 substituents selected from group B" means the "C _3-8 cycloalkenyl group" as defined above is optionally substituted with 1 to 5 substituents that are the same or different And an unsubstituted C _3-8 cycloalkenyl group. The substituents are the same or different and are selected from "Group B" as defined above.

"Heteroaryl group optionally substituted with the same or different 1 to 5 substituents selected from group B" means that the "heteroaryl group" as defined above is optionally substituted with the same or different 1 to 5 substituents, and unsubstituted heteroaryl Includes a flag. The substituents are the same or different and are selected from "Group B" as defined above.

In the above formula [I], preferred groups are as follows.

Partial structural formula:

Is a group represented by any of the following formulas:

As the partial structural formula, preferably, they are groups shown below.

As the partial structural formula, it is more preferably a group represented below.

R ¹ is

(1) a hydrogen atom,

(2) C _1-6 alkyl group,

(3) C _6-14 aryl group,

(4) C _3-8 cycloalkyl group,

(5) C _6-14 aryl-C _1-6 alkyl group, or

(6) C _3-8 cycloalkyl-C _1-6 alkyl group.

R ¹ is preferably

(1) a hydrogen atom,

(2) C _1-3 alkyl group (e.g. methyl),

(3) C _6-14 aryl group (eg, phenyl),

(4) C _3-5 cycloalkyl group (eg, cyclopropyl),

(5) C _6-14 aryl (e.g. phenyl)-C _1-3 alkyl (preferably straight-chain C _1-3 alkyl, e.g. ethyl) group,

(6) C _3-8 cycloalkyl (eg, cyclohexyl)-C _1-3 alkyl (eg, ethyl) groups.

R ¹ is more preferably a hydrogen atom.

R ² is

(1) a hydrogen atom,

(2) a C _1-10 alkyl group,

_{(3) a C 6-14} aryl group optionally substituted with the same or different 1 to 5 substituents selected from the group B,

_{(4) a C 3-8} cycloalkyl group optionally substituted with the same or different 1 to 5 substituents selected from the group B,

_{(5) a C 3-8} cycloalkenyl group optionally substituted with the same or different 1 to 5 substituents selected from the group B,

(6) a heteroaryl group optionally substituted with the same or different 1 to 5 substituents selected from the group B (here, the heteroaryl is 1 to 6 selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom) Having 4 heteroatoms),

(7) C _6-14 aryl-C _1-6 alkyl group (wherein C _6-14 aryl is optionally substituted with the same or different 1 to 5 substituents selected from the group B), or

(8) C _3-8 cycloalkyl-C _1-6 alkyl group, wherein C _3-8 cycloalkyl is optionally substituted with the same or different 1 to 5 substituents selected from group B above.

R ² is preferably

(1) a hydrogen atom,

(2) a C _1-10 alkyl group,

_{(3) a C 6-14} aryl group optionally substituted with the same or different 1 to 5 substituents selected from the group B,

(4) C _3-8 cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl),

(5) C _3-8 cycloalkenyl group (eg, cyclohexenyl),

(6) Group B above

(Yes, (a) a halogen atom (e.g., a chlorine atom), and

(b) C _1-6 alkyl group (eg, methyl))

A heteroaryl group optionally substituted with 1 to 5 (eg, 1) substituents selected from the same or different (preferably a monocyclic heteroaryl group, eg, thienyl) (wherein the heteroaryl is carbon In addition to the atom, it has 1 to 6 (eg, 1 to 4) heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms (eg, sulfur atoms)),

(7) C _6-14 aryl-C _1-6 alkyl group (wherein C _6-14 aryl is optionally substituted with the same or different 1 to 5 substituents selected from the group B), or

(8) C _3-8 cycloalkyl-C _1-3 alkyl group, wherein C _3-8 cycloalkyl is optionally substituted with the same or different 1 to 5 substituents selected from the group B above.

R ² is more preferably

(1) C _1-10 alkyl group (e.g., ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, tert-pentyl, hexyl, 1-ethylpropyl, 2-ethylbutyl, 3,3-dimethylbutyl , 3,3-dimethylpentyl),

(2) Group B above

(Yes, (a) halogen atom (e.g., chlorine atom, fluorine atom),

(b) a C _1-3 alkyl group (e.g. methyl),

(c) a C _3-5 cycloalkyl group (eg, cyclopropyl),

(d) a cyano group, and

(e) halo C _1-3 alkyl group (e.g. trifluoromethyl))

_{C 6-14} aryl group optionally substituted with 1 to 5 (eg, 1 to 3) substituents selected from the same or different (eg, phenyl),

(3) C _6-14 aryl (eg, phenyl) -C _1-6 alkyl (preferably straight chain C _1-6 alkyl, eg, methyl, ethyl, propyl) group (the C _6-14 aryl is the group B

(Yes, (a) halogen atom (e.g., chlorine atom, fluorine atom),

(b) a C _3-8 cycloalkyl group (eg, cyclopropyl), and

(c) halo C _1-3 alkyl group (e.g. trifluoromethyl))

Optionally substituted with the same or different 1 to 5 (eg, 1 to 3) substituents selected from), or

(4) C _3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) -C _1-3 alkyl (e.g., methyl, ethyl) group (the C _3-8 cycloalkyl is the group B Optionally substituted with the same or different 1 to 5 substituents selected from).

R ² is even more preferably

(1) C _1-6 alkyl group (e.g., butyl, pentyl, 1-ethylpropyl),

(2) (a) halogen atom (e.g., chlorine atom, fluorine atom),

(b) a C _1-3 alkyl group (e.g. methyl),

(c) a C _3-5 cycloalkyl group (eg, cyclopropyl), and

(d) halo C _1-3 alkyl group (e.g. trifluoromethyl)

Phenyl optionally substituted with the same or different 1 to 3 substituents selected from

(3) phenylethyl, or

(4) Cyclopentylethyl.

R ² is particularly preferably butyl, phenylethyl, 4-fluoro-3-trifluoromethylphenyl.

In another embodiment of the invention, R ² is preferably

(1) a C _1-10 alkyl group, or

(2) C _6-14 aryl-C _1-6 alkyl group, wherein C _6-14 aryl is optionally substituted with the same or different 1 to 5 substituents selected from the group B above.

R ³ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) C _1-6 alkyl group,

(4) C _6-14 aryl group,

(5) C _3-8 cycloalkyl group, or

(6) C _6-14 aryl-C _1-6 alkyl group.

R ³ is preferably

(1) a hydrogen atom,

(2) halogen atom (e.g. chlorine atom),

(3) C _1-6 alkyl group (e.g. ethyl, pentyl),

(4) C _6-14 aryl group (eg, phenyl), or

(5) C _6-14 aryl (eg phenyl)-C _1-6 alkyl (preferably straight chain C _1-6 alkyl, eg ethyl) group.

R ³ is more preferably a hydrogen atom.

R ⁴ and R ⁵ are each independently

(1) a hydrogen atom, or

(2) It is a C _1-6 alkyl group.

R ⁴ and R ⁵ are preferably each independently

(1) a hydrogen atom, or

(2) C _1-3 alkyl group (eg, methyl).

R ⁴ and R ⁵ are more preferably both hydrogen atoms.

In formula [I], a compound represented by the following formula [Ia] is more preferred:

[In the formula,

Partial structural formula:

Is a group represented by:

R ^1a is

(1) a hydrogen atom,

(2) C _1-3 alkyl group (e.g. methyl),

(3) C _6-14 aryl group (eg, phenyl),

(4) C _3-5 cycloalkyl group (eg, cyclopropyl),

(5) a C _6-14 aryl (e.g. phenyl)-C _1-3 alkyl (preferably straight-chain C _1-3 alkyl, e.g. ethyl) group, or

(6) a C _3-8 cycloalkyl (eg, cyclohexyl)-C _1-3 alkyl (eg, ethyl) group;

R ^2a is

(1) a hydrogen atom,

(2) a C _1-10 alkyl group,

_{(3) a C 6-14} aryl group optionally substituted with the same or different 1 to 5 substituents selected from the group B,

(4) C _3-8 cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl),

(5) C _3-8 cycloalkenyl group (eg, cyclohexenyl),

(6) Group B above

(Yes, (a) a halogen atom (e.g., a chlorine atom), and

(b) C _1-6 alkyl group (eg, methyl))

A heteroaryl group optionally substituted with 1 to 5 (eg, 1) substituents selected from the same or different (preferably a monocyclic heteroaryl group, eg, thienyl) (wherein the heteroaryl is carbon In addition to the atom, it has 1 to 6 (eg, 1 to 4) heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms (eg, sulfur atoms)),

(7) C _6-14 aryl-C _1-6 alkyl group (wherein C _6-14 aryl is optionally substituted with the same or different 1 to 5 substituents selected from the group B), or

(8) a C _3-8 cycloalkyl-C _1-3 alkyl group, wherein C _3-8 cycloalkyl is optionally substituted with the same or different 1 to 5 substituents selected from group B above;

R ^3a is

(1) a hydrogen atom,

(2) halogen atom (e.g. chlorine atom),

(3) C _1-6 alkyl group (e.g. ethyl, pentyl),

(4) C _6-14 aryl group (eg, phenyl), or

(5) C _6-14 aryl (eg, phenyl)-C _1-6 alkyl (preferably straight chain C _1-6 alkyl, eg ethyl) group;

R ^4a and R ^5a are each independently

(1) a hydrogen atom, or

(2) C _1-3 alkyl group (eg, methyl)].

As the compound of the present invention, as a compound represented by the above formula [Ia],

R ^1a is a hydrogen atom;

R ^2a is

(1) C _1-10 alkyl group (e.g., ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, tert-pentyl, hexyl, 1-ethylpropyl, 2-ethylbutyl, 3,3-dimethylbutyl , 3,3-dimethylpentyl),

(2) Group B above

(Yes, (a) halogen atom (e.g., chlorine atom, fluorine atom),

(b) a C _1-3 alkyl group (e.g. methyl),

(c) a C _3-5 cycloalkyl group (eg, cyclopropyl),

(d) a cyano group, and

(e) halo C _1-3 alkyl group (e.g. trifluoromethyl))

_{C 6-14} aryl group optionally substituted with 1 to 5 (eg, 1 to 3) substituents selected from the same or different (eg, phenyl),

(3) C _6-14 aryl (e.g., phenyl) -C _1-6 alkyl (preferably straight-chain C _1-6 alkyl, e.g. methyl, ethyl, propyl) group (where C _6-14 aryl is the above group B

(Yes, (a) halogen atom (e.g., chlorine atom, fluorine atom),

(b) a C _3-8 cycloalkyl group (eg, cyclopropyl), and

(c) halo C _1-6 alkyl group (e.g. trifluoromethyl))

Optionally substituted with the same or different 1 to 5 (eg, 1 to 3) substituents selected from), or

(4) C _3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) -C _1-3 alkyl (e.g., methyl, ethyl) group (where C _3-8 cycloalkyl is the above group Is optionally substituted with the same or different 1 to 5 substituents selected from B);

R ^3a is a hydrogen atom;

R ^4a and R ^5a are both hydrogen atoms

The compound is more preferred.

In another embodiment of the present invention, in the compound represented by formula [I], a compound represented by the following formula [I-1] is preferred:

[In the formula,

Partial structural formula:

Is a group represented by any of the following formulas:

R ¹¹ is

(1) a hydrogen atom,

(2) C _1-6 alkyl group (e.g. methyl),

(3) a phenyl group,

(4) C _3-8 cycloalkyl group (eg, cyclopropyl),

(5) a phenyl-C _1-6 alkyl group, or

(6) a C _3-8 cycloalkyl-C _1-6 alkyl group;

R ²¹ is

(1) a hydrogen atom,

(2) C _1-10 alkyl group (e.g., ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, 1-ethylpropyl, 3-methylbutyl, 2,2-dimethyl Propyl, 3,3-dimethylbutyl, 2-ethylbutyl, 3,3-dimethylpentyl),

(3) a phenyl group optionally substituted with the same or different 1 to 5 substituents selected from the group B (e.g., fluorine atom, chlorine atom, methyl, cyano, cyclopropyl, trifluoromethyl),

(4) C _3-8 cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl),

(5) C _3-8 cycloalkenyl group (eg, cyclohexenyl),

(6) a thienyl group optionally substituted with the same or different 1 to 5 substituents (eg, chlorine atom, methyl) selected from the group B,

(7) Phenyl-C _1-6 alkyl group (e.g., phenylmethyl, phenylethyl, phenylpropyl) (wherein, phenyl is the same or different 1 to 5 substituents selected from the group B (e.g., fluorine atom, chlorine atom, Cyclopropyl, trifluoromethyl)), or

(8) C _3-8 cycloalkyl-C _1-6 alkyl group (eg, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl);

R ³¹ is

(1) a hydrogen atom,

(2) halogen atom (e.g. chlorine atom),

(3) C _1-6 alkyl group (e.g. ethyl, n-pentyl),

(4) a phenyl group,

(5) C _3-8 cycloalkyl group, or

(6) a phenyl-C _1-6 alkyl group (eg, phenylethyl);

R ⁴¹ and R ⁵¹ are each independently

(1) a hydrogen atom, or

(2) C _1-6 alkyl group (eg, methyl)].

Among the compounds represented by formula [I-1],

R ¹¹ teeth

(1) a hydrogen atom,

(2) C _1-6 alkyl group (e.g. methyl),

(3) a phenyl group, or

(4) a C _3-8 cycloalkyl group (eg, cyclopropyl);

R ²¹ teeth

(1) a hydrogen atom,

(2) C _1-10 alkyl group (e.g., ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, 1-ethylpropyl, 3-methylbutyl, 2,2-dimethyl Propyl, 3,3-dimethylbutyl, 2-ethyltyl, 3,3-dimethylpentyl),

(3) a phenyl group optionally substituted with the same or different 1 to 5 substituents selected from the group B (e.g., fluorine atom, chlorine atom, methyl, cyano, cyclopropyl, trifluoromethyl),

(4) C _3-8 cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl),

(5) C _3-8 cycloalkenyl group (eg, cyclohexenyl),

(6) a thienyl group optionally substituted with the same or different 1 to 5 substituents (eg, chlorine atom, methyl) selected from the group B,

(7) Phenyl-C _1-6 alkyl group (e.g., phenylmethyl, phenylethyl, phenylpropyl) (wherein, phenyl is the same or different 1 to 5 substituents selected from the group B (e.g., fluorine atom, chlorine atom, Cyclopropyl, trifluoromethyl)), or

(8) C _3-8 cycloalkyl-C _1-6 alkyl group (eg, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl);

R ³¹ teeth

(1) a hydrogen atom,

(2) halogen atom (e.g. chlorine atom),

(3) C _1-6 alkyl group (e.g. ethyl, n-pentyl),

(4) a phenyl group, or

(6) a phenyl-C _1-6 alkyl group (eg, phenylethyl);

R ⁴¹ and R ⁵¹ are each independently

(1) a hydrogen atom, or

(2) C _1-6 alkyl group (eg, methyl) phosphorus

Compounds are preferred,

R ¹¹ is a hydrogen atom, methyl, phenyl, or cyclopropyl;

R ²¹ is a hydrogen atom; Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, 1-ethylpropyl, 3-methylbutyl, 2,2-dimethylpropyl, 3,3-dimethylbutyl, 2- Ethylbutyl, 3,3-dimethylpentyl; Phenyl optionally substituted with the same or different 1 to 5 substituents selected from fluorine atom, chlorine atom, methyl, cyano, cyclopropyl and trifluoromethyl; Cyclopentyl, cyclohexyl, cycloheptyl; Cyclohexenyl; Thienyl optionally substituted with the same or different 1 to 5 substituents selected from chlorine atom and methyl; Phenylmethyl, phenylethyl, phenylpropyl (the phenyl is optionally substituted with the same or different 1 to 5 substituents selected from fluorine atom, chlorine atom, cyclopropyl and trifluoromethyl); Cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, or cyclohexylethyl;

R ³¹ is a hydrogen atom, a chlorine atom, ethyl, n-pentyl, phenyl, or phenylethyl;

R ⁴¹ and R ⁵¹ are each independently a hydrogen atom or methyl

The compound is more preferred.

As the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof, the compounds described in Examples 1 to 122 are preferable, and Examples 1, 2, 21, 31, 40, 44, 47, 52, 60, The compounds described in 74, 79, 116, 118, 119, 120, 121 and 122 are particularly preferred.

The pharmaceutically acceptable salt of the compound represented by formula [I] may be any salt as long as it forms a non-toxic salt with the compound of the present invention. Examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids, and the like.

Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like.

Examples of salts with organic acids include salts of oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Includes.

Examples of salts with inorganic bases include sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts and the like.

Examples of salts with organic bases include methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinconine, meglumine.

Examples of salts with amino acids include salts with lysine, arginine, aspartic acid, glutamic acid, and the like.

Each salt can be obtained by reacting a compound represented by formula [I] with an inorganic base, an organic base, an inorganic acid, an organic acid or an amino acid according to a known method.

The "solvate" is a compound represented by formula [I] in which molecules of the solvent are coordinated, or a pharmaceutically acceptable salt thereof, and also includes a hydrate. The solvate is preferably a pharmaceutically acceptable solvate, and includes, for example, a compound represented by formula [I] or a hydrate, ethanolic product, dimethyl sulfoxide, or the like of a pharmaceutically acceptable salt thereof. Specific examples include hemihydrate, monohydrate, dihydrate and monoethanolate of the compound represented by formula [I], monohydrate of the sodium salt of the compound represented by formula [I], or 2/3 ethanolate of dihydrochloride. .

According to a method known per se, a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof can be obtained.

Further, the compound represented by the formula [I], a pharmaceutically acceptable salt thereof, or a solvate thereof has various "isomers". For example, when an E-form and a Z-form exist as geometric isomers, and an asymmetric carbon atom exists, enantiomers and diastereomers exist as stereoisomers based on them, and if axial chirality exists, it is based on these. Stereoisomers exist. In addition, tautomers may also exist. Accordingly, all of these isomers and mixtures thereof are included in the present invention.

In addition, the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, etc.).

As the compound represented by formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof, a compound represented by formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, each substantially purified, is preferable. More preferably, they are a compound represented by formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof, each purified so as to have a purity that can be used as a pharmaceutical.

In the present invention, a prodrug of a compound represented by formula [I] may also be a useful drug. "Prodrug" has a group capable of chemically or metabolically degradable, and after administration to a living body, it is restored to the original compound by, for example, hydrolysis, solvolysis or degradation under physiological conditions, showing its original efficacy. It is a derivative of the compound of the present invention. These include non-covalent complexes, and salts. Prodrugs are used, for example, for improving absorption of oral administration or for targeting to a target site.

Examples of the modified moiety include a highly reactive functional group such as a hydroxyl group, a carboxyl group, and an amino group in the compound of the present invention.

Specific examples of the hydroxyl-modifying group include acetyl group, propionyl group, isobutyryl group, pivaloyl group, palmitoyl group, benzoyl group, 4-methylbenzoyl group, dimethylcarbamoyl group, dimethylaminomethylcarbonyl group, sulfo group, It includes an alanyl group, a fumaryl group, and the like. Further, sodium salts such as 3-carboxybenzoyl group and 2-carboxyethylcarbonyl group can be mentioned.

Specific examples of the carboxyl-modifying group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pivaloyloxymethyl group, carboxymethyl group, dimethylaminomethyl group, 1-(acetyloxy )Ethyl group, 1-(ethoxycarbonyloxy)ethyl group, 1-(isopropyloxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl group, benzyl group, phenyl group, o-tolyl group, morpholinoethyl group, N,N-diethylcarbamoylmethyl group, phthalidyl group, and the like.

Specific examples of the amino-modifying group include tert-butyl group, docosanoyl group, pivaloyloxymethyl group, alanyl group, hexylcarbamoyl group, pentylcarbamoyl group, 3-methylthio-1-(acetylamino)propylcarbonyl group, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, (5-methyl-2-oxo -1,3-dioxol-4-yl)methoxycarbonyl group, tetrahydrofuranyl group, pyrrolidylmethyl group, and the like.

Examples of the "pharmaceutical composition" include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, suspensions, etc., or parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations, transpulmonary preparations, etc. do.

The pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable carrier according to the case of the compound represented by Formula [I] or a pharmaceutically acceptable salt or solvate thereof according to a method known in the technical field of pharmaceutical preparations. It is produced by mixing with an appropriate amount of such as. The content of the compound represented by formula [I] or a pharmaceutically acceptable salt or solvate thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc., and is, for example, 0.1 to 100% by weight of the total composition.

Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier materials commonly used as formulation materials, for example, excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid formulations, and liquids In the formulation, a solvent, a solubility aid, a suspending agent, an isotonic agent, a buffering agent, and a painless agent are included. If necessary, additives such as preservatives, antioxidants, colorants, sweeteners, and the like are used.

Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, Includes Arabian swords, etc.

Examples of "disintegrant" include carmellose, carmellose calcium, chamellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, and the like. do.

Examples of "binders" include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, sodium carmellose, gum arabic and the like.

Examples of "fluidizing agent" include light anhydrous silicic acid, magnesium stearate, and the like.

Examples of "lubricant" include magnesium stearate, calcium stearate, talc, and the like.

Examples of the "solvent" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

Examples of the "solubilizer" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like.

Examples of "suspending agents" include benzalkonium chloride, camelose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate, and the like.

Examples of “isolation agents” include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like.

Examples of "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like.

Examples of the "paining agent" include benzyl alcohol and the like.

Examples of "preservatives" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.

Examples of "antioxidants" include sodium sulfite, ascorbic acid, and the like.

Examples of the "coloring agent" include food coloring (eg, food red No. 2 or 3, food yellow No. 4 or 5, etc.), β-carotene, and the like.

Examples of “sweetening agents” include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.

The compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, has an EPO production-inducing activity by inhibiting prolyl hydroxylase (PHD), and various diseases and conditions (disorders ) Can be used for the prevention or treatment of.

As various diseases and conditions (disorders) resulting from the decrease in the production of EPO, anemia and the like can be mentioned.

In general, anemia is anemia due to hematopoietic abnormalities in the bone marrow, anemia due to a deficiency of iron, vitamin B ₁₂ or folic acid, bleeding during accidents or surgery, chronic inflammation (autoimmune disease, malignant tumor, chronic infection, trait Cell dysfunction, etc.), anemia accompanying endocrine diseases (hypothyroidism, polysilicon autoimmune syndrome, type IA diabetes, irregular uterine bleeding, etc.), anemia accompanying chronic heart failure, anemia accompanying ulcers, liver Anemia accompanying disease, senile anemia, drug-induced anemia, nephrotic anemia (anemia accompanying renal failure), anemia accompanying chemotherapy, and the like are included.

Examples of diseases that are expected to be improved by inhibiting PHD and stabilizing HIF include ischemic heart disease (angina pectoris, myocardial infarction, etc.), ischemic cerebrovascular disorders (cerebral infarction, cerebral embolism, transient cerebral ischemic attack, etc.), chronic renal failure (ischemic kidney disease, tubular epilepsy, etc.). Sexual disorders), diabetes complications (diabetic wounds, etc.), cognitive disorders (dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.).

The prolyl hydroxylase (PHD) inhibitor and the EPO production-inducing agent of the present invention are preferably used as a therapeutic agent for anemia, more preferably as a therapeutic agent for nephrotic anemia.

The pharmaceutical composition of the present invention is oral or parenteral for humans as well as non-human mammals (e.g., mice, rats, hamsters, mormots, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.) It can be administered (eg, topical, rectal, intravenous, etc.). The dosage varies depending on the subject to be administered, disease, symptoms, dosage form, route of administration, and the like. For example, when administered orally to an adult patient (weight: about 60 kg), the dosage is usually in the range of about 1 mg to 1 g based on the compound of the present invention as an active ingredient. This amount can be administered once to several times in divided doses.

The compound of the present invention, or a pharmaceutically acceptable salt thereof or a solvate thereof, inhibits PHD and induces the production of EPO, and thus can be used as an active ingredient in a therapeutic or prophylactic agent for anemia.

"Inhibits PHD" refers to specifically inhibiting the function as prolyl hydroxylase and loss or attenuation of the activity. For example, it means specifically inhibiting the function as prolyl hydroxylase based on the conditions of Test Example 1 described later. "Inhibits PHD" means to inhibit human PHD. As a "PHD inhibitor", it is preferably a "human PHD inhibitor".

"Induces the production of EPO" means that the production of erythropoietin in the kidney or the like is promoted. For example, it means that the production of erythropoietin is induced based on the conditions of Test Example 2 described later. "Induces the production of EPO" preferably means "induces the production of human EPO". As the "EPO production inducing agent", it is preferably a "human EPO production inducing agent".

The compound represented by the above formula [I] or a pharmaceutically acceptable salt or solvate thereof is combined with one or more other drugs (hereinafter also referred to as "combination drugs") according to a method generally employed in the field of medicine. It can be used (hereinafter also referred to as "combination").

The administration period of the compound represented by the formula [I], a pharmaceutically acceptable salt thereof, or a solvate thereof, and a combination drug is not limited, and these can be administered as a combination agent to the administration target, or both agents are simultaneously or constant. It can be administered at intervals. In addition, the pharmaceutical composition and combination drug of the present invention can be used as a kit-type drug. The dosage of the concomitant drug is similar to the dosage used clinically, and can be appropriately selected according to the administration target, disease, symptom, formulation, route of administration, administration time, combination, and the like. The dosage form of the concomitant drug is not particularly limited, as long as the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof and the concomitant drug are combined.

Examples of concomitant drugs include agents for treating and/or preventing anemia, and the like, and the compounds of the present invention may be used in combination.

Examples of "the agent for treating and/or preventing anemia" include ferrous citrate, iron sulfate, and the like.

As PHD, PHD2 and PHD3 can be mentioned.

Next, a method for preparing the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof will be described in detail. However, it goes without saying that the present invention is not limited to these manufacturing methods. In preparing the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, the reaction sequence may be appropriately changed. The reaction can be initiated from a substitution moiety or step that is considered reasonable.

In addition, an appropriate substituent conversion (conversion or additional modification of a substituent) step may be inserted between each step. When a reactive functional group is present, protection and deprotection can be appropriately performed. In addition, in order to accelerate the progress of the reaction, reagents other than the exemplified reagents can be appropriately used. In addition, the raw material compound for which the production method is not described is commercially available or can be produced by combining a known synthetic reaction.

The compound obtained in each step can be purified by conventional methods such as distillation, recrystallization, column chromatography, and the like. In some cases, the compound can be subjected to the next step without isolation and purification.

In the following manufacturing method, "room temperature" means 1-40 degreeC.

Manufacturing Method I-1

(In the formula, R ^11a and R ^11c are each a carboxyl-protecting group such as a methyl group, an ethyl group, a benzyl group, a tert-butyl group, and the like, and R ^11b is an acetyl group, a benzyl group, a methyl group, an ethyl group, an isopropyl group, a trimethylsilyl group. , A hydroxyl-protecting group such as a triethylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, and the like, and X ^11a and X ^11b are each a chlorine atom, a bromine atom, an iodine atom, Halogen atom such as fluorine atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc.)

Step 1

Compound [I-1-2] can be obtained by metallizing compound [I-1-1] according to a conventional method, and introducing a carboxyl group using carbon dioxide. Metallization is carried out in a single or mixed solvent such as hexane, benzene, toluene, tetrahydrofuran, diethyl ether, and 1,4-dioxane under low temperature conditions.N-butyllithium, sec-butyllithium, lithium diisopropylamide, lithium Conducted by reacting with organometallic reagents such as bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium amide, sodium amide, etc., and then reacted with carbon dioxide to compound [I-1 -2] is obtained.

Step 2

Compound [I-1-3] can be obtained by introducing a protecting group to the carboxyl group of compound [I-1-2] according to a conventional method. For example, when the protecting group is a tert-butyl group, p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid , Hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N, in the presence of an acid such as acetic acid, trifluoroacetic acid, etc. Compound [I-1-3] can be obtained by reacting with tert-butyl 2,2,2-trichloroacetimidate in a single or mixed solvent such as N-dimethylformamide and acetonitrile.

Step 3

Compound [I-1-4] can be obtained by introducing a hydroxyl group protected by a protecting group represented by ^{R 11b} into compound [I-1-3] according to a conventional method. For example, in the case of introducing a hydroxyl group protected by a benzyl group, compound [I-1-3] is treated with triethylamine, potassium tert-butoxide, potassium carbonate, sodium hydride, and n-butyllithium under low temperature to heating conditions. , In the presence of a base such as lithium diisopropylamide, hexane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, etc. Compound [I-1-4] can be obtained by reacting with benzyl alcohol in either alone or in a mixed solvent.

Step 4

Compound [I-1-4] under low temperature to heating conditions, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide, N Compound [I-1-5] can be obtained by reacting with hydrazine monohydrate in a single or mixed solvent such as ,N-dimethylformamide, acetonitrile, and water.

Step 5

Compound [I-1-5] in the presence of an acid such as p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trichloride, boron tribromide, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid and the like under low temperature to heating conditions, hexane, Chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide, N,N-dimethylformamide, aceto Compound [I-1-6] can be obtained by reacting with an orthoester compound such as trimethyl orthoformate, triethyl orthoformate, or formic acid in a single or mixed solvent or no solvent such as nitrile.

Step 6

Compound [I-1-6] from room temperature to heating conditions in the presence of a base such as sodium hydroxide, morpholine, piperidine, pyrrolidine, etc., in the presence of hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,2-dime Toxiethane, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, Compound [I-1-7] can be obtained by carrying out an endocyclic relocation reaction in a single or mixed solvent such as acetonitrile.

Step 7

Compound [I-1-8] can be obtained by removing the carboxyl-protecting group of compound [I-1-7] according to a conventional method. For example, when R ^11a is a tert-butyl group, under low temperature to heating conditions, hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, methanol , Ethanol, 2-propanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride, in a single or mixed solvent such as water, Compound [I-1-8] can be obtained by reacting with an acid such as boron trichloride, boron tribromide, aluminum trichloride, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like. When R ^11a is a methyl group, an ethyl group, or a tert-butyl group, compound [I-1-7] is mixed with methanol or ethanol in the presence of a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and lithium hydroxide under low temperature to heating conditions. , 2-propanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, acetonitrile, and the like by hydrolysis in a mixed solvent of water and a compound [I-1 -8] can be obtained.

Step 8

Compound [I-1-9] can be obtained by introducing a protecting group to the carboxyl group of compound [I-1-8] according to a conventional method. For example, when the protecting group is an ethyl group, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2- Compound [I-1] by reacting compound [I-1-8] with N,N-dimethylformamide diethyl acetal in a single or mixed solvent such as propanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, etc. -9] can be obtained.

Steps 7 and 8 can be omitted. In this case, R ^11a = R ^11c .

Step 9

Compound [I-1-10] can be obtained by introducing a leaving group onto the pyridine ring of compound [I-1-9] according to a conventional method. Disubstituted compounds [I-1-11] can be obtained. When the leaving group is an iodine atom, n-butyllithium, sec- in a single or mixed solvent such as hexane, toluene, 1,2-dimethoxyethane, diethyl ether, 1,4-dioxane, and tetrahydrofuran under low temperature conditions. Metallization by reaction with organometallic reagents such as butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium amide, sodium amide, etc. Then, by reacting with iodine after that, the compound [I-1-10] and the compound [I-1-11] can be obtained.

Manufacturing method I-2

(Wherein, R ^12a is a carboxyl-protecting group such as a methyl group, an ethyl group, a benzyl group, and a tert-butyl group, and other symbols are as defined above. [1-2-1] to [1-2-4] Even in the case where R ^{2 of} is other than defined, it may be used as long as the substituent defined by appropriate substituent conversion is finally obtained)

Step 1

Compound [I-2-1] can be obtained by introducing a ^{substituent R 2} or a precursor thereof to compound [I-1-10] according to a conventional method. For example, when R ² is a butyl group, compound [I-1-10] is mixed with [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, tetrakis(tri Palladium catalysts such as phenylphosphine) palladium, bis(triphenylphosphine) palladium(II) dichloride, palladium acetate-triphenylphosphine, etc. and potassium acetate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium phosphate, tri In the presence of a base such as ethylamine, diisopropylethylamine, sodium hydrogen phosphate, cesium carbonate, etc., by adding silver salts such as silver carbonate, silver nitrate, and silver (I) oxide as necessary, hexane, N,N-dimethylform Compound [I] by reacting with butylboronic acid in a single or mixed solvent such as amide, N,N-dimethylacetamide, acetonitrile, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, water, etc. -2-1] can be obtained.

Step 2

Compound [I-2-2] can be obtained by removing the carboxyl-protecting group of compound [I-2-1] in the same manner as in Step 7 of Production Method I-1.

Step 3

Compound [I-2-3] can be obtained by condensing compound [I-2-2] with a glycine derivative represented by _{H 2} NC(R ⁴ )(R ⁵ )COO ^R12a according to a conventional method. For example, compound [I-2-2] under low temperature to heating conditions, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl) In the presence of a condensing agent such as carbodiimide or a salt thereof, diphenylphosphoryl azide, and, if necessary, N-hydroxysuccinimide, 1-hydroxybenzotriazole, dimethylaminopyridine, etc., potassium carbonate if necessary , By adding a base such as sodium hydrogen carbonate, cesium carbonate, triethylamine, diisopropylethylamine, morpholine, pyridine, and the like, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, chloride Compound [I-2-3] can be obtained by condensation with a glycine derivative represented _{by H 2} NC(R ⁴ )(R ⁵ )COO ^R12a in a solvent such as methylene or toluene.

Step 4

Compound [I-2-4] can be obtained by removing the ^{hydroxyl-protecting group R 11b} of the compound [I-2-3] according to a conventional method. For example, when R ^11b is a benzyl group, in the presence of a catalyst such as palladium carbon, palladium hydroxide, platinum oxide, platinum carbon, Raney-nickel, etc., in the presence of a catalyst such as palladium carbon, palladium hydroxide, platinum oxide, platinum carbon, under hydrogen atmosphere under a hydrogen atmosphere under room temperature to heating conditions, hexane, methanol , Ethanol, 2-propanol, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, acetic acid, or a compound by hydrogenation in a mixed solvent such as water [I-2-4] Can be obtained.

Step 5

Compound [I-2-5] can be obtained by removing the carboxyl-protecting group of compound [I-2-4] in the same manner as in Step 7 of Production Method I-1.

Manufacturing Method I-3

^{(In the formula, even when R 2} and R ³ of [I-3-1] and [I-3-2] are other than the defined substituents, if the substituent defined by appropriate substituent conversion is finally obtained, May be used, and other symbols are as defined above)

Step 1

In the same manner as in Step 1 of Production Method I-2, compound [I-3-1] can be obtained by introducing ^{substituents R 2} and R ^{3 or a precursor thereof to compound [I-1-11].} For example, in ^{the case of introducing an alkenyl group as a precursor of R 2} and R ³ , the compound [I-1-11] is reacted with alkenylboronic acid in the same manner as in Step 1 of Production Method I-2. -3-1] can be obtained.

Step 2

Compound [I-3-2] can be obtained by deprotecting ^{R 11b} of compound [I-3-1] in the same manner as in Step 4 of Production Method I-2.

Step 3

Compound [I-3-3] can be obtained by reacting compound [I-3-2] with a glycine derivative represented _{by H 2} NC(R ⁴ )(R ^{5 )COOH.} For example, compound [I-3-2] was mixed with hexane, chloroform, methylene chloride, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, under heating conditions from room temperature. Compound [I-3-3] by reacting with the sodium salt of the glycine derivative in a single or mixed solvent such as 2-propanol, 2-methoxyethanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, water, etc. You can get it.

Manufacturing Method I-4

^{(In the formula, even in the case where R 3} of [I-4-2] and [I-4-3] is other than the defined substituent, it may be used as long as the substituent defined by appropriate substituent conversion is finally obtained, and , Other symbols are as defined above)

Step 1

Compound [I-1-11] under low temperature to heating conditions [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, tetrakis(triphenylphosphine)palladium, bis(triphenylphos) Hexane, chloroform, methylene chloride, ethyl acetate, benzene, toluene, 1 in the presence of a palladium catalyst such as pin) palladium (II) dichloride, palladium acetate-triphenylphosphine, and the like and a reducing agent such as tri-n-butyltin hydride, etc. Compound [I-4-1] can be obtained by stirring in a single or mixed solvent such as ,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethyl ether, acetonitrile, and water.

Step 2

In the same manner as in Step 1 of Production Method I-2, compound [I-4-2] can be obtained by substituting ^{X 11b} of compound [I-4-1] with R ^{3 or a precursor thereof.}

Step 3

Compound [I-4-3] can be obtained by deprotecting ^{R 11b} of compound [I-4-2] in the same manner as in Step 4 of Production Method I-2.

Step 4

In the same manner as in Step 3 of Preparation Method I-3, the compound [I-4-3] is reacted _{with a glycine derivative represented by H 2} NC(R ⁴ )(R ⁵ )COOH or a salt thereof with a metal species thereof, I-4-4] can be obtained.

Manufacturing Method I-5

(In the formula, each symbol is as defined above)

Step 1

Compound [I-5-1] can be obtained by introducing a ^{substituent R 3} to compound [I-1-10] according to a conventional method. For example, when R ³ is a chloro group, compound [I-1-10] is used under low temperature conditions for n-butyllithium, lithium hexamethyl disilazide, sodium bis(trimethylsilyl)amide, potassium hexamethyl disilazide, In the presence of organometallic reagents such as lithium diisopropylamide, tert-butoxide, etc., hexachloroethane, etc., in a single or mixed solvent such as hexane, benzene, toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, etc. Compound [I-5-1] can be obtained by reacting with a chlorinating agent.

Step 2

Compound [I-5-2] can be obtained by ^{substituting the substituent X 11b} of the compound [I-5-1] with a substituent R ² or a precursor thereof in the same manner as in Step 1 of Production Method I-2.

Step 3

Compound [I-5-3] can be obtained by deprotecting the ^{hydroxyl-protecting group R 11b} of the compound [I-5-2] in the same manner as in Step 4 of Production Method I-2.

Step 4

_{Compound [I-5-3] by reacting with a glycine derivative represented by H 2} NC(R ⁴ )(R ⁵ )COOH or a salt thereof with a metal species in the same manner as in Step 3 of Preparation Method I-3 [ I-5-4] can be obtained.

Manufacturing Method I-6

(In the formula, R ^16a is an acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group And a hydroxyl-protecting group such as, and R ^16b and R ^16c are each a carboxyl-protecting group such as a methyl group, an ethyl group, a benzyl group, a tert-butyl group, and the like, and X ^16a is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like. A halogen atom or a leaving group such as p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc., and other symbols are as defined above. ^{R 2} of -10] can be used as long as the substituent defined by appropriate substituent conversion is finally obtained, even when it is other than the defined substituent)

Step 1

In the same manner as in Step 3 of Production Method I-1, compound [I-6-2] can be obtained by introducing a hydroxyl group protected by a protecting group ^{R 16a into compound [I-6-1].}

Step 2

In the same manner as in Step 1 of Production Method I-1, compound [I-6-3] can be obtained by introducing a carboxyl group protected by a protecting group ^{R 16b into compound [I-6-2].}

Step 3

In the same manner as in Step 1 of Production Method I-2, compound [I-6-4] can be obtained by introducing a ^{substituent R 2 or a precursor thereof to compound [I-6-3].}

Step 4

In the same manner as in Step 4 of Production Method I-1, compound [I-6-5] can be obtained from compound [I-6-4].

Step 5

In the same manner as in Step 5 of Production Method I-1, compound [I-6-6] can be obtained from compound [I-6-5].

Step 6

In the same manner as in Step 6 of Production Method I-1, compound [I-6-7] can be obtained from compound [I-6-6].

Step 7

In the same manner as in Step 7 of Production Method I-1, compound [I-6-8] can be obtained by removing the carboxyl-protecting group of compound [I-6-7].

Step 8

Compound [I-6-9] by condensing _{compound [I-6-8] with a glycine derivative represented by H 2} NC(R ⁴ )(R ⁵ )COOR ^16c in the same manner as in Step 3 of Preparation Method I-2. Can be obtained.

Step 9

Compound [I-6-10] can be obtained by removing the ^{hydroxyl-protecting group R 16a} of the compound [I-6-9] in the same manner as in Step 4 of Production Method I-2.

Step 10

In the same manner as in Step 7 of Production Method I-1, compound [I-6-11] can be obtained by removing the carboxyl-protecting group of compound [I-6-10].

Manufacturing Method I-7

^(Wherein , R 17a is a carboxyl-protecting group such as a methyl group, an ethyl group, a benzyl group, a tert-butyl group, etc., and X ^17a is a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like, or p-toluenesulfo It is a leaving group such as niloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc.)

Step 1

Compound [I-7-1] under low temperature to heating conditions, hexane, ethyl acetate, chloroform, methylene chloride, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2 -Presence of organometallic reagents such as nickel (II) acetylacetonate in a single or mixed solvent such as propanol, dimethyl sulfoxide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, acetonitrile, water, etc. The compound [I-7-2] can be obtained by reacting with cyanamide.

Step 2

Compound [I-7-3] can be obtained by converting the hydroxyl group of compound [I-7-2] to a leaving group according to a conventional method. For example, when the leaving group X ^17a is a chlorine atom, compound [I-7-2] is used in hexane, ethyl acetate, acetone, chloroform, methylene chloride, toluene, 1,4-dioxane, tetra In a single or mixed solvent or no solvent such as hydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide, N,N-dimethylformamide, 2-pyrrolidone, and acetonitrile, If necessary, the presence of a base such as triethylamine, pyridine, 4-(dimethylamino)pyridine, N-methylmorpholine, diisopropylethylamine, tetramethylethylenediamine, etc. and N,N-dimethylformamide as necessary Then, the compound [I-7-3] can be obtained by chlorination using thionyl chloride, oxalyl chloride, triphosgene, phosphorus pentachloride, phosphorus oxychloride, or the like.

Step 3

Compound [I-7-3] under low temperature to heating conditions, ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide Compound [I-7-4] by reacting with N,N-dimethylformamide dialkyl acetal in a seed, N,N-dimethylformamide, acetonitrile, etc. alone or in a mixed solvent, and then reacting with hydroxylamine or its hydrochloride salt. ] Can be obtained.

Step 4

Compound [I-7-4] under low to high temperature conditions, hexane, ethyl acetate, acetone, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, N, By dehydration reaction using polyphosphoric acid, thionyl chloride, phosphorus oxychloride, p-toluenesulfonyl chloride, acetic anhydride, acetyl chloride, trifluoroacetic anhydride, etc. in a single or mixed solvent such as N-dimethylformamide and acetonitrile. A compound [I-7-5] can be obtained.

Manufacturing Method I-8

^(Wherein , R 18a is an acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group And a hydroxyl-protecting group such as, and R ^18b is a carboxyl-protecting group such as a methyl group, an ethyl group, a benzyl group, a tert-butyl group, and the like, and other symbols are as defined above)

Step 1

In the same manner as in Step 1 of Production Method I-2, compound [I-8-1] can be obtained by introducing a ^{substituent R 2 or a precursor thereof to compound [I-7-5] according to a conventional method.}

Step 2

Compound [I-8-2] can be obtained by introducing a hydroxyl group protected by a protecting group represented ^{by R 18a} into compound [I-8-1]. For example, when introducing a hydroxyl group protected by a methyl group, compound [I-8-1] is hexane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran under low temperature to heating conditions. , 1,4-dioxane, 1,2-dimethoxyethane, toluene, methanol, by reacting with sodium methoxide in a single or mixed solvent such as water, or under low temperature to heating conditions, methanol alone or hexane, dimethyl sulfoxide, In a mixed solvent of N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, etc., triethylamine, potassium tert-butoxide, sodium methoxide, Compound [I-8-2] can be obtained by reacting with a base such as potassium carbonate, sodium hydride, n-butyllithium, lithium diisopropylamide, or the like.

Step 3

In the same manner as in Step 7 of Production Method I-1, compound [I-8-3] can be obtained by removing the carboxyl-protecting group of compound [I-8-2].

Step 4

Compound [I-8-4] by condensing compound [I-8-3] with a glycine derivative represented _{by H 2} NC(R ⁴ )(R ⁵ )COOR ^18b in the same manner as in Step 3 of Preparation Method I-2. Can be obtained.

Step 5

Compound [I-8-5] can be obtained by removing the hydroxyl-protecting group R ^18a and the carboxyl-protecting group R ^18b of the compound [I-8-4] according to a conventional method. For example, when R ^18a is a methyl group and R ^18b is a tert-butyl group, compound [I-8-4] is used from room temperature to heating conditions under p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trifluoride-diethyl In the presence of an acid such as ether complex, boron trichloride, boron tribromide, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, etc., hexane, ethyl acetate, acetone, chloroform, methylene chloride, ethyl acetate, toluene, 1 ,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacet Compound [I-8-5] can be obtained by stirring in a single or mixed solvent such as amide, acetonitrile, acetic acid, and water.

Manufacturing Method I-9

(In the formula, R ^19a is a carboxyl-protecting group such as a methyl group, an ethyl group, a benzyl group, a tert-butyl group, etc., and R ^19b is a metal species forming a salt with a carboxylic acid or phenol such as lithium, sodium, calcium, etc., Other symbols are as described above)

Step 1

In the same manner as in Step 7 of Production Method I-1, compound [I-9-1] can be obtained by removing the carboxyl-protecting group of compound [I-8-1].

Step 2

Compound [I-9-2] by condensing _{compound [I-9-1] with a glycine derivative represented by H 2} NC(R ⁴ )(R ⁵ )COOR ^19a in the same manner as in Step 3 of Preparation Method I-2. Can be obtained.

Step 3

Compound [I-9-3] can be obtained by reacting compound [I-9-2] with a base. For example, when R ^19b is sodium, dimethyl sulfoxide, N,N-dimethylformamide, dimethylacetamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2- Compound [I-9-3] can be obtained by reacting with sodium hydroxide in a single or mixed solvent such as dimethoxyethane, toluene, methanol, ethanol, 2-methoxy ethanol, 2-ethoxy ethanol, and water.

Step 4

Compound [I-9-3] under low temperature to heating conditions, dimethyl sulfoxide, N,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, Acetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, etc. in a single or mixed solvent such as toluene, methanol, ethanol, 2-methoxy ethanol, 2-ethoxy ethanol, water, etc. Compound [I-9-4] can be obtained by reacting with the same acid.

Manufacturing Method II-1

(In the formula, R ^21a is benzyl group, acetyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyl dimethylsilyl group, triisopropyl silyl group, tert-butyldiphenylsilyl group A hydroxyl-protecting ^{group such as, etc., R 21b} is a carboxyl-protecting group such as a methyl group, an ethyl group, a benzyl group, a tert-butyl group, and the like, and other symbols are as described above. ^{R 2} of 1-9] may be used as long as the substituent defined by appropriate substituent conversion is finally obtained, even if it is other than the defined substituent)

Step 1

Compound [II-1-1] under low temperature to heating conditions p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, sulfamic acid, In the presence of an acid such as acetic acid, trifluoroacetic acid, hexane, chloroform, methylene chloride, ethyl acetate, methanol, ethanol, 2-propanol, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane , Dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, water, or the like, in a single or mixed solvent, reacting with 2,5-hexanedione to obtain a compound [II-1-2].

Step 2

In the same manner as in Step 3 of Production Method I-1, compound [II-1-3] can be obtained by introducing a hydroxyl group protected by a protecting group represented ^{by R 21a into compound [II-1-2].}

Step 3

Compound [II-1-3] under low temperature to heating conditions, methanol, ethanol, in the presence of a base such as triethylamine, potassium tert-butoxide, potassium carbonate, sodium hydride, lithium diisopropylamide and the like and hydroxylammonium chloride, Compound [II-1-4] can be obtained by stirring in a single or mixed solvent such as 2-propanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and water.

Step 4

Compound [II-1-4] from room temperature to heating conditions in ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide Reaction with N,N-dimethylformamide dimethyl acetal in a single or mixed solvent such as seed, N,N-dimethylformamide, acetonitrile, etc., to obtain a compound, which is hexane, ethyl acetate, acetone, chloroform under low to high temperature conditions , Toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, etc. In the presence of a base such as triethylamine, diisopropylethylamine, morpholine, pyridine, and reacting with hydroxylamine or a salt thereof, and reacting with polyphosphoric acid or hydroxylamine-O-sulfonic acid, the compound [II-1- 5] can be obtained.

Step 5

In the same manner as in Step 1 of Production Method I-1, compound [II-1-6] can be obtained by introducing a carboxyl group into compound [II-1-5].

Step 6

Compound [II-1-7] can be obtained by introducing a ^{protecting group R 21b} to the carboxyl group of compound [II-1-6] according to a conventional method. For example, when R ^21b is an ethyl group, compound [II-1-6] is mixed with hexane, chloroform, methylene chloride, ethyl acetate, toluene, 1,4-dioxane, tetrahydrofuran, 1, under room temperature to heating conditions. Compound [II-1-7] was obtained by reacting with N,N-dimethylformamide diethyl acetal in a single or mixed solvent such as 2-dimethoxyethane, dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile. I can.

Step 7

Compound [II-1-8] can be obtained by introducing a ^{substituent R 2} or a precursor thereof to compound [II-1-7] according to a conventional method. For example, in the case of introducing a tert-butylacetylene group, compound [II-1-7] is used from room temperature to heating conditions under [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, tetrakis Palladium catalysts such as (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, palladium acetate-triphenylphosphine, etc., potassium acetate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium phosphate Hexane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, 1,2 -Compound [II-1-8] can be obtained by reacting with tert-butylacetylene in a single or mixed solvent such as dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, and water.

Step 8

Compound [II-1-9] can be obtained by deprotecting the ^{hydroxyl-protecting group R 21a} of the compound [II-1-8] in the same manner as in Step 4 of Production Method I-2.

Step 9

In the same manner as in Step 3 of Production Method I-3, compound [II-1-10] can be obtained from compound [II-1-9].

In this production method, a production method in the case where R ¹ is a hydrogen atom has been described. When R ¹ is the aforementioned substituent and is other than a hydrogen atom, in step 4, instead of N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide dimethyl acetal substituted with a desired substituent can be used. And, in step 5 and after, it can be carried out in a method similar to the method described in this manufacturing method.

Manufacturing Method III-1

(In the formula, R ^31a and R ^31d are each a carboxyl-protecting group such as a methyl group, an ethyl group, a benzyl group, a tert-butyl group, and the like, and R ^31b and R ^31c are each a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a benzyl group, etc. The same is an amino-protecting group, and X ^31a and X ^31b are each halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. Leaving group, other symbols are as defined above)

Step 1

^{Compound [III-1-1] obtained by deprotecting R 11b} of compound [I-1-4] in the same manner as in Step 4 of Preparation Method I-2 by introducing a ^{leaving group X 31b according to a conventional method} [III-1-2] can be obtained. For example, when X ^31b is a bromine atom, compound [III-1-1] is used under low temperature to heating conditions in hexane, chloroform, methylene chloride, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, and aceto. Compound [III-1-2] can be obtained by reacting with bromine or N-bromosuccinimide in a single or mixed solvent such as nitrile and water.

Step 2

Compound [III-1-3] can be obtained by introducing ^{R 31b} to compound [III-1-2] according to a conventional method. For example, when R ^31b is a benzyl group, compound [III-1-2] may be selected from ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, Compounds by reacting with benzyl chloride or benzyl bromide in the presence of a base such as potassium carbonate, potassium tert-butoxide, sodium hydride, cesium carbonate, or the like in a single or mixed solvent such as N,N-dimethylformamide, acetonitrile, water, etc. III-1-3] can be obtained.

Step 3 and Step 4

^{R 31a} of compound [III-1-3] was deprotected in the same manner as in step 7 of Preparation Method I-1, converted to acid chloride according to a conventional method, and the acid chloride was converted to triethyl under low temperature to heating conditions. _{H 2} NC(R ⁴ )(R ⁵ )COOR ^{31d in} a single or mixed solvent such as hexane, chloroform, methylene chloride, ethyl acetate, toluene, and tetrahydrofuran in the presence of a base such as amine, diisopropylethylamine, pyridine, etc. Compound [III-1-4] is obtained by reacting with a glycine derivative represented by, and the compound is hexane, chloroform, methylene chloride in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, etc. under low temperature to heating conditions. , [III-1-6] can be obtained by reacting with compound [III-1-5] in a single or mixed solvent such as ethyl acetate, toluene, tetrahydrofuran, and 1,4-dioxane.

Step 5

In the same manner as in Step 1 of Production Method I-2, compound [III-1-7] can be obtained from compound [III-1-6].

Step 6

Compound [III-1-8] can be obtained by deprotecting ^{R 31b} of compound [III-1-7] in the same manner as in Step 4 of Production Method I-2.

Step 7

Compound [III-1-9] can be obtained by removing ^{the amino-protecting group R 31c} of the compound [III-1-8] according to a conventional method. For example, when R ^31c is a tert-butoxycarbonyl group, hexane, chloroform, methylene chloride, ethyl acetate in the presence of an acid such as hydrogen chloride, sulfuric acid, hydrogen bromide, phosphoric acid, acetic acid, trifluoroacetic acid or the like under low to room temperature conditions , Toluene, methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, water, or the like alone or in a mixed solvent to obtain a compound [III-1-9].

Step 8

In the same manner as in Step 5 of Production Method I-1, compound [III-1-10] can be obtained from compound [III-1-9].

Step 9

Compound [III-1-11] can be obtained by removing the carboxyl-protecting group of compound [III-1-10] in the same manner as in Step 7 of Production Method I-1.

Manufacturing Method III-2

(In the formula, R ^32a is a carboxyl-protecting group such as methyl group, ethyl group, benzyl group, tert-butyl group, etc., and other symbols are as described above)

Step 1

In the same manner as in Step 5 of Production Method I-1, compound [III-2-1] can be obtained from compound [I-6-5].

Step 2

Compound [III-2-2] can be obtained by removing the carboxyl-protecting group of compound [III-2-1] in the same manner as in Step 7 of Production Method I-1.

Step 3

Compound [III-2-3] by condensing compound [III-2-2] with a glycine derivative represented _{by H 2} NC(R ⁴ )(R ⁵ )COOR ^32a in the same manner as in Step 3 of Preparation Method I-2. Can be obtained.

Step 4

Compound [III-2-4] can be obtained by deprotecting ^{R 16a} of compound [III-2-3] in the same manner as in Step 4 of Production Method I-2.

Step 5

Compound [III-2-5] can be obtained by removing the carboxyl-protecting group of compound [III-2-4] in the same manner as in Step 7 of Production Method I-1.

Manufacturing Method IV-1

^(Wherein , R 41a is an acetyl group, benzyl group, methyl group, ethyl group, isopropyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group a protecting group, R ^41b is a methyl group, an ethyl group, a benzyl group, a carboxyl group, such as tert- butyl-a protecting group, a halogen atom such as X ^41a and X ^41b each are a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group, such as leaving groups such as p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyl group, methanesulfonyl group, etc., and other symbols are as defined above)

Step 1

^{Compound [IV-1-2] can be obtained by converting the leaving group X 41a} of the compound [IV-1-1] to a formyl group according to a conventional method. Compound [IV-1-1] in a single or mixed solvent such as hexane, benzene, toluene, tetrahydrofuran, diethyl ether, and 1,4-dioxane under low temperature conditions, n-butyllithium, sec-butyllithium, lithium After reacting with organometallic reagents such as diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium amide, sodium amide, etc., N,N-dimethylform By reacting with an amide, the compound [IV-1-2] can be obtained.

Step 2 and Step 3

Compound [IV-1-2] under room temperature to heating conditions, ethyl acetate, chloroform, toluene, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, isopropanol, dimethyl sulfoxide, ^{By reacting with hydrazine having a leaving group X 41b} in a single or mixed solvent such as N,N-dimethylformamide, acetonitrile, etc., adding a base such as morpholine, piperidine, pyrrolidine, and the like, and stirring the mixture, The compound [IV-1-4] can be obtained.

Step 4

In the same manner as in Step 1 of Production Method I-1, compound [IV-1-5] can be obtained from compound [IV-1-4].

Step 5

Compound [IV-1-6] can be obtained by condensing compound [IV-1-5] with a glycine derivative in the same manner as in Step 3 of Production Method I-2.

Step 6

Compound [IV-1-7] can be obtained by deprotecting ^{R 41a} of compound [IV-1-6] in the same manner as in Step 4 of Production Method I-2.

Step 7

Compound [IV-1-8] can be obtained by removing the carboxyl-protecting group of compound [IV-1-7] in the same manner as in Step 7 of Production Method I-1.

In this production method, a production method in the case where R ¹ is a hydrogen atom has been described. When R ¹ is the aforementioned substituent and is other than a hydrogen atom, in step 1, instead of N,N-dimethylformamide, N,N-dimethylformamide substituted with a desired substituent may be used, and step 2 And hereinafter, it can be carried out by a method similar to the method described in the present manufacturing method.

Example

Now, a method for preparing the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof will be described in detail by examples. However, the present invention is not limited by these examples.

Example 1

{[5-(4-fluoro-3-trifluoromethylphenyl)-7-hydroxy[1,2,4]triazolo[1,5-a]pyridin-8-carbonyl]amino}acetic acid hydrochloride Manufacture of

Step 1-1

Under a stream of nitrogen, diisopropylamine (198 ml) and tetrahydrofuran (1000 ml) were mixed, and n-butyllithium (2.76M, 500 ml) was added dropwise under cooling in a dry ice/hexane bath. After stirring for 1 hour in a dry ice/hexane bath, 2,4-dichloropyridine was added dropwise. After stirring under cooling for 1 hour in a dry ice/hexane bath, carbon dioxide was blown out until the temperature increase was stopped while the temperature did not reach -60°C or higher. Under cooling in a dry ice/hexane bath, carbon dioxide was further flushed for 30 minutes, and 4N hydrochloric acid (1000 ml) was added dropwise. The aqueous layer was extracted twice with ethyl acetate (1000 ml, 500 ml each). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was slurried in hexane to obtain the compound described in the scheme (243 g, 96%).

Step 1-2

The compound (234 g) and tetrahydrofuran (1200 ml) obtained in step 1-1 were mixed, and boron trifluoride-diethyl ether complex (8 ml) was added. Then, tert-butyl 2,2,2-trichloroacetimidate (361 ml) was added dropwise under ice cooling. A saturated aqueous sodium hydrogen carbonate solution (1200 ml) and water (1200 ml) were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (1200 ml). The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Hexane (1800 ml) was added to the obtained residue. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain the compound described in the above scheme (326 g) as a crude product.

Step 1-3

Under a stream of nitrogen, sodium hydride (60% oil suspension) (58 g) and N,N-dimethylformamide (1000 ml) were mixed under ice cooling. The compound (326 g) obtained in step 1-2 was dissolved in N,N-dimethylformamide (300 ml) and added thereto. To this mixture was added a mixture of benzyl alcohol (136 ml) and N,N-dimethylformamide (200 ml). After stirring for 15 minutes under ice cooling, sodium hydride (60% oil suspension) (5.2 g) was added. After stirring for an additional 20 minutes under ice cooling, water (3000 ml) was added, the precipitated solid was filtered, and the filtrate was dried at 50° C. overnight under reduced pressure. The solid was purified by column chromatography (eluent: hexane/ethyl acetate=10/1-ethyl acetate alone). The obtained solid was further slurried in hexane to obtain the desired product. At this time, the filtrate was concentrated, purified by column chromatography, and slurried in hexane to obtain the desired product. These were collected to obtain the compound described in the above scheme (334 g, 83% yield).

Step 1-4

The compound obtained in step 1-3 (167 g), hydrazine monohydrate (127 ml) and 1,4-dioxane (1200 ml) were mixed, and the reaction mixture was stirred at 94° C. for 17 hours. After cooling to room temperature, ethyl acetate (1700 ml) was added, and the mixture was mixed with a saturated aqueous sodium hydrogen carbonate solution (500 ml)/water (500 ml), a saturated aqueous sodium hydrogen carbonate solution (250 ml)/water (250 ml), and It was washed successively with saturated aqueous sodium hydrogen carbonate solution (200 ml)/water (200 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. By carrying out the above operation twice, the compound described in the scheme (266 g) was obtained as a crude product.

Step 1-5

The compound (266 g) and trimethyl orthoformate (1000 ml) obtained in the same manner as in steps 1-4 were mixed, p-toluenesulfonic acid monohydrate (80 g) was added, and the mixture was stirred at 56° C. for 1 hour. Stirred. The reaction mixture was concentrated under reduced pressure, and the obtained residue was slurried in hexane/ethyl acetate = 2/1. Furthermore, the residue was slurried in a saturated aqueous sodium hydrogen carbonate solution/water=1/1 to obtain the compound described in the above scheme (209 g, 76%).

Step 1-6

The compound (200 g) and ethyl acetate (600 ml) obtained in steps 1-5 were mixed, morpholine (160 ml) was added, and the mixture was stirred at 74° C. for 3 hours. The mixture was allowed to cool to room temperature and water (600 ml) was added. The aqueous layer was extracted with ethyl acetate (400 ml), the organic layers were combined, and washed successively with a 5% aqueous potassium hydrogen sulfate solution (600 ml) and saturated brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound described in the scheme (194 g, 97%).

Step 1-7

Under a stream of nitrogen, the compound (194 g) and tetrahydrofuran (600 ml) obtained in steps 1-6 were mixed under cooling in a dry ice/hexane bath, and iodine (151 g) in tetrahydrofuran (500 ml) was mixed. The solution was added dropwise. To this mixture, 1.6M lithium bis(trimethylsilyl)amide (788 ml) was added dropwise while keeping the temperature not higher than -60°C. After stirring for 2 hours under cooling in a dry ice/hexane bath, 4N hydrochloric acid-ethyl acetate (315 ml) was added dropwise while keeping the temperature not higher than -60°C. Sodium sulfite (76 g) was added to the reaction mixture, and saturated aqueous ammonium chloride solution (1000 ml), water (800 ml) and hexane/ethyl acetate=1/1 (1000 ml) were added. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution (500 ml) and saturated brine (800 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried in hexane to obtain the compound described in the scheme (188 g, 70%).

Step 1-8

Compound obtained in step 1-7 (60 g), 4-fluoro-3-(trifluoromethyl)phenylboronic acid (29 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) Dichloride dichloromethane complex (1:1) (5.4 g), potassium phosphate (113 g) and 1,2-dimethoxyethane (600 ml) were mixed, and the mixture was stirred at 80°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform/ethyl acetate=10/1) to obtain a crude product of the compound described in the above scheme. This was slurried in diisopropyl ether/hexane=1/1 (500 ml) to obtain the compound described in the above scheme (45 g, 70%).

Step 1-9

The compound (45 g) and 1,4-dioxane (450 ml) obtained in steps 1-8 were mixed, and a 4N aqueous sodium hydroxide solution (116 ml) was added at room temperature. After stirring at 100°C for 17 hours, the reaction mixture was concentrated under reduced pressure. Water (450 ml) was added thereto, and the mixture was neutralized under ice-cooling with 6N hydrochloric acid (77 ml), and the precipitated solid was collected by filtration to obtain the compound described in the scheme (43 g).

Step 1-10

The compound obtained in steps 1-9 (43 g), glycine ethyl ester hydrochloride (15 g), 1-hydroxybenzotriazole hydrate (17 g) and N,N-dimethylformamide (430 ml) were mixed, and , Triethylamine (15 ml) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (21 g) were added at room temperature. After stirring at room temperature for 1 hour, water (860 ml) and saturated aqueous sodium hydrogen carbonate solution (215 ml) were added, and the precipitated solid was collected by filtration to obtain the compound described in the scheme (43 g, 84%). .

Step 1-11

The compound (43 g) and trifluoroacetic acid (430 ml) obtained in step 1-10 were mixed, and after stirring at 80° C. for 6 hours, the reaction mixture was concentrated under reduced pressure. Methanol (86 ml) and water (430 ml) were added to the residue, the mixture was stirred at room temperature for 30 minutes, and the precipitated solid was collected by filtration. This was purified by column chromatography (eluent: chloroform/ethyl acetate=10/1) to obtain the compound described in the scheme (28 g, 79%).

Step 1-12

The compound (27 g) and 2-propanol (540 ml) obtained in steps 1-11 were mixed, and a 4N aqueous lithium hydroxide solution (64 ml) was added at room temperature. After stirring at 70° C. for 1 hour, 6N hydrochloric acid (43 ml) was added. When this was allowed to cool slowly under stirring, crystals precipitated at 37°C. Water (270 ml) was added, and the crystals were collected by filtration to give the compound described in the scheme (22 g, 87%).

The obtained compound was converted to hydrochloride according to a conventional method to obtain the compound of Example 1.

Example 2

Preparation of [(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridin-8-carbonyl)amino]acetic acid hydrochloride

Step 2-1

The compound obtained in steps 1-7 (5.00 g), toluene (35 ml) and phenylacetylene (1.34 ml) were mixed, bis(triphenylphosphine)palladium dichloride (0.233 g), copper iodide (0.063 g) And triethylamine (1.85 ml) were successively added under ice cooling. After stirring at room temperature for 2 hours, 5% aqueous ammonia (35 ml) was added to the reaction mixture. The organic layer was further washed successively with 5% aqueous ammonia, saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: hexane/ethyl acetate = 3/1-1/1). The obtained compound was slurried in hexane to obtain the compound described in the above scheme (3.84 g, 82%).

Step 2-2

The compound obtained in step 2-1 (3.84 g), toluene (29 ml) and ethyl acetate (9.5 ml) were mixed, and a mixture of methanesulfonic acid (2.34 ml) and ethyl acetate (2.34 ml) was brought to room temperature over 10 minutes. It was added dropwise under stirring at. After stirring at room temperature for 3 hours, ethyl acetate (9.5 ml) was added to the reaction mixture, and the solid was collected by filtration to give the compound described in the scheme (4.94 g, 98%).

Step 2-3

The compound (4.94 g) and N,N-dimethylformamide (30 ml) obtained in step 2-2 were mixed at room temperature, and water (50 ml) was added dropwise at 0° C. over 10 minutes. The precipitated solid was collected by filtration to obtain the compound described in the above scheme (3.20 g, 98%).

Step 2-4

The compound (3.20 g) obtained in step 2-3 was reacted with glycine ethyl ester hydrochloride (1.33 g) by a method similar to that of step 1-10 of Example 1 to obtain the compound described in the above scheme (3.38 g, 81%).

Step 2-5

5% palladium carbon (0.34 g) was added to a solution of the compound (3.38 g) obtained in step 2-4 in tetrahydrofuran (34 ml) and methanol (17 ml), and the mixture was stirred under a hydrogen atmosphere and atmospheric pressure for 4 hours. I did. The reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: chloroform/methanol=20/0-20/1) and slurried in hexane/diisopropyl ether=1/1 to obtain the compound described in the scheme (2.29 g). , 83%).

Step 2-6

The compound (2.28 g) obtained in step 2-5 was hydrolyzed by a method similar to that of steps 1-12, and the obtained compound was changed to hydrochloride according to a conventional method to obtain the title compound (2.16 g).

Example 3

Preparation of [(5-butyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridin-8-carbonyl)amino]acetic acid hydrochloride

Step 3-1

The compound obtained in step 1-7 (0.2 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (0.011 g), butylboronic acid (0.050 g), silver (I) oxide (0.12 g), potassium carbonate (0.15 g) and tetrahydrofuran (1.6 ml) were mixed, and the mixture was stirred at 80°C for 40 hours. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: hexane/ethyl acetate=8/2-6/4) to obtain the compound described in the scheme (0.13 g, 77%).

Step 3-2

The carboxyl-protecting group of the compound (53.7 g) obtained in step 3-1 was removed in the same manner as in step 2-2 to obtain a carboxylic acid product as a mixture with methanesulfonic acid (290 mol%) (69.8 g, 80%). The mixture was treated in the same manner as in step 2-3 to give the compound described in the scheme above as a mixture with methanesulfonic acid (50 mol%) (42.8 g, 99%).

Step 3-3

By a method similar to steps 1-10, the compound (42.8 g) obtained in step 3-2 was reacted with glycine ethyl ester hydrochloride (19.3 g) to obtain the compound described in the above scheme (43.5 g, 92%). .

Step 3-4

In the same manner as in step 2-5, the compound described in the scheme (5.0 g, 90%) was obtained from the compound (7.2 g) obtained in step 3-3.

Step 3-5

In the same manner as in steps 1-12, the compound described in the scheme (4.56 g) was obtained from the compound (4.94 g) obtained in step 3-4.

Step 3-6

The compound obtained in step 3-5 (4.56 g) and a 4N hydrochloric acid/ethyl acetate solution (91 ml) were mixed, and the mixture was stirred at room temperature for 1.5 hours. The reaction suspension was concentrated under reduced pressure, hexane (100 ml) was added to the residue, and the mixture was concentrated under reduced pressure twice. A mixed solution (100 ml) of diethyl ether/hexane = 1/2 was added to the residue, and the mixture was stirred for 30 minutes. The solid was collected by filtration to give the title compound (4.88 g, 96%).

Example 4

Preparation of [(5,6-diethyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridin-8-carbonyl)amino]acetic acid hydrochloride

Step 4-1

Under a stream of nitrogen, the compound (3.98 g) and tetrahydrofuran (40 ml) obtained in the same manner as in steps 1-6 were mixed, and a solution of iodine (3.4 g) in tetrahydrofuran (16 ml) was added to dry ice. /Added dropwise under cooling using denatured ethanol. To this mixture, 1M lithium bis(trimethylsilyl)amide (26.8 ml) was added dropwise over 10 minutes. After stirring as it is for 2.5 hours, the reaction mixture was poured into a mixture of saturated aqueous ammonium chloride solution (40 ml) and water (40 ml) under ice cooling. Sodium sulfite (1.7 g) was added to this mixture, and the organic layer was separated from the mixture. The organic layer was concentrated under reduced pressure, the obtained residue was combined with an aqueous layer, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine (70 ml), dried over sodium sulfate, sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography. The obtained purified product was recrystallized from heptane/chloroform to obtain the compound described in the above scheme (0.295 g, 4%).

Step 4-2

In the same manner as in steps 1-8 of Example 1, the compound described in the scheme (0.019 g, 30%) was obtained from the compound (0.1 g) obtained in step 4-1.

Step 4-3

In the same manner as in step 2-5 of Example 2, the compound described in the scheme (0.020 g, 75%) was obtained from the compound (0.036 g) obtained in step 4-2.

Step 4-4

The compound obtained in step 4-3 (0.020 g) and 2-methoxyethanol (2 ml) were mixed, and glycine sodium salt (0.030 g) was added. After stirring at 130° C. for 1.5 hours, the mixture was cooled to room temperature. 1N hydrochloric acid (0.34 ml) and water (10 ml) were added to the reaction mixture and the mixture was stirred. The precipitate was collected by filtration and dried under reduced pressure. Ethyl acetate (1 ml) and 4N hydrochloric acid-ethyl acetate (0.1 ml) were added to the obtained solid, and the mixture was stirred at room temperature for 20 minutes. The solid was collected by filtration to give the title compound (0.052 mg, 67%).

Example 5

Preparation of [(7-hydroxy-6-phenethyl[1,2,4]triazolo[1,5-a]pyridin-8-carbonyl)amino]acetic acid hydrochloride

Step 5-1

Compound (1.31 g), tetrakis (triphenylphosphine) palladium (0) (0.137 g) and tetrahydrofuran (15 ml) obtained by a method similar to step 4-1 of Example 4 were mixed, and tri -n-Butyltin hydrate (0.7 ml) was added under ice cooling. After stirring for 20 minutes under ice cooling, the mixture was stirred at room temperature for 20 minutes and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: hexane/ethyl acetate = 10/0-1/1) to obtain the compound described in the scheme (0.44 g, 44%).

Step 5-2

In the same manner as in steps 1-8 of Example 1, the compound described in the scheme (0.078 g, 109%) was obtained from the compound (0.070 g) obtained in step 5-1.

Step 5-3

In the same manner as in step 2-5 of Example 2, the compound described in the scheme (0.037 g, 72%) was obtained from the compound (0.070 g) obtained in step 5-2.

The compound obtained in this step was converted to hydrochloride in the same manner as in Steps 4-4 of Example 4 and according to a conventional method to obtain the title compound.

Example 6

Preparation of [(5-butyl-6-chloro-7-hydroxy[1,2,4]triazolo[1,5-a]pyridin-8-carbonyl)amino]acetic acid hydrochloride

Step 6-1

A compound (200 mg), hexachloroethane (224 mg) and tetrahydrofuran (4.0 ml) obtained by a method similar to step 4-1 of Example 4 were mixed, and lithium bis(trimethylsilyl)amide (0.473 ml) ) Was added at -78°C. After stirring at -78°C for 2 hours, the mixture was slowly warmed to -40°C. Then, the mixture was added dropwise to a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate was added. The organic layer was separated from the mixture, and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (eluent: hexane/ethyl acetate=3/1-2/1) to obtain a crude product (180 mg) containing the compound described in the above scheme as a main component.

Step 6-2

In the same manner as in step 3-1 of Example 3, the compound (71 mg) described in the above scheme was obtained from the compound (180 mg) obtained in step 6-1.

Step 6-3

The compound (70 mg) and trifluoroacetic acid (1 ml) obtained in step 6-2 were mixed, and the mixture was stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture, and the mixture was concentrated under reduced pressure. 4N hydrochloric acid-ethyl acetate (1 ml) was added to the concentrated residue, and the mixture was stirred. Hexane (3 ml) was added and the mixture was stirred. The solid was collected by filtration to give the compound described in the scheme (50 mg, 83%).

Step 6-4

In the same manner as in step 4-4 of Example 4, the compound described in the scheme (48 mg, 88%) was obtained from the compound (50 mg) obtained in step 6-3.

Example 7

Preparation of [(7-hydroxy-2-methyl-5-phenethyl[1,2,4]triazolo[1,5-a]pyridin-8-carbonyl)amino]acetic acid hydrochloride

Step 7-1

2,4,6-trichloropyridine (50 g) and N,N-dimethylformamide (400 ml) were mixed, and sodium hydride (60% oil suspension) (11.5 g) was added in portions under ice cooling. Benzyl alcohol (28 ml) was added dropwise to this mixture over 40 minutes under ice cooling, and the mixture was stirred at the same temperature for 3 hours. Water (550 ml) was added dropwise under ice cooling, and the resulting solid was collected by filtration to give the compound described in the scheme (50 g, 72%).

Step 7-2

Under cooling in a dry ice/acetone bath, tetrahydrofuran (250 ml) and n-butyllithium (1.65M, 119 ml) were mixed, and the compound (50) obtained in step 7-1 in tetrahydrofuran (110 ml) g) was added dropwise over 30 minutes. To this mixture, a solution of di-tert-butyl-dicarbonate (45 ml) in tetrahydrofuran (100 ml) was added dropwise over 1 hour, and the mixture was stirred at the same temperature for 30 minutes. The reaction was quenched by addition of water (450 ml), ethyl acetate (200 ml) was added to separate the organic layer, and the organic layer was washed with water (200 ml) and saturated brine (200 ml). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: hexane/ethyl acetate = 50/0-11/1), and the obtained solid was further slurried in hexane (100 ml) as described in the scheme. The compound was obtained (15.7 g, 31%).

Step 7-3

The compound (15 g) and 1,4-dioxane (150 ml) obtained in step 7-2 were mixed, potassium carbonate (18 g), phenylvinylboric acid (7.1 g), [1,1'-bis( Diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (1.8 g) and water (45 ml) were added, and the mixture was stirred under heating at 80° C. for 1.5 hours. Phenylvinylboric acid (0.64 g) was added, and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature, and water, ethyl acetate and saturated brine were added to separate the organic layer. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: chloroform). Isopropyl alcohol (100 ml) was added to the obtained solid, and the mixture was slurried at 70° C. for 0.5 hours and ice-cooled to obtain the compound described in the above scheme (11.5 g, 62%).

Step 7-4

The compound obtained in step 7-3 (11.5 g), ethyl acetate (120 ml) and 2% platinum-carbon (2.5 g) were mixed, and the mixture was stirred at room temperature under a ^{hydrogen atmosphere (3.8 kgf/cm 2) for 23 hours.} Stirred. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the compound described in the scheme (11.5 g, 100%).

Step 7-5

In the same manner as in step 1-4 of Example 1, the compound described in the scheme (11.9 g, 104%) was obtained from the compound (11.5 g) obtained in step 7-4.

Step 7-6

The compound obtained in step 7-5 (126 mg), p-toluenesulfonic acid monohydrate (50 mg) and trimethyl orthoformate (1 ml) were mixed, toluene (1 ml) was added, and the mixture was brought to 60°C. Heated for 1 hour. The reaction mixture was added dropwise to a saturated aqueous sodium hydrogen carbonate solution at room temperature, and ethyl acetate was added to separate the organic layer. The organic layer was concentrated under reduced pressure, and the concentrated residue was purified by thin layer chromatography (eluent: chloroform/methanol = 9:1) to obtain the compound described in the scheme (32 mg, 24%).

Step 7-7

In the same manner as in steps 1-6 of Example 1, the compound described in the scheme (29 mg, 53%) was obtained from the compound (55 mg) obtained in step 7-6.

Step 7-8

The compound (54 mg) and chloroform (0.5 ml) obtained in step 7-7 were mixed, trifluoroacetic acid (0.22 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was azeotropically distilled using toluene to obtain a crude product (69 mg) containing the compound described in the above scheme as a main component.

The compound obtained in this step was treated in the same manner as in Steps 1-10 to 1-12 of Example 1, and the obtained compound was converted to hydrochloride by a conventional method to obtain the title compound.

Example 8

Preparation of {[8-(3,3-dimethyl-butyl)-6-hydroxy[1,2,4]triazolo[1,5-a]pyridin-5-carbonyl]amino}acetic acid hydrochloride

Step 8-1

2-Amino-3,5-dibromopyridine (50.4 g), 2,5-hexanedione (23.5 g) and p-toluenesulfonic acid monohydrate (2.7 g) were dissolved in toluene (300 ml), and the mixture was It was heated under reflux for 5 hours while removing water. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine (once each). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product (66.6 g) of the compound described in the above scheme.

Step 8-2

In the same manner as in steps 1-3 of Example 1, the compound described in the scheme (58.4 g, 82%) was obtained from the compound (66.6 g) obtained in step 8-1.

Step 8-3

The compound obtained in step 8-2 (58.4 g), hydroxylammonium chloride (233 g), ethanol (600 ml) and water (350 ml) were mixed. Triethylamine (46 ml) was added dropwise to this mixture at room temperature, ethanol (100 ml) was added, and the mixture was heated under reflux for 89 hours at a bath temperature of 95°C. The reaction mixture was ice-cooled, and 50% aqueous sodium hydroxide solution (96 ml), 8N aqueous sodium hydroxide solution (134 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml) were successively added. Water (1800 ml) was added at room temperature, the mixture was stirred for 1 hour, and the precipitated solid was collected by filtration. The precipitated solid was dried overnight under reduced pressure, and the crude product (49 g) was slurried in 2-propanol (120 ml) to obtain the compound described in the scheme (34.3 g, 75%).

Step 8-4

The compound obtained in step 8-3 (7.25 g), N,N-dimethylformamide (11 ml) and N,N-dimethylformamide dimethyl acetal (11 ml) were mixed, and the mixture was heated at 130° C. for 15 minutes. Under stirring. After stirring at room temperature for 20 minutes, the mixture was concentrated under reduced pressure. Methanol (58 ml) and pyridine (4.2 ml) were added to the obtained residue, and hydroxylamine-O-sulfonic acid (4.1 g) was added to the mixture under ice cooling. After stirring at room temperature overnight, water (29 ml) and saturated aqueous sodium hydrogen carbonate solution (58 ml) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The obtained solid was collected by filtration to obtain the compound described in the scheme (6.13 g, 78%).

Step 8-5

In the same manner as in step 1-1 of Example 1, the compound described in the scheme (5.67 g, 49%) was obtained from the compound (10 g) obtained in step 8-4.

Step 8-6

Toluene (57 ml) was added to the compound (5.68 g) obtained in step 8-5, and N,N-dimethylformamide diethyl acetal (4.5 ml) was added in three portions at 80°C. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: chloroform/ethyl acetate=10/1-4/1). Hexane was added to the obtained compound, and the precipitated solid was slurried to obtain the compound described in the scheme (4.68 g, 69%).

Step 8-7

The compound obtained in step 8-6 (100 mg), tert-butylacetylene (0.1 ml), bis (triphenylphosphine) palladium (II) dichloride (18 mg), and copper (I) iodide (5 mg) Was added to the screw bottle. Tetrahydrofuran (0.4 ml) and triethylamine (0.8 ml) were added to this mixture, and the bottle was tightly sealed. The mixture was stirred at room temperature for 1 hour, passed through a small amount of silica gel, and concentrated under reduced pressure. The residue was purified twice by thin layer chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the compound described in the scheme (85 mg, 85%).

Step 8-8

In the same manner as in step 2-5 of Example 2, the compound described in the scheme (62 mg, 94%) was obtained from the compound (85 mg) obtained in step 8-7.

In the same manner as in steps 4-4 of Example 4, the title compound was obtained from the compound obtained in this step.

Example 9

Preparation of [(7-hydroxy-6-phenyl[1,2,4]triazolo[4,3-a]pyridin-8-carbonyl)amino]acetic acid

Step 9-1

The hydroxyl-protecting group of the compound obtained in Steps 1-3 of Example 1 was removed in the same manner as in Steps 2-5 of Example 2. To a solution of the obtained compound (3.30 g) in chloroform (30 ml) was added N-bromosuccinimide (2.82 g) under ice cooling. After stirring at room temperature for 5 hours, a saturated aqueous sodium hydrogen carbonate solution (20 ml) was added to separate the reaction mixture. The organic layer was further washed with an aqueous sodium sulfite solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to obtain the compound described in the above scheme as a crude product (5.37 g).

Step 9-2

Potassium carbonate (2.19 g) and benzyl bromide (1.88 ml) were added under ice-cooling to a solution of the compound (5.37 g) obtained in step 9-1 in N,N-dimethylformamide, and the mixture was stirred at room temperature for 20 hours. . Water (50 ml) and ethyl acetate (50 ml) were added to separate the reaction mixture. The organic layer was further washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: hexane/ethyl acetate=3/1-1/2) to obtain the compound described in the scheme (3.73 g, 2 step 65%).

Step 9-3

Trifluoroacetic acid (180 ml) was added to the compound (610 mg) obtained in step 9-2 under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with chloroform (6 ml) and concentrated under reduced pressure. Chloroform (6 ml) was added to the residue again, thionyl chloride (0.18 ml) and N,N-dimethylformamide (1 drop) were added, and the mixture was heated at 70° C. for 30 minutes. The obtained solution was concentrated under reduced pressure to obtain the compound described in the scheme (540 mg, 98%).

Step 9-4

Diisopropylethylamine (0.29 ml) and glycine tert-butyl ester (0.21 ml) were added under ice-cooling to a solution of the compound (540 mg) obtained in step 9-3 in tetrahydrofuran (6 ml), and the mixture was It was stirred for 2 hours. Diisopropylethylamine (0.29 ml) and tert-butyl carbazate were added to the reaction mixture, and the mixture was heated at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: hexane/ethyl acetate=3/1-3/2) to obtain the compound described in the scheme (790 mg, 92%).

Step 9-5

In the same manner as in steps 1-8 of Example 1, the compound described in the scheme (280 g, 84%) was obtained from the compound (330 mg) obtained in step 9-4.

Step 9-6

In the same manner as in step 2-5 of Example 2, the compound described in the scheme (86 mg, 87%) was obtained from the compound (120 mg) obtained in step 9-5.

Step 9-7

To a solution of the compound (110 mg) obtained in step 9-6 in chloroform (0.3 ml) was added a 4N hydrochloric acid dioxane solution (1 ml), and the mixture was stirred under ice cooling for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the compound described in the scheme (84 mg, 87%).

Step 9-8

Trimethyl orthoformate (0.41 ml) was added to the compound (41 mg) obtained in step 9-7, and the mixture was heated at 100° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform (1 ml). Trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, a 4N hydrochloric acid dioxane solution (1 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was slurried in water to obtain the title compound (29 mg, 89%).

Example 10

Preparation of [(7-hydroxy[1,2,4]triazolo[4,3-a]pyridin-8-carbonyl)amino]acetic acid hydrochloride

Step 10-1

In the same manner as in the deprotection reaction of the carboxyl-protecting group in Steps 9-8 of Example 9, a crude product containing the compound described in the above scheme as a main component was obtained from Steps 1-5 of Example 1 (0.050 g).

Step 10-2

In the same manner as in steps 1-10 of Example 1, the compound described in the scheme (0.024 g, 41%) was obtained from the compound obtained in step 10-1.

The compound obtained in this step was removed from the hydroxyl-protecting group and the carboxyl-protecting group in the same manner as above, and the obtained compound was converted to hydrochloride by a conventional method to obtain the title compound.

Example 11

Preparation of [(6-hydroxy[1,2,3]triazolo[1,5-a]pyridin-7-carbonyl)amino]acetic acid

Step 11-1

2-bromo-5-hydroxypyridine (5.8 g), N,N-dimethylformamide (58 ml) and potassium carbonate (5.1 g) were mixed, benzyl bromide (4.4 ml) was added under ice cooling, and the mixture Was stirred at room temperature for 13 hours. Ethyl acetate (58 ml) and water (87 ml) were added to the reaction mixture, and the organic layer was separated from the mixture, and washed successively with water (60 ml, 30 ml) twice and saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent: hexane/ethyl acetate=10/1-7/1) to obtain the compound described in the above scheme (7.4 g, 83%).

Step 11-2

To n-butyllithium (25 ml of 1.54 mol/l hexane solution) was added dropwise a solution of the compound (1 g) obtained in step 11-1 in toluene (4 ml) at -78°C over 7 minutes. The reaction mixture was stirred at -78°C for 50 minutes, and a solution of N,N-dimethylformamide (0.352 ml) in toluene (4 ml) was added dropwise. The reaction mixture was further stirred at -78°C for 1 hour, water (6 ml) was added at -10°C, and the mixture was stirred at room temperature for 2 hours. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted twice with toluene (5 ml). The organic layers were combined and washed with saturated brine (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: hexane/ethyl acetate=10/1-7/1) to obtain the compound described in the scheme (641 mg, 79%).

Step 11-3

The compound obtained in step 11-2 (637 mg), methanol (6.4 ml) and tosylhydrazide (574 mg) were mixed, and the mixture was heated under reflux for 10 minutes. The reaction mixture was concentrated under reduced pressure, morpholine (6.4 ml) was added, and the mixture was heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (12 ml), 2M aqueous sodium carbonate solution (6 ml) and water (5 ml) were added. Further, tetrahydrofuran (6 ml) was added, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (5 ml), and the organic layers were combined and washed with saturated brine (10 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained solid was slurried in diisopropyl ether to obtain the compound described in the above scheme (566 mg, 84%).

Step 11-4

The compound obtained in step 11-3 (200 mg) and tetrahydrofuran (2 ml) were mixed, and lithium diisopropylamide (2M tetrahydrofuran, heptane, ethylbenzene solution, 0.45 ml) was added at -40°C. I did. After stirring at -40°C for 1 hour, dry ice was added, and the mixture was stirred for 1 hour to warm to room temperature. Then, methanol (2 ml) was added, and the reaction mixture was concentrated under reduced pressure, and the compound described in the above scheme was obtained as a crude product. This was used as it is in the next step.

Step 11-5

In the same manner as in steps 1-10 of Example 1, the compound described in the scheme (85 mg, 28% (step 2)) was obtained from the crude product obtained in steps 11-4.

Step 11-6

In the same manner as in step 2-5 of Example 2, the compound described in the scheme (40 mg, 76%) was obtained from the compound (72 mg) obtained in step 11-5.

The title compound was obtained by removing the carboxyl group from the compound obtained in this step in the same manner as described above.

Example 116

Preparation of [(7-hydroxy-5-phenethyl[1,2,4]triazolo[1,5-a]pyridin-8-carbonyl)amino]acetic acid

Step 116-1

Cyanamide (1.4 g) and 1,4-dioxane (20 ml) were mixed, and dimethyl 1,3-acetonedicarboxylate (2.0 g) and nickel (II) acetylacetonate (0.30 g) were added. . The mixture was heated under reflux for 16 hours. The mixture was cooled to room temperature, stirred for 1 hour, and the obtained solid was collected by filtration. Methanol (6.0 ml) was added to the obtained solid, and the mixture was stirred at room temperature for 1.5 hours. The solid was collected by filtration to give the compound described in the scheme (1.4 g, 64%).

Step 116-2

The compound obtained in step 116-1 (30 g), phosphorus oxychloride (150 ml) and N,N-diisopropylethylamine (30 ml) were mixed, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated and azeotropically distilled three times using toluene. Under ice cooling, methanol (30 ml) and water (150 ml) were added, and the mixture was stirred at room temperature for 1 hour. The obtained solid was collected by filtration and combined with the solid produced in the filtrate. Methanol (50 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to give primary crystals. The filtrate was concentrated, methanol (10 ml) was added to the residue, and the obtained solid was collected by filtration to give secondary crystals. The first crystal and the second crystal were collected to obtain the compound described in the scheme (21 g, 59%).

Step 116-3

The compound (2.2 g) and 2-propanol (31 ml) obtained in step 116-2 were mixed, and N,N-dimethylformamide dimethyl acetal (2.9 ml) was added. The mixture was stirred for 30 minutes under reflux. The reaction mixture was cooled to room temperature, hydroxylamine hydrochloride (1.4 g) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to an amount of about half, and water (40 ml) and 2-propanol (6.6 ml) were added. The mixture was stirred at room temperature for 30 minutes, and the obtained solid was collected by filtration to obtain the compound described in the scheme (2.2 g, 84%).

Step 116-4

The compound (0.66 g) and tetrahydrofuran (6.6 ml) obtained in step 116-3 were mixed, and trifluoroacetic anhydride (0.37 ml) was added. The mixture was heated under reflux for 22 hours. The reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was separated. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: chloroform/ethyl acetate = 4/1) to obtain the compound described in the scheme (0.32 g, 51%).

Step 116-5

The compound obtained in step 116-4 (1.0 g), phenethylboronic acid (1.2 g), potassium carbonate (1.7 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Dichloromethane complex (1:1) (0.083 g), cyclopentyl methyl ether (6.0 ml) and water (0.15 ml) were mixed, and the mixture was stirred under heating at 50° C. for 6 hours. The reaction mixture was cooled to room temperature, and the organic layer was washed twice with 3% aqueous diethylenetriamine solution (10 ml) and saturated brine (5 ml). Sodium sulfate and metal scavenger silica gel (1 g) were added, and the mixture was stirred at room temperature for 1 hour and filtered through a Kiriyama funnel filled with silica gel (1 g). The filtrate was concentrated under reduced pressure to obtain the compound described in the above scheme as a crude product (1.87 g).

Step 116-6

The compound (1.87 g) obtained in step 116-5 and tetrahydrofuran were mixed, and a 4N aqueous sodium hydroxide solution (4.0 ml) was added under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was neutralized with concentrated hydrochloric acid (1.4 ml) under ice cooling. Ethanol (5 ml) and water (1.3 ml) were added to the suspension, and the mixture was stirred for 1 hour. The solid was collected by filtration to give the compound described in the scheme (0.847 g, 69%).

Step 116-7

The compound obtained in step 116-6 (0.200 g), acetonitrile (1.0 ml), 1-hydroxybenzotriazole monohydrate (0.122 g) and glycine methyl ester hydrochloride (0.100 g) were mixed, and triethylamine (0.111 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.153 g) were added under ice cooling. The mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution (2 ml) was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain the compound described in the scheme (0.194 g, 78%).

Step 116-8

The compound obtained in step 116-7 (0.150 g), 2-ethoxyethanol (0.75 ml) and 8N aqueous sodium hydroxide solution (0.23 ml) were mixed, and the mixture was stirred at 90° C. for 18 hours. Ethanol (0.75 ml) and water (0.23 ml) were added to this mixture, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to give the crude product of the compound described in the scheme (0.19 g).

Step 116-9

The compound (0.19 g) and water (0.63 ml) obtained in step 116-8 were mixed, and the mixture was warmed to 50°C. Acetone (0.78 ml) and 6N hydrochloric acid (0.2 ml) were added, and the mixture was stirred at the same temperature for 1 hour. After stirring for 1 hour under ice cooling, the solid was collected by filtration to obtain the compound described in the scheme (0.11 g, 80%).

Step 116-10

The compound (0.050 g) and methanol (3 ml) obtained in step 116-9 were mixed, and the mixture was heated to 60°C. The solution was cooled to room temperature and stirred for 1 day. The solid was collected by filtration to give the title compound (0.031 g, 61%).

Example 117

Preparation of [(5-butyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyridin-8-carbonyl)amino]acetic acid

Step 117-1

The compound obtained in step 116-4 (0.050 g), butylboronic acid (0.042 g), silver (I) oxide (0.071 g), potassium carbonate (0.084 g), [1,1'-bis(diphenylphosphino) Ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (0.008 g) and tetrahydrofuran (1.0 ml) were mixed, and the mixture was heated under reflux for 10 hours. The insoluble matter was filtered off through celite, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated from the mixture. The organic layer was washed twice with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (eluent: hexane/ethyl acetate=1/1) to obtain the compound described in the scheme (0.046 g, 77%).

Step 117-2

The compound (0.043 g) and methanol (0.22 ml) obtained in step 117-1 were mixed, and a 28% sodium methoxide methanol solution (0.014 ml) was added. The mixture was stirred at room temperature for 4 hours. Water (0.22 ml) was added and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid (0.16 ml) was added to the reaction mixture, and the obtained solid was collected by filtration to give the compound described in the scheme (0.026 g, 66%).

Step 117-3

The compound obtained in step 117-2 (0.025 g) and N,N-dimethylformamide (0.50 ml) were mixed, and 1-hydroxybenzotriazole monohydrate (0.016 g) and glycine tert-butyl ester (0.015 ml ) And 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.020 g) were added. The mixture was stirred at room temperature for 1.5 hours. Under ice-cooling, a 5% aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and the obtained solid was collected by filtration to obtain the compound described in the scheme (0.033 g, 94%).

Step 117-4

The compound obtained in step 117-3 (0.030 g) and a 25% hydrogen bromide acetic acid solution (0.60 ml) were mixed, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure. Water (0.60 ml) and 4N aqueous sodium hydroxide solution (0.23 ml) were added to the obtained residue under ice cooling. Thereafter, 2N hydrochloric acid (0.23 ml) was added under ice cooling, and the obtained solid was collected by filtration to obtain the compound described in the above scheme (0.010 g, 42%).

Step 117-5

The compound obtained in step 117-4 (0.100 g) and methyl ethyl ketone (1.0 ml) were mixed and heated to 80°C. Heptane (1.0 ml) was added to the solution and the mixture was stirred at room temperature overnight. The solid was collected by filtration to give the title compound (0.089 g, 89%).

In the same manner as in Examples 1 to 11, 116 or 117, or other conventional methods as necessary, to prepare the compounds of Examples 12 to 115 and Examples 118 to 122 shown in Tables 3 to 24 below. I did.

Structural formulas and characteristic data of the compounds of Examples 1 to 122 are shown in Tables 1 to 24 below.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

Examples of the formulation examples of the present invention include the following formulations. However, the present invention is not limited by these formulation examples.

Formulation Example 1 (Preparation of capsules)

1) Compound of Example 1 30 mg

2) microcrystalline cellulose 10 mg

3) lactose 19 mg

4) magnesium stearate 1 mg

1), 2), 3) and 4) are mixed and filled into gelatin capsules.

Formulation Example 2 (Preparation of tablet)

1) Compound of Example 1 10 g

2) lactose 50 g

3) corn starch 15 g

4) carmellose calcium 44 g

5) magnesium stearate 1 g

The total amount of 1), 2), and 3) and 30 g of 4) were kneaded with water, dried under vacuum, and sieved. The sieve powder is mixed with 14 g of 4) and 1 g of 5), and the mixture is tableted with a tablet press. In this way, 1000 tablets containing 10 mg of the compound of Example 1 were obtained per tablet.

Next, a method for evaluating the human PHD inhibitory activity and human EPO production-inducing activity of the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof will be described.

Test Example 1 Measurement of human PHD inhibitory activity

i) Expression and purification of human PHD2

Human PHD2 was expressed in insect cells (Sf9 cells). A FLAG-tag was inserted into the N-terminus of the translation region of the human PHD2-registration sequence (NM_022051), the sequence was introduced into the pVL1393 vector, and the sequence was confirmed. The vector and baculovirus were cotransfected into Sf9, and human PHD2-expressing baculovirus was isolated from Sf9. Using this virus, human PHD2 expressing cells were prepared. After culturing the cells at 27°C for 72 hours, a cell lysis solution containing various protease inhibitors was added, and the cells were disrupted by ultrasonic treatment. The cell lysate was poured into a column filled with ANTI-FLAG M2 Affinity Gel Freezer Safe (SIGMA), washed, and recovered by eluting the N-terminal FLAG-tag-added human PHD2. It was confirmed that the purified product was a human PHD2 enzyme by Western-Blotting using an anti-FLAG antibody and an anti-PHD2 antibody.

ii) Expression and purification of VBC complex

The VBC complex (VHL/Elongin B/Elongin C) was expressed in E. coli (BL21(DE3)). GST-fusion was inserted into the N-terminus of the translation region of the human VHL-registration sequence (NM_000551). A FLAG-tag was inserted into the N-terminus of the translation region of the human Elongin B-registration sequence (NM_207013), and the sequence was introduced into the pETDuet-1 vector to confirm the sequence. A His-tag was inserted into the N-terminus of the translation region of the human Elongin C-registration sequence (NM_005648), and the sequence was introduced into the pRSFDuet-1 vector to confirm the sequence. These expression vectors were transfected into E. coli (BL21(DE3)), and E. coli was cultured in an IPTG-containing medium at 37°C. The recovered E. coli was crushed by ultrasonic treatment, flowed to a column filled with Ni-NTA superflow (QIAGEN), washed, and the product was eluted and recovered. The eluate was poured onto a column filled with Glutathione Sepharose 4B, washed, and the product was eluted and recovered. It was confirmed that the purified products were human VHL/human Elongin B and human Elongin C by Western-Blotting using an anti-GST antibody/anti-FLAG antibody and an anti-His antibody.

iii) binding activity of VBC complex

The 19-residue biotin-labeled partial peptide (HIF-1α-C19) based on the sequence of the VBC complex and HIF-1α obtained in ii) above or the biotin-labeled partial peptide (HIF- The binding activity of 1α-C19 (Hyp)) was measured on a streptavidin coated plate. For detection, ELISA using an anti-GST antibody was performed, and it was confirmed that the VBC complex only binds to the hydroxylated HIF-1α partial peptide.

iv) Measurement of human PHD inhibitory activity

For human PHD2 enzyme activity, the hydroxylation of the proline residue contained as a substrate in the 19 residue partial peptide based on the sequence of HIF-1α was measured by the Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method.

Enzyme and substrate are diluted in 50 mM Tris-HCl buffer (pH 7.5) containing 50 μM iron sulfate, 120 mM NaCl, 0.1% BSA, 0.1 mM ascorbic acid, 10 μM 2-oxoglutaric acid, 0.2 mM CHAPS, respectively. And the test compound was diluted with dimethyl sulfoxide (DMSO).

Test compound and substrate solutions were added to a 96-well plate. The reaction was initiated by adding a human PHD2 enzyme solution to the reaction system (final concentration 1 nM). After incubation at 25° C. for 30 minutes, a stop solution containing EDTA was added, a VBC complex solution containing europium (Eu) and Xlent was added, and the amount of hydrated proline residue was determined by time-resolved fluorescence spectroscopy. Quantified. The time-resolved fluorescence of each well was measured, and the human PHD inhibitory activity (%) of the test compound was calculated based on the values of the enzyme-free well and the test compound-free well. The human PHD inhibitory activity of each compound _{is shown in Tables 25 to 29 below by IC 50} (µM) or as human PHD inhibitory activity (%) at 30 µM. In these tables, values consisting only of numerical values represent IC ₅₀ (μM), and values including% represent human PHD inhibitory activity (%) at 30 μM.

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

Test Example 2 Human EPO production activity

The activity of the test compound on the production of human EPO was measured using Hep3B (ATCC) established from a human liver-derived cell line.

Hep3B cells were cultured in Eagle-MEM medium containing 10% fetal bovine serum, and the test compound was diluted with dimethyl sulfoxide (DMSO).

Hep3B cells were cultured in 96-well plates, and test compounds were added at each concentration after 24 hours. After incubation at 37°C for 24 hours, the culture supernatant was recovered. The concentration of human EPO produced in the culture supernatant was measured according to the manufacturer's instructions using a human EPO-ELISA kit (manufactured by StemCell Technologies, 01630), and the human EPO production activity (%) of the test compound was determined as the maximum production value and test under the above conditions. It was calculated based on the value of no compound added. The human EPO production activity of each compound _{is shown in Tables 30 to 34 below by EC 50} (µM) or as human EPO production activity (%) at 30 µM. In these tables, values consisting only of numerical values represent EC ₅₀ (μM), and values including% represent human EPO production activity (%) at 30 μM.

[Table 30]

[Table 31]

[Table 32]

[Table 33]

[Table 34]

As is clear from the above results, the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof has human PHD inhibitory activity and human EPO production activity.

Industrial applicability

The compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof can promote EPO production by inhibiting the binding of HIF and PHD and stabilizing HIF based on its PHD inhibitory activity.

Therefore, the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof can be an effective agent for the prevention or treatment of various diseases and conditions (disorders) caused by the decrease in the production of EPO, and for the treatment of anemia. It can be used effectively.

Claims (1)

Use of a compound represented by the following formula [I], a pharmaceutically acceptable salt thereof, or a solvate thereof:

[In the formula,
Partial structural formula:

Is the following formula:

It is a group represented by;
R ¹ is
(1) a hydrogen atom,
(2) C _1-6 alkyl group,
(3) C _6-14 aryl group,
(4) C _3-8 cycloalkyl group,
(5) C _6-14 aryl-C _1-6 alkyl group, or
(6) a C _3-8 cycloalkyl-C _1-6 alkyl group;
R ² is
(1) a hydrogen atom,
(2) a C _1-10 alkyl group,
_{(3) a C 6-14} aryl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B,
_{(4) a C 3-8} cycloalkyl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B,
_{(5) a C 3-8} cycloalkenyl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B,
(6) a heteroaryl group optionally substituted with the same or different 1 to 5 substituents selected from the following group B (wherein, the heteroaryl is 1 to 6 selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom) Having 4 heteroatoms),
(7) C _6-14 aryl-C _1-6 alkyl group (wherein C _6-14 aryl is optionally substituted with the same or different 1 to 5 substituents selected from the following group B), or
(8) a C _3-8 cycloalkyl-C _1-6 alkyl group, wherein C _3-8 cycloalkyl is optionally substituted with the same or different 1 to 5 substituents selected from Group B below;
R ³ is
(1) a hydrogen atom,
(2) a halogen atom,
(3) C _1-6 alkyl group,
(4) C _6-14 aryl group,
(5) C _3-8 cycloalkyl group, or
(6) a C _6-14 aryl-C _1-6 alkyl group;
R ⁴ and R ⁵ are each independently
(1) a hydrogen atom, or
(2) It is a C _1-6 alkyl group.
Group B:
(a) a halogen atom,
(b) a C _1-6 alkyl group,
(c) a C _3-8 cycloalkyl group,
(d) a cyano group, and
(e) halo C _1-6 alkyl group].