WO2014017087A1

WO2014017087A1 - Pyrazolopyridine derivative or pharmacologically acceptable salt thereof

Info

Publication number: WO2014017087A1
Application number: PCT/JP2013/004507
Authority: WO
Inventors: 茂樹瀬戸; 洋輔西ヶ谷; 麻生谷岡; 田谷　和也; 近藤　敦志
Original assignee: 杏林製薬株式会社; キッセイ薬品工業株式会社
Priority date: 2012-07-25
Filing date: 2013-07-24
Publication date: 2014-01-30
Also published as: JP2015178457A

Abstract

[Problem] To provide a novel compound having EP₁ receptor antagonist activity. [Solution] A pyrazolopyridine derivative indicated by general formula (I) or a pharmacologically acceptable salt thereof was found to have powerful EP₁ receptor antagonist activity. The compound (I) or a pharmacologically acceptable salt thereof is effective as a therapeutic medication or preventative medication for lower urinary tract symptoms (LUTS), for example, and for overactive bladder syndromes (OABs), etc., in particular. In addition, same are highly useful in the treatment, prevention, or suppression of a variety of conditions involving EP₁ receptors, in addition to lower urinary tract symptoms (LUTS), (e.g., inflammatory conditions, painful conditions, osteoporosis, cancer, etc.).

Description

Pyrazolopyridine derivative or a pharmacologically acceptable salt thereof

The present invention relates to a pyrazolopyridine derivative having an EP ₁ receptor antagonistic action, or a pharmacologically acceptable salt thereof.

With the progress of aging society and stress society, the number of patients with lower urinary tract dysfunction (LUTD) is increasing. LUTD is a general term for urinary storage disorder and dysuria, and the symptoms that develop from LUTD are lower urinary tract symptoms (LUTS). One type of LUTS is overactive bladder syndrome (OABs). OABs are also sometimes referred to as overactive bladder (OAB). In any case, OABs are diseases defined as "symptom syndrome requiring urgency of urine, usually accompanied by frequent urination and nocturia. Imminent urinary incontinence is not essential." is there. These symptoms associated with OABs interfere with overall life such as work, daily life, and mental activity, and lower the quality of life (QOL). Currently, anticholinergic drugs are first-line drugs for the treatment of OABs. However, anticholinergic drugs need to be used with sufficient consideration for antimuscarinic effects such as dry mouth and residual urine, and are not necessarily effective for all patients (for example, non-patent literature). 1). Under such circumstances, development of a therapeutic agent having a mechanism different from that of an anticholinergic agent is desired (see, for example, Non-Patent Document 1).

In recent years, the role of urothelium has attracted attention in LUTS, especially in OABs. Also in LUTS, it has been clarified that various chemical mediators are released in urothelial cells and cause a micturition reflex through a receptor of bladder sensory nerve endings. Among them, prostaglandin E ₂ (PGE ₂ ), one of chemical transmitters, binds to prostaglandin E receptor 1 (EP ₁ receptor) of afferent nerve (especially C fiber) in urothelium. Increases the micturition reflex. PGE ₂ also contracts the bladder by binding to the EP ₁ receptor present in bladder smooth muscle. In fact, it has been reported that an EP ₁ receptor antagonist suppresses both the enhancement of micturition reflex and the enhancement of afferent nerve activity by PGE ₂ (see, for example, Non-Patent Document 2 and Non-Patent Document 3). ). These suggest that PGE ₂ is involved in bladder smooth muscle contraction and bladder sensory nerve enhancement via the EP ₁ receptor. Furthermore, EP ₁ receptor antagonists have also been reported to increase bladder capacity without increasing residual urine volume (see, for example, Non-Patent Document 4).

In addition to EP ₁ , there are four subtypes of receptors for PGE ₂ , EP ₂ , EP ₃ and EP ₄ . The EP ₁ receptor is present in the lung, skeletal muscle, kidney collecting duct and the like in addition to the bladder and urothelium (see, for example, Non-Patent Document 2). However, it is expected that therapeutic agents for a desired disease can be developed by changing the selectivity of the PGE ₂ receptor subtype and the target organ or target tissue of the drug.

Patent Document 1 discloses a benzofuran derivative represented by the chemical structural formula (A) as a compound having an EP ₁ receptor antagonistic action.

In formula (A), R ¹ represents a hydrogen atom, a halogen atom or the like, R ^2a represents a hydrogen atom or the like, R ^2b represents a C _1-4 alkyl group (straight or branched chain having 1 to 4 carbon atoms). R ^2c represents a hydrogen atom or the like, and R ³ represents a group represented by the following general formula (B) or the like.

In formula (B), R ⁴ represents a carboxy group or the like.

Patent Document 2 discloses a benzofuran derivative represented by the chemical structural formula (C) as a compound having an EP ₁ receptor antagonistic action.

In formula (C), R ¹ represents a hydrogen atom, a halogen atom or the like, R ² represents a thienyl group or the like, and R ³ represents a group represented by the following general formula (B) or the like.

In formula (B), R ⁴ represents a carboxy group or the like.
However, these compounds differ in basic chemical structural formula from the compounds according to the present invention. In addition, it cannot be overemphasized that these compounds are not contained in a claim of this application.

International Publication No. 2007/113289 International Publication No. 2008/098978

At present, no compound has been found as a prophylactic and therapeutic agent for the various pathologies described above, which can be a sufficiently satisfactory pharmaceutical from the viewpoint of having excellent EP ₁ receptor antagonism and few side effects.

An object of the present invention is to provide a novel compound having an EP ₁ receptor antagonistic action.

As a result of intensive studies, the present inventors have found that a pyrazolopyridine derivative represented by the following general formula (I) (hereinafter sometimes referred to as compound (I)) or a pharmacologically acceptable salt thereof. The present invention was completed by finding that it has a strong EP ₁ receptor antagonistic action.

That is, the gist of the present invention is as follows.

[1] A pyrazolopyridine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

In formula (I), A is a group selected from the group consisting of a) to d) below:

R ^a is a group selected from the group consisting of e) to g) below:
e) a hydrogen atom f) a halogen atom g) a C _1-6 alkyl group W ¹ is CH or a nitrogen atom;
W ² is an oxygen atom or a sulfur atom;
Y ¹ is C _1-6 alkylene;
R ¹ is a group selected from the group consisting of h) to n) below:
h) —C (═O) —OZ ¹
i) —C (═O) —NHSO ₂ Z ²
j) -C (= O) -NHOH
k) -C (= O) -NHCN
l) —NH—C (═O) —Z ³
m) an acidic 5-membered heterocyclic group n) a 6-membered cyclic group substituted with a phenolic hydroxyl group Z ¹ is a hydrogen atom, a C _1-6 alkyl group or a C _7-10 aralkyl group;
Z ² and Z ³ are groups selected from the group consisting of o) to s) below;
o) C _1-6 alkyl group p) halo C _1-6 alkyl group q) C _3-6 cycloalkyl group r) unsubstituted or halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group and C An aryl group whose ring is substituted with a group selected from the group consisting of _1-6 alkoxy groups s) a heterocyclic group R ² is a group selected from the group consisting of A) to F) below;
A) C _1-6 alkyl group B) Unsubstituted or C _3-6 cycloalkyl group substituted by one C _1-6 alkyl group C) Unsubstituted or halogen atom, amino group, 1 or 2 An amino group substituted with a C _1-6 alkyl group, a C _1-9 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-7 alkanoyl group, a C _7-10 aralkyloxy group, An aryl group in which the ring is substituted with a group selected from the group consisting of an aryl group, a (C _1-6 alkoxy) carbonylamino group, a (C _1-6 alkoxy) carbonyl group and a carboxy group D) a 5-membered aromatic ring Heterocyclic group E) Amino group F) substituted with 1 or 2 C _1-6 alkyl groups F) 5 or 6 membered cyclic amino group R ³ is selected from the group consisting of G) to P) below A group;
G) hydrogen atom H) halogen atom I) cyano group J) C _2-6 alkenyl group K) C _1-7 alkanoyl group L) C _1-6 alkoxy group M) C _5-8 cycloalkenyl group N) C _{1- 6} alkyl group O) halo C _1-6 alkyl group P) hydroxyl group R ⁴ and R ⁵ each independently represents a hydrogen atom, a halogen atom, or a C _1-6 alkoxy group. A bond marked with (*) binds to Y ^1, and a bond marked with (**) denotes bonded to R ¹ .

[2] In the above general formula (I), A is a group selected from the group consisting of the following a1), a2), b1), c1), d1) and d2) Zolopyridine derivative or a pharmacologically acceptable salt thereof.

R ^a has the same meaning as described above. A bond marked with (*) binds to Y ^1, and a bond marked with (**) denotes bonded to R ¹ .

[3] In the general formula (I), A is a group selected from the group consisting of the following a1), b1) and c1): Its pharmacologically acceptable salt.

[4] The pyrazolopyridine derivative or a pharmacologically acceptable salt thereof according to any one of [1] to [3], wherein Y ¹ in the general formula (I) is methylene.

[5] The pyrazolopyridine derivative according to any one of [1] to [4] or a pharmacologically acceptable salt thereof, wherein, in the general formula (I), R ⁴ and R ⁵ are hydrogen atoms. Salt.

[6] In the general formula (I), when R ¹ is —C (═O) —OZ ¹ , Z ¹ is a hydrogen atom or a C _1-6 alkyl group, and R ¹ is —C (═O ) —NHSO ₂ Z ² , wherein Z ² is a C _1-6 alkyl group, the pyrazolopyridine derivative according to any one of [1] to [5] or a pharmacologically acceptable salt thereof Salt.

[7] In the general formula (I), R ³ is a hydrogen atom, a halogen atom, a cyano group, a C _5-8 cycloalkenyl group, a C _2-6 alkenyl group, an acetyl group, a trifluoromethyl group, a methyl group or The pyrazolopyridine derivative or a pharmaceutically acceptable salt thereof according to any one of [1] to [6], which is a methoxy group.

[8] The pyrazolopyridine derivative or the derivative thereof according to any one of [1] to [7], wherein R ^a is a hydrogen atom or a C _1-6 alkyl group in the general formula (I) Pharmacologically acceptable salt.

[9] In the general formula (I), R ² is selected from the group consisting of A), B), C1), D1), D2), E), F1), F2), and F3) below. A pyrazolopyridine derivative or a pharmaceutically acceptable salt thereof according to any one of [1] to [8].
A) C _1-6 alkyl group B) Unsubstituted or C _3-6 cycloalkyl group in which the ring is substituted with one C _1-6 alkyl group C1) Unsubstituted or halogen atom, 1 or 2 C _1-1 An amino group substituted with a ₆ alkyl group, a C _1-9 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-7 alkanoyl group, a C _7-10 aralkyloxy group, an aryl group, (C _1-6 alkoxy) aryl group wherein the ring is substituted with a group selected from the group consisting of a carbonylamino group and a carboxyl group D1) furanyl group D2) thienyl group E) 1 or 2 C _1-6 alkyl Amino groups substituted by groups F1) Pyrrolidinyl group F2) Piperidinyl group F3) Morpholinyl group

[10] The compound represented by the general formula (I) is:
5-methyl-1-[(2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-N- (methylsulfonyl) -1H-pyrazole-3-carboxamide,
5-chloro-7-[[5-methyl-3- (2H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2-phenylpyrazolo [1,5-a] pyridine,
2-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] oxazole-4-carboxylic acid,
1-[(5-chloro-2-cyclohexylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2-phenyl-5- (propen-2-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-propyl-1H-pyrazole-3-carboxylic acid,
5-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] furan-2-carboxylic acid,
6-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] pyridine-2-carboxylic acid,
3-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] benzoic acid,
1-[[5-chloro-2- (3-methoxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (3-fluorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (2-fluorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (diethylamino) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (piperidin-1-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (1-methylcyclopropyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N-cyano-5-methyl-1H-pyrazole-3-carboxamide,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N- (ethylsulfonyl) -5-methyl-1H-pyrazole-3-carboxamide,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N- (propylsulfonyl) -5-methyl-1H-pyrazole-3-carboxamide,
3- [1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] -1,2,4 -Oxadiazol-5 (4H) -one, or 3- [1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H -Pyrazol-3-yl] -1,2,4-oxadiazole-5 (4H) -thione, the pyrazolopyridine derivative or the pharmaceutically acceptable salt thereof according to [1].

[11] A medicament comprising the pyrazolopyridine derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [10].

[12] An EP ₁ receptor antagonist containing the pyrazolopyridine derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [10].

[13] A therapeutic or prophylactic agent for lower urinary tract symptoms comprising the pyrazolopyridine derivative or the pharmacologically acceptable salt thereof according to any one of [1] to [10].

[14] A method for treating or preventing a lower urinary tract symptom comprising administering to a patient the pyrazolopyridine derivative or the pharmacologically acceptable salt thereof according to any one of [1] to [10] .

[15] A pyrazolopyridine derivative or a pharmacologically acceptable salt thereof according to any one of [1] to [10] for producing a medicament for preventing or treating lower urinary tract symptoms Use of.

[16] The pyrazolopyridine derivative or a pharmaceutically acceptable salt thereof according to any one of [1] to [10] for use in the prevention or treatment of lower urinary tract symptoms.

According to the present invention, a novel compound having an EP ₁ receptor antagonistic action can be provided.

Hereinafter, the compound (I) of the present embodiment will be described in detail.
In the following, the definition of the functional group of the general formula may be omitted with reference to the definition already described. It should be understood that the definitions cited refer to the definitions described in the description of the embodiments described below, and do not refer to the definitions of the functional groups of the compounds described as the prior art. it can.

This embodiment relates to a pyrazolopyridine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

R ^a is a group selected from the group consisting of e) to g) below:
e) a hydrogen atom f) a halogen atom g) a C _1-6 alkyl group W ¹ is CH or a nitrogen atom;
W ² is an oxygen atom or a sulfur atom;
Y ¹ is C _1-6 alkylene;
R ¹ is a group selected from the group consisting of h) to n) below:
h) —C (═O) —OZ ¹
i) —C (═O) —NHSO ₂ Z ²
j) -C (= O) -NHOH
k) -C (= O) -NHCN
l) —NH—C (═O) —Z ³
m) an acidic 5-membered heterocyclic group n) a 6-membered cyclic group substituted with a phenolic hydroxyl group Z ¹ is a hydrogen atom, a C _1-6 alkyl group or a C _7-10 aralkyl group;
Z ² and Z ³ are groups selected from the group consisting of o) to s) below;
o) C _1-6 alkyl group p) halo C _1-6 alkyl group q) C _3-6 cycloalkyl group r) unsubstituted or halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group and C An aryl group whose ring is substituted with a group selected from the group consisting of _1-6 alkoxy groups s) a heterocyclic group R ² is a group selected from the group consisting of A) to F) below;
A) C _1-6 alkyl group B) C _3-6 cycloalkyl group unsubstituted or substituted with one C _1-6 alkyl group C) unsubstituted or halogen atom, amino group, 1 or 2 An amino group substituted with a C _1-6 alkyl group, a C _1-9 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-7 alkanoyl group, a C _7-10 aralkyloxy group, An aryl group in which the ring is substituted with a group selected from the group consisting of an aryl group, a (C _1-6 alkoxy) carbonylamino group, a (C _1-6 alkoxy) carbonyl group and a carboxy group D) a 5-membered aromatic ring Heterocyclic group E) Amino group F) substituted with 1 or 2 C _1-6 alkyl groups F) 5 or 6 membered cyclic amino group R ³ is selected from the group consisting of G) to P) below A group;
G) hydrogen atom H) halogen atom I) cyano group J) C _2-6 alkenyl group K) C _1-7 alkanoyl group L) C _1-6 alkoxy group M) C _5-8 cycloalkenyl group N) C _{1- 6} alkyl group O) halo C _1-6 alkyl group P) hydroxyl group R ⁴ and R ⁵ each independently represents a hydrogen atom, a halogen atom, or a C _1-6 alkoxy group. A bond marked with (*) binds to Y ^1, and a bond marked with (**) denotes bonded to R ¹ .
When Z ² or Z ³ is an aryl group having a substituent, the aryl group has one or more (for example, 2 to 5) substituents. When the aryl group has a plurality of substituents, these substituents may be the same or different. Of course, Z ² and Z ³ may be the same or different.
When R ² is an aryl group having a substituent, the aryl group has one or a plurality of (for example, 2 to 5) substituents. When the aryl group has a plurality of substituents, these substituents may be the same or different.
Also, “independently” means that they may be the same or different between two or more substituents that may be present.

“C _1-6 alkylene” means a divalent straight chain or branched saturated hydrocarbon chain having 1 to 6 carbon atoms. As C _1-6 alkylene, for example, —CH ₂ —, — (CH ₂ ) ₂ —, —CH (CH ₃ ) —, — (CH ₂ ) ₃ —, —CH (CH ₃ ) CH ₂ —, —CH ₂ CH (CH ₃ ) —, —CH (CH ₂ CH ₃ ) —, —C (CH ₃ ) ₂ —, — (CH ₂ ) ₄ —, —CH (CH ₃ ) — (CH ₂ ) ₂ —, — (CH ₂ ) ₂ —CH (CH ₃ ) —, —CH (CH ₂ CH ₃ ) —CH ₂ —, —C (CH ₃ ) ₂ CH ₂ —, —CH ₂ —C (CH ₃ ) ₂ —, — CH (CH ₃ ) —CH (CH ₃ ) —, — (CH ₂ ) ₅ —, —CH (CH ₃ ) — (CH ₂ ) ₃ —, —C (CH ₃ ) ₂ CH ₂ CH ₂ —, — ( CH ₂ ) ₆ —, —C (CH ₃ ) ₂ — (CH ₂ ) ₃ — and the like. Preferably, —CH ₂ — and the like are mentioned. In the present specification, —CH ₂ — may be referred to as methylene.

“C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the C _1-6 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, and 1-methylbutyl. Group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, hexyl group, isohexyl group and the like. Preferably, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, and 1-ethylpropyl group are used.
The “C _1-9 alkyl group” means a linear or branched alkyl group having 1 to 9 carbon atoms. Examples of the C _1-9 alkyl group include a heptyl group, isoheptyl group, octyl group, isooctyl group, nonyl group, isononyl group and the like in addition to the above alkyl group.

The “C _2-6 alkenyl group” means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms having at least one double bond. Examples of the C _2-6 alkenyl group include a vinyl group, 2-propenyl group, 1-propenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 1-buten-4-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-penten-1-yl group, 1-penten-2-yl group, 1-pentene-3 -Yl group, 2-penten-1-yl group, 2-penten-2-yl group, 2-penten-3-yl group, 1-hexen-1-yl group, 1-hexen-2-yl group, -Hexen-3-yl group, 2-methyl-1-propen-1-yl group and the like.

The “C _5-8 cycloalkenyl group” means a monocyclic unsaturated alicyclic hydrocarbon group having 5 to 8 carbon atoms. Examples of the C _5-8 cycloalkenyl group include a cyclopenten-1-yl group, a cyclohexen-1-yl group, a cyclohepten-1-yl group, and a cycloocten-1-yl group.

“Halogen atom” includes fluorine atom, chlorine atom, bromine atom and iodine atom.

The “C _1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of the C _1-6 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an isobutoxy group, a butoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group. . Preferably, a methoxy group and an ethoxy group are mentioned.

The “C _1-7 alkanoyl group” means an acyl group derived from a linear or branched aliphatic carboxylic acid having 1 to 7 carbon atoms. Examples of the C _1-7 alkanoyl group include formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group and the like.

“C _7-10 aralkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a phenyl group. Examples of the C _7-10 aralkyl group include benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like.

The “halo C _1-6 alkyl group” means a C _1-6 alkyl group substituted with 1 to 5 same or different halogen atoms. Examples of the halo C _1-6 alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2,2-difluoroethyl group, and a 1,1-difluoroethyl group. 1,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2,2,2-pentafluoroethyl group, 2,2,2-trichloroethyl group, 3-fluoropropyl group 2-fluoropropyl group, 1-fluoropropyl group, 3,3-difluoropropyl group, 2,2-difluoropropyl group, 1,1-difluoropropyl group, 4-fluorobutyl group, 5-fluoropentyl group, 6 -Fluorohexyl group and the like. Preferably, a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group are mentioned.

The “C _3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms. As C _3-6 cycloalkyl groups, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group.

The “C _3-6 cycloalkyl group in which the ring is substituted with one C _1-6 alkyl group” refers to the above C _3-6 cycloalkyl group in which the ring is substituted with the above C _1-6 alkyl group. Examples of the C _3-6 cycloalkyl group in which the ring is substituted with one C _1-6 alkyl group include a 1-methylcyclopropyl group, a 1-ethylcyclopropyl group, a 1-methylcyclobutyl group, and a 2-methylcyclo Examples include a butyl group, 1-methylcyclopentyl group, 2-methylcyclopentyl group, 1-methylcyclohexyl group, 2-methylcyclohexyl group and the like. A 1-methylcyclopropyl group and a 1-ethylcyclopropyl group are preferable, and a 1-methylcyclopropyl group is more preferable.

The “C _7-10 aralkyloxy group” means an alkoxy group having 1 to 4 carbon atoms substituted with a phenyl group. Examples of the C _7-10 aralkyloxy group include a benzyloxy group, a phenethyloxy group, a 1-phenylethyloxy group, a 3-phenylpropyloxy group, and a 4-phenylbutyloxy group.

“(C _1-6 alkoxy) carbonylamino group” means a linear or branched alkoxycarbonylamino group having 1 to 6 carbon atoms. (C _1-6 alkoxy) carbonylamino group includes, for example, methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, isobutoxycarbonylamino group, butoxycarbonylamino group, sec-butoxycarbonyl Examples thereof include an amino group, a tert-butoxycarbonylamino group, a pentyloxycarbonylamino group, and a hexyloxycarbonylamino group. Preferable examples include methoxycarbonylamino group and tert-butoxycarbonylamino group.

The “aryl group” means, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group, or an anthracenyl group. “C _6-10 aryl group” is preferable, which means an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include a phenyl group, an indenyl group, and a naphthyl group.

“Heterocyclic group” means a 5- to 7-membered heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom. Examples of heterocyclic groups include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl Group, thiadiazolyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group and other aromatic heterocyclic groups, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyranyl group and other unsaturated heterocyclic groups, and morpholinyl And saturated heterocyclic groups such as a group, a thiomorpholinyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidinyl group, and a piperazinyl group. When the “heterocyclic group” is a condensed cyclic group, a monocyclic or condensed heterocyclic group and a cyclic group other than the heterocyclic ring may be condensed. Examples of the heterocyclic group in which the heterocyclic group and other cyclic group other than the heterocyclic ring are condensed include, for example, an isobenzofuranyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, a benzo Isothiazolyl group, chromenyl group, chromanonyl group, xanthenyl group, phenoxathiinyl group, indolizinyl group, isoindolidinyl group, indolyl group, indazolyl group, purinyl group, quinolidinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, Examples thereof include a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a carbazolyl group, a carbolinyl group, an acridinyl group, and an isoindolinyl group.

The “(C _1-6 alkoxy) carbonyl group” means a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms. (C _1-6 alkoxy) carbonyl group includes, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, isobutoxycarbonyl group, butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group , A pentyloxycarbonyl group, a hexyloxycarbonyl group, and the like. Preferably, an ethoxycarbonyl group is mentioned.

“5-membered aromatic heterocyclic group” means a 5-membered aromatic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms in the ring. To do. For example, furyl group, pyrrolyl group, thienyl group, imidazolyl group, pyrazolyl group, 1,2,4-triazolyl group, isothiazolyl group, isoxazolyl group, oxazolyl group, thiazolyl group, 1,3,4-oxadiazolyl group, 1,2 , 4-oxadiazolyl group and the like.

Examples of the “5-membered or 6-membered cyclic amino group” include groups selected from the group consisting of cyclic amino groups having the following structures.

Preferably, it is a group selected from the group consisting of cyclic amino groups having the following structure.

More preferably, it is a group selected from the group consisting of cyclic amino groups having the following structure.

The “acidic 5-membered heterocyclic group” means a 5-membered ring containing a nitrogen atom bonded to an acidic proton in the ring or a 5-membered nitrogen-containing heterocyclic ring having a phenolic hydroxyl group. Examples of the acidic 5-membered heterocyclic group include groups selected from the group consisting of 5-membered nitrogen-containing heterocyclic groups having the following structures.

Preferably, it is a group selected from the group consisting of a 5-membered nitrogen-containing heterocyclic group having the structure shown below.

More preferably, it is a 5-membered nitrogen-containing heterocyclic group having the structure shown below.

"6-membered ring group substituted with phenolic hydroxyl group" means a 6-membered heterocyclic group or aromatic ring group having a phenolic hydroxyl group. Examples of the 6-membered ring group substituted with a phenolic hydroxyl group include groups selected from the group consisting of 6-membered ring groups having the following structures.

Preferably, any 6-membered cyclic group having the structure shown below is exemplified.

In the compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof, preferred substituents are as follows.
A is preferably a group represented by a) wherein W ¹ is CH or a nitrogen atom, a group represented by b) wherein W ² is an oxygen atom, W ¹ is a nitrogen atom, and W ² is oxygen A group selected from the group consisting of a group represented by c) which is an atom and a group represented by d) wherein W ¹ is CH or a nitrogen atom. In addition, when A is a group represented as a), b), or d), R ^a has the same meaning as described above.
A is more preferably a group selected from the group consisting of the following a1), a2), b1), c1), d1) and d2). A is more preferably a group selected from the group consisting of a1), b1), c1), d1) and d2). A is particularly preferably a group selected from the group consisting of a1), b1) and c1). In addition, when A is a group represented by a1), R ^a is preferably ^a hydrogen atom or a C _1-6 alkyl group.

In the formula, a bond marked with (*) is bonded to Y ^1, and a bond marked with (**) is bonded to R ¹ .

Y ¹ is preferably methylene.

R ¹ is preferably —C (═O) —OZ ¹ , —C (═O) —NHSO ₂ Z ² or an acidic 5-membered heterocyclic group. More preferably, R ¹ is —C (═O) —OZ ¹ , —C (═O) —NHSO ₂ Z ² or a tetrazolyl group. Furthermore, when R ¹ is —C (═O) —OZ ¹ , Z ¹ is a hydrogen atom or a C _1-6 alkyl group, and R ¹ is —C (═O) —NHSO ₂ Z ² In some cases, Z ² is preferably a C _1-6 alkyl group.
R ¹ is particularly preferably —C (═O) —OH, —C (═O) —OEt, —C (═O) —NHSO ₂ Me, or a 5-tetrazolyl group.

R ² is preferably a C _1-6 alkyl group, unsubstituted or a C _3-6 cycloalkyl group substituted with one C _1-6 alkyl group, unsubstituted or halogen atom, 1 or 2 C Amino group substituted with _1-6 alkyl group, C _1-9 alkyl group, halo C _1-6 alkyl group, C _1-6 alkoxy group, C _1-7 alkanoyl group, C _7-10 aralkyloxy group, aryl An aryl group in which the ring is substituted with a group selected from the group consisting of a group, a (C _1-6 alkoxy) carbonylamino group, and a carboxyl group, a 5-membered aromatic heterocyclic group, 1 or 2 C ₁ An amino group substituted with a _-6 alkyl group, or a 5- or 6-membered cyclic amino group.
R ² is more preferably a C _1-6 alkyl group, an unsubstituted or C _3-6 cycloalkyl group in which the ring is substituted by one C _1-6 alkyl group, an unsubstituted or halogen atom, 1 or 2 An amino group substituted with a C _1-6 alkyl group, a C _1-9 alkyl group, a halo C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-7 alkanoyl group, a C _7-10 aralkyloxy group An aryl group, a furanyl group, a thienyl group, or 1 or 2 C _1-6 , wherein the ring is substituted with a group selected from the group consisting of an aryl group, a (C _1-6 alkoxy) carbonylamino group, and a carboxyl group An amino group, a pyrrolidinyl group, a piperidinyl group, or a morpholinyl group substituted with an alkyl group.
R ² is more preferably a C _1-6 alkyl group, an unsubstituted or C _3-6 cycloalkyl group in which the ring is substituted with one C _1-6 alkyl group, a phenyl group, or a halogen atom. A phenyl group whose ring is substituted with a C _1-9 alkyl group, a phenyl group whose ring is substituted with a halo C _1-6 alkyl group, a phenyl group whose ring is substituted with a C _1-6 alkoxy group, A thienyl group, a dimethylamino group, a diethylamino group, a pyrrolidinyl group, a piperidinyl group or a morpholinyl group;
R ² is particularly preferably a cyclohexyl group, 1-methylcyclopropyl group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-methylphenyl group, 3- A methylphenyl group, 3- (trifluoromethyl) phenyl group, 3-thienyl group, dimethylamino group, diethylamino group, 1-pyrrolidinyl group, 1-piperidinyl group or 4-morpholinyl group;

R ³ is preferably a hydrogen atom, a halogen atom, a cyano group, a C _2-6 alkenyl group, a C _1-7 alkanoyl group, a C _5-8 cycloalkenyl group, a C _1-6 alkyl group, or a haloC _1-6 alkyl. Or a C _1-6 alkoxy group.
R ³ is more preferably a hydrogen atom, a halogen atom, a cyano group, a C _2-6 alkenyl group, an acetyl group, a C _5-8 cycloalkenyl group, a methyl group, a trifluoromethyl group, or a methoxy group.
R ³ is particularly preferably a hydrogen atom, chlorine atom, bromine atom, cyano group, vinyl group, 2-propenyl group, acetyl group, methyl group, trifluoromethyl group, or methoxy group.

R ⁴ is preferably a hydrogen atom.

R ⁵ is preferably a hydrogen atom.

As a preferable compound of this embodiment, for example,
5-methyl-1-[(2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylate, 1-[[2- (4-methoxyphenyl) ) Pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[2- (4-chlorophenyl) pyrazolo [1,5-a] ] Pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[(5-methoxy-2-phenylpyrazolo [1,5-a] pyridin-7-yl) Methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl- 1H-pyrazole-3-carvone Ethyl, 1-[[2- (2-methoxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[2 -(3-Methoxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[2- (2-chlorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[2- (3-chlorophenyl) pyrazolo [1,5-a] pyridine -7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[(2-cyclopropylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5 Methyl-1H-pyra Ethyl 3-carboxylate, 1-[[2- (furan-2-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carvone Ethyl 1-[[2- (furan-3-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 5-methyl -1-[[2- (thiophen-2-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylate, 5-methyl-1-[[2 -(Thiophen-3-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylate, 1-[[2- (2-fluorophenyl) pyrazolo [1 , 5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[2- (3-fluorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H- Ethyl pyrazole-3-carboxylate, 5-methyl-1-[[2- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3 -Ethyl carboxylate, ethyl 5-methyl-1-[[2- (2-benzyloxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylate, 5 -Ethyl-1-[[2- (3-benzyloxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylate, 5-methyl-1- [ [2- ( -Methylphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylate, 1-[[2- (4-ethylphenyl) pyrazolo [1,5-a ] Pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[2- (4-tert-butylphenyl) pyrazolo [1,5-a] pyridine-7- Yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 5-methyl-1-[[2- (4-nonylphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl ] -1H-pyrazole-3-carboxylate, 1-[[2- (biphenyl-2-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole- 3-carvone Ethyl, 1-[[2- [4- (dimethylamino) phenyl] pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1- [[2- [4- (Ethoxycarbonyl) phenyl] pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[2- (3-Acetylphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[2- (3-formylphenyl) pyrazolo [1,5-a] Pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[(5-chloro-2-cyclohexylpyrazolo [1,5-a] Pyridine-7- Yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[(5-chloro-2-cyclopropylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5 -Methyl-1H-pyrazole-3-carboxylate, 1-[[2- (tert-butyl) -5-chloropyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H- Ethyl pyrazole-3-carboxylate, ethyl 1-[(5-chloro-2-cyclopentylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[(2-butyl-5-chloropyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[(5-chloro- 2-isobuty Pyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate, 5-methyl-1-[(2-phenyl-5-vinylpyrazolo [1,5 -A] Pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylate, 5-methyl-1-[[2-phenyl-5- (propen-2-yl) pyrazolo [1,5-a ] Pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylate, (E) -1-[[5- (1-hexen-1-yl) -2-phenylpyrazolo [1,5- a] ethyl pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5- (1-cyclohexen-1-yl) -2-phenylpyrazolo [1,5 -A] pyridin-7-yl] methyl] Ethyl 5-methyl-1H-pyrazole-3-carboxylate, 1-[(5-acetyl-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole Ethyl-3-carboxylate, ethyl 1-[(5-cyano-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate, 5-methyl-1-[(5-methyl-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylate, 5-methyl-1- [ [2-Phenyl-5- (trifluoromethyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylate, 1-[(5-chloro-2-phenyl) Pyrazolo [1,5-a ] Pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylate, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5 -Ethyl-1H-pyrazole-3-carboxylate, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-propyl-1H-pyrazole- Ethyl 3-carboxylate, ethyl 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-isopropyl-1H-pyrazole-3-carboxylate, 1 -[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-isobutyl-1H-pyrazole-3-carboxylate, 1-[(5-chloro- 2-phenylpyrazo [1,5-a] pyridin-7-yl) methyl] -1H-pyrrole-3-carboxylate, 5-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridine-7- Yl) methyl] furan-2-carboxylate, 2-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] oxazole-4-carboxylate, 6- [(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] pyridine-2-carboxylate methyl, 3-[(5-chloro-2-phenylpyrazolo [1, 5-a] pyridin-7-yl) methyl] benzoate, 1-[[5-chloro-2- (4-chlorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5 Methyl-1H-pyrazole-3-carvone Ethyl, 1-[[5-chloro-2- (3-chlorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, [[5-Chloro-2- (2-chlorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5- Chloro-2- (4-methoxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro-2 -(3-Methoxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro-2- (2 -Methoxyphenyl) pyrazo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro-2- (4-fluorophenyl) pyrazolo [1 , 5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro-2- (3-fluorophenyl) pyrazolo [1,5- a] Pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro-2- (2-fluorophenyl) pyrazolo [1,5-a] pyridine -7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro-2- (dimethylamino) pyrazolo [1,5-a] pyridin-7-yl] Methyl] -5-methyl-1H- Ethyl lazole-3-carboxylate, 1-[[5-chloro-2- (methylamino) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carvone Ethyl 1-[[5-chloro-2- (ethylamino) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, [[5-Chloro-2- (diethylamino) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro- 2- (piperidin-1-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro-2- (Pyrrolidin-1-yl Ethyl pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro-2- (morpholin-4-yl) pyrazolo [ 1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[(5-hydroxy-2-phenylpyrazolo [1,5-a] pyridine -7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[[5-chloro-2- (1-methylcyclopropyl) pyrazolo [1,5-a] pyridine-7 -Yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate, 1-[(5-chloro-2-cyclohexylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5 -Methyl-1H-pyrazo 3-carboxylic acid, 1-[(5-chloro-2-cyclopropylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid , 1-[[2- (tert-butyl) -5-chloropyrazolo [1,5-a] pyridin-7-yl
] Methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[(5-chloro-2-cyclopentylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl- 1H-pyrazole-3-carboxylic acid, 1-[(2-butyl-5-chloropyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1 -[(5-chloro-2-isobutylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 5-methyl-1-[(2 -Phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylic acid, 1-[[2- (4-methoxyphenyl) pyrazolo [1,5-a] pyridine -7-yl] methyl] -5-me 1H-pyrazole-3-carboxylic acid, 1-[[2- (4-chlorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid Acid, 1-[(5-methoxy-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[(5- Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (2-methoxyphenyl) pyrazolo [ 1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (3-methoxyphenyl) pyrazolo [1,5-a] pyridine- 7-yl] methyl] -5-methyl 1H-pyrazole-3-carboxylic acid, 1-[[2- (2-chlorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (3-Chlorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[(2-cyclopropylpyra Zolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (furan-2-yl) pyrazolo [1,5-a ] Pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (furan-3-yl) pyrazolo [1,5-a] pyridin-7-yl] Methyl] -5-methyl-1H-pyrazole- 3-carboxylic acid, 5-methyl-1-[[2- (thiophen-2-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid, 5- Methyl-1-[[2- (thiophen-3-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid, 1-[[2- (2- Fluorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (3-fluorophenyl) pyrazolo [1,5 -A] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (4-fluorophenyl) pyrazolo [1,5-a] pyridin-7-yl ] Methyl] -5-methyl-1H-pyrazo -3-carboxylic acid, 5-methyl-1-[[2- [2- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carvone Acid, 5-methyl-1-[[2- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid, 1- [[2- [2- (benzyloxy) phenyl] pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- [ 3- (benzyloxy) phenyl] pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 5-methyl-1-[[2- (2 -Methylphenyl) pyrazolo [1,5 a] Pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid, 1-[[2- (4-ethylphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5 -Methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (4-tert-butylphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid, 5-methyl-1-[[2- (4-nonylphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid, 1- [[2- (biphenyl-2-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- [4- (Dimethylamino) phenyl] pyrazolo [1 , 5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (3-acetylphenyl) pyrazolo [1,5-a] pyridine-7 -Yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (3-formylphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5 Methyl-1H-pyrazole-3-carboxylic acid, 1-[[2- (4-aminophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3- Carboxylic acid, 1-[(5-hydroxy-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 5-methyl-1 -[(2-Phenyl-5-vinylpi Zolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylic acid, 5-methyl-1-[[2-phenyl-5- (propen-2-yl) pyrazolo [1 , 5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid, (E) -1-[[5- (1-hexen-1-yl) -2-phenylpyrazolo [1] , 5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5- (1-cyclohexen-1-yl) -2-phenylpyrazolo [1 , 5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[(5-acetyl-2-phenylpyrazolo [1,5-a] pyridine-7 -Yl) methyl] -5-methyl-1H-pyrazole-3-ca Boronic acid, 1-[(5-cyano-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 5-methyl-1 -[(5-Methyl-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylic acid, 5-methyl-1-[[2-phenyl-5 -(Trifluoromethyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid, 1-[(5-chloro-2-phenylpyrazolo [1,5- a] Pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylic acid, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5 -Ethyl-1H-pyrazole-3-carboxylic acid, 1- [(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-propyl-1H-pyrazole-3-carboxylic acid, 1-[(5-chloro-2- Phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-isopropyl-1H-pyrazole-3-carboxylic acid, 1-[(5-chloro-2-phenylpyrazolo [1,5- a] Pyridin-7-yl) methyl] -5-isobutyl-1H-pyrazole-3-carboxylic acid, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) Methyl] -1H-pyrrole-3-carboxylic acid, 5-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] furan-2-carboxylic acid, 2- [ (5-chloro-2-phenylpyrazolo [1, -A] pyridin-7-yl) methyl] oxazole-4-carboxylic acid, 6-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] pyridine-2- Carboxylic acid, 3-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] benzoic acid, 1-[[5-chloro-2- (4-chlorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (3-chlorophenyl) pyrazolo [1,5- a] Pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (2-chlorophenyl) pyrazolo [1,5-a] pyridine-7 -Yl] methyl] -5-methyl-1 -Pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (4-methoxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3 -Carboxylic acid, 1-[[5-chloro-2- (3-methoxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (2-methoxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[ 5-chloro-2- (4-fluorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro- 2- (3-Fluorophenyl) pyra Zolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (2-fluorophenyl) pyrazolo [1, 5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (methylamino) pyrazolo [1,5-a] pyridine- 7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (dimethylamino) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (ethylamino) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H -Pyrazole-3-carboxylic acid, 1-[[5 Chloro-2- (diethylamino) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (piperidine- 1-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (morpholin-4-yl) ) Pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[5-chloro-2- (pyrrolidin-1-yl) pyrazolo [ 1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridine- 7-yl) methyl] -N-hydroxy 5-methyl-1H-pyrazole-3-carboxamide, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N-cyano-5-methyl- 1H-pyrazole-3-carboxamide, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-N- (methylsulfonyl) -1H -Pyrazole-3-carboxamide, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N- (ethylsulfonyl) -5-methyl-1H- Pyrazole-3-carboxamide, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N- (propylsulfonyl) -5-methyl-1H-pyrazole - 3-Carboxamide, 3- [1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl]- 1,2,4-oxadiazol-5 (4H) -one, 5-chloro-7-[[5-methyl-3- (2
H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2-phenylpyrazolo [1,5-a] pyridine, 3- [1-[(5-chloro-2-phenylpyrazolo) [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] -1,2,4-oxadiazole-5 (4H) -thione, 3- [1 -[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] -1,2,4-thiadiazole-5 (4H) -one, 4- [1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] -2,6-difluorophenol, 2-[[1-[(5-chloro-2- Enylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] thio] phenol, N- [1-[(5-chloro-2-phenylpyrazolo [ 1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] acetamide, 1-[[2- (1-methylcyclopropyl) pyrazolo [1,5-a] Pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid and the like.

The pharmacologically acceptable salt of Compound (I) means a salt of Compound (I) with a pharmaceutically acceptable non-toxic base or acid (for example, an inorganic or organic base and an inorganic or organic acid).
Examples of the salt derived from a pharmaceutically acceptable non-toxic base of compound (I) include aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium. Salts with inorganic bases (particularly preferred are ammonium, calcium, manganese, potassium and sodium salts) or primary amines, secondary amines, tertiary amines, substituted amines (eg naturally occurring substitutions) Amines), cyclic amines, and organic bases such as basic ion exchange resins (eg, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanol) Amine, ethylenediamine, N-ethylmorpholine, N -Ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.) and compounds ( Illustrative of salts with I).
Examples of the salt derived from a pharmaceutically acceptable non-toxic acid of compound (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid and lactic acid. And salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid and palmitic acid.

Furthermore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may exist as a hydrate or a solvate. Any hydrate and solvate formed by the pyrazolopyridine derivative represented by the general formula (I) or a salt thereof including the preferred compounds specifically described above are within the scope of the present invention. Is included. Solvents that can form solvates include methanol, ethanol, 2-propanol, acetone, ethyl acetate, dichloromethane, diisopropyl ether, and the like.

In addition, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may have an optically active substance, a stereoisomer, or a rotational isomer in addition to the racemate. Furthermore, proton tautomers may exist in the compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof. These optically active isomers, stereoisomers and rotational isomers are also included in the scope of the present invention.

In the present specification, “EP ₁ receptor antagonism” means an action of inhibiting the binding of prostaglandin E ₂ (PGE ₂ ) to prostaglandin E receptor 1 (EP ₁ receptor).

EP ₁ receptor antagonism decreases the amount of calcium inflow into the cell and decreases or suppresses the intracellular calcium concentration. As a result, effects such as smooth muscle relaxation and sensory nerve stimulation inhibitory action are induced by the EP ₁ receptor antagonistic action. In particular, EP ₁ receptor antagonism occurs in the bladder, urothelium and the like, which is useful for the treatment or prevention of symptoms such as LUTS, especially OABs.

Further, the EP ₁ receptor antagonism can be evaluated by the potency of inhibiting the amount of calcium inflow into cells by the stimulating action of PGE _{2 on} the EP ₁ receptor. This efficacy can be evaluated by an in vitro test or an in vivo test according to “Pharmacological Test Examples” described in JP-A-2008-214224.

Compound (I) of the present embodiment can be produced by various synthesis methods. Next, a typical production method of the compound (I) of this embodiment will be described.

(Method A)
Among the compounds (I), the following compounds (Ia) and (Ib) can be produced, for example, by Method A described below.

In the formula, R ² , R ³ , R ⁴ , R ⁵ and A are as defined above; X represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and the like; Q ¹ _{Represents a} C _1-6 alkyl group or a C _7-10 aralkyl group; Q ² and Q ³ independently represent a hydrogen atom, a C _1-6 alkyl group or the like. When Q ² and Q ³ are C _1-6 alkyl groups, Q ² and Q ³ may be bonded to form a ring.

Step 1-1
This step is a step for producing compound (2) by formylating compound (1). Compound (2) can be produced, for example, by treating compound (1) with a base such as a lithium salt in a solvent and reacting with N, N-dimethylformamide or the like. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, and it is preferably carried out at −78 ° C. to 0 ° C. Examples of the base such as lithium salt used include bases such as n-butyllithium. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 1-2
This step is a step of producing compound (3) by reducing the aldehyde moiety of compound (2). Compound (3) can be produced, for example, by reacting compound (2) with a reducing agent in a solvent. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, propanol, 2-propanol, butanol, water, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, and it is preferably carried out at −78 ° C. to 0 ° C. Examples of the reducing agent used include reducing agents such as sodium borohydride and lithium aluminum hydride. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 1-3
This step is a step for producing a compound (3) by introducing a hydroxymethyl group into the compound (1). Compound (3) can be produced, for example, by treating compound (1) with a base such as a lithium salt in a solvent to lithiate, and then reacting the resulting compound with paraformaldehyde. Examples of the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like. Examples of the lithium salt used include lithium diisopropylamide, n-butyllithium, sec-butyllithium and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, and is preferably carried out at −78 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 1-4
This step is a step for producing the compound (4) by converting the hydroxy group of the compound (3) into an appropriate leaving group (X).
Compound (4) can be produced, for example, by chlorinating compound (3) using thionyl chloride or the like in a solvent when X is a chlorine atom. Examples of the solvent used include thionyl chloride, dichloromethane, chloroform, benzene, toluene, N, N, -dimethylformamide, tetrahydrofuran, pyridine, diethyl ether, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
In addition, for example, when X is a bromine atom, the compound (4) is produced by reacting a brominating agent such as carbon tetrabromide and a phosphorus reagent such as triphenylphosphine with a compound (3) in a solvent. can do. Examples of the solvent used include dichloromethane and the like. Examples of the brominating agent used include carbon tetrabromide. Examples of the phosphorus reagent used include triphenylphosphine. The reaction temperature is usually 0 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 1-5
This step is a step for producing compound (Ia) by reacting compound (4) with compound (5). Compound (Ia) can be produced, for example, by treating compound (5) with a base in solvent A and reacting with compound (4) dissolved in solvent B. Examples of the solvent A used include dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, acetonitrile, a mixed solvent thereof and the like. Examples of the solvent B used include dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, acetonitrile, a mixed solvent thereof and the like. As the base to be used, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3. 0] non-5-ene (DBN) and the like can be used. The reaction temperature can usually be carried out at −78 ° C. to the solvent reflux temperature, preferably at −20 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 1-6
This step is a step for producing compound (Ia) by reacting compound (4) with compound (6). Compound (Ia) can be produced, for example, by reacting compound (4) and compound (6) in a solvent and using a palladium reagent as a catalyst in the presence or absence of a base. Solvents used include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof A solvent etc. are mentioned. Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like. Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. Is mentioned. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 1-7
This step is a step for producing compound (Ia) by reacting compound (1) with compound (7). Compound (Ia) is obtained by, for example, lithiating compound (1) using a lithium salt or the like in a solvent, and reacting zinc iodide with the resulting compound to form a zinc complex in the presence or absence of a palladium catalyst. It can be produced by reacting the obtained zinc complex with the compound (7). Examples of the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like. Examples of the lithium salt used include lithium diisopropylamide, n-butyllithium, sec-butyllithium and the like. Examples of the palladium catalyst used include tetrakis (triphenylphosphine) palladium (0). The reaction temperature can usually be carried out at -78 ° C to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 1-8
This step is a step of producing compound (Ib) by hydrolyzing the ester moiety of compound (Ia). Compound (Ib) can be produced, for example, by reacting compound (Ia) with a base in a solvent. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, propanol, 2-propanol, butanol, water, a mixed solvent thereof and the like. The reaction temperature is usually 0 ° C. to solvent reflux temperature. Examples of the base used include alkali metal salts such as potassium hydroxide and sodium hydroxide. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

The compound (1) can be obtained, for example, by any of the following methods a, b, c, and d.

(Method a)

In the formula, R ² , R ³ , R ⁴ , R ⁵ and Q ¹ are as defined above; L ¹ represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, etc .; L ² is an iodine atom , Mesitylsulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, acetyloxy group and the like.

Step 2-1
This step is a step of producing compound (10) by reacting compound (8) with compound (9). Compound (10) is obtained by, for example, treating a bromo compound obtained by reacting compound (8) with carbon tetrabromide and triphenylphosphine in solvent A with a base such as n-butyllithium in solvent B. It can be produced by lithiation and subsequent reaction of the compound obtained with compound (9). Examples of the solvent A used include dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the solvent B used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to the solvent reflux temperature, preferably at −20 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. In addition, as the compounds (8) and (9) used in this step, commercially available products can be used, and other methods described in the literature or a method analogous thereto can also be used.

Step 2-2
This step is a step for producing a compound (12) by N-amination of the compound (11). Compound (12) can be produced, for example, by reacting compound (11) with ethyl O-mesitylsulfonylacetohydroxamate or the like in a solvent in the presence of an acid such as perchloric acid. When ethyl O-mesitylsulfonylacetohydroxamic acid is used, compound (12) can be obtained as mesityl sulfonate. Examples of the solvent used include 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to the solvent reflux temperature, preferably at −20 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. Moreover, the compound (11) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.

Step 2-3
This step is a step of producing compound (13) by reacting compound (10) with compound (12). Compound (13) can be produced, for example, by reacting compound (10) and compound (12) in the presence of a base in a solvent. Examples of the solvent used include methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to the solvent reflux temperature, preferably at −20 ° C. to 20 ° C. Examples of the base used include potassium carbonate and sodium carbonate. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. In addition, as the compound (10) and compound (12) used in this step, those obtained in Step 2-1 and Step 2-2 can be used, and commercially available products can be used. Moreover, you may use the compound (10) and the compound (12) which were manufactured according to the method of other literature description, or the method according to them.

Step 2-4
This step is a step of producing compound (14) by hydrolyzing the ester moiety of compound (13). Compound (14) can be produced, for example, by reacting compound (13) with a base in a solvent. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, propanol, 2-propanol, butanol, water and the like. The reaction temperature is usually 0 ° C. to solvent reflux temperature. Examples of the base used include alkali metal salts such as potassium hydroxide and sodium hydroxide. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 2-5
This step is a step of producing compound (1) by decarboxylation of compound (14). Compound (1) can be produced, for example, by subjecting compound (14) to a temperature condition in which decarboxylation occurs in a solvent in the presence or absence of an acid. Examples of the solvent used include 1,2-dichlorobenzene, diphenyl ether, xylene, toluene, ethanol and the like. Examples of the acid used include concentrated sulfuric acid. The reaction temperature is usually from 50 ° C. to the solvent reflux temperature, preferably from 100 ° C. to 180 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

(Method b)

In the formula, R ² , R ³ , R ⁴ , R ⁵ and Q ¹ are as defined above.

Step 3-1
This step is a step of producing compound (17) by reacting compound (15) with compound (16). Compound (17) can be produced, for example, by reacting compound (15) and compound (16) in a solvent in the presence of a base. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, diethyl ether, dimethyl sulfoxide, N, N-dimethylformamide, a mixed solvent thereof and the like. Examples of the base used include lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, sodium amide, potassium amide and the like. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. In addition, the compound (15) and (16) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.

Step 3-2
This step is a step for producing compound (1) by reacting compound (17) with an aminating agent. Compound (1) can be produced, for example, by reacting compound (17) with an aminating agent in a solvent and then cyclizing the compound obtained in the presence or absence of a base. Examples of the solvent used include methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to the solvent reflux temperature, preferably at −20 ° C. to 20 ° C. Examples of the aminating agent used include ethyl O-mesitylsulfonylacetohydroxamic acid. Examples of the base used include potassium carbonate and sodium carbonate. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 3-3
This step is a step for producing compound (18) by reacting compound (17) with hydroxylamine. Compound (18) can be produced, for example, by reacting compound (17) with hydroxylamine hydrochloride in the presence of a base in a solvent. Examples of the solvent used include methanol, ethanol, N, N-dimethylformamide, a mixed solvent thereof and the like. Examples of the base used include sodium hydroxide and potassium hydroxide. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 50 ° C. to the solvent reflux temperature.

Step 3-4
This step is a step of producing compound (1) by intramolecular cyclization of compound (18). Compound (1) is produced, for example, by allowing an acid anhydride such as trifluoroacetic anhydride and a base to act on compound (18) in a solvent and then reacting a metal salt such as iron (II) chloride. can do. Examples of the solvent used include 1,2-dimethoxyethane. Examples of the base used include triethylamine. Examples of the metal salt used include iron (II) chloride and iron (III) chloride. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

(Method c)

In the formula, R ² , R ³ , R ⁴ , R ⁵ , L ² , Q ¹ , Q ² and Q ³ are as defined above.

Step 4-1
This step is a step of producing compound (20) by reacting compound (12) with compound (19). Compound (20) can be produced, for example, by reacting compound (12) and compound (19) in the presence of a base in a solvent. Examples of the solvent used include methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to the solvent reflux temperature, preferably at −20 ° C. to 20 ° C. Examples of the base used include potassium carbonate and sodium carbonate. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. Compound (12) and compound (19) used in this step can be commercially available products, and can also be produced according to other methods described in the literature or a method analogous thereto.

Step 4-2
This step is a step of producing compound (21) by hydrolyzing the ester moiety of compound (20). This step can be performed according to the above-mentioned method a, step 2-4.

Step 4-3
This step is a step of producing compound (22) by decarboxylation of compound (21). This step can be performed according to the above-mentioned method a, step 2-5.

Step 4-4
This step is a step of producing compound (23) by substituting the amino group of compound (22) with a hydroxyl group. Compound (23) can be produced, for example, by treating compound (22) with an acid in a solvent. Examples of the solvent used include water. Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid and the like. The reaction temperature can usually be carried out at 20 ° C. to solvent reflux temperature, and is preferably carried out at 100 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 4-5
This step is a step of producing the compound (24) by trifluoromethanesulfonylation of the hydroxyl group of the compound (23). Compound (24) can be produced, for example, by reacting compound (23) with a trifluoromethanesulfonylating agent in the presence of a base in a solvent. Examples of the solvent used include dichloromethane, 1,2-dichloroethane, pyridine, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, acetonitrile, diethyl ether, a mixed solvent thereof and the like. Examples of the trifluoromethanesulfonylating agent include N-phenylbis (trifluoromethanesulfonimide) and trifluoromethanesulfonic anhydride. Examples of the base include potassium carbonate, sodium carbonate, sodium hydride, potassium phosphate, N, N-diisopropylethylamine, triethylamine, 2,6-lutidine and the like. The reaction temperature can usually be carried out at −78 ° C. to the solvent reflux temperature, preferably at −20 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 4-6
This step is a step for producing the compound (1) by substituting the trifluoromethanesulfonate portion of the compound (24) with R ² . Compound (1) can be produced, for example, by reacting compound (24) and compound (25) in a solvent and using a palladium reagent as a catalyst in the presence of a base. Solvents used include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water A mixed solvent etc. are mentioned. Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like. Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. Is mentioned. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

(Method d)

In the formula, R ² , R ³ , R ⁴ and R ⁵ are as defined above.

Step 5-1
This step is a step of producing compound (28) by reacting compound (26) with compound (27). Compound (28) can be produced, for example, by reacting compound (26) and compound (27) in the presence of a palladium catalyst, a copper catalyst, and a base in a solvent. Examples of the solvent used include methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C. Examples of the palladium catalyst used include dichlorobis (triphenylphosphine) palladium (II). Examples of the copper catalyst used include copper (I) iodide. Examples of the base used include triethylamine. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. Moreover, the compound (26) and compound (27) used at this process can use a commercial item, and can also manufacture them according to the method of other literature description, or the method according to them.

Step 5-2
In this step, compound (28) is reacted with an aminating agent and then cyclized to produce compound (1). This step can be performed according to the above-mentioned method b, step 3-2.

(Method B)
Among the compounds (I), the compounds (Ia) and (Ib) can also be produced, for example, by Method B described below.

In the formula, R ² , R ³ , R ⁴ , R ⁵ , A, Q ¹ , Q ² and Q ³ are as defined above; X ¹ and X ² are each independently a chlorine atom, bromine atom, iodine An atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, etc. are shown.

Step 6-1
This step is a step for producing compound (30) by cyanating X ¹ contained in compound (29). Compound (30) can be produced, for example, by reacting compound (29) with a cyanating agent in a solvent. Examples of the cyanating agent include potassium cyanide and sodium cyanide. Examples of the solvent used include dimethyl sulfoxide. The reaction temperature can usually be -78 ° C to 100 ° C, preferably 0 ° C to 50 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. In addition, the compound (29) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.

Step 6-2
This step is a step for producing compound (31) by reducing the ester moiety of compound (30). Compound (31) can be produced, for example, by reacting compound (30) with a reducing agent such as sodium borohydride in a solvent. Examples of the solvent used include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 6-3
This step is a step for producing compound (32) by reacting compound (31) with an aminating agent. This step can be performed according to the above-mentioned method b, step 3-2.

Step 6-4
This step is a step for producing a compound (33) by converting the amino group of the compound (32) into a hydroxyl group. This step can be performed according to the above-mentioned method c, step 4-4.

Step 6-5
This step is to introduce the leaving group represented by the general formula X ² in the compound (33) is a step for preparing a compound (34). Compound (34) is produced, for example, by reacting compound (33) with a brominating agent such as carbon tetrabromide and a phosphorus reagent such as triphenylphosphine in a solvent when X ² is a bromine atom. Can do. Examples of the solvent used include dichloromethane and the like. Examples of the brominating agent used include carbon tetrabromide. Examples of the phosphorus reagent used include triphenylphosphine. The reaction temperature is usually 0 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 6-6
This step is a step for producing a compound (35) by converting a hydrogen atom in the hydroxyl group of the compound (34) into a trifluoromethanesulfonyl group or the like to obtain a trifluoromethanesulfonyloxy group or the like. This step can be performed according to the above-mentioned method c, step 4-5.

Step 6-7
This step is a step for producing the compound (36) by converting the hydroxyl group of the compound (23) into a chlorine atom. Compound (36) can be produced, for example, by reacting compound (23) with phosphorus oxychloride or the like. This reaction can be performed using, for example, a solution of compound (23) using phosphorus oxychloride or the like as a solvent. The reaction temperature can usually be carried out at −78 ° C. to 200 ° C., preferably 100 ° C. to 150 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 6-8
This step is a step for producing a compound (37) by introducing a hydroxymethyl group into the compound (36). This step can be carried out according to the above-mentioned method A, step 1-3.

Step 6-9
This step is a step for producing a compound (38) by converting the hydroxyl group of the compound (37) into an appropriate leaving group (X ² ). This step can be performed according to the above-mentioned method A, step 1-4.

Step 6-10
In this step, compound (39) is produced by reacting compound (38) with compound (5). This step can be performed according to the above-mentioned Method A, Step 1-5. In the compound (39) obtained by this step, X ¹ is a chlorine atom.

Step 6-11
In this step, compound (39) is produced by reacting compound (35) with compound (5). This step can be performed according to the above-mentioned Method A, Step 1-5. In the compound (39) obtained by this step, X ¹ is a trifluoromethanesulfonyloxy group.

Step 6-12
This step is a step for producing compound (Ia) by reacting compound (39) with compound (25). This step can be performed according to the above-mentioned method c, step 4-6.

Step 6-13
This step is a step of producing compound (41) by cyanating X ¹ contained in compound (40). This step can be performed according to the above-mentioned method B, step 6-1.

Step 6-14
This step is a step of producing compound (42) by reacting compound (41) with an aminating agent. This step can be performed according to the above-mentioned method B, step 6-3.

Step 6-15
In this step, compound (43) is produced by reacting compound (42) with compound (5). This step can be performed according to the above-mentioned Method A, Step 1-5.

Step 6-16
This step is a step of producing compound (Ia) by alkylating the primary amino group of compound (43) when R ² site of compound (Ia) is a mono- or dialkylamino group or a cyclic amino group. is there. Compound (Ia) can be produced, for example, by reacting compound (43) with an alkylating agent such as various alkyl halides in a solvent in the presence or absence of a base. Examples of the alkylating agent include iodomethane, iodoethane, 1,4-dibromobutane and the like. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dichloromethane, ethanol, diethyl ether, 1,2-dimethoxyethane, a mixed solvent thereof and the like. Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, Sodium hydride etc. are mentioned. The reaction temperature can usually be carried out at −20 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 6-17
This step is a step of producing compound (Ib) by hydrolyzing the ester moiety of compound (Ia). This step can be performed according to the above-mentioned Method A, Step 1-8.

(Method C)
Of compound (I), compound (Ia) and compound (Ib) can also be produced by, for example, Method C described below.

In the formula, R ² , R ³ , R ⁴ , R ⁵ , A, Q ¹ , Q ² , Q ³ and X are as defined above.

Step 7-1
This step is a step of producing compound (3b) by demethylating the methoxy group of compound (3a). Compound (3b) can be produced, for example, by treating compound (3a) with an acid in a solvent. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, toluene, a mixed solvent thereof and the like. Examples of the acid used include boron tribromide. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. The compound (3a) used in this step is one of the compounds (3), and can be produced, for example, by the above-described Method A, Step 1-1, 1-2 or Step 1-3. .

Step 7-2
This step is a step for producing the compound (4a) by converting the hydroxyl group of the compound (3b) into an appropriate leaving group (X). This step can be performed according to the above-mentioned method A, step 1-4.

Step 7-3
In this step, compound (44) is produced by reacting compound (4a) with compound (5). This step can be performed according to the above-mentioned Method A, Step 1-5.

Step 7-4
This step is a step for producing the compound (45) by trifluoromethanesulfonylation of the hydroxyl group of the compound (44). This step can be performed according to the above-mentioned method c, step 4-5.

Step 7-5
This step is a step for producing compound (Ia) by reacting compound (45) with compound (46). This step can be performed according to the above-mentioned method c, step 4-6.

Step 7-6
This step is a step for producing compound (Ia) in which R ³ is a cyano group by reacting compound (45) with a cyanating agent. When R ³ of compound (Ia) is a cyano group, for example, compound (Ia) is produced by reacting compound (45) with a cyanating agent in the presence of a palladium catalyst and a phosphorus ligand in a solvent. be able to. Examples of the solvent used include tetrahydrofuran, N, N-dimethylformamide, water, a mixed solvent thereof and the like. Examples of the cyanating agent used include zinc cyanide. Examples of the palladium catalyst used include palladium (II) acetate and bis (dibenzylideneacetone) palladium (0). Examples of the phosphorus ligand used include triphenylphosphine and 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 7-7
This step is a step for producing a compound (Ia) in which R ³ is an acetyl group by reacting the compound (45) with an acetylating agent. When R ³ of compound (Ia) is an acetyl group, for example, compound (45) is subjected to a coupling reaction with vinyl ether using a palladium catalyst and a phosphorus ligand in the presence of a base in a solvent to produce vinyl ether. Then, compound (Ia) can be produced by hydrolyzing the resulting vinyl ether with an acid. Examples of the solvent used for the coupling reaction include tetrahydrofuran, N, N-dimethylformamide, a mixed solvent thereof and the like. Examples of the vinyl ether used include methyl vinyl ether and n-butyl vinyl ether. Examples of the palladium catalyst used include palladium (II) acetate and bis (dibenzylideneacetone) palladium (0). Examples of the phosphorus ligand used include triphenylphosphine and 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 60 ° C. to 100 ° C.
Examples of the solvent used for the hydrolysis reaction with an acid include 1,4-dioxane, water, a mixed solvent thereof and the like. Examples of the acid used include hydrochloric acid and sulfuric acid. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 60 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 7-8
This step is a step of producing compound (Ib) by hydrolyzing the ester moiety of compound (Ia). This step can be performed according to the above-mentioned Method A, Step 1-8.

(Method D)
Of the compound (I), the following compound (Id) can be produced, for example, by Method D described below.

In the formula, R ² , R ³ , R ⁴ , R ⁵ and A are as defined above.

Step 8-1
This step is a step of producing compound (Id) from compound (Ic). Compound (Id) can be produced, for example, by reacting compound (Ic) with hydroxylamine in a solvent in the presence of a base. Examples of the solvent used include ethanol. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. Examples of the base used include lithium hydroxide. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. In addition, the compound (Ic) used at this process is one of the compounds (Ib), for example, can be manufactured by the above-mentioned Method A or Method C.

(E method)
Among the compounds (I), the following compounds (Ie) and (If) can be produced, for example, by the E method described below.

In the formula, R ² , R ³ , R ⁴ , R ⁵ , A and Z ² are as defined above.

Step 9-1
This step is a step of producing compound (47) from compound (Ib). Compound (47) can be produced, for example, by reacting compound (Ib) with a compound serving as an amine source such as ammonium chloride in the presence of a condensing agent in a solvent in the presence or absence of a base. Examples of the solvent used include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, and mixed solvents thereof. Examples of the condensing agent used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like. If necessary, N, N-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. Examples of the base used include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine and the like. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 9-2
This step is a step of producing compound (If) from compound (47). Compound (If) can be produced, for example, by reacting compound (47) with a compound such as ethanesulfonyl chloride in the presence of a base in a solvent. Examples of the solvent used include 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 30 ° C. to 70 ° C. Examples of the base used include sodium hydride. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 9-3
This step is a step of producing compound (Ie) from compound (Ib). Compound (Ie) can be produced, for example, by reacting compound (Ib) with cyanamide or the like in a solvent in the presence of a condensing agent and in the presence or absence of a base. Examples of the solvent used include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, and mixed solvents thereof. Examples of the condensing agent used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like. If necessary, N, N-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. As the base to be used, potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine or the like can be used. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 9-4
This step is a step of producing compound (If) by a condensation reaction of compound (Ib) and compound (48). Compound (If) can be produced, for example, by reacting compound (Ib) with compound (48) in a solvent in the presence or absence of a base in the presence of a condensing agent. Examples of the solvent used include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, and mixed solvents thereof. Examples of the condensing agent used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like. If necessary, N, N-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 50 ° C. Examples of the base used include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine and the like. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

(F method)
Among the compounds (I), the following compounds (Ig) to (Ij) can be produced, for example, by Method F described below.

In the formula, R ² , R ³ , R ⁴ , R ⁵ and A are as defined above.

Step 10-1
This step is a step of producing compound (49) by dehydration reaction of compound (47). Compound (49) can be produced, for example, by reacting compound (47) with trifluoroacetic anhydride in the presence of a base in a solvent. Examples of the solvent used include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, a mixed solvent thereof and the like. As the base to be used, triethylamine or the like can be used. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 10-2
This step is a step for producing compound (Ig) by reaction of compound (49) with sodium azide. Compound (Ig) can be produced, for example, by reacting compound (49) with sodium azide in a solvent in the presence of an acid such as zinc bromide. Examples of the solvent used include N, N-dimethylformamide. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 50 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 10-3
This step is a step of producing compound (50) by reaction of compound (49) with hydroxylamine. Compound (50) can be produced, for example, by reacting compound (49) with hydroxylamine in a solvent. Examples of the solvent used include ethanol. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 10-4
This step is a step for producing compound (Ih) by reaction of compound (50) with ethyl chloroformate. Compound (Ih) is obtained, for example, by reacting compound (50) with ethyl chloroformate or the like in solvent A in the presence of a base such as pyridine, and then reacting the resulting compound with 1,8-diazabicyclo [ 5.4.0] can be prepared by treatment with a base such as undec-7-ene (DBU). Examples of the solvent A include N, N-dimethylformamide. Examples of the solvent B include xylene. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 10-5
In this step, compound (Ii) is produced by reacting compound (50) with 1,1′-thiocarbonyldiimidazole. Compound (Ii) can be produced, for example, by reacting compound (50) with 1,1′-thiocarbonyldiimidazole in a solvent and then treating the obtained compound with silica gel. Tetrahydrofuran etc. are mentioned as a solvent used. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 10-6
In this step, compound (Ij) is produced by reacting compound (50) with 1,1′-thiocarbonyldiimidazole. Compound (Ij) can be produced, for example, by reacting compound (50) with 1,1′-thiocarbonyldiimidazole in the presence of a base in a solvent. Examples of the solvent used include acetonitrile. Examples of the base used include 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and the like. It is done. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

(G method)
Of the compounds (I), the following compounds (Ik) to (Im) can be produced, for example, by Method G described below.

In the formula, R ² , R ³ , R ⁴ , R ⁵ , A, Q ² , Q ³ and Z ³ are as defined above.

Step 11-1
This step is a step of producing compound (51) by converting the carboxylic acid moiety of compound (Ib) into an amino group protected with a Boc group. Compound (51) can be produced, for example, by reacting compound (Ib) with diphenyl phosphate azide or the like in the presence of a base in a solvent. Examples of the solvent used include tert-butanol. Examples of the base used include triethylamine. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 11-2
This step is a step of producing compound (52) by removing the Boc group of compound (51) by deprotection. Compound (52) can be produced, for example, by treating compound (51) with an acid in a solvent. Examples of the solvent used include tetrahydrofuran and 1,4-dioxane. Examples of the acid used include hydrogen chloride-1,4-dioxane, trifluoroacetic acid and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 11-3
This step is a step for producing a compound (53) by converting the amino group of the compound (52) into an iodine atom. Compound (53) can be produced, for example, by reacting compound (52) in a solvent with a compound that forms an iodine source such as potassium iodide and a compound that forms a diazonium ion in the presence of an acid. Examples of the solvent used include acetonitrile. Examples of the compound serving as an iodine source include potassium iodide. Examples of the compound that forms diazonium ions include sodium nitrite. Examples of the acid used include p-toluenesulfonic acid. The reaction temperature can usually be carried out at −78 ° C. to the solvent reflux temperature, preferably at −78 ° C. to 30 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 11-4
This step is a step of producing compound (55) by reacting the iodine moiety of compound (53) with compound (54). This step can be performed according to the above-mentioned method c, step 4-6.
Compound (54) can be obtained from, for example, commercially available 5-bromo-1,3-difluoro-2- (methoxymethoxy) benzene as a starting material (Journal of Medicinal Chemistry (2011), 54 (2), 433- 448). For example, 5-bromo-1,3-difluoro-2- (methoxymethoxy) benzene is present in a solvent such as 1,4-dioxane, a palladium catalyst such as dichlorodiphenylphosphinoferrocenepalladium, and a base such as potassium ethylhexanoate. Then, 2- [3,5-difluoro-4- (methoxymethoxy) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane is prepared by reacting with bispinacol diboron. be able to.

Step 11-5
This step is a step of producing compound (Ik) by converting a methoxymethyloxy group of compound (55) into a hydroxyl group. Compound (Ik) can be produced, for example, by reacting compound (55) with an acid such as hydrogen chloride in a solvent. Examples of the solvent used include 1,4-dioxane. Examples of the acid used include hydrogen chloride-1,4-dioxane. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 11-6
This step is a step of producing compound (57) by reacting compound (53) with compound (56). Compound (57) can be produced, for example, by reacting compound (53) and compound (56) in a solvent using a palladium reagent as a catalyst in the presence of a phosphorus ligand and a base. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like. Examples of the palladium catalyst used include tris (dibenzylideneacetone) dipalladium (0). Examples of the phosphorus ligand used include 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene. Examples of the base used include N, N-diisopropylethylamine. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

Step 11-7
This step is a step of producing compound (Il) by converting the methoxymethyloxy group of compound (57) into a hydroxyl group. This step can be performed according to the above-mentioned Method G, Step 11-5.

Step 11-8
This step is a step of producing compound (Im) by acylating compound (52). Compound (Im) can be produced, for example, by reacting compound (52) with an acylating agent in a solvent in the presence or absence of a base. Examples of the acylating agent used include acetic anhydride, acetyl chloride, and propionyl chloride. Examples of the solvent used include tetrahydrofuran and pyridine. Examples of the base used include triethylamine. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.

The pharmacologically acceptable salt of compound (I) of this embodiment can be produced according to a conventional method using compound (I) of this embodiment.

The scheme shown above is an example of a method for producing the compound (I) of the present embodiment or a production intermediate thereof. These can be variously modified into schemes that can be easily understood by those skilled in the art.

In addition, when a protective group is required depending on the type of functional group, the introduction and desorption operations can be appropriately combined according to a conventional method. Regarding the type, introduction, and elimination of protecting groups, see, for example, Theodora W. et al. Greene & Peter G. M.M. Edited by Wuts, “Greene's Protective Groups in Organic”
Synthesis ", fourth edition, Wiley-Interscience, 2006.

The intermediate used for producing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may be isolated and purified by means well known to those skilled in the art, if necessary. It can be isolated and purified by certain solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, and the like.

The pharmaceutical containing the compound (I) of this embodiment or a pharmacologically acceptable salt thereof The pharmaceutical containing the compound (I) of this embodiment or a pharmacologically acceptable salt thereof as an active ingredient Various dosage forms can be obtained depending on Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.

These medicaments are prepared by a known method according to the dosage form, as an active ingredient, compound (I) of the present embodiment or a pharmacologically acceptable salt thereof, a pharmacologically acceptable additive, It can comprise as a pharmaceutical composition containing this. Additives contained in the pharmaceutical composition include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stable agents. An agent, a solubilizing agent, etc. can be mentioned. The pharmaceutical composition comprises compound (I) of the present embodiment or a pharmacologically acceptable salt thereof and an appropriate additive appropriately mixed, or compound (I) or a pharmacologically acceptable salt thereof. It can be prepared by diluting and dissolving with additives. Further, when used in combination with drugs other than the EP ₁ receptor antagonist, simultaneously or separately each of active ingredients, it can be prepared by formulating the same manner as described above.

Medicinal Use of Compound (I) or a Pharmacologically Acceptable Salt of the Present Embodiment Compound (I) or a pharmacologically acceptable salt of the present embodiment is an EP ₁ receptor antagonistic confirmation test, etc. Shows strong EP ₁ receptor antagonism. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can suppress or decrease the intracellular calcium concentration.
Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is based on the EP ₁ receptor antagonism confirmation test, and is a disease caused by activation of EP ₁ receptor by PGE ₂ stimulation. It can be used for the treatment, prevention, or suppression of symptoms. Examples of the disease or symptom that activates the EP ₁ receptor by PGE ₂ stimulation include lower urinary tract symptoms (LUTS), inflammatory diseases, painful diseases, osteoporosis, cancer and the like. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is used for the treatment, prevention or suppression of lower urinary tract symptoms (LUTS), inflammatory diseases, painful diseases, osteoporosis, cancer and the like. Can be used for Here, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of LUTS, inflammatory disease or pain disease, and lower urinary tract symptoms More preferably it is used for the treatment or prevention of (LUTS).
In addition, the pharmaceutical composition containing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof as an active ingredient has a disease or symptom caused by activation of EP ₁ receptor by PGE ₂ stimulating action. It can be used as a therapeutic or prophylactic agent.
Specifically, the pharmaceutical composition containing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof as an active ingredient includes lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, It can be used as a therapeutic or prophylactic agent for diseases or symptoms such as osteoporosis and cancer. Among these, the pharmaceutical composition according to the present embodiment is preferably used as a therapeutic or prophylactic agent for LUTS, inflammatory disease or pain disease, and more preferably used as a therapeutic or prophylactic agent for LUTS. preferable.

Examples of the causative diseases of lower urinary tract symptoms include overactive bladder (OAB), prostatic hypertrophy (BPH), cystitis such as interstitial cystitis, prostatitis and the like.

“Lower urinary tract symptoms” means, for example, urine storage symptoms, urination symptoms, and post-urination symptoms.

The compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of urine storage symptoms.

Urinary urgency, daytime frequent urination, nighttime frequent urination, stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, persistent urinary incontinence, and bladder It includes bladder perception, such as increased perception, decreased bladder perception, lack of bladder perception, and nonspecific bladder perception.
Compound (I) or a pharmacologically acceptable salt thereof according to this embodiment includes urinary urgency, daytime frequent urination, nocturia, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, increased bladder perception Alternatively, it is preferably used for treatment or prevention of nonspecific bladder perception. More preferably, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is used for the treatment or prevention of urgency, daytime frequent urination, nocturia, urinary urinary incontinence or increased bladder perception. Used for.
In addition, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is particularly preferable for the treatment or prevention of OABs.

Compound (I) of the present embodiment or a pharmacologically acceptable salt thereof, or a combination thereof Compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof is an EP ₁ receptor antagonist It can also be used in combination with at least one kind of drug other than

Examples of the drug that can be used in combination with the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof include overactive bladder (OAB) and prostatic hypertrophy having a mechanism of action different from that of the EP ₁ receptor antagonist. And therapeutic agents for cystitis (BPH), cystitis such as interstitial cystitis, prostatitis and the like. Examples of such agents, anticholinergics, alpha ₁ antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, acetylcholinesterase inhibitors, antiandrogens, progesterone-based hormone, LH-RH analogs, neurokinin inhibitors , Antidiuretic, calcium channel blocker, smooth muscle direct acting drug, tricyclic antidepressant, potassium channel modulator, sodium channel blocker, H ₁ blocker, serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine reuptake inhibitors, GABA agonists, TRPVl modulators, endothelin antagonists, _{5-HT 1A} antagonist, alpha ₁ agonists, opioid agonists, _{P 2} X antagonists, COX inhibitors, sigma agonists, et al include muscarinic agonists such as That. Preferred are anticholinergic agents, α ₁ antagonists, β agonists, 5α-reductase inhibitors, PDE inhibitors, progesterone hormones, antidiuretics, smooth muscle direct acting agents or tricyclic antidepressants.

The drug used in combination with the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is specifically exemplified as follows. However, the contents of the present invention are not limited to these. In addition, specific compounds include free forms thereof and other pharmacologically acceptable salts.

Examples of the “anticholinergic agent” include oxybutynin, propiverine, solifenacin, torte mouth gin, imidafenacin, temiverine, darifenacin, fesoterodine, trospium, propantelin and the like.

Examples of the “α ₁ antagonist” include urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin, alfuzosin, doxazosin, CR-2991, feduxin and the like.

Examples of the “β agonist” include mirabegron, KUC-7383, KRP-204, SM-350300, TRK-380, amibegron, clenbuterol, SAR-150640, sorabegron and the like.

Examples of the “5α-reductase inhibitor” include dutasteride, TF-505, finasteride, and izonsteride.

“PDE inhibitor” means a phosphodiesterase inhibitor, and examples thereof include tadalafil, vardenafil, sildenafil, avanafil, UK-369003, T-0156, AKP-002, etazolate and the like.

Examples of the “acetylcholinesterase inhibitor” include distigmine, donepezil, Z-338, rivastigmine, ganstigmine, BGC-20-1259, galantamine, itopride, NP-61, SPH-1286, tolserine, ZT-1 and the like. .

Examples of the “anti-androgen” include guestnolone, oxendron, bicalutamide, BMS-641988, CB-03-01, CH-489789, flutamide, MDV-3100, nilutamide, TAK-700, YM-580 and the like.

Examples of “progesterone hormones” include chromazinone and allylestrenol.

“LH-RH analog” means a gonadotropin releasing hormone analog. Gonadotropin releasing hormone may also be referred to as luteinizing hormone releasing hormone. For example, AEZS-108, buserelin, deslorelin, goserelin, histrelin, leuprorelin, lutropin, nafarelin, triptorelin, AEZS-019, cetrorelix, degarelix, elagorix, ganilelex, ozarelix, PTD-634, TAK-385, Taverix 448, TAK-683 and the like.

Examples of the “neurokinin inhibitor” include KRP-103, aprepitant, AV-608, Casopitant, CP-122721, DNK-333, fosprepitant, LY-686017, netpitant, olbepitant, lolapitant, TA-5538, T-2328, Vestipitant, AZD-2624, Z-501, 1144814, MEN-15596, MEN-11420, SAR-102779, SAR-102279, Saleduant, SSR-241586, and the like.

Examples of the “antidiuretic” include desmopressin, VA-106483 and the like.

Examples of “calcium channel blockers” include amlodipine, cilnidipine, puffer piverine, temiverine, PD-299685, alanidipine, azelnidipine, balnidipine, benidipine, bevantolol, clevidipine, CYC-381, diltiazem, efonidipine, fasudil, felodipine, gabamil Examples include isradipine, lacidipine, lercanidipine, lomerizine, manidipine, MEM-1003, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, SB-751689, verapamil, YM-58483, and ziconotide.

“Smooth muscle direct acting drugs” include flavoxate and the like.

Examples of “tricyclic antidepressants” include imipramine, clomipramine, amitriptyline and the like.

Examples of the “potassium channel modulator” include nicorandil, NIP-141, NS-4591, NS-1643, andlast, diazoxide, ICA-105665, minoxidil, pinacidil, tirisolol, VRX-698 and the like.

Examples of the “sodium channel blocker” include bepridil, dronedarone, propafenone, safinamide, SUN-N8075, SMP-986, 1014802, 552-02, A-803467, brivaracetam, cibenzoline, eslicarbazepine, F-15845, flecainide Phosphenytoin, lacosamide, lamotrigine, levobupivacaine, M-58373, mexiletine, moracidin, nerispyridine, NW-3509, oxcarbazepine, pilsicainide, pirmenol, propafenone, NW-1029, ropivacaine, vanacarant, etc. it can.

Examples of the “H ₁ blocker” include acribastine, alcaftadine, bepotastine, bilastine, cetirizine, desloratadine, ebastine, efletirizine, epinastine, fexofenadine, GSK-835726, levocabastine, levocetirizine, loratadine, mequitadine, mizolastine, NBI-7, 43 -1869, terfenadine, UCB-35440, vapitadine, YM-344484, diphenhydramine, chlorpheniramine and the like.

“Serotonin reuptake inhibitors” include UCB-46331, 424887, AD-337, BGC-20-1259, BMS-505130, citalopram, dapoxetine, desvenlafaxine, DOV-102673, DOV-216303, DOV-21947 , Duloxetine, escitalopram, F-2695, F-98214-TA, fluoxetine, fluvoxamine, IDN-5491, milnacipran, minaprine, NS-2359, NSD-644, paroxetine, PF-184298, SD-726, SEP-225289 , SEP-227162, SEP-228425, SEP-228432, sertraline, sibutramine, tesofensin, tramadol, trazodone, UCB-46331, venlafa Singh, mention may be made Birazodon, the WAY-426, WF-516 and the like.

Examples of “norepinephrine reuptake inhibitors” include AD-337, desvenlafaxine, DOV-102677, DOV-216303, DOV-21947, duloxetine, F-2695, F-98214-TA, milnacipran, NS-2359 , NSD-644, PF-184298, SD-726, SEP-225289, SEP-227162, SEP-228425, SEP-228432, Sibutramine, Tesofensin, Tramadol, Venlafaxine, Bupropion, Radafaxin, Atomoxetine, DDP-225, LY -2216684, nevogramin, NRI-193, reboxetine, tapentadol, WAY-256805, WAY-260022, and the like.

Examples of the “dopamine reuptake inhibitor” include DOV-102777, DOV-216303, DOV-21947, IDN-5491, NS-2359, NSD-644, SEP-225289, SEP-228425, SEP-228432, sibutramine, tesofensin, Examples thereof include tramadol, brasofensin, bupropion, NS-27100, radafaxin, safinamide and the like.

“GABA agonists” include retigabine, eszopiclone, indipron, pagok mouth, SEP-225441, acamprosate, baclofen, AZD-7325, BL-1020, brotizolam, DP-VPA, progabide, propofol, topiramate, zopiclone EVT-201, AZD-3043, ganaxolone, NS-11394, albaclofen, AZD-3355, GS-39783, ADX-71441, ADX-71943, and the like.

“TRPV1 modulators” include force psaicin, resiniferatoxin, DE-096, GRC-6611, AMG-8562, JTS-653, SB-705498, A-4256619, A-784168, ABT-102, AMG- 628, AZD-1386, JNJ-17203212, NGD-8243, PF-386486, SAR-115740, SB-784243, and the like.

“Endothelin antagonists” include SB-234551, ACT-064992, ambrisentan, atrasentan, bosentan, clazosentan, darsentan, fundsentan, S-0139, TA-0201, TBC-3711, dibotentane, BMS-509701, PS -433540 and the like.

Examples of the “5-HT _1A antagonist” include espindolol, lecozotan, lurasidone, E-2110, REC-0206, SB-649915, WAY-426, WF-516 and the like.

Examples of the “α ₁ agonist” include CM-2236, armodafinil, midodrine, modafinil and the like.

“Opioid agonists” include morphine, TRK-130, DPI-125, DPI-3290, fentanyl, LIF-301, loperamide, loperamide oxide, remifentanil, tapentadol, WY-16225, oxycodone, PTI-202, PTI-721 ADL-5747, ADL-5589, DPI-221, DPI-353, IPP-102199, SN-11, ADL-10-0101, ADL-10-0116, asimadoline, buprenorphine, CR-665, CR-845, eptazosin Nalbuphine, nalflaphine, pentazocine, XEN-0548, W-212393, ZP-120, nalmefene and the like.

Examples of the “P ₂ X antagonist” include A-740003, AZ-1157312, AZD-9056, GSK-14482160, GSK-31481A and the like.

“COX inhibitor” means a cyclooxygenase inhibitor such as aceclofenac, ST-679, aspirin, bromfenac, dexketoprofen, flurbiprofen, FYO-750, ibuprofen, ketoprofen, ketorolac, lycoferon, lornoxicam, loxoprofen, LT -NS001, diclofenac, mofezolac, nabumetone, naproxen, oxaprozin, piroxicam, pranoprofen, suprofen, tenoxicam, thiaprofenic acid, tolfenamic acid, zaltoprofen, 644784, ABT-963, ajulemic acid, apricoxib, celecoxib, citricoxib, citricoxib Lumiracoxib, meloxicam, nimesulide, parecoxib, RO-26-21 8, it can be mentioned valdecoxib and the like.

Examples of the “σ agonist” include ANAVEX-27-1041, PRS-013, SA-4503, ANAVEX-2-73, silamesine, ANAVEX-7-1037, ANAVEX-1-41, and the like.

Examples of “muscarinic agonists” include AC-260584, cevimeline, MCD-386, NGX-267, NGX-292, subcomerin, pilocarpine, bethanechol and the like.

When the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof and one or more of the above drugs are used in combination, the present invention is selected from the following 1) to 5) Any one method of administration is included.
1) Simultaneous administration with combination drug,
2) As separate formulations, co-administration by the same route of administration,
3) As separate formulations, co-administration by different routes of administration,
4) Administration at different times by the same route of administration as separate formulations, or 5) Administration at different times by different routes of administration as separate formulations Also at different times as separate formulations as in 4) or 5) The administration order of the compound (I) of the present invention and the above drug is not particularly limited.

In addition, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can be used as an additive effect in preventing or treating the above diseases by using one or more of the above drugs in appropriate combination. The above advantageous effects can be obtained. Similarly, it is possible to reduce the amount of use compared to the case of using it alone, or to reduce the side effects of the drugs used in combination, or to avoid or reduce the side effects of the drugs used in combination.

Usage / Dosage of Compound (I) of this Embodiment The medicament according to this embodiment can be used systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, muscle, transdermal). Etc.).

When the medicament according to the present embodiment is used for actual treatment, the dose of compound (I) of the present embodiment, which is an active ingredient thereof, or a pharmacologically acceptable salt thereof is determined by the patient's age, sex, body weight, It is determined appropriately depending on the disease and the degree of treatment. For example, in the case of oral administration, an adult (with a body weight of 60 kg) can be appropriately administered once or in several divided doses within a range of about 3 to 1000 mg / body per day. The daily dose as an oral preparation is preferably 6 to 540 mg / body, more preferably 18 to 180 mg / body. In the case of parenteral administration, it can be appropriately administered once or in several divided doses in the range of about 0.01 to 300 mg per day for an adult. The daily dose as a parenteral preparation is preferably 1 to 100 mg / body, more preferably 6 to 60 mg / body. In addition, the dose of the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can be reduced according to the dose of a drug other than the EP ₁ receptor antagonist.

Hereinafter, the present invention will be described in more detail based on test examples, examples, and reference examples. Moreover, since the new compound is contained also in the raw material compound used for manufacture of compound (I), the manufacture example of a raw material compound is demonstrated as a reference example. The present invention is not limited to the compounds described in the following examples, and may be changed without departing from the scope of the present invention.

Ethyl 3- (4-methoxyphenyl) propiolate Under an argon atmosphere, triphenylphosphine (93 g) was added to a solution of carbon tetrabromide (58 g) in dichloromethane (147 mL) under ice cooling, and under ice cooling. Stir for 30 minutes. 4-Methoxybenzaldehyde (20.0 g) was added to the resulting mixture, and the mixture was further stirred for 30 minutes under ice cooling. After evaporating the solvent under reduced pressure, the residue was filtered using silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain a dibromo compound as a yellow liquid.
Under an argon atmosphere, n-butyllithium (124 mL, 2.6 M in hexane) was added to a tetrahydrofuran solution (294 mL) of the obtained dibromo compound under ice cooling, and the mixture was stirred for 3 hours under ice cooling. Ethyl chloroformate (33.6 mL) was added to the resulting mixture to obtain a reaction solution, and the reaction solution was further stirred for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give the title compound as a yellow liquid (13.5 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.35 (3H, t, J = 7.3 Hz), 3.83 (3H, s), 4.29 (2H, q, J = 7.3 Hz), 6.88 (2H, d, J = 7.0 Hz), 7.54 (2H, d, J = 7.0 Hz).

Ethyl 3- (4-chlorophenyl) propiolate 4-chlorobenzaldehyde was used in place of 4-methoxybenzaldehyde, and the title compound was obtained in the same manner as in Reference Example 1-1.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.36 (3H, t, J = 7.3 Hz), 4.30 (2H, q, J = 7.3 Hz), 7.36 (2H, d, J = 8.5 Hz), 7.52 ( 2H, d, J = 8.5 Hz).

Methyl 2-phenylpyrazolo [1,5-a] pyridine-3-carboxylate To a solution of 1-aminopyridinium iodide (27.8 g) in methanol (312 mL) under an argon atmosphere, potassium carbonate under ice-cooling (34.5 g) and methyl 3-phenylpropiolate (10 g) were added to prepare a reaction solution. The reaction solution was stirred for 30 minutes under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate under reduced pressure to obtain the title compound as a yellow solid (12.1 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.84 (3H, s), 6.98 (1H, td, J = 7.3, 1.2 Hz), 7.59-7.62 (1H, m), 7.71 (2H, t, J = 7.3 Hz), 7.78-7.80 (2H, m), 7.94-7.99 (1H, m), 8.21 (1H, d, J = 9.1 Hz), 8.54 (1H, d, J = 6.7 Hz).

<Reference Examples 2-2 to 2-10>
The following compounds of Reference Examples 2-2 to 2-10 were obtained in the same manner as in Reference Example 2-1, using the corresponding phenylpropiolic acid esters. Their structures and spectral data are shown in Tables 1 and 2.

2-Phenylpyrazolo [1,5-a] pyridine-3-carboxylic acid Methanol solution of methyl 2-phenylpyrazolo [1,5-a] pyridine-3-carboxylate (12.0 g) under argon atmosphere (238 mL) was added 2 mol / L potassium hydroxide aqueous solution (119 mL) under ice cooling to prepare a reaction solution. The reaction was stirred at 80 ° C. for 5 hours. A 1 mol / L aqueous hydrochloric acid solution (480 mL) was added to the reaction solution, and the precipitated solid was collected by filtration. The resulting solid was dried under reduced pressure to give the title compound as an orange solid (10.2 g).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.15 (1H, td, J = 6.7, 1.4 Hz), 7.42-7.46 (3H, m), 7.55-7.58 (1H, m), 7.74-7.77 ( 2H, m), 8.15 (1H, d, J = 4.5 Hz), 8.84 (1H, d, J = 6.7 Hz).

<Reference Examples 3-2 to 3-10>
Using the corresponding ester, the following Reference Examples 3-2 to 3-10 were obtained in the same manner as Reference Example 3-1. Their structures and spectral data are shown in Tables 3 and 4.

2-Phenylpyrazolo [1,5-a] pyridine Under argon atmosphere, 2-phenylpyrazolo [1,5-a] pyridine-3-carboxylic acid (10.0 g) in o-dichlorobenzene solution (42 mL) ) Was stirred at 160 ° C. for 2 hours. The solvent was removed under reduced pressure, and the resulting solid was washed with n-hexane to give the title compound as a yellow solid (9.45 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.72 (1H, td, J = 7.3, 1.2 Hz), 6.79 (1H, s), 7.05-7.11 (1H, m), 7.18-7.21 (2H, m) , 7.34-7.39 (1H, m), 7.44-7.49 (1H, m), 7.97 (2H, d, J = 7.3 Hz), 8.47 (1H, d, J = 7.9 Hz).

<Reference Examples 4-2 to 4-10>
The following compounds of Reference Examples 4-2 to 4-10 were obtained in the same manner as in Reference Example 4-1, using the corresponding carboxylic acid compounds. Their structures and spectral data are shown in Tables 5 and 6.

2- (4-Chloropyridin-2-yl) -1-phenylethanone A tetrahydrofuran solution of 4-chloro-2-methylpyridine (5.0 g) and ethyl benzoate (9.8 mL) under an argon atmosphere ( 39 mL) was added lithium bistrimethylsilylamide (79 mL, 1.0 mol / L tetrahydrofuran solution) under ice cooling to prepare a reaction solution. The reaction was stirred at room temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a yellow powder (6.0 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.48 (2H, s), 7.00 (1H, dd, J = 5.4, 1.8 Hz), 7.09 (1H, d, J = 1.8 Hz), 7.21 (1H. Dd , J = 5.4, 1.8 Hz), 7.35 (1H, d, J = 1.8 Hz), 7.56-7.61 (1H, m), 8.07 (1H, d, J = 1.2 Hz), 8.23 (1H, d, J = 5.4 Hz), 8.46 (1H, d, J = 5.4 Hz).

<Reference Examples 5-2 to 5-5>
The corresponding compounds of Reference Examples 5-2 to 5-5 were obtained in the same manner as in Reference Example 5-1, using the corresponding 2-methylpyridine compound. These structures and spectral data are shown in Table 7.

5-chloro-2-cyclohexylpyrazolo [1,5-a] pyridine In an argon atmosphere, a solution of ethyl O-mesitylsulfonylacetohydroxamate (1.00 g) in 1,4-dioxane (0.900 mL) was added. A 70% aqueous perchloric acid solution (0.366 mL) was added under ice-cooling to give a first reaction solution. The first reaction solution was stirred for 30 minutes under ice cooling. Ice water (10.0 mL) was added to the first reaction solution, the precipitated solid was filtered, and the resulting solid was dissolved in dichloromethane (1.50 mL) to separate the layers. The organic layer was dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the obtained filtrate was added to a dichloromethane solution (1.40 mL) of 2- (4-chloropyridin-2-yl) -1-cyclohexylethanone (700 mg) under ice-cooling. To give a second reaction solution. After stirring the second reaction solution at room temperature for 1 hour, the second reaction solution was concentrated under reduced pressure to obtain a crude product.
Under an argon atmosphere, potassium carbonate (814 mg) was added to an N, N-dimethylformamide solution (2.90 mL) of the obtained crude product at room temperature to obtain a third reaction solution. The third reaction was stirred at room temperature for 1 hour. Water was added to the third reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 19: 1) to give the title compound as a yellow powder (93.8 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.24-1.53 (6H, m), 1.70-1.88 (4H, m), 2.79-2.84 (1H, m), 6.24 (1H, s), 6.61 (1H, dd, J = 7.3, 1.8 Hz), 7.40 (1H, d, J = 1.8 Hz), 8.27 (1H, d, J = 7.3 Hz).

<Reference Examples 6-2 to 6-4>
Using the corresponding ketone bodies, the following compounds of Reference Examples 6-2 to 6-4 were obtained in the same manner as Reference Example 6-1. These structures and spectral data are shown in Table 8.

(Z) -2- (4-Chloropyridin-2-yl) -1-phenylethanone oxime Under argon atmosphere, 2- (4-chloropyridin-2-yl) -1-phenylethanone (2.6 g Hydroxylamine hydrochloride (3.9 g) and 10% aqueous sodium hydroxide solution (22.5 mL) were added to a methanol solution (26 mL) at room temperature to give a reaction solution. The reaction was stirred at 70 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate to obtain the title compound as a colorless powder (2.4 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.40 (2H, s), 7.15 (1H, dd, J = 5.4, 1.8 Hz), 7.32 (1H, d, J = 1.8 Hz), 7.33-7.38 (3H , m), 7.71-7.75 (2H, m), 8.31 (1H, brs), 8.43 (1H, d, J = 5.4 Hz).

5-chloro-2-phenylpyrazolo [1,5-a] pyridine (Z) -2- (4-chloropyridin-2-yl) -1-phenylethanone oxime (1.0 g) under argon atmosphere To a dimethoxyethane solution (4.0 mL) was added trifluoroacetic anhydride (0.6 mL) under ice cooling to prepare a reaction solution. The reaction was stirred at room temperature for 10 minutes. The reaction mixture was ice-cooled again, triethylamine (1.1 mL) was added, and the mixture was stirred at room temperature for 16 hr. Next, iron (II) chloride (52 mg) was added to the reaction solution, and the mixture was stirred at 110 ° C. for 2 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound as a yellow powder (560 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.70 (1H, dd, J = 7.6, 1.8 Hz), 6.75 (1H, s), 7.38 (1H, t, J = 7.3 Hz), 7.46 (2H, t , J = 7.6 Hz), 7.50 (1H, d, J = 1.8 Hz), 7.94 (2H, d, J = 7.3 Hz), 8.38 (1H, d, J = 7.3 Hz).

Ethyl 2-aminopyrazolo [1,5-a] pyridine-3-carboxylate To a methanol solution (256 mL) of 1-aminopyridinium iodide (57 g) under argon atmosphere, potassium carbonate (70.6 g) Ethyl 3-ethoxy-3-iminopropanoate hydrochloride (25 g) was added to give a reaction solution. The reaction solution was stirred for 19 hours under ice cooling. A 1 mol / L aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate under reduced pressure to obtain the title compound as a yellow liquid (20.5 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.43 (3H, t, J = 7.3 Hz), 4.38 (2H, q, J = 7.3 Hz), 5.24 (2H, brs), 6.79 (1H, t, J = 9.2 Hz), 7.31 (1H, t, J = 7.9 Hz), 7.81 (1H, d, J = 9.2 Hz), 8.22 (1H, d, J = 7.9 Hz).

Pyrazolo [1,5-a] pyridin-2-ol A solution of ethyl 2-aminopyrazolo [1,5-a] pyridine-3-carboxylate (5.2 g) in ethanol (51 mL) at room temperature under an argon atmosphere. 2 mol / L aqueous potassium hydroxide solution (64 mL) was added to give a first reaction solution. The first reaction solution was stirred at 100 ° C. for 5 hours. A 1 mol / L hydrochloric acid aqueous solution (300 mL) was added to the first reaction solution, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain a crude product of 2-aminopyrazolo [1,5-a] pyridine-3-carboxylic acid as a colorless powder.
Concentrated sulfuric acid (1.0 mL) was added to an ethanol solution (250 mL) of a crude product of 2-aminopyrazolo [1,5-a] pyridine-3-carboxylic acid (4.5 g) under an argon atmosphere at room temperature. In addition, a second reaction solution was obtained. The second reaction solution was stirred at 100 ° C. for 1 hour. The solvent was distilled off under reduced pressure to obtain a crude product of pyrazolo [1,5-a] pyridin-2-amine as a yellow liquid.
Concentrated hydrochloric acid (25 mL) was added to the crude product of pyrazolo [1,5-a] pyridin-2-amine (4.2 g) under an argon atmosphere at room temperature to obtain a third reaction solution. The third reaction solution was stirred at 120 ° C. for 10 hours. A 20% aqueous sodium hydroxide solution (130 mL) was added to the reaction mixture to adjust the pH of the reaction mixture to 7, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a yellow powder (1.6 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.83 (1H, s), 6.60-6.64 (1H, m), 7.07-7.11 (1H, m), 7.31 (1H, d, J = 8.6 Hz), 8.17 (1H, d, J = 7.4 Hz)

2- (Trifluoromethanesulfonyloxy) pyrazolo [1,5-a] pyridine Mixture of tetrahydrofuran-N, N-dimethylformamide with pyrazolo [1,5-a] pyridin-2-ol (3.1 g) under argon atmosphere To the solution (34 mL, 1: 1), N-phenylbis (trifluoromethanesulfonimide) (9.9 g) and sodium hydride (1.0 g, 60% in oil) were added under ice cooling, It was set as the reaction liquid. The reaction solution was stirred for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, silica gel (FUJI SILYSIA NH silica gel 100-200 mm) was added, and the mixture was filtered. The solvent was distilled off to give the title compound as a yellow solid (6.9 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.37 (1H, s), 6.89 (1H, td, J = 7.3, 1.2 Hz), 7.22-7.25 (1H, m), 7.51 (1H, d, J = 8.5 Hz), 8.37 (1H, dt, J = 7.3, 1.2 Hz)

2- (2-Chlorophenyl) pyrazolo [1,5-a] pyridine A 1,2-dimethoxyethane solution of 2- (trifluoromethanesulfonyloxy) pyrazolo [1,5-a] pyridine (500 mg) under an argon atmosphere ( 6.3 mL) at room temperature was added 2-chlorophenylboronic acid (441 mg), 2 mol / L aqueous sodium carbonate solution (2.8 mL), dichlorobis (triphenylphosphine) palladium (II) (132 mg), It was set as the reaction liquid. The reaction was stirred at 90 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a yellow liquid (371 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.77 (1H, td, J = 6.7, 1.2 Hz), 7.03 (1H, s), 7.10-7.14 (1H, m), 7.28-7.39 (2H, m) , 7.50 (1H, dd, J = 7.9, 1.2 Hz), 7.56 (1H, d, J = 9.1 Hz), 7.91 (1H, dd, J = 7.9, 1.8 Hz), 8.49 (1H, d, J = 6.7 Hz).

2- (3-Chlorophenyl) pyrazolo [1,5-a] pyridine The title compound was obtained in the same manner as in Reference Example 12-1, except that 3-chlorophenylboronic acid was used instead of 2-chlorophenylboronic acid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.74-6.77 (1H, m), 6.78 (1H, s), 7.11 (1H, dd, J = 9.1, 6.7 Hz), 7.32-7.40 (2H, m) , 7.53 (1H, d, J = 9.1 Hz), 7.84 (1H, dt, J = 7.3, 1.2 Hz), 7.97 (1H, t, J = 1.8 Hz), 8.47 (1H, d, J = 6.7 Hz) .

4-Chloro-2- (cyclopentylethynyl) pyridine Under an argon atmosphere, ethynylcyclopentane (1.80 mL) was added to a tetrahydrofuran solution (21.0 mL) of 2-bromo-4-chloropyridine (2.00 g) at room temperature. ), Dichlorobis (triphenylphosphine) palladium (II) (70.0 mg), copper (I) iodide (40.0 mg), and triethylamine (14.5 mL) were added to obtain a reaction solution. The reaction was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a brown oil (1.66 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.57-1.65 (2H, m), 1.70-1.83 (4H, m), 1.97-2.07 (2H, m), 2.81-2.90 (1H, m), 7.19 ( 1H, dd, J = 5.4, 1.8 Hz), 7.38 (1H, d, J = 1.8 Hz), 8.42 (1H, d, J = 5.4 Hz).

<Reference Examples 13-2 and 13-3>
The corresponding compounds of Reference Examples 13-2 and 13-3 were obtained in the same manner as in Reference Example 13-1, using the corresponding acetylene compound. Their structures and spectral data are shown in Table 9.

5-Chloro-2-cyclopentylpyrazolo [1,5-a] pyridine Under argon atmosphere, ethyl O-mesitylsulfonylacetohydroxamate (2.70 g) in a 1,4-dioxane solution (2.40 mL) Under ice cooling, 70% aqueous perchloric acid solution (1.00 mL) was added to obtain a first reaction solution. The first reaction solution was stirred for 30 minutes under ice cooling. Ice water (27.0 mL) was added to the reaction solution, the precipitated solid was filtered, and the obtained solid was dissolved in dichloromethane (4.00 mL) to separate the layers. The organic layer was dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, a solution of 4-chloro-2- (cyclopentylethynyl) pyridine (1.65 g) in dichloromethane (4.00 mL) was added to the obtained filtrate under ice cooling to give a second solution. It was set as the reaction liquid. The second reaction was stirred at room temperature for 72 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the second reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give the title compound as a yellow powder (832 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.66-1.85 (6H, m), 2.08-2.17 (2H, m), 3.20-3.29 (1H, m), 6.25 (1H, s), 6.61 (1H, dd, J = 7.3, 2.4 Hz), 7.39 (1H, d, J = 2.4 Hz), 8.27 (1H, d, J = 7.3 Hz).

<Reference Examples 14-2 and 14-3>
The corresponding compounds of Reference Examples 14-2 and 14-3 were obtained in the same manner as in Reference Example 14-1, using the corresponding acetylene compound. These structures and spectral data are shown in Table 10.

(5-Chloro-2-cyclohexylpyrazolo [1,5-a] pyridin-7-yl) methanol Under argon atmosphere, 5-chloro-2-cyclohexylpyrazolo [1,5-a] pyridine (169 mg) N-Butyllithium (0.538 mL, 1.6 mol / L n-hexane solution) was added to a tetrahydrofuran solution (3.60 mL) at -78 ° C, and the mixture was stirred at -78 ° C for 30 minutes. N, N-dimethylformamide (0.279 mL) was added to the obtained mixture at −78 ° C. to obtain a first reaction solution. Thereafter, the first reaction liquid was stirred at −78 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the first reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate to obtain a crude product of 5-chloro-2-cyclohexylpyrazolo [1,5-a] pyridine-7-carbaldehyde.
Under an argon atmosphere, a solution of the crude 5-chloro-2-cyclohexylpyrazolo [1,5-a] pyridine-7-carbaldehyde in methanol (3.60 mL) was added to sodium borohydride (3.6 mL) under ice cooling. 33.0 mg) was added to give a second reaction solution. The second reaction liquid was stirred for 2 hours and 30 minutes under ice cooling. A saturated aqueous ammonium chloride solution was added to the second reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a yellow oil (102 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.26-1.53 (7H, m), 1.71-1.79 (1H, m), 1.84 (2H, dt, J = 12.8, 3.7 Hz), 2.80-2.86 (1H, m), 4.60 (1H, t, J = 5.5 Hz), 4.96 (2H, d, J = 5.5 Hz), 6.29 (1H, s), 6.63 (1H, d, J = 2.4 Hz), 7.40 (1H , d, J = 2.4 Hz).

<Reference Examples 15-2 to 15-23>
The corresponding compounds of Reference Examples 15-2 to 15-23 were obtained in the same manner as in Reference Example 15-1, using the corresponding pyrazolo [1,5-a] pyridine. Their structures and spectral data are shown in Tables 11-14.

7- (Bromomethyl) -5-chloro-2-phenylpyrazolo [1,5-a] pyridine (5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) under argon atmosphere Triphenylphosphine (176 mg) and carbon tetrabromide (259 mg) were added to a dichloromethane solution (2.8 mL) of methanol (145 mg) at room temperature to prepare a reaction solution. The reaction was stirred at room temperature for 1 hour. After the solvent was distilled off, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound as a yellow powder (174 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.95 (2H, s), 6.85 (1H, s), 6.90 (1H, d, J = 1.8 Hz), 7.39 (1H, t, J = 7.3 Hz), 7.47 (2H, t, J = 7.3 Hz), 7.53 (1H, d, J = 1.8 Hz), 8.01 (2H, d, J = 7.3 Hz).

Methyl 4-chloro-6- (cyanomethyl) pyridine-2-carboxylate To a solution of methyl 4-chloro-6- (chloromethyl) pyridine-2-carboxylate (1.00 g) in dimethyl sulfoxide (4.5 mL), water (1.5 mL) and potassium cyanide (310 mg) were added at room temperature to obtain a reaction solution. The reaction solution was heated and stirred at 50 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the solvent was distilled off. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as yellow crystals (550 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.03 (3H, s), 4.06 (2H, s), 7.73 (1H, d, J = 1.8 Hz), 8.11 (1H, d, J = 1.8 Hz).

4-chloro-6- (hydroxymethyl) pyridine-2-acetonitrile Sodium borohydride at room temperature in a methanol solution (11 mL) of methyl 4-chloro-6- (cyanomethyl) pyridine-2-carboxylate (474 mg) (100 mg) was added to prepare a reaction solution. The reaction was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with dichloromethane, and then dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound as a yellow oil (270 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.16 (1H, brs), 3.93 (2H, s), 4.76 (2H, s), 7.31 (1H, s), 7.37 (1H, s).

(2-Amino-5-chloropyrazolo [1,5-a] pyridin-7-yl) methanol A solution of ethyl O-mesitylsulfonylacetohydroxamate (2.02 g) in an argon atmosphere (35. 5 mL) was added 70% aqueous perchloric acid solution (7.58 mL) under ice-cooling to give a first reaction solution. The first reaction liquid was stirred for 30 minutes under ice cooling. Ice water (200 mL) was added to the reaction solution, the precipitated solid was filtered, and the obtained solid was dissolved in dichloromethane (300 mL) to separate the layers. The organic layer was dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off, a dichloromethane solution (100 mL) of 4-chloro-6- (hydroxymethyl) pyridine-2-acetonitrile (8.40 g) was added to the obtained filtrate under ice-cooling. It was set as the reaction liquid. The second reaction solution was stirred at room temperature for 1 hour. The solvent was distilled off to give 1-amino-4-chloro-2- (cyanomethyl) -7- (hydroxymethyl) pyridinium 2,4,6-trimethylbenzenesulfonate.
In an argon atmosphere, 1% -amino-4-chloro-2- (cyanomethyl) -7- (hydroxymethyl) pyridinium 2,4,6-trimethylbenzenesulfonate in methanol solution (250 mL) at 0 ° C. with potassium carbonate (19.19). 3 g) was added to obtain a third reaction solution. The third reaction was stirred at room temperature for 2 hours. Water was added to the third reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a brown solid (4.43 g).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 4.71 (2H, d, J = 6.1 Hz), 5.48 (2H, brs), 5.66 (1H, s), 5.67 (1H, t, J = 6.1 Hz ), 6.54 (1H, d, J = 2.4 Hz), 7.30 (1H, d, J = 2.4 Hz).

(5-Chloro-2-hydroxypyrazolo [1,5-a] pyridin-7-yl) methanol (2-amino-5-chloropyrazolo [1,5-a] pyridin-7-yl) methanol (2.00 g 50% sulfuric acid (50 mL) was added to the reaction solution. The reaction solution was heated and stirred at 100 ° C. for 3 hours. After cooling the reaction solution, it was poured into a saturated aqueous solution of sodium hydrogen carbonate to adjust the pH of the mixture to 11. Extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound as a light brown solid (1.42g)
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 4.75 (2H, d, J = 5.5 Hz), 5.73 (1H, t, J = 5.5 Hz), 5.79 (1H, s), 6.69 (1H, s ), 7.45 (1H, d, J = 1.8 Hz), 10.73 (1H, brs).

7- (Bromomethyl) -5-chloropyrazolo [1,5-a] pyridin-2-ol (5-chloro-2-hydroxypyrazolo [1,5-a] pyridin-7-yl) methanol (100 mg) in tetrahydrofuran (2.5 mL) solution was added triphenylphosphine (160 mg) and carbon tetrabromide (240 mg) to obtain a reaction solution. The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound as a pale yellow solid (92.5 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.74 (2H, s), 5.93 (1H, s), 6.77 (1H, d, J = 1.8 Hz), 7.34 (1H, d, J = 1.8 Hz).

7- (Bromomethyl) -5-chloropyrazolo [1,5-a] pyridin-2-yl trifluoromethanesulfonate 7- (Bromomethyl) -5-chloropyrazolo [1,5-a] pyridin-2-ol under argon atmosphere (262 mg) in tetrahydrofuran (10 mL) was added triethylamine (112 mg) to -78 ° C. Next, trifluoromethanesulfonic anhydride (253 mg) was added to the mixture to prepare a reaction solution. The reaction was stirred at −78 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 20: ˜1: 1) to give the title compound as a pale yellow liquid (251 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.79 (2H, s), 6.45 (1H, s), 7.05 (1H, d, J = 2.4 Hz), 7.53 (1H, d, J = 2.4 Hz).

2-Chloropyrazolo [1,5-a] pyridine A solution of pyrazolo [1,5-a] pyridin-2-ol (650 mg) in phosphorus oxychloride (19 mL) was used as a reaction solution in a sealed tube. The reaction solution was stirred at 145 ° C. for 6 hours. The reaction solution was added dropwise to a saturated aqueous solution of sodium bicarbonate under ice cooling, stirred for 1 hour, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless liquid (509 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.42 (1H, s), 6.76 (1H, td, J = 7.3, 1.2 Hz), 7.14 (1H, td, J = 7.3, 1.2 Hz), 7.42 (1H , d, J = 8.5 Hz), 8.35 (1H, dd, J = 7.9, 1.2 Hz).

(2-Chloropyrazolo [1,5-a] pyridin-7-yl) methanol Under argon atmosphere, a solution of 2-chloropyrazolo [1,5-a] pyridine (500 mg) in tetrahydrofuran (7.0 mL) was added to -78. Lithium diisopropylamide (4.0 mL, 1.0 mol / L tetrahydrofuran solution) was added at 0 ° C., and the mixture was stirred at −78 ° C. for 30 min. Paraformaldehyde (990 mg) was added to the obtained mixture at −78 ° C. to prepare a reaction solution. Thereafter, the reaction solution was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless powder (402 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.01 (2H, s), 6.49 (1H, s), 6.79 (1H, d, J = 6.7 Hz), 7.18 (1H, dd, J = 9.1, 6.7 Hz ), 7.42 (1H, d, J = 9.1 Hz).

2-Chloro-7- (chloromethyl) pyrazolo [1,5-a] pyridine Under argon atmosphere, (2-chloropyrazolo [1,5-a] pyridin-7-yl) methanol (85 mg) in dichloromethane solution (2 (4 mL) was added with thionyl chloride (0.17 mL) under ice cooling to prepare a reaction solution. The reaction was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless liquid (71 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.02 (2H, s), 6.53 (1H, s), 6.98 (1H, d, J = 7.3 Hz), 7.19 (1H, dd, J = 9.1, 7.3 Hz ), 7.47 (1H, d, J = 9.1 Hz).

Ethyl 1-[(2-chloropyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 5-methyl-1H-pyrazole-3- under argon atmosphere To a solution of ethyl carboxylate (1.0 g) in N, N-dimethylformamide (14 mL) was added sodium hydride (242 mg, 60% in oil) under ice cooling, and the mixture was stirred at room temperature for 1 hour. An N, N-dimethylformamide solution (13 mL) of 2-chloro-7- (chloromethyl) pyrazolo [1,5-a] pyridine (1.1 g) was added dropwise to the resulting mixture to prepare a reaction solution. . Thereafter, the reaction solution was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a yellow powder (1.7 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 2.31 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.78 (2H, s), 6.03 (1H, d, J = 7.3 Hz), 6.53 (1H, s), 6.70 (1H, s), 7.09 (1H, dd, J = 9.1, 7.3 Hz), 7.42 (1H, d, J = 9.1 Hz ).

1-[[5-Chloro-2-[[(trifluoromethyl) sulfonyl] oxy] pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid Instead of ethyl 2-chloro-7- (chloromethyl) pyrazolo [1,5-a] pyridine, 7- (bromomethyl) -5-chloropyrazolo [1,5-a] pyridin-2-yl trifluoromethanesulfonate was used. In the same manner as in Reference Example 26-1, the title compound was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ1.40 (3H, t, J = 7.3 Hz), 2.37 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.71 (2H, s) , 6.23 (1H, t, J = 1.2 Hz), 6.42 (1H, s), 6.70 (1H, s), 7.51 (1H, d, J = 1.8 Hz).

2- [4-Chloro-6- (chloromethyl) pyridin-2-yl] acetonitrile A solution of 4-chloro-2,6-bis (chloromethyl) pyridine (11.7 g) in dimethyl sulfoxide (138) under an argon atmosphere. To the reaction mixture, sodium cyanide (3.27 g) was added. The reaction was stirred at room temperature for 100 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a colorless powder (3.09 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.93 (2H, s), 4.63 (2H, s), 7.42 (1H, s), 7.50 (1H, s).

5-chloro-7- (chloromethyl) pyrazolo [1,5-a] pyridin-2-ylamine 1,4-dioxane solution of ethyl O-mesitylsulfonylacetohydroxamate (6.59 g) under argon atmosphere ( 7.4 mL) was added 70% aqueous perchloric acid solution (2.20 mL) under ice cooling to prepare a reaction solution. The reaction solution was stirred for 30 minutes under ice cooling. Ice water was added to the reaction solution, the precipitated solid was filtered, and the resulting solid was dissolved in dichloromethane (62 mL) to separate the layers. The organic layer was dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the obtained filtrate was added to a dichloromethane solution (21 of 2- [4-chloro-6- (chloromethyl) pyridin-2-yl] acetonitrile (3.09 g) under ice cooling. 0.0 mL) was added to form a second reaction solution. The second reaction was stirred at room temperature for 6 hours. Thereafter, the second reaction solution was concentrated under reduced pressure to obtain a crude product.
Under an argon atmosphere, potassium carbonate (8.50 g) was added to a N, N-dimethylformamide solution (84.0 mL) of the obtained crude product at room temperature to obtain a third reaction solution. The third reaction was stirred at room temperature for 1 hour. Water was added to the third reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a brown powder (200 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.88 (2H, s), 5.80 (1H, s), 6.71 (1H, d, J = 2.4 Hz), 7.23 (1H, d, J = 2.4 Hz).

1-[(2-Amino-5-chloropyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 2-chloro-7- (chloromethyl) pyrazolo According to the same method as in Reference Example 26-1, using 5-chloro-7- (chloromethyl) pyrazolo [1,5-a] -pyridin-2-ylamine instead of [1,5-a] pyridine, The title compound was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.41 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 4.10 (2H, s), 4.42 (2H, q, J = 7.3 Hz), 5.67 (2H, s), 5.68 (1H, s), 5.78 (1H, s), 6.70 (1H, s), 7.18 (1H, s).

7- (Hydroxymethyl) -2-phenylpyrazolo [1,5-a] pyridin-5-ol Under an argon atmosphere, (5-methoxy-2-phenylpyrazolo [1,5-a] pyridin-7-yl ) Boron tribromide (28 mL, 1.0 mol / L dichloromethane solution) was added to a dichloromethane solution (19.0 mL) of methanol (2.4 g) under ice cooling to prepare a reaction solution. The reaction was stirred at room temperature for 30 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1-1: 1) to give the title compound as a colorless powder (1.5 g).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 4.89 (2H, d, J = 6.1 Hz), 5.67 (1H, t, J = 6.1 Hz), 6.60 (1H, d, J = 1.8 Hz), 6.72 (1H, d, J = 1.8 Hz), 6.73 (1H, s), 7.34 (1H, t, J = 7.3 Hz), 7.43 (2H, t, J = 7.3 Hz), 7.92 (2H, d, J = 7.3 Hz), 10.09 (1H, s).

5-Methyl-1-[[2-phenyl-5-[[(trifluoromethyl) sulfonyl] oxy] pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid Ethyl 1-[(5-hydroxy-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (20 mg) under argon atmosphere ) To an N, N-dimethylformamide solution (0.3 mL) under ice-cooling, N-phenylbis (trifluoromethanesulfonimide) (23 mg) and sodium hydride (2 mg) were added to obtain a reaction solution. . The reaction solution was stirred for 1 hour under ice cooling. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless powder (30 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 2.38 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.89 (2H, s), 5.95 (1H, d, J = 1.8 Hz), 6.73 (1H, s), 7.00 (1H, s), 7.29 (1H, s), 7.42 (1H, t, J = 7.3 Hz), 7.49 (2H, t , J = 7.3 Hz), 7.97 (2H, d, J = 7.3 Hz).

1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxamide 1-[(5-chloro-2 -Phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid (1.00 g) in N, N-dimethylformamide (20 mL) Ammonium chloride (146 mg), N, N-diisopropylethylamine (1.42 mL) and O- (benzotriazoyl-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphorus Acid salt (1.24 g) was added to prepare a reaction solution. The reaction was stirred at room temperature for 2 hours. Ammonium chloride (73.0 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 21.5 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was washed successively with water and methanol to give the title compound as a colorless solid (925 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.40 (3H, s), 5.33 (1H, s), 5.79 (2H, s), 6.01 (1H, d, J = 1.8 Hz), 6.72 (2H, s ), 6.85 (1H, s), 7.38-7.44 (1H, m), 7.45-7.53 (3H, m), 7.95-8.00 (2H, m).

1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carbonitrile 1-[(5 -Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxamide (500 mg) in dichloromethane (9.0 mL) Triethylamine (0.38 mL) and trifluoroacetic anhydride (0.38 mL) were added to prepare a reaction solution. The reaction was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to adjust the pH to about 10, and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a colorless solid (431 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.47 (3H, s), 5.81 (2H, s), 6.20 (1H, s), 6.54 (1H, s), 6.84 (1H, s), 7.38-7.43 (1H, m), 7.44-7.50 (2H, m), 7.54 (1H, d, J = 1.8 Hz), 7.94 (2H, d, J = 7.3 Hz).

(Z) -1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N′-hydroxy-5-methyl-1H-pyrazole-3-carboxyimi Damide 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carbonitrile (371 mg) in ethanol ( Hydroxylamine hydrochloride (74.0 mg) and triethylamine (0.15 mL) were added to 5.3 mL) to prepare a reaction solution. The reaction solution was stirred at room temperature for 10 minutes and then stirred for 4 hours under heating to reflux. Hydroxylamine hydrochloride (148 mg) and triethylamine (0.30 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes, and then stirred under heating to reflux for 3 hours. The reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration and washed with ethanol. The obtained solid was recrystallized with a mixed solvent of chloroform and methanol (chloroform: methanol = 10: 1) to obtain the title compound as a colorless solid (265 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.43 (3H, s), 5.35 (2H, s), 5.77 (2H, s), 6.27 (1H, d, J = 2.4 Hz), 6.30 (1H , s), 7.16 (1H, s), 7.38-7.44 (1H, m), 7.47-7.53 (2H, m), 7.89 (1H, d, J = 2.4 Hz), 7.98-8.02 (2H, m), 9.49 (1H, s).

[1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] carbamate tert-butyl 1- [ (5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid (200 mg) in tert-butanol (2. 7 mL) was added triethylamine (0.10 mL) and diphenyl phosphate azide (0.15 mL) to give a reaction solution. The reaction was stirred for 2.5 hours under heating to reflux. Water was added to the reaction solution, and the mixture was extracted with a mixed solvent of chloroform and methanol (chloroform: methanol = 10: 1). The organic layer was dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified using silica gel chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a pale yellow solid (194 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.52 (9H, s), 2.32 (3H, s), 5.64 (2H, s), 6.07 (1H, s), 6.82 (1H, s), 6.89 (1H , brs), 7.39 (2H, t, J = 7.3 Hz), 7.43-7.50 (3H, m), 7.98 (2H, d, J = 7.3 Hz).

1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-amine [1-[(5-chloro-2 -Phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] carbamate tert-butyl (187 mg) in 4 mol / L hydrogen chloride-1, 4-Dioxane solution (0.40 mL) was added to prepare a reaction solution. The reaction was stirred at room temperature for 4 hours. 1,4-Dioxane (0.60 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. A 2 mol / L sodium hydroxide aqueous solution was added to the reaction solution to adjust the pH to about 10. The precipitated solid was collected by filtration and washed with water. The obtained solid was extracted with dichloromethane, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow solid (106 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.26 (3H, s), 3.64 (2H, s), 5.56 (1H, s), 5.58 (2H, s), 6.11 (1H, t, J = 1.2 Hz ), 6.81 (1H, s), 7.39 (1H, t, J = 7.3 Hz), 7.47 (3H, t, J = 7.3 Hz), 7.98 (2H, d, J = 7.3 Hz).

5-chloro-7-[[3- [3,5-difluoro-4- (methoxymethoxy) phenyl] -5-methyl-1H-pyrazol-1-yl] methyl] -2-phenylpyrazolo [1,5 -A] pyridine 5-chloro-7-[(3-iodo-5-methyl-1H-pyrazol-1-yl) methyl] -2-phenylpyrazolo [1,5-a] pyridine (50.0 mg) And 1,4-dioxane solution of 2- [3,5-difluoro-4- (methoxymethoxy) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (66.9 mg) Water (0.37 mL), potassium carbonate (77.0 mg) and tetrakis (triphenylphosphine) palladium (0) (12.9 mg) were added to (1.1 mL) to obtain a reaction solution. The reaction was stirred for 100 minutes under heating to reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a pale yellow solid (42.9 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.38 (3H, s), 3.61 (3H, s), 5.18 (2H, s), 5.82 (2H, s), 6.05 (1H, s), 6.40 (1H , s), 6.84 (1H, s), 7.32-7.43 (3H, m), 7.45-7.52 (3H, m), 7.99 (2H, d, J = 7.9 Hz).

5-chloro-7-[[3-[[2- (methoxymethoxy) phenyl] thio] -5-methyl-1H-pyrazol-1-yl] methyl] -2-phenylpyrazolo [1,5-a] 4,5′-bis (diphenylphosphino) -9,9′-dimethyl in 1,4-dioxane solution (0.20 mL) of pyridine tris (dibenzylideneacetone) dipalladium (0) (12.8 mg) Xanthene (16.1 mg) was added to give a reaction solution. The reaction was stirred for 30 minutes under heating to reflux. To the reaction solution was added 5-chloro-7-[(3-iodo-5-methyl-1H-pyrazol-1-yl) methyl] -2-phenylpyrazolo [1,5-a] pyridine (62.6 mg). 1,4-dioxane solution (0.50 mL), N, N-diisopropylethylamine (0.05 mL) and 2- (methoxymethoxy) benzenethiol (28.5 mg) in 1,4-dioxane solution (0. 30 mL) was added and stirred at 80 ° C. for 30 minutes. Ethyl acetate was added to the reaction solution, the insoluble material was filtered off using celite, and the filtrate was washed with ethyl acetate. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a pale yellow amorphous product (69.2 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.38 (3H, s), 3.52 (3H, s), 5.25 (2H, s), 5.82 (2H, s), 6.14 (1H, t, J = 1.2 Hz ), 6.26 (1H, s), 6.83 (1H, s), 6.86-6.91 (1H, m), 7.05 (1H, dd, J = 7.9, 1.2 Hz), 7.07-7.16 (2H, m), 7.37- 7.43 (1H, m), 7.44-7.53 (3H, m), 7.95-8.00 (2H, m).

5-chloro-7-[(3-iodo-5-methyl-1H-pyrazol-1-yl) methyl] -2-phenylpyrazolo [1,5-a] pyridine under ice-cooling, 1-[(5- Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-amine (210 mg) in acetonitrile (2.7 mL) was added p- Toluenesulfonic acid monohydrate (355 mg), an aqueous solution (0.25 mL) of sodium nitrite (85.8 mg) and an aqueous solution (0.30 mL) of potassium iodide (258 mg) were added, and the reaction solution was added. It was. The reaction solution was stirred for 1.5 hours under ice cooling. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering off anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a pale yellow solid (127 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.36 (3H, s), 5.78 (2H, s), 6.11 (1H, d, J = 1.8 Hz), 6.32 (1H, s), 6.82 (1H, s ), 7.37-7.43 (1H, m), 7.43-7.51 (3H, m), 7.94-7.99 (2H, m).

2- [3,5-difluoro-4- (methoxymethoxy) phenyl)]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 5-bromo-1,3-difluoro-2-phenol To a solution of (2.50 g) in tetrahydrofuran (1 mL), diisopropylethylamine (3.10 g) and methoxymethyl chloride (1.45 g) were sequentially added at room temperature to obtain a first reaction solution. The first reaction solution was stirred at the same temperature for 1 hour. Water and ethyl acetate were added to the reaction solution to separate it. The organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain 5-bromo-1,3-difluoro-2- (methoxymethoxy) benzene as a colorless oily substance (3.05 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 3.58 (3H, s), 5.13 (2H, s), 7.05-7.14 (2H, m).
To a solution of 5-bromo-1,3-difluoro-2- (methoxymethoxy) benzene (2.00 g) in 1,4-dioxane (30 mL) was added bispinacol diboron (2.21 g), 2-ethyl. Potassium hexanoate (1.73 g) and Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (0.322 g) were sequentially added to obtain a second reaction solution. The second reaction solution was stirred at 80 ° C. for 4 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a colorless oil (2.50 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.32 (12H, s), 3.60 (3H, s), 5.19 (2H, s), 7.29-7.32 (2H, m).

1-[(5-Chloro-2-cyclohexylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[(5 Ethanol solution (1.10 mg) of ethyl -chloro-2-cyclohexylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (86.0 mg) 2 mL / L aqueous potassium hydroxide solution (0.536 mL) was added to the reaction solution at room temperature. The reaction was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid (2.20 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration to give the title compound as a colorless powder (71.2 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.37-1.53 (5H, m), 1.69-1.77 (1H, m), 1.77-1.84 (2H, m), 1.97-2.04 (2H, m), 2.49 (3H, s), 2.77-2.85 (1H, m), 5.73 (2H, s), 6.39 (1H, d, J = 1.8 Hz), 6.55 (1H, s), 6.57 (1H, s), 7.83 (1H, d, J = 1.8 Hz).

<Examples 1-2 to 1-80>
The following compounds of Examples 1-2 to 1-80 were obtained in the same manner as in Example 1-1 using the corresponding esters. Their structures and spectral data are shown in Tables 15-32.

1-[[2- (4-Aminophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[2 -[4- (tert-Butoxycarbonylamino) phenyl] pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid (42 mg) in 4 mol / L Hydrogen chloride-1,4-dioxane solution (0.9 mL) was added, and the mixture was stirred at room temperature for 17 hours. After evaporating the solvent, the residue was washed with n-hexane to obtain the title compound as a brown powder (29 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.47 (3H, s), 3.91 (2H, brs), 5.79 (2H, s), 6.38 (1H, dd, J = 6.7, 1.2 Hz), 6.57 (1H, d, J = 1.2 Hz), 7.05 (2H, s), 7.21 (1H, dd, J = 9.1, 6.7 Hz), 7.65-7.70 (2H, m), 7.88 (2H, d, J = 7.9 Hz).

1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N-hydroxy-5-methyl-1H-pyrazole-3-carboxamide hydroxylamine hydrochloride ( To a solution of 123 mg) in ethanol (0.60 mL) was added lithium hydroxide monohydrate (149 mL) to give a reaction solution. The reaction was stirred at room temperature for 30 minutes. To the reaction solution, ethyl 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (70.0 mg ) In ethanol (1.8 mL) was added and stirred at room temperature for 5 hours. Under ice-cooling, 1 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to about 6, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The precipitated solid was collected by filtration and washed with a mixed solvent of diisopropyl ether and ethyl acetate (diisopropyl ether: ethyl acetate = 5: 1) to obtain the title compound as a light red solid (44.0 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.42 (3H, s), 5.77 (2H, s), 6.02 (1H, d, J = 1.2 Hz), 6.71 (1H, s), 6.84 (1H, s ), 7.38-7.43 (1H, m), 7.45-7.53 (3H, m), 7.94-7.99 (2H, m), 9.26 (1H, brs).

1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N-cyano-5-methyl-1H-pyrazole-3-carboxamide 1-[(5 -Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid (70.0 mg) in N, N-dimethylformamide solution (1.0 mL) was added cyanamide (40.2 mL), 4-dimethylaminopyridine (28.0 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (43.9 mg). In addition, a reaction solution was obtained. The reaction was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with a mixed solvent of chloroform and methanol (chloroform: methanol = 10: 1). The organic layer was dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The precipitated solid was collected by filtration and washed with methanol to give the title compound as a colorless solid (18.4 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.48 (3H, s), 5.78 (2H, s), 6.13 (1H, d, J = 1.2 Hz), 6.80 (1H, s), 6.86 (1H, s ), 7.38-7.51 (3H, m), 7.55 (1H, d, J = 2.4 Hz), 7.92-7.97 (2H, m).

1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-N- (methylsulfonyl) -1H-pyrazole-3-carboxamide Argon atmosphere Below, dichloromethane solution of 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid (30 mg) (2 mL) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (21 mg), 4-dimethylaminopyridine (12 mg), methanesulfonamide (10 mg) at room temperature, and the reaction Liquid. The reaction was stirred at room temperature for 48 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 3: 1) to obtain the title compound as a colorless liquid. (26 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.42 (3H, s), 2.90 (3H, s), 5.75 (2H, s), 6.38 (1H, brs), 6.80 (2H, s), 7.15 (1H, s), 7.39-7.43 (1H, m), 7.46-7.52 (2H, m), 7.89 (1H, d, J = 2.4 Hz), 8.00 (2H, dd, J = 7.3, 1.2 Hz).

<Examples 5-2 and 5-3>
The following compounds of Examples 5-2 and 5-3 were obtained in the same manner as in Example 5-1, using the corresponding sulfonamides. Their structure and spectral data are shown in Table 33.

3- [1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] -1,2,4 -Oxadiazol-5 (4H) -one (Z) -1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N'-hydroxy-5 -Methyl-1H-pyrazole-3-carboxyimidamide (50.0 mg) in N, N-dimethylformamide solution (0.66 mL) in pyridine (0.01 mL) and ethyl chloroformate (0.020 mL) Was added under ice cooling to obtain a first reaction solution. The first reaction liquid was stirred for 70 minutes under ice cooling. Water was added to the first reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the solvent was distilled off under reduced pressure to obtain a colorless solid. To the obtained colorless solid xylene solution (0.66 mL), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.02 mL) was added, and the second reaction solution and did. The second reaction solution was stirred at 80 ° C. for 2.5 hours. A 10% aqueous citric acid solution was added to the second reaction solution to adjust the pH to about 5, followed by extraction with dichloromethane. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The precipitated solid was washed with methanol to obtain the title compound as a colorless solid (30.5 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.57 (3H, s), 5.86 (2H, s), 6.61 (1H, d, J = 1.8 Hz), 6.65 (1H, s), 7.15 (1H , s), 7.41 (1H, t, J = 7.3 Hz), 7.49 (2H, t, J = 7.3 Hz), 7.92 (1H, d, J = 1.8 Hz), 7.96 (2H, d, J = 7.3 Hz) ), 12.81 (1H, brs).

5-chloro-7-[[5-methyl-3- (2H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2-phenylpyrazolo [1,5-a] pyridine Argon atmosphere Below, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carbonitrile (50.0 mg) Water (0.36 mL), zinc bromide (34.0 mg) and sodium azide (15.0 mg) were added to an N, N-dimethylformamide solution (1.1 mL) to prepare a reaction solution. The reaction was stirred at 80 ° C. for 18.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified using preparative thin layer chromatography (chloroform: methanol = 10: 1) to give the title compound as a colorless solid (13.9 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.58 (3H, s), 5.88 (2H, s), 6.59 (1H, d, J = 1.8 Hz), 6.76 (1H, s), 7.15 (1H , s), 7.38-7.44 (1H, m), 7.46-7.52 (2H, m), 7.92 (1H, d, J = 1.8 Hz), 7.95-8.00 (2H, m).

3- [1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] -1,2,4 -Oxadiazole-5 (4H) -thione (Z) -1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N'-hydroxy-5 -Methyl-1H-pyrazole-3-carboxyimidamide (50.0 mg) in acetonitrile (0.66 mL) was added to 1,1′-thiocarbonyldiimidazole (35.1 mg) and 1,8-diazabicyclo [ 5.4.0] Undec-7-ene (DBU) (0.08 mL) was added to give a reaction solution. The reaction was stirred at room temperature for 4 hours. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The residue was recrystallized with a mixed solvent of chloroform and methanol (chloroform: methanol = 10: 1) to obtain the title compound as a colorless solid (12.8 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.59 (3H, s), 5.86 (2H, s), 6.67 (1H, d, J = 2.4 Hz), 6.71 (1H, s), 7.15 (1H , s), 7.38-7.44 (1H, m), 7.45-7.52 (2H, m), 7.92 (1H, d, J = 1.8 Hz), 7.94-7.99 (2H, m).

3- [1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] -1,2,4 -Thiadiazol-5 (4H) -one (Z) -1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N'-hydroxy-5-methyl 1,1′-thiocarbonyldiimidazole (49.1 mg) was added to a tetrahydrofuran solution (2.0 mL) of −1H-pyrazole-3-carboxyimidamide (70.0 mg) to prepare a reaction solution. The reaction was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the solvent was distilled off under reduced pressure to obtain a pale yellow solid.
Silica gel (1.66 g) was added to a chloroform / methanol solution (12 mL / 2.5 mL) of the obtained pale yellow solid, and the mixture was stirred at room temperature for 15 hours. The insoluble material was collected by filtration and washed with a mixed solvent of chloroform and methanol (chloroform: methanol = 3: 1). After evaporating the solvent under reduced pressure, the precipitated solid was washed with a mixed solvent of chloroform and methanol (chloroform: methanol = 3: 1) to obtain the title compound as a colorless solid (25.7 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.53 (3H, s), 5.83 (2H, s), 6.53 (1H, s), 6.66 (1H, s), 7.15 (1H, s), 7.41 (1H, t, J = 7.3 Hz), 7.49 (2H, t, J = 7.3 Hz), 7.91 (1H, d, J = 1.8 Hz), 7.98 (2H, d, J = 7.9 Hz), 13.18 (1H , brs).

4- [1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] -2,6-difluoro Phenol 5-chloro-7-[[3- [3,5-difluoro-4- (methoxymethoxy) phenyl] -5-methyl-1H-pyrazol-1-yl] methyl] -2-phenylpyrazolo [1, 5-mol] pyridine (41.4 mg) in 1,4-dioxane (4.2 mL) was added with 4 mol / L hydrogen chloride-1,4-dioxane (0.02 mL) to obtain a reaction solution. . The reaction was stirred at room temperature for 75 minutes. 4 mol / L hydrogen chloride-1,4-dioxane (0.02 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 60 minutes. 4 mol / L hydrogen chloride-1,4-dioxane (0.02 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Further, 4 mol / L hydrogen chloride-1,4-dioxane (0.04 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 10 hours. After evaporating the solvent under reduced pressure, the residue was purified using preparative thin layer chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a pale yellow solid (21.6 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.47 (3H, s), 5.78 (2H, s), 6.36 (1H, s), 6.60 (1H, s), 7.16 (1H, s), 7.34 (2H, d, J = 7.3 Hz), 7.41 (1H, t, J = 7.3 Hz), 7.50 (2H, t, J = 7.3 Hz), 7.90 (1H, d, J = 2.4 Hz), 8.00 (2H , d, J = 7.3 Hz), 10.26 (1H, brs).

2-[[1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] thio] phenol 5- Chloro-7-[[3-[[2- (methoxymethoxy) phenyl] thio] -5-methyl-1H-pyrazol-1-yl] methyl] -2-phenylpyrazolo [1,5-a] pyridine ( To a solution of 64.2 mg) in 1,4-dioxane (6.5 mL) was added 4 mol / L hydrogen chloride-1,4-dioxane (0.16 mL) to obtain a reaction solution. The reaction was stirred at room temperature for 23 hours. After distilling off the solvent under reduced pressure, the residue was purified using NH silica gel chromatography (hexane: ethyl acetate = 2: 1) and preparative thin layer chromatography (hexane: ethyl acetate = 2: 1), and colorless. The title compound was obtained as a solid (18.7 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.47-2.51 (3H, m), 5.78 (2H, s), 6.23 (1H, s), 6.42 (1H, t, J = 7.3 Hz), 6.53-6.57 (2H, m), 6.75 (1H, d, J = 7.9 Hz), 6.87-6.93 (1H, m), 7.15 (1H, s), 7.40 (1H, t, J = 7.3 Hz), 7.48 (2H, t, J = 7.3 Hz), 7.90 (1H, d, J = 2.4 Hz), 7.97 (2H, d, J = 7.3 Hz), 9.94 (1H, brs).

Ethyl 5-methyl-1-[(2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylate (2-phenylpyrazolo [1 , 5-a] pyridin-7-yl) methanol (196 mg) in dichloromethane (4.4 mL) was added with thionyl chloride (0.32 mL) under ice cooling to give a reaction solution. The reaction was stirred at room temperature for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. The residue was filtered using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give a crude product of 7- (chloromethyl) -2-phenylpyrazolo [1,5-a] pyridine as a green liquid. Obtained.
Under an argon atmosphere, sodium hydride (63 mg, 60% in oil) was added to a tetrahydrofuran solution (1.0 mL) of ethyl 5-methyl-1H-pyrazole-3-carboxylate (268 mg) under ice cooling. And stirred at room temperature for 10 minutes. A tetrahydrofuran solution (0.7 mL) of a crude product of 7- (chloromethyl) -2-phenylpyrazolo [1,5-a] pyridine (210 mg) was added dropwise to the resulting mixture to prepare a reaction solution. . Thereafter, the reaction solution was stirred at 50 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless powder (252 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 2.35 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.91 (2H, s), 6.06 (1H, dd, J = 7.0, 1.2 Hz), 6.70 (1H, s), 6.88 (1H, s), 7.03 (1H, dd, J = 8.8, 7.0 Hz), 7.36-7.41 (1H, m) , 7.44-7.56 (3H, m), 7.97-8.03 (2H, m).

<Examples 12-2 to 12-28>
The following compounds of Examples 12-2 to 12-28 were obtained in the same manner as in Example 12-1, using the corresponding alcohol. Their structures and spectral data are shown in Tables 34-39.

1-[[2- (Furan-2-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[[ To a solution of ethyl (2-chloropyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (100 mg) in dimethoxyethane (1.0 mL) at room temperature. 2-furylboronic acid (58 mg), 2 mol / L aqueous sodium carbonate solution (0.5 mL), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (12.7 mg), dichlorobis (acetonitrile) palladium (II) (8.2 mg) was added to prepare a reaction solution. The reaction was stirred at 60 ° 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 and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a colorless amorphous substance (46 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 2.31 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.78 (2H, s), 6.03 (1H, dd, J = 7.3, 1.2 Hz), 6.53 (1H, s), 6.70 (1H, s), 7.09 (1H, dd, J = 9.1, 7.3 Hz), 7.26-7.27 (3H, m) , 7.42 (1H, d, J = 9.1 Hz).

<Examples 13-2 to 13-31>
The following compounds of Examples 13-2 to 13-31 were obtained in the same manner as Example 13-1 using the corresponding boron compounds. Their structures and spectral data are shown in Tables 40-47.

Ethyl 5-methyl-1-[(2-phenyl-5-vinylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylate 5-methyl-1-under argon atmosphere [[2-Phenyl-5-[[(trifluoromethyl) sulfonyl] oxy] pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-ethyl pyrazole-3-carboxylate (100 mg) To a 1,2-dimethoxyethane solution (1.0 mL) at room temperature, 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane pyridine complex (72 mg), 2 A mol / L aqueous sodium carbonate solution (0.3 mL) and dichlorobis (triphenylphosphine) palladium (II) (14 mg) were added to prepare a reaction solution. The reaction was stirred at 60 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a yellow powder (63 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 2.39 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.31 (1H, d, J = 11.0 Hz), 5.62 (1H, d, J = 17.1 Hz), 5.90 (2H, s), 6.23 (1H, s), 6.62 (1H, dd, J = 17.1, 11.0 Hz), 6.71 (1H, s ), 6.85 (1H, s), 7.36-7.41 (2H, m), 7.47 (2H, t, J = 7.3 Hz), 7.98 (2H, d, J = 7.3 Hz).

<Examples 14-2 to 14-4>
The following compounds of Examples 14-2 to 14-4 were obtained in the same manner as Example 14-1 using the corresponding boron compounds. Their structure and spectral data are shown in Table 48.

1-[(5-Acetyl-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 5-methyl-under argon atmosphere Ethyl 1-[[2-phenyl-5-[[(trifluoromethyl) sulfonyl] oxy] pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylate (100 mg ) In acetonitrile solution (1.0 mL) at room temperature with n-butyl vinyl ether (0.1 mL), triphenylphosphine (10 mg), triethylamine (0.03 mL), palladium (II) acetate (4 mg) Was added to obtain a first reaction solution. The first reaction solution was stirred at 100 ° C. for 5 hours. The first reaction solution was subjected to filtration using celite and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. A hydrogen chloride solution (3 mL, 4.0 mol / L 1,4-dioxane solution) was added to the residue to obtain a second reaction solution. The second reaction solution was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the second reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. . After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a yellow liquid (72 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.24 (3H, t, J = 7.3 Hz), 2.17 (3H, s), 2.58 (3H, s), 3.63 (2H, q, J = 7.3 Hz), 5.14 (2H, s), 6.05 (1H, s), 6.58 (1H, s), 6.70 (1H, s), 7.12 (1H, s), 7.32 (1H, t, J = 7.3 Hz), 7.42 (2H , d, J = 7.3 Hz), 7.48 (2H, d, J = 7.3 Hz).

1-[(5-cyano-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 5-methyl- under argon atmosphere Ethyl 1-[[2-phenyl-5-[[(trifluoromethyl) sulfonyl] oxy] pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylate (100 mg ) In an N, N-dimethylformamide-water mixed solution (1.9 mL, 99: 1) at room temperature with zinc cyanide (46 mg), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (16 mg) and bis (dibenzylideneacetone) palladium (0) (12 mg) were added to obtain a reaction solution. The reaction was stirred at 60 ° C. for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless powder (73 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.41 (3H, t, J = 7.3 Hz), 2.39 (3H, s), 4.43 (2H, q, J = 7.3 Hz), 5.90 (2H, s), 6.14 (1H, d, J = 1.8 Hz), 6.74 (1H, s), 7.11 (1H, s), 7.44 (1H, t, J = 7.3 Hz), 7.50 (2H, t, J = 7.3 Hz), 7.94 (1H, d, J = 1.8 Hz), 8.00 (2H, d, J = 7.3 Hz).

5-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] furan-2-carboxylate 5-chloro-2-phenylpyrazolo [1 , 5-a] pyridine (300 mg) in tetrahydrofuran (3.3 mL) was added n-butyllithium (0.8 mL, 1.6 mol / L, n-hexane solution) at −78 ° C., Stir at −78 ° C. for 30 minutes. To the obtained mixture was added a solution of zinc iodide (441 mg) in tetrahydrofuran (1.7 mL) at −78 ° C., and the mixture was stirred at room temperature for 30 minutes. Thereafter, methyl 5- (bromomethyl) furan-2-carboxylate (315 mg) and tetrakis (triphenylphosphine) palladium (0) (150 mg) were added to the resulting mixture to prepare a reaction solution. The reaction was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 19: 1) to give the title compound as a yellow liquid (81 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.90 (3H, s), 4.64 (2H, s), 6.48 (1H, d, J = 3.6 Hz), 6.49 (1H, d, J = 1.8 Hz), 6.80 (1H, s), 7.17 (1H, d, J = 3.6 Hz), 7.38 (1H, t, J = 7.3 Hz), 7.43-7.48 (3H, m), 7.98 (2H, d, J = 7.3 Hz) ).

<Examples 16-2 to 16-4>
The corresponding compounds of Examples 16-2 to 16-4 were obtained in the same manner as in Example 16-1, using the corresponding aryl bromides. Their structure and spectral data are shown in Table 49.

N- [1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] acetamide 1-[(5 -Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-amine (80.0 mg) in tetrahydrofuran (1.2 mL) Acetic anhydride (0.05 mL) was added to the reaction solution. The reaction was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The precipitated solid was collected by filtration and washed with a mixed solvent of diisopropyl ether and ethyl acetate (diisopropyl ether: ethyl acetate = 1: 1) to obtain the title compound as a colorless solid (71.4 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ2.16 (3H, s), 2.35 (3H, s), 5.65 (2H, s), 6.06 (1H, s), 6.63 (1H, s), 6.82 ( 1H, s), 7.40 (1H, t, J = 7.3 Hz), 7.44-7.51 (3H, m), 7.62 (1H, s), 7.97 (2H, d, J = 7.3 Hz).

1-[[5-Chloro-2- (piperidin-1-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate in a reaction vessel Of ethyl 1-[(2-amino-5-chloropyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (100 mg) 1,5-Dibromopentane (0.123 mL) and N, N-diisopropylethylamine (0.259 mL) were added to a dimethylformamide solution (1.5 mL) to prepare a reaction solution. The reaction vessel was heated with microwave (CEM) for 15 minutes (150 W, 120 ° C.). Next, the reaction solution was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the title compound as a colorless solid (36.6 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 1.57-1.73 (6H, m), 2.31 (3H, s), 3.35 (4H, t, J = 5.4 Hz ), 4.41 (2H, q, J = 7.3 Hz), 5.69 (2H, s), 5.72 (1H, d, J = 1.8 Hz), 5.78 (1H, s), 6.69 (1H, s), 7.17 (1H , d, J = 1.8 Hz).

<Examples 18-2 to 18-7>
The corresponding compounds of Examples 18-2 to 18-7 were obtained in the same manner as in Example 18-1, using the corresponding alkyl bromides. Their structures and spectral data are shown in Table 50 and Table 51.

Ethyl 1-[(5-hydroxy-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 7- (hydroxy Methyl) -2-phenylpyrazolo [1,5-a] pyridin-5-ol (100 mg) in tetrahydrofuran (2.1 mL) was added to triphenylphosphine (131 mg), tetrabromide under ice-cooling. Carbon (192 mg) was added to give a reaction solution. The reaction was stirred at room temperature for 1 hour. After the reaction solution was distilled off, the residue was filtered using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 7- (bromomethyl) -2-phenylpyrazolo [1,5-a] pyridine-5. A crude product of oals was obtained.
Under an argon atmosphere, ethyl 5-methyl-1H-pyrazole-3-carboxylate (160 mg) in N, N-dimethylformamide (1.1 mL) was added to sodium hydride (40 mg, 60%) under ice cooling. in oil) and stirred at room temperature for 10 minutes. To the resulting mixture was added an N, N-dimethylformamide solution (1.0 mL) of a crude product of 7- (bromomethyl) -2-phenylpyrazolo [1,5-a] pyridin-5-ol under ice-cooling. ) Was added dropwise to prepare a reaction solution. Thereafter, the reaction solution was stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a colorless powder (42 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.31 (3H, t, J = 7.3 Hz), 2.35 (3H, s), 4.31 (2H, q, J = 7.3 Hz), 5.65 (1H, d, J = 2.4 Hz), 5.76 (2H, s), 6.47 (1H, s), 6.52 (1H, d, J = 2.4 Hz), 6.68 (1H, s), 7.36 (1H, t, J = 7.3 Hz), 7.44 (2H, t, J = 7.3 Hz), 7.92 (2H, d, J = 7.3 Hz).

Methyl 3- (2-phenylpyrazolo [1,5-a] pyridin-7-ylmethyl) benzoate To an aqueous solution of sodium carbonate (73.8 mg) in water (0.56 mL) was added tetrahydrofuran (2.2 mL). ), 7- (bromomethyl) -2-phenylpyrazolo [1,5-a] pyridine (100 mg), 3- (methoxycarbonyl) phenylboronic acid (65.8 mg) and tetrakis (triphenylphosphine) palladium (0) (20.1 mg) was added. The mixture was stirred at 100 ° C. for 1 hour under microwave irradiation. The mixture was allowed to cool, diluted with ethyl acetate, and then filtered through a Celite® pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (103 mg).

Ethyl 5- (2-phenylpyrazolo [1,5-a] pyridin-7-ylmethyl) furan-2-carboxylate To an aqueous solution of sodium carbonate (142 mg) using water (0.9 mL) as a solvent, tetrahydrofuran (3 .6 mL), 7- (Bromomethyl) -2-phenylpyrazolo [1,5-a] pyridine (192 mg), 5- (4,4,5,5-tetramethyl [1,3,2] dioxaborolane-2 -Yl) ethyl furan-2-carboxylate (187 mg) and tetrakis (triphenylphosphine) palladium (0) (38.6 mg) were added. The mixture was stirred at 100 ° C. for 1 hour under microwave irradiation. The mixture was allowed to cool, diluted with ethyl acetate, and then filtered through a Celite® pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) and then aminopropylated silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (83.9 mg).

Next, the usefulness of the present invention will be explained by showing test examples using the compounds of the examples.

<Test Example 1>
EP ₁ receptor antagonism confirmation test
(1) Preparation of rat EP ₁ expression vector Using Rat Kidney BD Marathon-Ready cDNA (Nippon Becton Dickinson Co., Ltd.) as a template, using the forward primer shown in SEQ ID NO: 1 and the reverse primer shown in SEQ ID NO: 2, The first PCR was performed using KOD-Plus-Ver2.0 (Toyobo Co., Ltd.). Furthermore, using this amplification product as a template, the forward primer shown in SEQ ID NO: 3 and the reverse primer shown in SEQ ID NO: 4 were used, and a second PCR was performed in the same manner. The amplification product obtained by the second PCR was incorporated into a vector (pcDNA3.1 D / V5-His-TOPO (registered trademark), Invitrogen Corporation). By a conventional method, the vector incorporating this amplification product was introduced into E. coli (One-shot TOP10 competent cell, Invitrogen) and transformed. The transformed E. coli was cultured on LB agar medium for 1 day. After culture, colonies were selected and cultured in LB liquid medium containing 50 μg / mL ampicillin. After culture, the vector was purified using QIAprep Spin Miniprep Kit (Qiagen). When the base sequence (SEQ ID NO: 5) of the insertion site of this vector was compared with the base sequence (Ptger1) of rat EP ₁ registered under the accession number NM_013100 of the publicly known database (NCBI), all but one base was identical. It was. The amino acid sequence translated by this base sequence completely matched the amino acid sequence of the rat EP ₁ receptor registered under NCBI accession number NP_037232. Therefore, it was confirmed that the cloned gene sequence was the base sequence of rat EP ₁ receptor, and the obtained amino acid sequence was rat EP ₁ receptor. PcDNA3.1 D / V5-His-TOPO (registered trademark) into which the nucleic acid shown in SEQ ID NO: 5 was inserted was used as a rat EP ₁ expression vector.

(2) Preparation of rat EP ₁ receptor expressing cells
(2-1) C0S-1 cell culture
COS-1 cells (Dainippon Sumitomo Pharma) are penicillin-streptomycin solution (Invitrogen Corporation, final concentration: 100 U / mL as benzylpenicillin; 100 μg / mL as streptomycin) as antibiotics, MEM non-essential amino acids (Invitrogen Corporation, final) 1) and 2-dimethoxyethane M liquid medium (containing high glucose and L-glutamine, Invitrogen Corporation) supplemented with fetal bovine serum (MoregateBiotech, final concentration: 10%) The cells were cultured at 37 ° C. in an incubator under% CO ₂ gas conditions until they reached confluence.

(2-2) Cells reaching confluence of COS-1 cells were detached with 0.05% trypsin / 0.53 mM EDTA · 4Na (Invitrogen Corp.) and resuspended in the liquid medium. The resuspended cells were diluted with the above liquid medium so that the spread ratio was 1: 4 to 1: 8 and cultured.

(2-3) Preparation of cells for introduction of rat EP ₁ expression vector Cells that have reached confluence are removed with 0.05% trypsin / 0.53 mM EDTA · 4Na, MEM non-essential amino acids (final concentration: 0.1 mM) and fetal bovine serum ( It was resuspended in 1,2-dimethoxyethane M liquid medium (containing high glucose and L-glutamine, Invitrogen Corporation) supplemented with 10% final concentration. This resuspended cell suspension was poly D-lysine coated 96 well microplate (BD BioCoat (registered trademark), Nippon Becton Dickinson Co., Ltd.) in each well 5 × 10 ⁴ cells / liquid medium 100 μL / Well in a liquid medium so that it becomes a well, 100 μL of this cell preparation was dispensed into each well and seeded. After seeding, the cells were cultured at 37 ° C. in an incubator under 5% CO ₂ gas conditions. When the cells for introduction of the rat EP ₁ expression vector were adhered (about 2 hours after seeding), the rat EP ₁ expression vector was introduced by the following procedure.

(2-4) for the introduction of rat EP ₁ expression vector introduced rat EP ₁ expression vector, using Lipofectamine 2000 (Invitrogen Corporation). The rat EP ₁ expression vector was diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) to 200 ng / 25 μL / well. At the same time, Lipofectamine 2000 (Invitrogen Corporation) was diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) so as to be 0.5 μL / 25 μL / well, and incubated at room temperature for 5 minutes. After incubation for 5 minutes, diluted rat EP ₁ expression vector and diluted Lipofectamine 2000 were mixed and incubated at room temperature for 30 minutes for complex formation of rat EP ₁ expression vector / Lipofectamine 2000. After incubation for 30 minutes, the rat EP ₁ expression vector / Lipofectamine 2000 complex was dispensed into the rat EP ₁ expression vector introduction cells at 50 μL / well. The complex of rat EP ₁ expression vector / Lipofectamine 2000 for 24 hours at 37 ° C. The dispensed cells in an incubator at 5% CO ₂ gas conditions. After culturing for 24 hours, this cell was used as a rat EP ₁ receptor-expressing cell to measure intracellular calcium concentration.

(3) with considering the rat EP ₁ receptor-expressing cells in the intracellular calcium concentration elevation inhibitory action, examined by the method shown the inhibitory effect of each test compound is shown below for the increase in prostaglandin E ₂ induced intracellular calcium concentration did.
Method:
A 10 mM dimethyl sulfoxide solution of each test compound was diluted with an assay buffer (20 mM HEPES / Hank's Balanced Salt Solution (HBSS), pH 7.2).
Rat EP ₁ receptor-expressing cells were washed with assay buffer. Pluronic F-127 (Invitrogen Corporation) was mixed with a fluorescent calcium indicator (Fluo 4-AM (Dojindo Laboratories)) to a final concentration of 0.0004%, then assay buffer was added, and 4 μmol / L Fluo 4 -An AM solution was prepared. 100 μL of this solution was added to each well and incubated in an incubator at 37 ° C. for 90 minutes. Thereafter, all the cell supernatant was aspirated, and 100 μL of assay buffer containing 2.5 mM probenecid was added to each well. After incubation in the incubator for 15 minutes, the intracellular calcium concentration was measured. The intracellular calcium concentration was measured as a fluorescence signal using FlexStation (registered trademark) (manufactured by Molecular Devices). Twenty seconds after the start of reading the fluorescence signal, 50 μL of each test compound (final concentration: 0.1 nM to 10 μM) diluted with the assay buffer was added to each well, and the fluorescence signal was measured for 60 seconds. Then added 50μL prostaglandin E ₂ buffer solution to each well (final concentration 10 nM), was measured for 60 seconds the fluorescence signal. In the method shown above, the fluorescence signal obtained when prostaglandin E _{2 was} added when assay buffer was added instead of the test compound was obtained when 100% of the test signal and prostaglandin E ₂ were not added. The signal obtained was 0%. The concentration showing 50% inhibition from the dose-response curve of the test compound was taken as the IC ₅₀ value. The IC ₅₀ values of each test compound obtained are shown in Table I below.

From Table I, it can be seen that Compound (I) or a salt thereof exhibits excellent EP ₁ receptor antagonistic activity.

<Test Example 2>
Inhibitory effect on 17-phenyl trinor Prostaglandin E2 (17-PTP) -induced bladder contraction
(1) Preparation of experimental animals Anesthesia was induced in Wistar male rats by subcutaneous administration (s. C.) Of 10 w / v% urethane solution at a dose of 1.5 g / kg. About 40 minutes after urethane administration, it was confirmed that the rat was completely anesthetized, and the hair on the back, both sides of the thigh, the abdomen and the neck was shaved and fixed in the abdominal position. After midline incision of the back skin, the muscles on both sides of the back of the chest were incised along the spine, and the muscle layer was opened with a retractor to expose the thorax spine. While pulling the ninth thoracic vertebra to the head side, a small hole was made with bone forceps, and the spinal cord was cut from there using a soldering iron. At this time, if bleeding was severe, a gelatin sponge for hemostasis was packed in the cut portion. After closing the chest back incision layer with surgical adhesive, the rat was fixed in the dorsal position. The skin of the left thigh was incised, the femoral artery was exposed and peeled, and an arterial catheter filled with 200 heparin units / mL heparin was inserted 15 mm. The left femoral incision layer was closed with surgical adhesive. The skin of the right thigh was incised to expose the femoral artery and ligated after peeling. When the drug was administered intravenously, the right femoral vein was exposed and peeled, and a venous catheter was inserted. The right femoral incision layer was closed with surgical adhesive. A midline incision was made in the abdomen to expose the ureters on both sides, and after ligation, the kidney side was cut. Two Michel hemostatic forceps were applied to the top of the bladder at an interval of about 3 mm, an incision was made between them, a bladder catheter was inserted 5 mm therefrom, and a purse-string suture was performed. After the abdominal incision layer was sutured, the penis was exposed and ligated. A midline incision was made in the neck, the trachea was exposed, the incision was made, and the distal side was ligated. The tip of the Eppendorf tip was placed under the trachea, and the trachea was slightly lifted to secure the airway.

(2) Experimental method The rat was placed on a small animal on a heating pad, and a rectal temperature probe was inserted through the anus to maintain the body temperature at 37.5 ° C. After confirming that the body temperature reached 37.5 ° C., 0.1 mL of physiological saline was injected into the bladder and the intravesical pressure was measured. About 30 minutes later, it was confirmed that the intravesical pressure was stable, and 17-PTP was administered from an arterial catheter in 5 seconds. For individuals judged to have stable bladder contraction after intra-arterial administration (ia) of 17-PTP at 30-minute intervals, the test compound was administered intravenously via a venous catheter 5 minutes prior to 17-PTP administration. Administration (iv) (1 mg / kg) was performed. After administration of test compound, perform 17-PTP ia 9 times (5 min, 35 min, 65 min, 95 min, 125 min, 155 min, 185 min, 215 min, 245 min after test compound administration) The change in bladder contraction pressure was observed. The number of i-a. Of 17-PTP was appropriately changed depending on the strength and duration of the test compound.

(3) Analysis The value obtained by subtracting the average intravesical pressure for 30 seconds immediately before 17-PTP administration from the average intravesical pressure for 30 seconds near the maximum bladder contraction pressure after 17-PTP administration, and the change in intravesical pressure by 17-PTP ( ΔmmHg). The amount of change in the bladder pressure after administration of the test compound relative to the average value of the change in bladder pressure by 17-PTP twice before administration of the test compound was shown in%. The effect of the test compound was the amount of change in the intravesical pressure that decreased most up to 95 minutes after administration of the test compound. The amount of change in the intravesical pressure of the obtained test compound is shown in Table II below.

From Table II, it can be seen that compound (I) or a salt thereof exhibits an excellent inhibitory action on bladder contraction.

Since the compound of the present invention has a strong EP ₁ receptor antagonism, it is useful as a therapeutic or prophylactic agent for diseases or symptoms caused by the activation of EP ₁ receptor by the stimulating action of PGE ₂ . Among them, it is useful as a therapeutic agent or preventive agent for lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs).

<Sequence Listing 1>
SEQ ID NO: 1 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<Sequence Listing 2>
SEQ ID NO: 2 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<Sequence Listing 3>
SEQ ID NO: 3 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<SEQ ID NO: 4>
SEQ ID NO: 4 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<SEQ ID NO: 5>
SEQ ID NO: 5 is a DNA sequence for expressing the rat EP1 receptor amplified using the primers of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4.

Claims

A pyrazolopyridine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

In formula (I), A is a group selected from the group consisting of a) to d) below:

R a is a group selected from the group consisting of e) to g) below:
e) a hydrogen atom f) a halogen atom g) a C 1-6 alkyl group W 1 is CH or a nitrogen atom;
W 2 is an oxygen atom or a sulfur atom;
Y 1 is C 1-6 alkylene;
R 1 is a group selected from the group consisting of h) to n) below:
h) —C (═O) —OZ 1
i) —C (═O) —NHSO 2 Z 2
j) -C (= O) -NHOH
k) -C (= O) -NHCN
l) —NH—C (═O) —Z 3
m) an acidic 5-membered heterocyclic group n) a 6-membered cyclic group substituted with a phenolic hydroxyl group Z 1 is a hydrogen atom, a C 1-6 alkyl group or a C 7-10 aralkyl group;
Z 2 and Z 3 are groups selected from the group consisting of o) to s) below;
o) C 1-6 alkyl group p) halo C 1-6 alkyl group q) C 3-6 cycloalkyl group r) unsubstituted or halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group and C An aryl group whose ring is substituted with a group selected from the group consisting of 1-6 alkoxy groups s) a heterocyclic group R 2 is a group selected from the group consisting of A) to F) below;
A) C 1-6 alkyl group B) Unsubstituted or C 3-6 cycloalkyl group substituted by one C 1-6 alkyl group C) Unsubstituted or halogen atom, amino group, 1 or 2 An amino group substituted with a C 1-6 alkyl group, a C 1-9 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-7 alkanoyl group, a C 7-10 aralkyloxy group, An aryl group in which the ring is substituted with a group selected from the group consisting of an aryl group, a (C 1-6 alkoxy) carbonylamino group, a (C 1-6 alkoxy) carbonyl group and a carboxyl group D) a 5-membered aromatic ring Heterocyclic group E) Amino group F) substituted with 1 or 2 C 1-6 alkyl groups F) 5 or 6 membered cyclic amino group R 3 is selected from the group consisting of G) to P) below A group;
G) hydrogen atom H) halogen atom I) cyano group J) C 2-6 alkenyl group K) C 1-7 alkanoyl group L) C 1-6 alkoxy group M) C 5-8 cycloalkenyl group N) C 1- 6 alkyl group O) halo C 1-6 alkyl group P) hydroxyl group R 4 and R 5 each independently represents a hydrogen atom, a halogen atom, or a C 1-6 alkoxy group. The bond marked with (*) is linked to Y 1, and the bond marked with (**) is linked to R 1 .
The pyrazolopyridine derivative according to claim 1, wherein in the general formula (I), A is a group selected from the group consisting of a1), a2), b1), c1), d1) and d2) below. Or a pharmacologically acceptable salt thereof.

R a has the same meaning as described above. A bond marked with (*) binds to Y 1, and a bond marked with (**) denotes bonded to R 1 .
In the general formula (I), A is a group selected from the group consisting of the following a1), b1) and c1): Acceptable salt.

R a has the same meaning as described above. A bond marked with (*) binds to Y 1, and a bond marked with (**) denotes bonded to R 1 .
In the general formula (I), Y 1 is methylene, pyrazolo pyridine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3.
The pyrazolopyridine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, wherein, in the general formula (I), R 4 and R 5 are hydrogen atoms.
In the general formula (I), when R 1 is —C (═O) —OZ 1 , Z 1 is a hydrogen atom or a C 1-6 alkyl group, and R 1 is —C (═O) —NHSO. Z 2 when it is 2 Z 2 is a C 1-6 alkyl group, pyrazolo pyridine derivative or a pharmacologically acceptable salt thereof according to claim 1, any one of 5.
In the general formula (I), R 3 is a hydrogen atom, a halogen atom, a cyano group, a C 5-8 cycloalkenyl group, a C 2-6 alkenyl group, an acetyl group, a trifluoromethyl group, a methyl group or a methoxy group. A pyrazolopyridine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6.
In the general formula (I), R a is a hydrogen atom or a C 1-6 alkyl group, or a pyrazolopyridine derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. Salt.
In the general formula (I), R 2 is a group selected from the group consisting of A), B), C1), D1), D2), E), F1), F2), and F3) below. A pyrazolopyridine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 8.
A) C 1-6 alkyl group B) Unsubstituted or C 3-6 cycloalkyl group in which the ring is substituted with one C 1-6 alkyl group C1) Unsubstituted or halogen atom, 1 or 2 C 1-1 An amino group substituted with a 6 alkyl group, a C 1-9 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-7 alkanoyl group, a C 7-10 aralkyloxy group, an aryl group, (C 1-6 alkoxy) aryl group wherein the ring is substituted with a group selected from the group consisting of a carbonylamino group and a carboxyl group D1) furanyl group D2) thienyl group E) 1 or 2 C 1-6 alkyl Amino group substituted by a group F1) Pyrrolidinyl group F2) Piperidinyl group F3) Molliformyl group
The compound represented by the general formula (I) is:
5-methyl-1-[(2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-N- (methylsulfonyl) -1H-pyrazole-3-carboxamide,
5-chloro-7-[[5-methyl-3- (2H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2-phenylpyrazolo [1,5-a] pyridine,
2-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] oxazole-4-carboxylic acid,
1-[(5-chloro-2-cyclohexylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2-phenyl-5- (propen-2-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-propyl-1H-pyrazole-3-carboxylic acid,
5-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] furan-2-carboxylic acid,
6-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] pyridine-2-carboxylic acid,
3-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] benzoic acid,
1-[[5-chloro-2- (3-methoxyphenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (3-fluorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (2-fluorophenyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (diethylamino) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (piperidin-1-yl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (1-methylcyclopropyl) pyrazolo [1,5-a] pyridin-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N-cyano-5-methyl-1H-pyrazole-3-carboxamide,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N- (ethylsulfonyl) -5-methyl-1H-pyrazole-3-carboxamide,
1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -N- (propylsulfonyl) -5-methyl-1H-pyrazole-3-carboxamide,
3- [1-[(5-Chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazol-3-yl] -1,2,4 -Oxadiazol-5 (4H) -one, or 3- [1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H The pyrazolopyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is -pyrazol-3-yl] -1,2,4-oxadiazole-5 (4H) -thione.
A medicament comprising the pyrazolopyridine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10.
An EP 1 receptor antagonist comprising the pyrazolopyridine derivative according to any one of claims 1 to 10 or a pharmacologically acceptable salt thereof.
A therapeutic or prophylactic agent for lower urinary tract symptoms, comprising the pyrazolopyridine derivative according to any one of claims 1 to 10 or a pharmacologically acceptable salt thereof.
A method for treating or preventing a lower urinary tract symptom comprising administering to a patient the pyrazolopyridine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10.
Use of the pyrazolopyridine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10 for the manufacture of a medicament for preventing or treating lower urinary tract symptoms.
The pyrazolopyridine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, for use in the prevention or treatment of lower urinary tract symptoms.