JP2015178458A - Benzene ring condensed nitrogen-containing 5-membered heterocyclic compound, or pharmacologically acceptable salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide compounds having an EPreceptor antagonism and their pharmacologically permissible salts, a pharmaceutical composition containing them and their medicinal applications.SOLUTION: Benzene ring-condensed nitrogen-containing five-membered heterocyclic compounds of formula (I) and their pharmacologically permissible salts have a powerful EPreceptor antagonism. The compounds (I) and their pharmacologically permissible salts are useful as a therapeutic agent and a preventive against lower urinary tract symptoms(LUTS), especially overactive bladder syndromes(OABs), etc. and also highly useful for therapy, prevention and control of various diseases involving the EPreceptor, including lower urinary tract symptoms(LUTS), inflammatory diseases, pain diseases, osteoporosis, cancer, etc.

Description

The present invention relates to a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound having an EP ₁ receptor antagonistic activity useful as a pharmaceutical, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof About.

  With the progress of an 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, it is a disease defined as “a symptom syndrome requiring urinary urgency, usually accompanied by frequent urination and nocturia. Imminent urinary incontinence is not essential”. 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 the anticholinergic agent is desired (for example, see 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.

Currently, Patent Document 1 discloses a chemical structural formula (A) that is a benzofuran derivative as a compound having an EP ₁ receptor antagonistic activity:

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

R ⁴ represents a carboxy group or the like. )

Similarly, as a benzofuran derivative, Patent Document 2 discloses a chemical structural formula (C) as a compound having an EP ₁ receptor antagonistic activity:

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

R ⁴ represents a carboxy group or the like. )

The compound represented by these is disclosed. However, this compound is different in basic chemical structural formula from the compound of the present invention. In addition, it cannot be overemphasized that such a compound is not contained in a claim of this application.

WO2007 / 113289 WO2008 / 098978

Seki adult, "The Journal of Japanese Pharmacology", 2007, 129, p. 368-373 Xiaojun Wang, et al., `` Biomedical Research '', 2008, 29, p.105-111 Masahito Kawatani, “PAIN RESEARCH”, 2004, 19, p.185-190 Masanobu Maekawa, “The Journal of Japan Urinary Function Society”, 2008, 19, p.169

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 compound having an EP ₁ receptor antagonistic action or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the compound, and a pharmaceutical use thereof.

As a result of intensive studies, the present inventors have found that the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the following general formula (I) (hereinafter sometimes referred to as compound (I)) or its pharmacology The present invention was completed by finding that a chemically acceptable salt has a strong EP ₁ receptor antagonism.

  That is, the present invention is as follows.

[1] A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof:

[Wherein the ring containing Y ¹ and Y ² represents the following a) to d):

A nitrogen-containing 5-membered heterocycle selected from the group consisting of:
A is the following e) to i):

A group selected from the group consisting of:
R ^a is a hydrogen atom, a halogen atom or a C _1-6 alkyl group;
W ¹ is —CH═ or a nitrogen atom;
W ² is an oxygen atom or a sulfur atom;
One of W ³ and W ⁴ is a nitrogen atom, and the other is —CH═ or a nitrogen atom;
Y ³ is C _1-6 alkylene, —O—, —S— or —NR ^b —;
R ^b is a hydrogen atom, a C _1-6 alkyl group or a (C _1-6 alkoxy) carbonyl group;
R ¹ represents the following j) to o):
j) -C (= O) -OZ ¹
k) —C (═O) —NHSO ₂ Z ²
l) -C (= O) -NHOH
m) -C (= O) -NHCN
n) a group selected from the group consisting of —NH—C (═O) —Z ³ , and o) an acidic 5-membered heterocyclic 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 independently the following p) to t):
p) a C _1-6 alkyl group,
q) a halo C _1-6 alkyl group,
r) a C _3-6 cycloalkyl group,
s) unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of halogen atoms, C _1-6 alkyl groups, halo C _1-6 alkyl groups and C _1-6 alkoxy groups An aryl group, and t) a group selected from the group consisting of heterocyclic groups;
R ² represents the following aa) to ll):
aa) a C _1-6 alkyl group or a C _1-6 alkoxy C _1-6 alkyl group,
bb) a C _3-6 cycloalkyl group that is unsubstituted or substituted on the ring by one C _1-6 alkyl group,
cc) a C _2-6 alkenyl group,
dd) a C _5-8 cycloalkenyl group,
ee) a phenyl group whose ring is substituted with 1 to 5 groups independently selected from the group consisting of unsubstituted or halogen atoms, C _1-6 alkoxy groups and C _7-10 aralkyloxy groups;
ff) a heterocyclic group,
gg) Independent of a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkoxy C _1-6 alkyl group, a C _4-6 heterocycloalkyl group and a C _4-10 heteroaralkyl group An amino group substituted with one or two groups selected by
hh) a 4-7 membered cyclic amino wherein the ring is substituted with 1 to 3 groups independently selected from the group consisting of unsubstituted, C _1-6 alkyl groups, and C _1-6 alkylenedioxy groups Group,
ii) a C _1-6 alkoxy group,
jj) C _7-10 aralkyl group,
kk) C _1-6 alkylsulfanyl group, and ll) 6-membered aliphatic cyclic amino group is a radical selected from the group consisting of C _1-6 alkyl group substituted;
R ³ represents the following A) to N):
A) a hydrogen atom,
B) a halogen atom,
C) a cyano group,
D) Nitro group,
E) a C _3-6 cycloalkyl group or a C _5-8 cycloalkenyl group,
F) a C _2-8 alkenyl group,
G) a C _1-7 alkanoyl group,
H) an amino group which is unsubstituted or substituted by one or two C _1-6 alkyl groups,
I) a C _1-6 alkyl group,
J) C _1-6 alkoxy group,
K) a halo C _1-6 alkoxy group,
L) a phenyl group which is unsubstituted or substituted with 1 to 5 halogen atoms, a C _1-6 alkyl group or a C _1-6 alkoxy group,
M) a 5-membered aromatic heterocyclic group, and N) a carboxyl group,
A group selected from the group consisting of:
R ⁴ and R ⁵ each independently represent a hydrogen atom or a halogen atom (provided that a bond marked with (*) is bonded to Y ^3, and a bond marked with (**) is R ¹ and Represents binding.) ].

[2] In the general formula (I), A represents the following e), f), h) and i):

[R ^a , W ¹ , W ² , W ³ , W ⁴ are as defined above (provided that a bond marked with (*) is linked to Y ^3, and a bond marked with (**) is linked to R ¹ Represents binding.) ].
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [1], which is a group selected from the group consisting of:

[3] In the general formula (I), A represents the following e1), f1), h) and i1):

[R ^a has the same meaning as described above (provided that a bond marked with (*) is linked to Y ³ and a bond marked with (**) is linked to R ¹ ). ].
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [2], which is a group selected from the group consisting of:

[4] In the general formula (I), R ^a is a hydrogen atom or a C _1-6 alkyl group, and the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [3]. Salt.

[5] A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [4], wherein Y ³ in the general formula (I) is a methylene, oxygen atom or sulfur atom. .

[6] In the general formula (I), Z ¹ is a hydrogen atom or a C _1-6 alkyl group, and Z ² is a C _1-6 alkyl group. A heterocyclic compound or a pharmacologically acceptable salt thereof.

[7] In the general formula (I), R ³ is the following A) to C), F), G), I) to K) and M):
A) a hydrogen atom,
B) a halogen atom,
C) a cyano group,
F) a C _2-8 alkenyl group,
G) a C _1-7 alkanoyl group,
I) a C _1-6 alkyl group,
J) C _1-6 alkoxy group,
K) a halo C _1-6 alkoxy group, and M) a 5-membered aromatic heterocyclic group,
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [6], which is a group selected from the group consisting of:

[8] In the general formula (I), R ² represents the following aa1), bb) to dd), ee1), ff1), gg1) and hh1):
aa1) a C _1-6 alkyl group,
bb) a C _3-6 cycloalkyl group that is unsubstituted or substituted on the ring by one C _1-6 alkyl group,
cc) a C _2-6 alkenyl group,
dd) a C _5-8 cycloalkenyl group,
ee1) a phenyl group which is unsubstituted or whose ring is substituted with 1 to 5 halogen atoms,
ff1) a 6-membered aromatic heterocyclic group,
gg1) an amino group substituted with one or two groups independently selected from a C _1-6 alkyl group and a C _2-6 alkenyl group, and hh1) unsubstituted or independent from a C _1-6 alkyl group A 4- to 7-membered cyclic amino group in which the ring is substituted with 1 to 3 groups selected as
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [7], which is a group selected from the group consisting of:

[9] In the general formula (I), A is the following e1) or f1):

[R ^a has the same meaning as described above (provided that a bond marked with (*) is linked to Y ³ and a bond marked with (**) is linked to R ¹ ). ].
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [8], which is a group selected from the group consisting of:

[10] The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [9], wherein Y ³ in the general formula (I) is methylene.

[11] The general formula (I), wherein R ³ is a hydrogen atom, a halogen atom, a C _2-8 alkenyl group, a C _1-6 alkoxy group, or a halo C _1-6 alkoxy group. A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof.

[12] In the general formula (I), R ² represents the following cc), dd), gg2) and hh2):
cc) a C _2-6 alkenyl group,
dd) a C _5-8 cycloalkenyl group,
gg2) an amino group substituted with two independently selected C _1-6 alkyl groups, and hh2) a 4-7 membered cyclic amino group,
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [11], which is a group selected from the group consisting of:

[13] In the general formula (I), the ring containing Y ¹ and Y ² is the following a), b) and d):

[R ² is as defined above]
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [12], which is a nitrogen-containing 5-membered heterocyclic ring selected from the group consisting of

[14] In the general formula (I), the ring containing Y ¹ and Y ² is a):

[R ² is as defined above]
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [13], which is a nitrogen-containing 5-membered heterocyclic ring selected from the group consisting of

[15] The general formula (I) is
1-[[6-Bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1 -[[6-Chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (3 6-Dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (5-methyl) -3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- ( 1-propen-2-yl) Nzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-vinylbenzo [D] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 6-chloro-4-[[5-methyl-3- (1H-tetrazol-5-yl) -1H- Pyrazol-1-yl] methyl] -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole 1-[(5-chloro-2- (1-methylcyclopropyl) benzo [d ] Thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[(6-chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl- 1H-pyrazo 1-[(5-chloro-2- (3-chlorophenyl) benzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[ 2- (3,6-Dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[2 -(3,6-dihydropyridin-1 (2H) -yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1- [[2- (3,6-Dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro -2- (pipe Lysine-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (morpholin-4-yl) benzo [ d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] Methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole- 1-[[6-Chloro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1- [3-carboxylate [6-Chloro 2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2 -(4-Methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro 2- (Pyridin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (2-methyl-) 1-propen-1-yl Benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6- (dimethylamino) -2- (3,6-dihydropyridine-1 (2H)- Yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl] ) Benzo [d] thiazol-4-yl] oxy] furan-2-carboxylic acid 5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4 -Yl] thio] furan-2-carboxylic acid 1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazol-4-yl] methyl] -5 Methyl-1H-pyrazo The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to [1], which is ru-3-carboxylic acid.

[16] A pharmaceutical composition comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [15] as an active ingredient.

[17] EP ₁ receptor comprising, as an active ingredient, the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [15] Antagonists.

[18] Lower urinary tract symptom comprising as an active ingredient the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [15] Treatment or prevention drugs.

[19] A patient having a pharmaceutical composition comprising as an active ingredient the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [15] A method of treating or preventing lower urinary tract symptoms, comprising administering to a lower urinary tract.

[20] The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound according to any one of the above [1] to [15] for producing a pharmaceutical composition for preventing or treating lower urinary tract symptoms or Use of its pharmacologically acceptable salt.

[21] A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [15] for use in the prevention or treatment of lower urinary tract symptoms Salt.

The compound (I) of the present invention or a pharmacologically acceptable salt thereof exhibited a strong EP ₁ receptor antagonism in, for example, an EP ₁ receptor antagonism confirmation test. Furthermore, the compounds of the present invention and their salts are safe with low toxicity. Therefore, the compound (I) of the present invention or a pharmacologically acceptable salt thereof, such as lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs), etc., is based on the EP ₁ receptor antagonism confirmation test. It is useful as a therapeutic agent or its preventive agent.

Furthermore, the compound (I) of the present invention or a pharmacologically acceptable salt thereof is used for various pathological conditions involving the EP ₁ receptor (lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, osteoporosis). , Cancer, etc.) has high utility for treatment, prevention or suppression.

The present invention is described in detail below.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1 , 2-dimethylpropyl group, hexyl group, isohexyl 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. For example, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2-difluoroethyl group, 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, 2,2, 2-trifluoro-1-trifluoromethylethyl and the like can be mentioned. Preferably, a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group are mentioned.

“C _1-6 alkylene” means a divalent straight chain or branched saturated hydrocarbon chain having 1 to 6 carbon atoms. 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. In the present specification, —CH ₂ — may be referred to as methylene.

The “C _2-6 alkenyl group” means an unsaturated hydrocarbon group having 2 to 6 carbon atoms on a straight chain or branched chain, having at least one double bond. For example, 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-penten-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, 1-hexen-3-yl group, Examples include 2-methyl-1-propen-1-yl group.

The “C _2-8 alkenyl group” means an unsaturated hydrocarbon group having 2 to 8 carbon atoms on a straight chain or branched chain, having at least one double bond. For example, 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-penten-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, 1-hexen-3-yl group, Examples thereof include a 1-hepten-1-yl group, a 1-octen-1-yl group, and a 2-methyl-1-propen-1-yl group.

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

The “halo C _1-6 alkoxy group” means a C _1-6 alkoxy group substituted with 1 to 5 same or different halogen atoms. For example, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2,2-difluoroethoxy group, 1,1-difluoroethoxy group, 1,2-difluoroethoxy Group, 2,2,2-trifluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 2,2,2-trichloroethoxy group, 3-fluoropropoxy group, 2-fluoropropoxy group, 1-fluoropropoxy group, 3,3-difluoropropoxy group, 2,2-difluoropropoxy group, 1,1-difluoropropoxy group, 4-fluorobutoxy group, 5-fluoropentyloxy group, 6-fluorohexyloxy group, etc. Is mentioned. Preferably, a monofluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group are mentioned.

The “(C _1-6 alkoxy) carbonyl group” means a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms. For example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, isobutoxycarbonyl group, butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, etc. Is mentioned. Preferably, a methoxycarbonyl group and a tert-butoxycarbonyl group are used.

The “C _1-6 alkoxy C _1-6 alkyl group” means a C _1-6 alkyl group substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples thereof include a methoxymethyl group, an ethoxyethyl group, a propoxymethyl group, and an isopropoxymethyl group.

The “C _1-6 alkylenedioxy group” means a group represented by —O— (C _1-6 alkyl) -O—. For example, a methylenedioxy group, an ethylenedioxy group, a propylenedioxy group, etc. 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, for example, a formyl group, an acetyl group, a propanoyl group , Butanoyl group, pentanoyl group, hexanoyl group and the like.

The “C _1-6 alkylsulfanyl group” means a group represented by (C _1-6 alkyl) -S—. Examples thereof include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a butylsulfanyl group, an isobutylsulfanyl group, a sec-butylsulfanyl group, a pentylsulfanyl group, and a hexylsulfanyl group.

The “C _7-10 aralkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a phenyl group. For example, benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like can be mentioned.

The “C _7-10 aralkyloxy group” means an alkoxy group having 1 to 4 carbon atoms substituted with a phenyl group. For example, benzyloxy group, phenethyloxy group, 1-phenylethyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy group and the like can be mentioned.

The “C _4-10 heteroaralkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a heteroaryl group. For example, 2-furanylmethyl group, 3-furanylmethyl group, 2-pyridylmethyl group and the like can be mentioned.

The “C _4-6 heterocycloalkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a saturated heterocyclic group. For example, 2-tetrahydrofuranylmethyl group, 3-tetrahydrofuranylmethyl group, 2-pyrrolidinylmethyl group and the like can be mentioned.

The “C _3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

The "one _{C 1-6 C 3-6} cycloalkyl wherein the ring is substituted with an alkyl group" means the above _{C 3-6} cycloalkyl wherein the ring is substituted by the above _{C 1-6} alkyl group. For example, 1-methylcyclopropyl group, 1-ethylcyclopropyl group, 1-methylcyclobutyl group, 2-methylcyclobutyl group, 1-methylcyclopentyl group, 2-methylcyclopentyl group, 1-methylcyclohexyl group, 2- Examples include a methylcyclohexyl group. A 1-methylcyclopropyl group and a 1-ethylcyclopropyl group are preferable, and a 1-methylcyclopropyl group is more preferable.

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

The “heterocyclic group” is a 5- to 7-membered heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom. For example, a furyl group, a thienyl group, a pyrrolyl group , Azepinyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-oxadiazolyl group, triazolyl group, tetrazolyl group, thiadiazolyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl Group, aromatic heterocyclic group such as pyrazinyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group dihydropyranyl group, dihydrothiopyranyl group, dihydropyridyl group and other unsaturated heterocyclic groups, and morpholyl group, thiomorphonyl group, pyrrolidinyl Group, piperidyl group, piperazinyl group, tetrahydrofuranyl group It can be mentioned saturated heterocyclic group. The “heterocyclic group” may be condensed with another cyclic group, for example, an isobenzofuranyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, a benzoisothiazo group. Ryl, chromenyl, chromanonyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolidinyl, indolyl, indazolyl, purinyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl Quinoxalinyl group, quinazolinyl group, carbazolyl group, carbolinyl group, acridinyl group, isoindolinyl group and the like.

The “branched C _3-6 alkyl group” means a branched alkyl group having 3 to 6 carbon atoms. For example, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-ethyl A propyl group, an isohexyl group, etc. are mentioned. Preferably, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-ethylpropyl group and the like can be mentioned.

The “5-membered aromatic heterocyclic group” means a 5-membered aromatic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring. 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.

The “6-membered aromatic heterocyclic group” means a 6-membered aromatic group containing 1 to 4 nitrogen atoms in the ring. For example, a pyridyl group, a pyrimidyl group, a pyrazinyl group, a pyridazinyl group, etc. are mentioned.

“4-7 membered cyclic amino group wherein the ring is substituted with 1 to 3 groups independently selected from the group consisting of unsubstituted, C _1-6 alkyl group, and C _1-6 alkylenedioxy group As, for example, the following groups:

And a group selected from:

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. For example, the formula:

A group of groups consisting of Preferably the formula:

A group selected from the group consisting of More preferably, the formula:

A 5-tetrazolyl group represented by

The “C _1-6 alkyl group substituted with a 6-membered aliphatic cyclic amino group” means a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a morpholino group or a piperidino group. To do. For example, morpholinomethyl group, piperidinoethyl group, 1-morpholinoethyl group, 1-piperidinoethyl group, 2-morpholinoethyl group, 2-piperidinoethyl group and the like can be mentioned.

In the compound (I) of the present invention or a pharmacologically acceptable salt thereof, preferred substituents are as follows.

The nitrogen-containing 5-membered heterocyclic ring containing Y ¹ and Y ² is preferably the following a), b) and d):

More preferably, the following a):

It is.

Pyrazole A is preferably a C _1-6 pyrazole ring ring with an alkyl group is substituted, a pyrazole ring, a furan ring, a pyridine ring or a benzene ring, which is more preferably a ring substituted with a C _1-6 alkyl group A ring, a furan ring or a pyridine ring, particularly preferably a pyrazole ring or a furan ring in which the ring is substituted with a C _1-6 alkyl group.

Y ³ is preferably C _1-6 alkylene, an oxygen atom or a sulfur atom, more preferably C _1-6 alkylene, and particularly 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 —C (═O) —OH, — A C (═O) —O—C _1-6 alkyl group, a —C (═O) —NHSO ₂ —C _1-6 alkyl group or a tetrazolyl group.

R ² is preferably a _{C 3-6} alkyl group branched, unsubstituted or one _{C 3-6} cycloalkyl wherein the ring is substituted with _{C 1-6} alkyl _{groups, C 2-6} alkenyl groups, C _{A 5-8} cycloalkenyl group, a phenyl group, a pyridyl group, an amino group substituted with two independently selected C _1-6 alkyl, a 4- to 7-membered cyclic amino group,
More preferably, a vinyl group, 2-propenyl group, 1-isobutenyl group, 1-cyclopentenyl group, 1-methylcyclopropyl group, dimethylamino group, methyl (ethyl) amino group, diethylamino group, ethyl (n-propyl) amino Group, di (n-propyl) amino group, phenyl group, pyridyl group, pyrrolidin-1-yl group, piperidin-1-yl group, morpholin-4-yl group, thiomorpholin-4-yl group, 3,6- Dihydropyridin-1 (2H) -yl group.

R ³ is preferably a halogen atom, a cyano group, a C _2-6 alkenyl group, a C _1-7 alkanoyl group, an amino group which is unsubstituted or substituted with 1 or 2 C _1-6 alkyl groups, C _{1 A -6} alkoxy group, a halo C _1-6 alkoxy group,
More preferred are hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, vinyl group, 2-propenyl group, acetyl group, dimethylamino group, methoxy group and trifluoromethoxy group.

R ⁴ is preferably a hydrogen atom or a halogen atom, and more preferably a hydrogen atom.

R ⁵ is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom.

Preferred compounds of the present invention include, for example,
1-[(6-Chloro-2-phenylbenzo [d] oxazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[(5-Chloro-2-phenylbenzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-ethyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5- (propan-1-yl) -1H-pyrazole -3-carboxylic acid
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5- (propan-2-yl) -1H-pyrazole -3-carboxylic acid
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5- (2-methylpropan-1-yl)- 1H-pyrazole-3-carboxylic acid
1-[(6-Chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[(5-Chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
5-Methyl-1-[(2-phenylbenzo [d] thiazol-4-yl) methyl] -1H-pyrazole-3-carboxylic acid
1-[(7-Chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
5-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] furan-2-carboxylic acid
5-[(5-Chloro-2-phenylbenzo [d] oxazol-7-yl) methyl] furan-2-carboxylic acid
5-[(5-Chloro-2- (4-chlorophenyl) benzo [d] oxazol-7-yl) methyl] furan-2-carboxylic acid
1-[(5-Chloro-2- (3-chlorophenyl) benzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[(5-Chloro-2- (2-chlorophenyl) benzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Fluoro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Fluoro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Fluoro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Dimethylamino) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Diethylamino) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
6-[[6-Bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Bromo-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Bromo-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Bromo-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -Carboxylic acid
1-[[2- (Dimethylamino) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Diethylamino) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
5-Methyl-1-[[2- (piperidin-1-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
5-Methyl-1-[[2- (pyrrolidin-1-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
5-Methyl-1-[[2- (morpholin-4-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
1-[[2- (2,5-Dihydro-1H-pyrrol-1-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole- 3-carboxylic acid
1-[[2- (Dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[[2-Ethyl (propyl) amino] benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Dipropylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Diallylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Azetidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
5-Methyl-1-[[2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
5-Methyl-1-[[2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
1-[[2- (Azepan-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (2,5-Dihydro-1H-pyrrol-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
5-Methyl-1-[[2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
1-[[2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
5-methyl-1-[[2- (4-methylpiperazin-1-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
5-Methyl-1-[[2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
1-[[2- (1,4-Dioxa-8-azaspiro [4,5] decan-8-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- carboxylic acid
1-[[6-Bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[(6-Chloro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (4-methylpiperazin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Azepan-1-yl) -6-chlorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Azetidin-1-yl) -6-chlorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (1H-pyrazol-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- [ethyl (propyl) amino] benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (diallylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (2,5-dihydro-1H-pyrrol-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (5-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -Carboxylic acid
1-[[6-Chloro-2- (3,4-dimethyl-5,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid
1-[[6-Chloro-2- (4-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -Carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Dimethylamino) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Diethylamino) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (Ethyl (propyl) amino) -6-methoxobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
6-[[6-Chloro-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- (Azepan-1-yl) -6-chlorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- [ethyl (propyl) amino] benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- (Dimethylamino) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- (Diethylamino) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- [Ethyl (propyl) amino] -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- (Azetidin-1-yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Fluoro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Fluoro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- (Azepan-1-yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- (2,5-Dihydro-1H-pyrrol-1-yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Fluoro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Fluoro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
5-Methyl-1-[[2- (1-propen-2-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
1-[[2- (1-Cyclohexen-1-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
5-Methyl-1-[[2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
1-[[2- (2-Methyl-1-propen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (1-Cyclopenten-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (1-Cyclohexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (1-Cyclohepten-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (2-chlorophenyl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (3-chlorophenyl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (4-chlorophenyl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- [3- (Benzyloxy) phenyl] -6-chlorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (pyridin-3-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (pyridin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- [2- (Benzyloxy) phenyl] -6-chlorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (1-cyclohexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (phenylethyl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
(E) -1-[[6-Chloro-2- (1-hexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (2-methyl-1-propen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (1-cyclopenten-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (1-cyclohepten-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Chloro-2- (3,6-dihydro-2H-thiopyran-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Methoxy-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (1-Cyclohexen-1-yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[(6-Methoxy-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
6-[[6-Chloro-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (1-cyclopenten-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (1-cyclohexen-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Chloro-2- (1-cyclohepten-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[6-Fluoro-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[[2- (1-Cyclohexen-1-yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid
6-[(6-Fluoro-2-phenylbenzo [d] thiazol-4-yl) methyl] pyridine-2-carboxylic acid
5-Methyl-1-[[2- (morpholin-4-yl) -6-phenylbenzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid
1-[[6- (2-Methoxyphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6- (3-Methoxyphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6- (4-Methoxyphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6- (3-Methylphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6- (4-Methylphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6- (2-Fluorophenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6- (3-Fluorophenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6- (4-Fluorophenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-phenylbenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (furan-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (furan-3-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (thiophen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (thiophen-3-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-vinylbenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H -Pyrazole-3-carboxylic acid
(E) -1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (1-hexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5 -Methyl-1H-pyrazole-3-carboxylic acid
(E) -1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (1-octen-1-yl) benzo [d] thiazol-4-yl] methyl] -5 -Methyl-1H-pyrazole-3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (1-hexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H -Pyrazole-3-carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-methylbenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Acetyl-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
4-[(3-Carboxy-5-methyl-1H-pyrazol-1-yl) methyl] -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole-6-carboxylic acid
1-[[6-Cyano-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6-Amino-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[[6- (Methylamino) -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- carboxylic acid
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- carboxylic acid
1-[[6-Chloro-2- (propan-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[(6-Chloro-2-cyclohexylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
1-[(6-Chloro-2-cyclopropylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
6-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] oxy] pyridine-2-carboxylic acid
5-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] oxy] furan-2-carboxylic acid
6-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] pyridine-2-carboxylic acid
5-[(tert-butoxycarbonyl) [6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] furan-2-carboxylic acid
6-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] thio] pyridine-2-carboxylic acid
5-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] thio] furan-2-carboxylic acid
3-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] benzoic acid
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
6-chloro-4-[[5-methyl-3- (1H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2- (3,6-dihydropyridin-1 (2H) -yl ) Benzo [d] thiazole
3- [1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Yl] -1,2,4-oxadiazole-5 (4H) -thione
4- [1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Yl] -3H-1,2,3,5-oxathiadiazole-2-oxide,
1-[(5-Chloro-2- (1-methylcyclopropyl) benzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
Can be illustrated.

A pharmacologically acceptable salt means a salt with a pharmaceutically acceptable non-toxic base or acid (eg, an inorganic or organic base and an inorganic or organic acid). Salts derived from pharmaceutically acceptable non-toxic bases include inorganic bases such as aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium. Salts (particularly preferably ammonium, calcium, manganese, potassium and sodium salts) or primary, secondary, tertiary amines, substituted amines (eg naturally occurring substituted amines), cyclic amines and bases Organic bases such as ionic ion exchange resins (eg, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl) Morpholine, N-ethylpiperidine, guru Min, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like) salts and are exemplified. Examples of salts derived from pharmaceutically acceptable non-toxic acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid. And salts with organic acids such as citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid and palmitic acid.

  Furthermore, the compound (I) of the present invention or a pharmacologically acceptable salt thereof may exist as a hydrate or a solvate. Arbitrary hydrates and solvates formed by the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the general formula (I) or a salt thereof including the preferred compounds specifically described above are: These are all included in the scope of the present invention. Solvents that can form solvates include methanol, ethanol, 2-propanol, acetone, ethyl acetate, dichloromethane, diisopropyl ether, and the like.

  Compound (I) or a pharmacologically acceptable salt thereof of the present invention includes optically active forms, stereoisomers and rotational isomers in addition to racemates. The compound (I) of the present invention or a pharmacologically acceptable salt thereof also includes proton tautomers.

The “EP ₁ receptor antagonism” as used in the present invention 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, the EP ₁ receptor antagonism exhibits actions such as smooth muscle relaxation and sensory nerve stimulation inhibitory action. In particular, EP ₁ receptor antagonism is useful as a therapeutic or prophylactic agent for symptoms such as LUTS, especially OABs, by acting on the bladder, urothelium and the like.

Further, the EP ₁ receptor antagonism can be evaluated by the potency of inhibiting calcium influx into cells due to 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 invention can be produced by various synthetic methods. Next, typical production methods of the compound (I) of the present invention will be described.

(Method A)

(Wherein Y ¹ , Y ² , R ² , R ³ , R ⁴ , R ⁵ and A are as defined above; L ¹ represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, etc .; Q ¹ represents a C _1-6 alkyl group or a C _7-10 aralkyl group.

Step 1-1
In this step, compound (Ia) is produced by reacting compound (1) with compound (2). Compound (Ia) can be produced, for example, by reacting compound (1) and compound (2) in the presence of a base in a solvent. Examples of the solvent include N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like. Reaction temperature can be normally implemented at -78 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0-30 degreeC. As a base to be used, an inorganic base such as sodium hydride, potassium carbonate or sodium carbonate, or an organic base such as triethylamine, N, N-diisopropylethylamine or pyridine can be used. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1-2
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 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 0 ° C. to the 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, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.
Compound (1) can be obtained, for example, by any one of the following methods a, b, c, d, e, and f.

(Method a)

(In the formula, R ² , R ³ , R ⁴ , R ⁵ and L ¹ are as defined above; L ² represents a chlorine atom, a bromine atom, etc.)

Step 1a-1
This step is a step of producing compound (5) by a condensation reaction between compound (3) and compound (4). Compound (5) can be produced, for example, by reacting compound (3) with compound (4) in a solvent in the presence or absence of a base. Examples of the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. As the base to be used, potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine or the like can be used. Reaction temperature can be normally implemented at -78 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0-20 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days. Moreover, the compound (3) and compound (4) 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 1a-2
This step is a step of producing compound (6) from compound (5). Compound (6) can be produced, for example, by reacting compound (5) with a sulfur source compound such as Lawesson's reagent in a solvent. Examples of the solvent include toluene, dichloromethane, 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 solvent reflux temperature, and it is preferably carried out at 20 to 150 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1a-3
This step is a step of producing compound (7) from compound (6). Compound (7) can be produced, for example, by reacting compound (6) in the presence of a base in a solvent. Examples of the solvent include N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, a mixed solvent thereof and the like. As the base to be used, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), potassium carbonate, Sodium carbonate, cesium carbonate, sodium acetate and the like can be used. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, and it is preferably carried out at 20 to 100 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1a-4
This step is a step of producing compound (1a) from compound (7). Compound (1a) can be produced, for example, by brominating compound (7) with N-bromosuccinimide in a solvent when L ¹ is a bromine atom. In this reaction, benzoyl peroxide, azobisisobutyronitrile, or the like can be added as a radical initiator. Examples of the solvent include carbon tetrachloride, chloroform, dichloromethane, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, and mixed solvents thereof. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, and it is preferably carried out at 20 to 150 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

(Method b)

(Wherein R ² , R ³ , R ⁴ , R ⁵ and L ¹ are as defined above; L ³ represents a chlorine atom, a bromine atom, an iodine atom, etc .; L ⁴ represents a hydrogen atom, B (OH) shows _two such, Q is showing the NH ₄ and the like.)

Step 1b-1
This step is a step of producing compound (10) by reaction of compound (8) with compound (9). Compound (10) can be produced, for example, by reacting compound (8) and compound (9) in the presence of bromine in an acetic acid solvent. Reaction temperature can be normally implemented at -20 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0-20 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days. Moreover, the compound (8) and compound (9) 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 1b-2
This step is a step for producing compound (11) by introducing a tert-butoxycarbonyl group into the amino group of compound (10). Compound (11) can be produced, for example, by reacting di-tert-butyl dicarbonate with compound (10) in a solvent or without using a solvent. Examples of the solvent used in the reaction include 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, N, N-dimethylformamide, a mixed solvent thereof and the like. Further, when a base is used in this reaction, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be used. Reaction temperature can be normally implemented at -20 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0-150 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1b-3
This step is a step for producing a compound (12) by converting a bromine atom of the compound (11) into a hydroxymethyl group. Compound (12) can be produced, for example, by converting the bromine atom of compound (11) into a lithium salt, Grignard reagent or the like in a solvent and then reacting with paraformaldehyde or the like. 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 reagent used when preparing a lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like. Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium. Reaction temperature can be normally implemented at -78 degreeC-50 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.
Here, in the above reaction, after treating the lithium salt of compound (11) or Grignard reagent with N, N-dimethylformamide or the like to introduce a formyl group, the obtained compound having a formyl group is obtained in the presence of a solvent. Reduction to sodium borohydride, lithium aluminum hydride, lithium borohydride or the like can also lead to the compound (12). Examples of the solvent used include methanol, water, ethanol, tetrahydrofuran, and mixed solvents thereof. The reaction temperature can usually be carried out at -78 ° C to the solvent reflux temperature, and it is preferably carried out at 0 ° C to 100 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1b-4
This step is a step for producing the compound (13) by removing the tert-butoxycarbonyl group of the compound (12). Compound (13) can be produced, for example, by treating compound (12) with an appropriate acid in a solvent or without using a solvent. Examples of the solvent used for the reaction include dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, a mixed solvent thereof and the like. As the acid used, trifluoroacetic acid, hydrogen chloride and the like can be used. Reaction temperature can be normally implemented at -20 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0-50 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1b-5
This step is a step for producing a compound (13) by converting a bromine atom of the compound (10) into a hydroxymethyl group. This process can be performed according to said b method and process 1b-3.

Step 1b-6
This step is a step for producing a compound (14) by converting the amino group of the compound (13) into an appropriate leaving group (L ³ ). Compound (14) can be produced, for example, by reacting compound (13) with potassium iodide, sodium nitrite and the like in the presence of an acid in a solvent when L ³ is an iodine atom. Examples of the solvent used for the reaction include acetonitrile, water, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, N, N-dimethylformamide, acetic acid, a mixed solvent thereof and the like. Examples of the acid used in this reaction include p-toluenesulfonic acid, acetic acid, hydrochloric acid, trifluoroacetic acid and the like. Reaction temperature can be normally implemented at -50 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at -20-100 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1b-7
This step is a step for producing a compound (16) by reacting the compound (14) with the compound (15) and substituting L ³ with R ² . Compound (16) can be produced by replacing L ³ of compound (14) with R ² which is a substituted amino group by a nucleophilic substitution reaction. This reaction proceeds by reacting with an appropriate substituted amine in a solvent or without using a solvent. In order to supplement the acid generated in the reaction process, an excessive amount of substituted amine is used or a base is allowed to coexist. be able to. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do. Examples of the coexisting base include triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. Reaction temperature can be normally implemented at -78 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0-150 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Compound (16) can be produced by replacing L ³ of compound (14) with R ² which is an aryl group by Suzuki coupling reaction. This reaction proceeds, for example, in the presence of a base using compound (14) and arylboronic acid in a solvent and a palladium reagent as a catalyst. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do. 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 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, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1b-8
This step is a step for producing the compound (1a) by converting the hydroxyl group of the compound (16) into an appropriate leaving group (L ¹ ). Compound (1a) can be produced, for example, by reacting carbon tetrabromide with compound (16) in the presence of triphenylphosphine or the like in a solvent when L ¹ is a bromine atom. Examples of the solvent used for the reaction include tetrahydrofuran, dichloromethane, chloroform, a mixed solvent thereof and the like. The reaction temperature can usually be from −50 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

(Method c)

(Wherein R ² , R ³ , R ⁴ , R ⁵ , L ¹ and L ² are as defined above.)

Step 1c-1
This step is a step of producing compound (18) by a condensation reaction between compound (17) and compound (4). This process can be performed according to said a method and process 1a-1. Moreover, the compound (17) 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 1c-2
This step is a step of producing compound (19) from compound (18). This process can be performed according to said a method and process 1a-2.

Step 1c-3
This step is a step of producing compound (20) from compound (19). This process can be performed according to said a method and process 1a-3.

Step 1c-4
This step is a step of producing compound (1a) from compound (20). This process can be performed according to said a method and process 1a-4.

(Method d)

(Wherein R ² , R ³ , R ⁴ , R ⁵ , L ¹ and L ² are as defined above; Q ² represents a C _1-6 alkyl group or a C _7-10 aralkyl group.)

Step 1d-1
This step is a step of producing compound (22) by a condensation reaction between compound (21) and compound (4). This process can be performed according to said a method and process 1a-1. Moreover, the compound (21) 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 1d-2
This step is a step of producing compound (23) from compound (22). This process can be performed according to said a method and process 1a-2.

Step 1d-3
This step is a step of producing compound (24) from compound (23). This process can be performed according to said a method and process 1a-3.

Step 1d-4
This step is a step of producing compound (25) from compound (24).
Compound (25) can be produced, for example, by reducing the alkoxycarbonyl group of compound (24) to a hydroxymethyl group using lithium aluminum hydride, lithium borohydride, or the like in a solvent. Examples of the solvent used include tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at -78 ° C to the solvent reflux temperature, and it is preferably carried out at -20 ° C to 100 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1d-5
This step is a step for producing the compound (1b) by converting the hydroxyl group of the compound (25) into an appropriate leaving group (L ¹ ). This process can be performed according to said b method and process 1b-8.

(Method e)

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

Step 1e-1
This step is a step of producing compound (27) from compound (26) and compound (4). Compound (27) is obtained by, for example, treating a cyclization precursor obtained by a condensation reaction of compound (26) and compound (4) in a solvent according to the above-mentioned method a, step 1a-1 with an appropriate acid. Can be manufactured. Examples of the solvent used include xylene, toluene, benzene, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the acid used in this reaction include p-toluenesulfonic acid, acetic acid, hydrochloric acid, trifluoroacetic acid and the like. Reaction temperature can be normally implemented at -20 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0 degreeC-20 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days. Moreover, the compound (26) 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 1e-2
This step is a step for producing a compound (28) by converting a bromine atom of the compound (27) into a formyl group. Compound (28) is produced by, for example, converting the bromine atom of compound (27) into a lithium salt, Grignard reagent or the like in a solvent, and then reacting with a compound serving as a formyl source such as N, N-dimethylformamide. can do. 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 reagent used when preparing a lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like. Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium. Reaction temperature can be normally implemented at -78 degreeC-50 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1e-3
This step is a step for producing a compound (29) by converting a formyl group of the compound (28) into a hydroxymethyl group. Compound (29) can be produced, for example, by reducing compound (28) with sodium borohydride, lithium aluminum hydride, lithium borohydride or the like in the presence of a solvent. Examples of the solvent used include methanol, water, ethanol, tetrahydrofuran, and mixed solvents thereof. The reaction temperature can usually be carried out at -78 ° C to the solvent reflux temperature, and it is preferably carried out at 0 ° C to 100 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1e-4
This step is a step for producing a compound (1c) by converting the hydroxyl group of the compound (29) into an appropriate leaving group (L ¹ ). This process can be performed according to said b method and process 1b-8.

Step 1e-5
This step is a step of producing compound (30) from compound (26). Compound (30) can be produced, for example, by reacting compound (26) with cyanogen bromide in a solvent. Examples of the solvent used include ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like. Reaction temperature can be normally implemented at -20 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0 degreeC-30 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 1e-6
This step is a step of producing compound (31) by introducing a tert-butoxycarbonyl group into the amino group of compound (30). This process can be performed according to said b method and process 1b-2.

Step 1e-7
This step is a step for producing a compound (32) by converting a bromine atom of the compound (31) into a formyl group. This process can be performed according to said e method and process 1e-2.

Step 1e-8
This step is a step for producing a compound (33) by converting a formyl group of the compound (32) into a hydroxymethyl group. This process can be performed according to said e method and process 1e-3.

Step 1e-9
This step is a step for producing the compound (34) by converting the amino group generated by removing the tert-butoxycarbonyl group of the compound (33) into an appropriate leaving group (L ³ ). This process can be performed according to said b method, process 1b-4, and process 1b-6.

Step 1e-10
This step is a step for producing a compound (29) by reacting the compound (34) with the compound (15) and substituting L ³ with R ² . This process can be performed according to said b method and process 1b-7.

(Method f)

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

Step 1f-1
This step is a step of producing compound (36) from compound (35) and compound (4). This process can be performed according to said e method and process 1e-1. Moreover, the compound (35) 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 1f-2
This step is a step of producing compound (37) from compound (36). This process can be performed according to said d method and process 1d-4.

Step 1f-3
This step is a step for producing the compound (1d) by converting the hydroxyl group of the compound (37) into an appropriate leaving group (L ¹ ). This process can be performed according to said b method and process 1b-8.

(Method B)

Wherein R ² , R ³ , R ⁴ , R ⁵ , L ¹ , L ³ , L ⁴ , Q, Q ¹ , Q ² and A are as defined above; L ⁵ is a bromine atom, an iodine atom, ZnBr, indicates ZnCl like; ^{L 6} represents a bromine atom, an iodine atom, etc.).

Step 2-1
This step is a step of producing compound (10) by reaction of compound (8) with compound (9). This process can be performed according to said b method and process 1b-1.

Step 2-2
This step is a step for producing compound (11) by introducing a tert-butoxycarbonyl group into the amino group of compound (10). This process can be performed according to said b method and process 1b-2.

Step 2-3a
This step is a step of producing compound (39) by a coupling reaction of compound (11) and compound (38). Compound (39) can be produced, for example, by converting the bromine atom of compound (11) into a lithium salt, Grignard reagent, or the like in a solvent and then reacting with compound (38). 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 reagent used when preparing a lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like. Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium. Reaction temperature can be normally implemented at -78 degreeC-50 degreeC, and it is preferable to carry out at -20 degreeC-50 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 2-3b
This step is a step for producing the compound (40) by replacing the hydroxy group of the compound (39) with a hydrogen atom. Compound (40) can be produced, for example, by reacting phosphorus tribromide in a solvent or in the absence of a solvent. Examples of the solvent used include chloroform. The reaction temperature can usually be carried out at -78 ° C to the solvent reflux temperature, and it is preferably carried out at 0 ° C to 100 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 2-3c
This step is a step of producing compound (40) by a coupling reaction of compound (11) and compound (41). Compound (40) can be produced, for example, by utilizing a Negishi coupling reaction between compound (11) and compound (41) in a solvent. Examples of the solvent used include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, 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, and it is preferably carried out at 0 ° C to 50 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 2-3d
This step is a step of producing compound (43) from compound (11) and compound (42). Compound (43) is obtained by reacting, for example, a compound obtained by converting the bromine atom of compound (11) into a lithium salt or Grignard reagent in a solvent according to the aforementioned method b, step 1b-3 and reacting with compound (42). Then, it can be produced by treating with an appropriate acid. 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 acid used include hydrochloric acid. Reaction temperature can be normally implemented at -78 degreeC-50 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 2-3e
This step is a step for producing compound (40) by Suzuki coupling reaction of compound (43) and compound (44). Compound (40) can be produced, for example, by reacting compound (43) and compound (44) in a solvent and using a palladium reagent as a catalyst in the presence of a base. Examples of the solvent used include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, a mixed solvent thereof and the like. Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like. Examples of the base to be used include triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. In addition, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino as ligands -2 ', 4', 6'-triisopropylbiphenyl (XPhos) or the like can be used. Reaction temperature can be normally implemented at -78 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0 degreeC-20 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 2-3f
This step is a step for producing a compound (12) by converting a bromine atom of the compound (11) into a hydroxymethyl group. This process can be performed according to said b method and process 1b-3.

Process 2-3g
This step is a step for producing a compound (45) by converting the hydroxyl group of the compound (12) into an appropriate leaving group (L ¹ ). This process can be performed according to said b method and process 1b-8.

Step 2-3h
This step is a step of producing compound (40) by reacting compound (45) with compound (2). This process can be performed according to said A method and process 1-1.

Step 2-4
This step is a step for producing the compound (46) by removing the tert-butoxycarbonyl group of the compound (40). This process can be performed according to said b method and process 1b-4.

Step 2-5
This step is a step of producing compound (47) by a coupling reaction of compound (10) and compound (38). This process can be performed according to said B method and process 2-3a.

Step 2-6
This step is a step for producing the compound (46) by replacing the hydroxy group of the compound (47) with a hydrogen atom. This process can be performed according to said B method and process 2-3b.

Step 2-7
This step is a step for producing the compound (48) by converting the amino group of the compound (46) into an appropriate leaving group (L ³ ). This process can be performed according to said b method and process 1b-6.

Step 2-8
This step is a step of producing compound (Ic) by reacting compound (48) with compound (15) and substituting L ³ with R ² . This process can be performed according to said b method and process 1b-7.

Step 2-9
This step is a step of producing compound (Id) by hydrolyzing the ester moiety of compound (Ic). This process can be performed according to said A method and process 1-2.

(Method C)

Wherein Y ¹ , Y ² , R ² , R ⁴ , R ⁵ , A and Q ¹ are as defined above; Q ³ and Q ⁴ are a hydrogen atom and a C _1-6 alkyl group (bonded to each other And R ^3a represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-7 alkanoyl group, a cyano group, etc.)

Step 3-1
This step is a step of producing compound (If) by substituting the bromine atom of compound (Ie) with R ^3a . Compound (If) can be produced, for example, by reacting compound (Ie) with compound (49) in a solvent and using a palladium reagent as a catalyst in the presence of a base. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do. 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. In addition, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino as ligands -2 ', 4', 6'-triisopropylbiphenyl (XPhos) or the like can be used. The reaction temperature can usually be carried out at -78 ° C to the solvent reflux temperature, and it is preferably carried out at 0 ° C to 100 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days. Compound (Ie) can be produced according to Method A or Method B.

Step 3-2
This step is a step of producing compound (Ig) by hydrolyzing the ester moiety of compound (If). This process can be performed according to said A method and process 1-2.

(Method D)

(Wherein Y ¹ , Y ² , R ² , R ³ , R ⁴ , R ⁵ , A and Z ² are as defined above.)

Step 4-1
This step is a step of producing compound (Ih) by a condensation reaction between compound (Ib) and compound (50). Compound (Ih) can be produced, for example, by reacting compound (Ib) with compound (50) in a solvent in the presence or absence of a base in the presence of a condensing agent. Examples of the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the condensing agent used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), and 2- (1H-7-azabenzotriazol-1-yl) -1. 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like. If necessary, 4-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT), or the like can be used as a reaction accelerator. As the base to be used, potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine or the like can be used. The reaction temperature can usually be carried out at -78 ° C to the solvent reflux temperature, and it is preferably carried out at 0 ° C to 100 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

(E method)

(Wherein Y ¹ , Y ² , R ² , R ³ , R ⁴ , R ⁵ and A are as defined above.)

Step 5-1
This step is a step of producing compound (51) from compound (Ib). Compound (51) can be produced, for example, by reacting compound (Ib) with an amine source compound such as ammonium chloride in the presence of a base in the presence of a condensing agent in the presence or absence of a base. Examples of the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the condensing agent used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), and 2- (1H-7-azabenzotriazol-1-yl) -1. 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like. If necessary, 4-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT), or the like can be used as a reaction accelerator. As the base to be used, potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine or the like can be used. Reaction temperature can be normally implemented at -78 degreeC-solvent recirculation | reflux temperature, and it is preferable to carry out at 0 degreeC-20 degreeC. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 5-2
This step is a step of producing compound (52) by dehydration reaction of compound (51). Compound (52) can be produced, for example, by reacting compound (51) with thionyl chloride, phosphorus oxychloride or the like in a solvent. Examples of the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at -78 ° C to the solvent reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

Step 5-3
This step is a step for producing a compound (Ii) by converting a nitrile group of the compound (52) into a tetrazolyl group. Compound (Ii) can be produced, for example, by reacting compound (52) with sodium azide or the like in a solvent. Examples of the solvent include N, N-dimethylformamide, water, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. Moreover, zinc bromide, ammonium chloride, silver nitrate, acetic acid, etc. can be added as needed. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 20 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, and the like, but is usually 30 minutes to 3 days.

  The pharmacologically acceptable salt of the compound (I) of the present invention can be produced according to a conventional method using the compound (I) of the present invention.

  The scheme shown above is an example of a method for producing the compound (I) of the present invention 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. Mention may be made of the method described in Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006.

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

A pharmaceutical composition containing compound (I) of the present invention or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient Depending on the usage, various dosage forms are used. 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 pharmaceutical compositions are prepared according to known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents. It can be prepared by appropriately mixing or diluting / dissolving with pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents. 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) of the Present Invention or a Pharmacologically Acceptable Salt The Compound (I) of the present invention or a pharmacologically acceptable salt thereof is potent in EP ₁ receptor antagonistic action confirmation tests and the like. EP ₁ receptor antagonism. Therefore, the compound (I) of the present invention or a pharmacologically acceptable salt thereof can suppress or decrease the intracellular calcium concentration. Therefore, the pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is used for the treatment of a disease or symptom caused by activation of EP ₁ receptor by PGE ₂ stimulating action. It can be used as a medicine or a prophylactic.

Examples of diseases that activate the EP ₁ receptor by PGE ₂ stimulation include lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, osteoporosis, cancer, and the like. The pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is preferably used as a therapeutic or prophylactic agent for LUTS, inflammatory disease or pain disease. . More preferably, it is LUTS.

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 urinary accumulation symptoms, urination symptoms, and post-urination symptoms.
The compound (I) of the present invention or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of urinary retention symptoms.

"Urine accumulation symptoms" include urinary urgency, daytime frequent urination, night frequent urination, urinary incontinence (such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, persistent urinary incontinence), and Bladder perception (increased bladder perception, decreased bladder perception, lack of bladder perception, nonspecific bladder perception, etc.) is included. Compound (I) of the present invention or a pharmacologically acceptable salt thereof is urinary urgency, daytime frequent urination, nocturia, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, increased bladder perception, or It is preferably used for the treatment or prevention of nonspecific bladder perception. More preferred are urinary urgency, daytime frequent urination, nocturia, urge incontinence, or increased bladder perception. In addition, the compound (I) of the present invention or a pharmacologically acceptable salt thereof is particularly preferable for the treatment or prevention of OABs.

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

Examples of the drug that can be used in combination with the compound (I) of the present invention 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. (BPH), therapeutic agents for cystitis such as interstitial cystitis, prostatitis and the like. 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 , anti-diuretics, calcium channel blockers and foremost, smooth muscle direct action, tricyclic antidepressants, potassium channel modulators, sodium channel blocker and foremost, H ₁ blockers, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, 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. Preferably, anticholinergics, alpha ₁ antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, progesterone-based hormone, antidiuretic agents, smooth muscle direct agonists or tricyclic antidepressants.

  Moreover, although it illustrates concretely as follows about the chemical | medical agent used in combination, the content of this invention is 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, tortue oral gin, imidafenacin, temiverine, darifenacin, fesoterodine, trospium, propantheline 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, solabegron 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 gestroneone, 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, lutropine, nafarelin, triptorelin, AEZS-019, cetrorelix, degarelix, elagorix, ganilelex, ozarelics, 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 the “calcium channel blocker” include amlodipine, cilnidipine, puffer piverine, temiverine, PD-29985, alanidipine, azelnidipine, valnidipine, 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.

Examples of the “smooth muscle direct acting drug” include flavoxate.

Examples of the “tricyclic antidepressant” 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, tyrisolol, 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, banacarant, etc. it can.

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

Examples of “serotonin reuptake inhibitors” include UCB-46331, 424887, AD-337, BGC-20-1259, BMS-505130, citalopram, dapoxetine, desvenlafaxine, DOV-102303, 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, venlafaqui Mention may be made of down, Birazodon, the WAY-426, WF-516 and the like.

Examples of the “norepinephrine reuptake inhibitor” include AD-337, desvenlafaxine, DOV-102676, 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 “dopamine reuptake inhibitors” include DOV-102777, DOV-216303, DOV-21947, IDN-5491, NS-2359, NSD-644, SEP-225289, SEP-228425, SEP-228432, sibutramine, tesofensin, Examples include tramadol, brassofensin, bupropion, NS-27100, radafaxin, safinamide and the like.

As “GABA agonist”, retigabine, eszopiclone, indipron, pagok mouth, SEP-225441, acamprosate, baclofen, AZD-7325, BL-1020, brotizolam, DP-VPA, progabide, propofol, topiramate, Examples thereof include 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-6221, 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-78443 and the like.

Examples of the “endothelin antagonist” 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-5858, 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-1482160, 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-26-219 , Mention may be made of the valdecoxib and the like.

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

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

When the compound (I) of the present invention or a pharmacologically acceptable salt thereof and one or more of the above drugs are used in combination, the present invention includes the following 1) to 5):
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,
It includes any one method of administration selected from 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. Moreover, when administering at different time as a separate formulation like 4) or 5), there is no restriction | limiting in particular about the administration order of the compound (I) of this invention, and said agent.

  In addition, the compound (I) of the present invention or a pharmacologically acceptable salt thereof is more than an additive effect in preventing or treating the above diseases by using one or more of the above drugs in appropriate combination. The advantageous effects of 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 / Dose of Compound (I) of the Present Invention The pharmaceutical of the present invention is systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal, etc.) Can be administered.

When the pharmaceutical composition organism of the present invention is used for actual treatment, the dose of the compound (I) of the present invention, which is an active ingredient thereof, or a pharmacologically acceptable salt thereof depends on the age, sex, body weight, disease of the patient. It is appropriately determined depending on 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 several times 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 invention or a pharmacologically acceptable salt thereof can be reduced according to the dose of a drug other than the EP ₁ receptor antagonist.

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

<Reference Example 1-1>

Methyl 3-amino-2,5-dichlorobenzoate Thionyl chloride (0 mL) was added to a solution of 3-amino-2,5-dichlorobenzoic acid (5.00 g) in methanol (250 mL) under argon atmosphere. 35.5 mL) was added dropwise over 1 hour, and the mixture was heated and stirred at 80 ° C. for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound as a yellow oil (5.86 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.92 (3H, s), 4.33 (2H, brs), 6.87 (1H, d, J = 2.4 Hz), 7.14 (1H, d, J = 2.4 Hz).

 <Reference Example 2-1>

Methyl 3- (benzoylamino) -2,5-dichlorobenzoate in a toluene (38 mL) solution of methyl 3-amino-2,5-dichlorobenzoate (2.20 g) at room temperature under an argon atmosphere. After potassium carbonate (1.39 g) and benzoyl chloride (1.16 mL) were added, the mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a colorless solid (3.03 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.69 (3H, s), 7.52-7.58 (2H, m), 7.60 (1H, d, J = 2.4 Hz), 7.60-7.65 (1H, m), 7.90 -7.95 (2H, m), 8.69 (1H, brs), 8.88 (1H, d, J = 2.4 Hz).

 <Reference Example 2-2>

To a solution of methyl 2-amino-5-chlorobenzoate (2.50 g) in dichloromethane (20 mL) under an argon atmosphere of methyl 5-chloro-2-[(1-methylcyclopropylcarbonyl) amino] benzoate, Triethylamine (8.5 mL) and 1-methylcyclopropanecarboxylic acid chloride (2.37 g) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound as a light brown solid (2.35 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.72 (2H, dd, J = 6.7, 4.2 Hz), 1.31 (2H, dd, J = 6.7, 4.2 Hz), 1.54 (3H, s), 3.95 (3H , s), 7.47 (1H, dd, J = 9.1, 2.4 Hz), 8.01 (1H, d, J = 2.4 Hz), 8.73 (1H, d, J = 9.1 Hz), 11.34 (1H, brs).

 <Reference Example 3-1>

Methyl 2,5-dichloro-3- (thiobenzoylamino) benzoate in an argon atmosphere, methyl 3- (benzoylamino) -2,5-dichlorobenzoate (3.00 g), Lawesson's reagent (3.75 g) ) And toluene (24 mL) were heated to reflux for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound as a colorless solid (2.24 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.96 (3H, s), 7.47 (2H, t, J = 7.9 Hz), 7.56 (1H, t, J = 7.9 Hz), 7.74 (1H, d, J = 2.4 Hz), 7.88 (2H, d, J = 7.9 Hz), 9.08 (1H, brs), 9.44 (1H, brs).

 <Reference Example 3-2>

Methyl 5-chloro-2-[(1-methylcyclopropylthiocarbonyl) amino] benzoate under an argon atmosphere, methyl 5-chloro-2-[(1-methylcyclopropylcarbonyl) amino] benzoate (2.27) g), a mixture of Lawson's reagent (3.50 g) and toluene (40 mL) was heated to reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound as a yellow solid (1.55 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.93 (2H, dd, J = 6.7, 3.6 Hz), 1.63 (2H, dd, J = 6.7, 3.6 Hz), 1.65 (3H, s), 3.97 (3H , s), 7.52 (1H, dd, J = 9.1, 2.4 Hz), 8.03 (1H, d, J = 2.4 Hz), 9.39 (1H, d, J = 9.1 Hz), 12.11 (1H, brs).

 <Reference Example 4-1>

Methyl 5-chloro-2-phenylbenzo [d] thiazole-7-carboxylate N, N- of methyl 2,5-dichloro-3- (thiobenzoylamino) benzoate (2.12 g) under argon atmosphere To a dimethylformamide (31 mL) solution was added 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (1.20 mL) at room temperature, 3 hours at room temperature, followed by 50. Stir at 1 ° C. for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as colorless crystals (1.81 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.05 (3H, s), 7.50-7.55 (3H, m), 8.09 (1H, d, J = 2.4 Hz), 8.12-8.18 (2H, m), 8.23 (1H, d, J = 2.4 Hz).

 <Reference Example 4-2>

To a solution of methyl 6-chloro-2- (1-methylcyclopropyl) benzo [d] thiazole-4-carboxylate K ₃ [Fe (CN) ₆ ] (7.10 g) in water (5.5 mL) at 85 ° C. Solution of methyl 5-chloro-2-[(1-methylcyclopropylthiocarbonyl) amino] benzoate (1.53 g) in ethanol (2.7 mL), 30% aqueous sodium hydroxide (4.52 mL) ) And stirred at 85 ° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into 1 mol / L hydrochloric acid (30 mL), extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in a mixed solvent of methanol (5 mL) and diethyl ether (10 mL), and trimethylsilyldiazomethane (5 mL, 2 mol / L diethyl ether solution) was added. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound as a colorless oil (209 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.09 (2H, dd, J = 7.3, 4.2 Hz), 1.49 (2H, dd, J = 7.3, 4.2 Hz), 1.67 (3H, s), 4.00 (3H , s), 7.94 (1H, d, J = 2.4 Hz), 7.97 (1H, d, J = 2.4 Hz).

 <Reference Example 5-1>

2-Amino-3-bromo-5-chlorophenol To a solution of 2-amino-5-chlorophenol (12.5 g) in dichloromethane (350 mL) under argon atmosphere, bromine (4.90 mL) at 0 ° C. ) Was added dropwise over 0.5 hours and then stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a brown solid (2, 64 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.03 (2H, brs), 5.30 (1H, brs), 6.71 (1H, d, J = 2.4 Hz), 7.05 (1H, d, J = 2.4 Hz).

 <Reference Example 6-1>

2-amino-4-bromo-6-chlorobenzo [d] oxazole ethanol of 2-amino-3-bromo-5-chlorophenol (9.00 g) and cyanogen bromide (4.72 g) under argon atmosphere The (400 mL) suspension was stirred at room temperature for 3 days. The reaction solution was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a yellow solid (6.34 g).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.39 (1H, d, J = 1.8 Hz), 7.55 (1H, d, J = 1.8 Hz), 7.86 (2H, brs).

 <Reference Example 7-1>

4-Bromo-6-chloro-2-phenylbenzo [d] oxazole xylene of 2-amino-3-bromo-5-chlorophenol (2.60 g) and pyridine (1.0 mL) under argon atmosphere 80 mL) solution was added benzoyl chloride (1.50 mL) at 0 ° C. The reaction solution was stirred at 0 ° C. for 1 hour, p-toluenesulfonic acid monohydrate (11.1 g) was added, and the mixture was heated and stirred at 140 ° C. for 5 hours. After the reaction solution was cooled to room temperature, saturated sodium hydrogen carbonate was added to adjust the pH to 11, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a yellow solid (1.87 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.50-7.60 (5H, m), 8.25-8.30 (2H, m).

 <Reference Example 8-1>

5-chloro-4-methyl-2-phenylbenzo [d] thiazole To a suspension of N-benzoyl-3-chloro-2-methylaniline (500 mg) in toluene (5.1 mL) under argon atmosphere, Lawson After adding a reagent (823 mg), it heated and refluxed for 1 hour. After allowing to cool to room temperature, purification by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 4: 1) gave a yellow liquid. Next, [bis (trifluoroacetoxy) iodo] benzene (877 mg) was added to a solution of the obtained yellow liquid in trifluoroacetic acid (4.6 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 4: 1) to give the title compound as a pale yellow solid (500 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.86 (3H, s), 7.47-7.50 (3H, m), 7.65 (1H, d, J = 9.1 Hz), 7.71 (1H, d, J = 9.1 Hz ), 8.09-8.12 (2H, m).

The following reference examples 8-2 to 8-3 were obtained in the same manner as in Reference Example 8-1, using the corresponding aniline. These structures and spectral data are shown in Table 1.

 <Reference Example 9-1>

2-Amino-4-bromo-6-chlorobenzo [d] thiazole Acetic acid (100 mL) of 2-bromo-4-chloroaniline (15.5 g) and ammonium thiocyanate (23.0 g) under argon atmosphere To the suspension, a solution of bromine (7.8 mL) in acetic acid (20 mL) was added dropwise at 0 ° C. over 1 hour, followed by stirring at room temperature for 3 hours. The yellow solid obtained by filtration was suspended in water, and potassium carbonate was added to adjust to pH = 11. The precipitated solid was collected by filtration and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as a yellow solid (14.2 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.49 (1H, d, J = 1.8 Hz), 7.81 (1H, d, J = 1.8 Hz), 7.96 (2H, brs).

The following Reference Examples 9-2 to 9-5 were obtained in the same manner as Reference Example 9-1 using the corresponding aniline. These structures and spectral data are shown in Table 2.

 <Reference Example 10-1>

4-Bromo-2- (tert-butoxycarbonylamino) -6-chlorobenzo [d] thiazole 2-amino-4-bromo-6-chlorobenzo [d] thiazole (14.1 g) was added to dichloromethane (14.1 g) under an argon atmosphere. 300 mL) and tetrahydrofuran (200 mL), Boc ₂ O (13.0 g), triethylamine (15.0 mL), 4-dimethylaminopyridine (650 mg) were added at 0 ° C., and 2 at 0 ° C. Stir for hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a colorless solid (15.8 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.55 (9H, s), 7.59 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 1.8 Hz), 8.47 (1H, brs).

The following reference examples 10-2 to 10-4 were obtained in the same manner as in Reference Example 10-1, using the corresponding amine. These structures and spectral data are shown in Table 3.

 <Reference Example 11-1>

6-[[2- (tert-Butoxycarbonylamino) -6-chlorobenzo [d] thiazol-4-yl] (hydroxy) methyl] pyridine-2-carboxylate 4-bromo-2- ( To a tetrahydrofuran solution (150 mL) of tert-butoxycarbonylamino) -6-chlorobenzo [d] thiazole (7.00 g) at −10 ° C., isopropylmagnesium chloride lithium chloride complex (36.0 mL, 1.3 mol / L tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 2 hours. A tetrahydrofuran solution (40 mL) of methyl 6-formylpyridine-2-carboxylate (3.81 g) was added to the obtained mixture over 0.5 hours at −40 ° C., and then the temperature was gradually raised to room temperature. . 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, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title as a yellow solid. Compound was obtained (7.10 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.58 (9H, s), 4.02 (3H, s), 5.78 (1H, d, J = 5.5 Hz), 6.57 (1H, d, J = 5.5 Hz), 7.37 (1H, d, J = 1.8 Hz), 7.56 (1H, d, J = 7.9 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.72 (1H, t, J = 7.9 Hz), 8.01 ( 1H, d, J = 7.9 Hz), 8.27 (1H, brs).

The following reference examples 11-2 to 11-4 were obtained in the same manner as in Reference Example 11-1, using the corresponding bromo compound. These structures and spectral data are shown in Table 4.

 <Reference Example 12-1>

2- (tert-Butoxycarbonylamino) -6-chlorobenzo [d] oxazole-4-carboxaldehyde 4-bromo-2- (tert-butoxycarbonylamino) -6-chlorobenzo [d] oxazole (4 1.00 g) in tetrahydrofuran (120 mL) was added isopropylmagnesium chloride lithium chloride complex (21.5 mL, 1.3 mol / L in tetrahydrofuran) at −10 ° C. and stirred at room temperature for 2 hours. N, N-dimethylformamide (10 mL) was added to the obtained mixture at −78 ° C. over 0.5 hour, and then the temperature was gradually raised to 0 ° C. 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, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give a pale yellow solid. The title compound was obtained (2.80 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.57 (9H, s), 7.67 (1H, s), 7.80 (1H, s), 8.06 (1H, brs), 10.52 (1H, brs).

The following reference examples 12-2 to 12-5 were obtained in the same manner as in Reference Example 12-1, using the corresponding bromo compound. These structures and spectral data are shown in Table 5.

 <Reference Example 13-1>

2- (tert-Butoxycarbonylamino) -6-chlorobenzo [d] thiazole-4-boronic acid under argon atmosphere 4-bromo-2- (tert-butoxycarbonylamino) -6-chlorobenzo [d] thiazole (5 1.00 g) in tetrahydrofuran (110 mL) was added isopropylmagnesium chloride lithium chloride complex (26.0 mL, 1.3 mol / L in tetrahydrofuran) at −10 ° C. and stirred at room temperature for 2 hours. Trimethoxyborane (8.5 mL) was added to the obtained mixture at −78 ° C. over 0.5 hour, and then the temperature was gradually raised to 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Removal of the solvent gave the title compound as a pale yellow solid (4.50 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.51 (9H, s), 7.71 (1H, d, J = 1.8 Hz), 8.15 (1H, d, J = 1.8 Hz), 8.65 (2H, brs), 12.06 (1H, brs).

 <Reference Example 14-1>

6-[(2-Amino-6-chlorobenzo [d] thiazol-4-yl) methyl] pyridine-2-carboxylate 6-[[2- (tert-butoxycarbonylamino) -6- 6 under argon atmosphere To a suspension of methyl chlorobenzo [d] thiazol-4-yl] (hydroxy) methyl] pyridine-2-carboxylate (3.00 g) in chloroform (65 mL) at room temperature is phosphorous tribromide (1.90 mL). ) And stirred at room temperature for 0.5 hours and then at 80 ° C. for 3 hours. The reaction mixture was cooled to 0 ° C., water and saturated aqueous sodium hydrogen carbonate solution were added to adjust to pH = 11, and the mixture was extracted with ethyl acetate. The residue obtained by distilling off the solvent was dissolved in dichloromethane (30 mL), trifluoroacetic acid (5.0 mL) was added at room temperature, and the mixture was further stirred at room temperature for 24 hours. The reaction mixture was poured into 1 mol / L aqueous potassium carbonate solution (100 mL), and the precipitated solid was collected by filtration to give the title compound as colorless crystals (1.37 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.87 (3H, s), 4.37 (2H, s), 7.03 (1H, d, J = 1.8 Hz), 7.35 (1H, dd, J = 6.7, 1.8 Hz ), 7.65-7.72 (3H, m), 7.83-7.90 (2H, m).

The following reference examples 14-2 to 14-4 were obtained in the same manner as in Reference Example 14-1, using the corresponding hydroxymethyl compound. These structures and spectral data are shown in Table 6.

 <Reference Example 15-1>

2- (tert-butoxycarbonylamino) -6-chloro-4- (hydroxymethyl) benzo [d] oxazole 2- (tert-butoxycarbonylamino) -6-chlorobenzo [d] oxazole-4-under argon atmosphere Sodium borohydride (400 mg) was added to a solution of carboxaldehyde (2.80 g) in methanol (50 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 3 hours. The reaction mixture was cooled to 0 ° C., water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a colorless solid (2. 93 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.57 (9H, s), 3.52 (1H, brs), 4.93 (2H, brs), 7.29 (1H, d, J = 1.8 Hz), 7.39 (1H, d , J = 1.8 Hz), 8.64 (1H, brs).

The following Reference Examples 15-2 to 15-7 were obtained in the same manner as Reference Example 15-1 using the corresponding aldehyde form. Their structures and spectral data are shown in Tables 7 and 8.

 <Reference Example 16-1>

6-[(6-Chloro-2-iodobenzo [d] thiazol-4-yl) methyl] pyridine-2-carboxylate 6-[(2-amino-6-chlorobenzo [d] thiazole-under argon atmosphere 4-yl) methyl] p-toluenesulfonic acid monohydrate (5.77 g) was added at 10 ° C. to a suspension of methyl pyridine-2-carboxylate (3.37 g) in acetonitrile (45 mL). After stirring at 10 ° C. for 0.5 hour, a solution of sodium nitrite (1.41 g) in water (3 mL) and a solution of potassium iodide (4.20 g) in water (3.5 mL) were sequentially added. added. The reaction solution was stirred at 10 ° C. for 0.5 hour and at room temperature for 24 hours, and then a saturated aqueous sodium hydrogen carbonate solution was added to adjust to pH = 11, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as a yellow solid (3. 20 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.03 (3H, s), 4.76 (2H, s), 7.29 (1H, d, J = 2.4 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.72 (1H, t, J = 7.8 Hz), 8.00 (1H, d, J = 7.8 Hz).

The following reference examples 16-2 to 16-14 were obtained in the same manner as in Reference Example 16-1, using the corresponding amino form. Their structures and spectral data are shown in Tables 9-11.

 <Reference Example 17-1>

2- (tert-Butoxycarbonylamino) -6-fluoro-4- (hydroxymethyl) benzo [d] thiazole 4-bromo-2- (tert-butoxycarbonylamino) -6-fluorobenzo [d ] To a tetrahydrofuran solution (180 mL) of thiazole (6.32 g) was added isopropylmagnesium chloride lithium chloride complex (34.0 mL, 1.3 mol / L tetrahydrofuran solution) at -10 ° C, and 2 at room temperature. Stir for hours. Paraformaldehyde (5.00 g) was added to the obtained mixture at −40 ° C., and then the temperature was gradually raised to room temperature. 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, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title as a yellow solid. Compound was obtained (2.88 g).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.49 (9H, s), 4.84 (2H, d, J = 5.5 Hz), 5.34 (1H, t, J = 5.5 Hz), 7.23 (1H, dd , J = 10.3, 2.4 Hz), 7.69 (1H, dd, J = 8.5, 2.4 Hz), 11.83 (1H, s).

 <Reference Example 18-1>

2-Amino-6-fluoro-4- (hydroxymethyl) benzo [d] thiazole 2- (tert-butoxycarbonylamino) -6-fluoro-4- (hydroxymethyl) benzo [d] thiazole (under argon atmosphere) To a solution of 2.85 g) in dichloromethane (50 mL) was added trifluoroacetic acid (7.1 mL) at room temperature, and the mixture was further stirred at room temperature for 24 hours. The reaction solution was poured into 1 mol / L potassium carbonate aqueous solution (150 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a yellow solid (1. 21 g).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 4.71 (2H, s), 7.06 (1H, dd, J = 10.3, 2.4 Hz), 7.43 (1H, dd, J = 10.3, 2.4 Hz), 7.53 (2H, brs).

 <Reference Example 19-1>

2-Chloro-4- (chloromethyl) -6-fluorobenzo [d] thiazole Dichloromethane of 6-fluoro-4- (hydroxymethyl) -2-iodobenzo [d] thiazole (1.04 g) under argon atmosphere (17 mL) To the solution, thionyl chloride (1.3 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour, then N, N-dimethylformamide (3 drops) was added, and the mixture was stirred at room temperature for 10 hours. While cooling the reaction solution to 0 ° C., a saturated aqueous sodium hydrogen carbonate solution was added to adjust to pH = 11, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a yellow oil (792 mg). ).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.04 (2H, s), 7.36 (1H, dd, J = 9.8, 2.4 Hz), 7.44 (1H, dd, J = 7.8, 2.4 Hz).

The following reference examples 19-2 to 19-5 were obtained in the same manner as in Reference Example 19-1, using the corresponding hydroxymethyl compound. Their structures and spectral data are shown in Table 12.

 <Reference Example 20-1>

7- (Bromomethyl) -5-chloro-2-phenylbenzo [d] oxazole Under argon atmosphere, 5-chloro-7- (hydroxymethyl) -2-phenylbenzo [d] oxazole (1.00 g) in dichloromethane ( 26 mL) suspension was added with imidazole (341 mg) and carbon tetrabromide (1.53 g). Next, triphenylphosphine (1.11 g) was added and the reaction mixture became a solution. After stirring at room temperature for 30 minutes, the resulting solution was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 1: 1) to give the title compound as a colorless solid (853 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.74 (2H, s), 7.37 (1H, d, J = 1.8 Hz), 7.50-7.61 (3H, m), 7.70 (1H, d, J = 2.4 Hz ), 8.26 (1H, d, J = 1.8 Hz), 8.29 (1H, d, J = 1.2 Hz).

The following reference examples 20-2 to 20-4 were obtained in the same manner as in Reference Example 20-1, using the corresponding hydroxymethyl compound. Their structures and spectral data are shown in Table 13.

 <Reference Example 21-1>

1-[(5-Chloro-2-hydroxy-3-nitrophenyl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 5-chloro-2-hydroxy-3-nitrobenzaldehyde (23.0 g ) In dichloromethane (570 mL) was added tert-butylcarbazate (15.1 g) and acetic acid (6.51 mL), and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (34.0 g) was added and stirred at room temperature for 19 hours. The reaction solution was ice-cooled, and an aqueous hydrogen chloride solution (1.0 mol / L, 300 mL) was added for extraction. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, dichloromethane (450 mL) and trifluoroacetic acid (200 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, acetic acid (200 mL) and ethyl 2,4-dioxoheptanoate (16.0 mL) were added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 to 2: 1) to give the title compound as a pale yellow solid (33.4 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.44 (2H, s), 6.64 (1H, s), 6.67 (1H, s), 7.00 (1H, d, J = 3.0 Hz), 8.06 (1H, d, J = 3.0 Hz).

 <Reference Example 21-2>

1-[(3-Amino-5-chloro-2-hydroxyphenyl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[(5-chloro-2-hydroxy-3-nitrophenyl) To a solution of ethyl [methyl] -5-methyl-1H-pyrazole-3-carboxylate (20.0 g) in acetic acid (30 mL) and methanol (258 mL) under an argon atmosphere was added iron (14.5 g). Heated to reflux for minutes. The pH was adjusted to 9 with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 to 1: 1) to give the title compound as a yellow solid (14.0 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.1 Hz), 2.40 (3H, s), 4.00 (2H, s), 4.36 (2H, q, J = 7.1 Hz), 5.11 (2H, s), 6.54 (1H, d, J = 1.8 Hz), 6.67 (2H, td, J = 2.4 Hz), 9.72 (1H, s).

 <Reference Example 22-1>

1-[(2-Chloro-6-fluorobenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 5-methyl-1H-pyrazole-under argon atmosphere To a solution of ethyl 3-carboxylate (420 mg) in N, N-dimethylformamide (5 mL) was added sodium hydride (120 mg, 60% oil suspension) under ice-cooling, and 0.5 hours at room temperature. Stir. To the resulting mixture was added dropwise a solution of 2-chloro-4- (chloromethyl) -6-fluorobenzo [d] thiazole (810 mg) in N, N-dimethylformamide (5 mL) at −78 ° C., followed by ice Stir for 1 hour under 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 evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless powder (570 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.41 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.83 (2H, s), 6.66 (1H, s), 6.68 (1H, dd, J = 9.7, 2.4 Hz), 7.40 (1H, dd, J = 7.3, 2.4 Hz).

The following reference examples 22-2 to 22-3 were obtained in the same manner as in Reference Example 22-1, using the corresponding chloromethyl compound. Their structure and spectral data are shown in Table 14.

 <Reference Example 23-1>

1-[(2-Iodobenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 2-iodo-4-methylbenzo [d] thiazole (20 To a carbon tetrachloride solution (145 mL) of g), N-bromosuccinimide (15.5 g) and benzoyl peroxide (1.1 g) were added at room temperature, and the mixture was stirred at 90 ° C. for 4 hours. A saturated aqueous sodium thiosulfate 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. When the solvent was distilled off, 4- (bromomethyl) -2-iodobenzo [d] thiazole was obtained as a yellow solid (26.0 g).
To an N, N-dimethylformamide solution (182 mL) of ethyl 5-methyl-1H-pyrazole-3-carboxylate (13.4 g) under an argon atmosphere was added sodium hydride (3.2) under ice-cooling. g, 60% oil suspension) was added, and the mixture was stirred at room temperature for 10 minutes. 4- (Bromomethyl) -2-iodobenzo [d] thiazole (26.0 g) in N, N-dimethylformamide (182 mL) was added dropwise to the resulting mixture, and the mixture 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 evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a colorless powder (17.6 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.91 (2H, s), 6.64 (1H, s), 6.89 (1H, dd, J = 7.9, 1.2 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.76 (1H, dd, J = 7.9, 1.2 Hz).

The following reference examples 23-2 to 23-5 were obtained in the same manner as in Reference Example 23-1, using the corresponding methyl form. Their structures and spectral data are shown in Table 15.

 <Reference Example 24-1>

6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) -4- (hydroxymethyl) benzo [d] oxazole Under argon atmosphere, 6-chloro-4- (hydroxymethyl) -2- To a tetrahydrofuran solution (1 mL) of iodobenzo [d] oxazole (80.0 mg) was added 1,2,3,6-tetrahydropyridine (0.1 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a colorless solid (27.0 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.26-2.34 (2H, m), 3.27-3.37 (1H, m), 3.79 (2H, t, J = 5.5 Hz), 4.12-4.18 (2H, m) , 4.88 (2H, d, J = 2.4 Hz), 5.75-5.82 (1H, m), 5.90-5.97 (1H, m), 7.07 (1H, d, J = 1.8 Hz), 7.18 (1H, d, J = 1.8 Hz).

Using the corresponding iodine bodies, the following Reference Examples 24-2 to 24-3 were obtained in the same manner as Reference Example 24-1. Their structures and spectral data are shown in Table 16.

 <Reference Example 25-1>

1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carbonitrile argon 1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 under atmosphere -To a solution of carboxamide (400 mg) in N, N-dimethylformamide (10 mL) was added thionyl chloride (0.2 mL) at room temperature, and the mixture was stirred at room temperature for 2 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 evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a yellow powder (312 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.31 (3H, s), 2.32-2.36 (2H, m), 3.75 (2H, t, J = 5.8 Hz), 4.09 (2H, t, J = 2.7 Hz ), 5.60 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.93-5.99 (1H, m), 6.44 (1H, s), 6.92 (1H, d, J = 1.8 Hz), 7.53 (1H, d, J = 1.8 Hz).

 <Reference Example 26-1>

6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) -4-hydroxybenzo [d] thiazole 6-chloro-2- (3,6-dihydropyridine-1 (2H) under argon atmosphere -Il) A solution of benzo [d] thiazole-4-boronic acid (530 mg) in tetrahydrofuran (1.2 mL), aqueous sodium hydroxide (1.0 mol / L, 7.2 mL), and hydrogen peroxide An aqueous solution (4.5 mL) was added and stirred at room temperature for 2 hours, and then an aqueous hydrogen chloride solution was added to adjust to pH = 1. Next, diethyl ether was added. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 1: 1) to give the title compound as a colorless solid (434 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.27-2.32 (2H, m), 3.69 (2H, t, J = 5.8 Hz), 4.01-4.04 (2H, m), 5.73-5.78 (1H, m) , 5.89-5.95 (1H, m), 6.84 (1H, d, J = 1.8 Hz), 6.87 (1H, bs), 7.11 (1H, d, J = 1.8 Hz).

 <Reference Example 27-1>

3-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] thio] propionic acid 2-ethylhexyl 4-bromo-6 under argon atmosphere To a solution of -chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole (200 mg) in 1,4-dioxane (3.0 mL), 3-mercaptopropionic acid 2- Ethylhexyl (55.0 mg), xanthophos (32.4 mg), N, N-diisopropylethylamine (0.206 mL), and tris (dibenzylideneacetone) dipalladium (0) (23.2 mg) were added. . The reaction vessel was heated with microwave (CEM) for 30 minutes (150 W, 130 ° C.). After cooling to room temperature and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1-4: 1) to give the title compound as a pale yellow oil (228) mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.89 (6H, t, J = 7.9 Hz), 1.23-1.41 (8H, m), 1.52-1.62 (1H, m), 2.28-2.35 (2H, m) , 2.68 (2H, t, J = 7.6 Hz), 3.36 (2H, t, J = 7.6 Hz), 3.75 (2H, t, J = 6.1 Hz), 4.01 (2H, dd, J = 6.1, 2.4 Hz) , 4.07-4.09 (2H, m), 5.73-5.80 (1H, m), 5.89-5.96 (1H, m), 7.19 (1H, d, J = 1.8 Hz), 7.42 (1H, d, J = 1.8 Hz ).

 <Reference Example 28-1>

(Z) -1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -N′-hydroxy-5-methyl- 1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] under 1H-pyrazole-3-carboxyimidamide argon atmosphere To a mixed solution of N, N-dimethylformamide-ethanol (2.8 mL, 1: 1) of -5-methyl-1H-pyrazole-3-carbonitrile (100 mg) at room temperature, hydroxylamine hydrochloride (38 mg ), Triethylamine (0.075 mL) was added, and the mixture was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. When the solvent was distilled off, the title compound was obtained as a pale yellow powder (109 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.26 (3H, s), 2.32-2.36 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 4.10 (2H, t, J = 2.4 Hz ), 5.18 (2H, brs), 5.56 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.92-5.98 (1H, m), 6.35 (1H, s), 6.76 (1H, d, J = 1.8 Hz), 7.48 (1H, d, J = 1.8 Hz).

 <Reference Example 29-1>

1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxamidoargon 1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 under atmosphere -A solution of carboxylic acid (480 mg) in N, N-dimethylformamide (6.2 mL) at room temperature with ammonium chloride (66 mg), 2- (1H-7-azabenzotriazol-1-yl) -1 , 1,3,3-Tetramethyluronium hexafluorophosphate metanaminium (HATU) (563 mg), diisopropylethylamine (0.7 mL) were added, and 3 hours at room temperature. Stir for a while. 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 evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a yellow powder (412 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.30 (3H, s), 2.32-2.37 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 4.08-4.11 (2H, m), 5.56 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.96 (1H, d, J = 10.3 Hz), 6.61 (1H, s), 6.79 (1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 1.8 Hz).

<Example 1-1>

1-[(6-Chloro-2-phenylbenzo [d] oxazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[(6-chloro-2-phenylbenzo [d ] To a solution of ethyl oxazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (111 mg) in ethanol (1.4 mL) and tetrahydrofuran (1.4 mL), an aqueous potassium hydroxide solution (2 mol) / L, 0.7 mL), and then stirred at room temperature for 3 hours. Hydrochloric acid (2 mol / L, 0.8 mL) was added to the reaction solution to adjust the pH to 1, and the precipitated crystals were collected by filtration to give the title compound as colorless crystals (80.8 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.40 (3H, s), 5.76 (2H, s), 6.59 (1H, s), 7.52-7.68 (4H, m), 7.80 (1H, d, J = 8.5 Hz), 8.04 (1H, d, J = 1.2 Hz), 8.07 (1H, s), 12.58 (1H, brs).

The following Examples 1-2 to 1-182 were obtained in the same manner as Example 1-1 using the corresponding esters. Their structures and spectral data are shown in Tables 17-63.

<Example 2-1>

1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate argon To a solution of 6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) -4- (hydroxymethyl) benzo [d] oxazole (1.04 g) in dichloromethane (1 mL) under an atmosphere, Thionyl chloride (0.05 mL) was added at room temperature, and the mixture was stirred at room temperature for 24 hours. While cooling the reaction solution to 0 ° C., a saturated aqueous sodium hydrogen carbonate solution was added to adjust to pH = 11, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give 6-chloro-4- (chloromethyl) -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d as a yellow oil. Oxazole was obtained (28.0 mg).
In an argon atmosphere, ethyl 5-methyl-1H-pyrazole-3-carboxylate (19.0 mg) in N, N-dimethylformamide (0.5 mL) was added to sodium hydride (120 mL) under ice-cooling. mg, 60% oil suspension) was added and stirred at room temperature for 0.5 hour. To the resulting mixture, N, N-dimethylformamide of 6-chloro-4- (chloromethyl) -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazole (28.0 mg) was added. The solution (0.5 mL) was added dropwise at −78 ° C., and then stirred for 3 hours under ice cooling. The reaction solution was diluted with ethanol (1 mL), aqueous sodium hydroxide solution (2 mol / L, 1.0 mL) was added, and the mixture was stirred at room temperature for 2 hr. Hydrochloric acid (2 mol / L, 0.6 mL) was added to the reaction solution to adjust to pH = 4, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 5: 1) to obtain the title compound as a colorless solid (11.5 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.19-2.29 (2H, m), 2.37 (3H, s), 3.72 (2H, t, J = 5.5 Hz), 4.07-4.13 (2H, m) , 5.43 (2H, s), 5.77-5.85 (1H, m), 5.87-5.94 (1H, m), 6.49 (1H, s), 6.78 (1H, d, J = 1.8 Hz), 7.54 (1H, d , J = 1.8 Hz), 12.56 (1H, brs).

<Example 3-1>

6-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] pyridine-2-carboxylate in an argon atmosphere under 4-bromo To a solution of -6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole (100 mg) in 1,4-dioxane (2.5 mL), 6-aminopyridine- Methyl 2-carboxylate (38.4 mg), xanthophos (8.1 mg), cesium carbonate (247 mg), and tris (dibenzylideneacetone) dipalladium (0) (5.8 mg) were added. The reaction vessel was heated with microwave (CEM) for 45 minutes (150 W, 140 ° C.). After cooling to room temperature and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-2: 1) to give the title compound as a pale yellow solid (47. 0 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.31-2.38 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 4.03 (3H, s), 4.07-4.10 (2H, m), 5.77 -5.83 (1H, m), 5.92-5.98 (1H, m), 7.15 (1H, dd, J = 7.9, 1.2 Hz), 7.21 (1H, d, J = 1.8 Hz), 7.63-7.71 (2H, m ), 7.85 (1H, s), 8.36 (1H, d, J = 1.8 Hz).

<Example 3-2>

5-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] furan-2-carboxylate in an argon atmosphere under 4-bromo To a solution of -6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole (100 mg) in 1,4-dioxane (2.5 mL), 5-aminofuran- Methyl 2-carboxylate (64.0 mg), xanthophos (16.2 mg), cesium carbonate (247 mg), and tris (dibenzylideneacetone) dipalladium (0) (11.6 mg) were added. The reaction vessel was heated with microwave (CEM) for 30 minutes (150 W, 140 ° C.). After cooling to room temperature and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1-4: 1) to give the title compound as a pale yellow solid (60. 0 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.31-2.38 (2H, m), 3.75 (2H, t, J = 5.8 Hz), 3.89 (3H, s), 4.06-4.09 (2H, m), 5.76 -5.84 (1H, m), 5.90-5.99 (2H, m), 7.13 (1H, d, J = 1.8 Hz), 7.16 (1H, d, J = 1.8 Hz), 7.25 (1H, s), 7.78 ( 1H, s).

<Example 4-1>

6-chloro-4-[[5-methyl-3- (1H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2- (3,6-dihydropyridin-1 (2H) -yl ) Benzo [d] thiazole 1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5 under argon atmosphere To a mixed solution of methyl-1H-pyrazole-3-carbonitrile (20 mg) in N, N-dimethylformamide-water (1.3 mL, 3: 1) at room temperature, sodium azide (6 mg), bromide Zinc (13 mg) was added, and the mixture was stirred at 80 ° C. for 2 hours, and then stirred at 150 ° C. for 3 hours. To the reaction solution was added 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as a yellow liquid (18 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.22-2.29 (2H, m), 2.72 (3H, s), 3.72 (2H, t, J = 5.4 Hz), 4.05-4.08 (2H, m) , 5.55 (2H, s), 5.82 (1H, d, J = 10.3 Hz), 5.92 (1H, d, J = 10.3 Hz), 6.56 (1H, s), 6.86 (1H, s), 7.85 (1H, s), 7.94 (1H, s).

<Example 5-1>

Methyl 5-[(tert-butoxycarbonyl) [6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] furan-2-carboxylate 5 Dichloromethane of methyl [[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] furan-2-carboxylate (35.0 mg) (1.0 mL) To the solution, di-tert-butyl dicarbonate (39.0 mg) and 4-dimethylaminopyridine (catalytic amount) were added and stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography (NH, hexane: ethyl acetate = 10: 1 to 4: 1) to obtain the title compound as a colorless oil (18.3 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.43 (9H, s), 2.25-2.32 (2H, m), 3.71 (2H, t, J = 5.8 Hz), 3.83 (3H, s), 4.00-4.05 (2H, m), 5.71-5.78 (1H, m), 5.88-5.95 (1H, m), 6.30 (1H, d, J = 3.6 Hz), 7.14 (1H, d, J = 3.6 Hz), 7.27 ( 1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 1.8 Hz).

<Example 6-1>

3- [1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Yl] -1,2,4-oxadiazole-5 (4H) -thione under an argon atmosphere, (Z) -1-[[6-chloro-2- (3,6-dihydropyridine-1 (2H)- Yl) Benzo [d] thiazol-4-yl] methyl] -N′-hydroxy-5-methyl-1H-pyrazole-3-carboxyimidamide (20 mg) in acetonitrile (1 mL) at room temperature. , 8-diazabicyclo [5.4.0] undecene (0.03 mL) and thiocarbonyldiimidazole (13 mg) were added, and the mixture 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 evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a colorless powder (21 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.32-2.37 (2H, m), 2.38 (3H, s), 3.76 (2H, t, J = 5.4 Hz), 4.07-4.11 (2H, m), 5.60 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.96 (1H, d, J = 10.3 Hz), 6.67 (1H, s), 6.87 (1H, d, J = 1.8 Hz), 7.51 (1H, d, J = 1.8 Hz), 11.48 (1H, brs).

<Example 6-2>

4- [1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Yl] -3H-1,2,3,5-oxathiadiazole-2-oxide under an argon atmosphere (Z) -1-[[6-chloro-2- (3,6-dihydropyridine-1 (2H)- Yl) benzo [d] thiazol-4-yl] methyl] -N′-hydroxy-5-methyl-1H-pyrazole-3-carboxyimidamide (20 mg) in tetrahydrofuran (1 mL) under ice cooling. Then, pyridine (0.008 mL) and thionyl chloride (0.004 mL) were added, and the mixture 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 and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless liquid (15 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.31-2.35 (2H, m), 2.36 (3H, s), 3.75 (2H, t, J = 5.8 Hz), 4.08 (2H, t, J = 2.4 Hz ), 5.56 (2H, s), 5.79 (1H, d, J = 10.3 Hz), 5.93-5.98 (1H, m), 6.62 (1H, s), 6.85 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 2.4 Hz).

<Example 7-1>

1-[(6-Chloro-2-phenylbenzo [d] oxazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate in an argon atmosphere 5-methyl-1H-pyrazole- To a solution of ethyl 3-carboxylate (98.5 mg) in N, N-dimethylformamide (1 mL) was added sodium hydride (25.5 mg, 60% oil suspension) under ice cooling, and at room temperature. Stir for 0.5 hour. To the resulting mixture was added dropwise a solution of 6-chloro-4- (chloromethyl) -2-phenylbenzo [d] oxazole (146 mg) in N, N-dimethylformamide (2 mL) at −78 ° C., followed by ice Stir for 2 hours under cooling. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as colorless crystals (132 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 2.25 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.80 (2H, s), 6.69 (1H, s), 7.41 (1H, d, J = 8.5 Hz), 7.43-7.55 (3H, m), 7.64 (1H, d, J = 8.5 Hz), 8.01 (1H, d, J = 1.2 Hz ), 8.04 (1H, s).

The following Examples 7-2 to 7-9 were obtained in the same manner as in Example 7-1 using the corresponding chloromethyl compound. Their structures and spectral data are shown in Tables 64-66.

<Example 8-1>

1-[(6-Chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 6-chloro-4-methyl-2 under argon atmosphere -N-bromosuccinimide (246 mg) was added to a solution of phenylbenzo [d] thiazole (300 mg) in carbon tetrachloride (7.5 mL), followed by addition of azoisobutyronitrile (19 mg) for 8 hours. Heated to reflux. After the reaction solution was concentrated about half, diethyl ether was added. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane) to obtain a colorless solid (220 mg). Next, under argon atmosphere, a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (82.1 mg) in N, N-dimethylformamide (0.9 mL) was ice-cooled, and sodium hydride ( 38.0 mg) was added. The mixture was warmed to room temperature, stirred for 10 minutes, and then ice-cooled again. Next, the colorless solid (220 mg) was slowly added and stirred for 30 minutes, and then ethyl acetate and a saturated aqueous ammonium chloride solution were added. Hexane was added to the organic layer, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 2: 1) to give the title compound as a colorless solid (53.0 mg).
¹ H NMR (CDCl _3, 400 MHz) δ 1.41 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 4.43 (2H, q, J = 7.1 Hz), 5.96 (2H, s), 6.66 (1H, s), 6.97 (1H, d, J = 1.8 Hz), 7.51-7.53 (3H, m), 7.81 (1H, d, J = 1.8 Hz), 8.07-8.12 (2H, m).

The following Examples 8-2 to 8-4 were obtained in the same manner as in Example 8-1, using the corresponding methyl form. Their structures and spectral data are shown in Table 67.

<Example 9-1>

5-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] furan-2-carboxylate in an argon atmosphere (Bromomethyl) -6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole (20 mg) in tetrahydrofuran (0.6 mL) was added tetrakis (tri Phenylphosphine) palladium (0) (7 mg) and 5- (ethoxycarbonyl) -2-furanyl zinc bromide (0.2 mL, 0.5 mol / L tetrahydrofuran solution) were added, and the mixture was stirred at 50 ° 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 evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give the title compound as a yellow powder (17 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.37 (3H, t, J = 7.3 Hz), 2.29-2.35 (2H, m), 3.73 (2H, t, J = 5.8 Hz), 4.06 (2H, t , J = 2.4 Hz), 4.35 (2H, q, J = 7.3 Hz), 4.36 (2H, s), 5.78 (1H, d, J = 10.3 Hz), 5.89-5.96 (1H, m), 6.13 (1H , d, J = 3.6 Hz), 7.08 (1H, d, J = 3.6 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.46 (1H, d, J = 1.8 Hz).

The following Examples 9-2 to 9-3 were obtained in the same manner as Example 9-1 using the corresponding bromomethyl compound. Their structure and spectral data are shown in Table 68.

<Example 10-1>

1-[(5-Chloro-2- (3-chlorophenyl) benzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[(3-amino-5 -Chloro-2-hydroxyphenyl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (250 mg) in xylene (4.0 mL) solution with pyridine (0.065 mL), 3-chlorobenzoyl Chloride (0.120 mL) was added. After stirring at room temperature for 0.5 hour, p-toluenesulfonic acid monohydrate (460 mg) was added and stirred at room temperature for 5 minutes. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 2: 1) to give the title compound as a colorless solid (277 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.41 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.69 (2H, s), 6.69 (1H, s), 6.98 (1H, d, J = 1.8 Hz), 7.48 (1H, t, J = 7.9 Hz), 7.54-7.56 (1H, m), 7.68 (1H, d, J = 2.4 Hz) , 8.08 (1H, dd, J = 9.1, 1.2 Hz), 8.17 (1H, t, J = 1.8 Hz).

<Example 10-2>

1-[(5-Chloro-2- (2-chlorophenyl) benzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[(3-amino-5 -Chloro-2-hydroxyphenyl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (500 mg) in xylene (8.0 mL) solution in pyridine (0.130 mL), 2-chlorobenzoyl Chloride (0.246 mL) was added. After stirring at room temperature for 0.5 hour, p-toluenesulfonic acid monohydrate (230 mg) was added and heated to reflux for 5 hours. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 2: 1) to give the title compound as a colorless solid (190 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 4.42 (2H, q, J = 7.1 Hz), 5.67 (2H, s), 6.66 (1H, s), 7.03 (1H, s), 7.42-7.59 (2H, m), 7.59 (1H, dd, J = 7.9, 1.2 Hz), 7.75 (1H, d, J = 1.8 Hz), 8.11 ( (1H, dd, J = 7.9, 1.8 Hz).

<Example 11-1>

1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate Ethyl 1-[[2-chloro-6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (78.0 mg) and 1 under argon atmosphere , 2,3,6-tetrahydropyridine (18.0 mg) was dissolved in N, N-dimethylformamide (0.5 mL), potassium carbonate (30.0 mg) was added at room temperature, and the mixture was stirred at room temperature for 24 hours. Stir. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as a pale yellow powder (83.0 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.30-2.38 (2H, m), 3.75 (2H, t, J = 5.5 Hz ), 4.06-4.13 (2H, m), 4.41 (2H, q, J = 7.3 Hz), 5.70 (2H, s), 5.77-5.84 (1H, m), 5.92-6.00 (1H, m), 6.55 ( 1H, dd, J = 9.7, 2.4 Hz), 6.62 (1H, s), 7.22 (1H, dd, J = 7.8, 2.4 Hz).

The following Examples 11-2 to 11-93 were obtained in the same manner as Example 11-1 using the corresponding halogen compounds. Their structures and spectral data are shown in Tables 69-93.

<Example 12-1>

Ethyl 1-[[2- (1-propen-2-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate 1 1,2-[[2-Iodo-6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (41.2 mg) -Dimethoxyethane (0.3 mL) solution with 4,4,5,5-tetramethyl-2- (1-propen-2-yl) -1,3,2-dioxaborolane (20.0 mg), saturated carbonic acid Aqueous sodium solution (0.12 mL) and dichlorobis (triphenylphosphine) palladium (II) (5.6 mg) were added. The reaction solution was reacted at 90 ° C. for 1 hour using a microwave (CEM, 150 W). The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 1: 1) to give the title compound as a light brown liquid (27.3 mg).
¹ H NMR (CDCl _3, 400 MHz) δ1.40 (3H, t, J = 7.3 Hz), 2.27 (3H, s), 2.32 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.58 (1H, d, J = 1.2 Hz), 5.90 (2H, s), 5.98 (1H, s), 6.64 (1H, s), 6.87 (1H, s), 7.63 (1H, s).

Using the corresponding halogen compounds, the following Examples 12-2 to 12-33 were obtained in the same manner as in Example 12-1. Their structures and spectral data are shown in Tables 94-101.

<Example 13-1>

5-methyl-1-[[2- (morpholin-4-yl) -6-phenylbenzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylate in an argon atmosphere 1,4-[[6-Chloro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (1,4 mg) To a dioxane solution (1.2 mL), phenylboronic acid (17 mg), 2 mol / L aqueous sodium carbonate solution (0.2 mL), tetrakis (triphenylphosphine) palladium (0) (14 mg) at room temperature, 2-dicyclohexylphosphino-2′-dimethylaminobiphenyl (9 mg) was added, and the mixture was stirred at 60 ° 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 evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a pale yellow powder (48 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 3.65-3.69 (4H, m), 3.84-3.88 (4H, m), 4.40 (2H, q, J = 7.3 Hz), 5.77 (2H, s), 6.61 (1H, s), 7.11 (1H, d, J = 1.8 Hz), 7.30 (1H, dt, J = 7.3, 1.2 Hz) , 7.38 (2H, t, J = 7.3 Hz), 7.47 (1H, d, J = 1.2 Hz), 7.48-7.50 (1H, m), 7.75 (1H, d, J = 1.8 Hz).

The following Examples 13-2 to 13-23 were obtained in the same manner as in Example 13-1, using the corresponding halogen compound. Their structures and spectral data are shown in Tables 102-109.

<Example 14-1>

1-[[6-Amino-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-nitrobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 under argon atmosphere -Iron powder (8 mg) was added to an ethanol-acetic acid mixed solution (1.5 mL, 10: 9) of ethyl carboxylate (60 mg) at room temperature, and the mixture was stirred at 80 ° C for 1 hour. 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 evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a yellow amorphous (41 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 2.29-2.36 (2H, m), 3.71 (2H, t, J = 5.4 Hz ), 4.06 (2H, t, J = 2.7 Hz), 4.42 (2H, q, J = 7.3 Hz), 5.66 (2H, s), 5.79 (1H, d, J = 10.3 Hz), 5.93 (1H, d , J = 10.3 Hz), 6.26 (1H, d, J = 2.4 Hz), 6.59 (1H, s), 6.86 (1H, d, J = 2.4 Hz).

<Example 15-1>

１−［［２−（３，６−ジヒドロピリジン−１（２Ｈ）−イル）−６−（メチルアミノ）ベンゾ［ｄ］チアゾール−４−イル］メチル］−５−メチル−１Ｈ−ピラゾール−３−カルボン酸エチル
１−［［２−（３，６−ジヒドロピリジン−１（２Ｈ）−イル）−６−（ジメチルアミノ）ベンゾ［ｄ］チアゾール−４−イル］メチル］−５−メチル−１Ｈ−ピラゾール−３−カルボン酸エチル
アルゴン雰囲気下にて１−［［６−アミノ−２−（３，６−ジヒドロピリジン−１（２Ｈ）−イル）ベンゾ［ｄ］チアゾール−４−イル］メチル］−５−メチル−１Ｈ−ピラゾール−３−カルボン酸エチル（４２ ｍｇ）のアセトン溶液（０．６ ｍＬ）に、室温にてヨードメタン（０．０３ ｍＬ）、炭酸カリウム（１４６ ｍｇ） を加え、室温で２時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：４）にて精製すると、それぞれ無色液体として表題化合物が得られた（メチルアミノ体（１６ ｍｇ）、ジメチルアミノ体（１９ ｍｇ））。
メチルアミノ体
¹H-NMR (400 MHz, CDCl₃) δ 1.38 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 2.29-2.35 (2H, m), 2.76 (3H, s), 3.66-3.74 (2H, m), 4.02-4.08 (2H, m), 4.40 (2H, q, J = 7.3 Hz), 5.67 (2H, s), 5.79 (1H, d, J = 10.4 Hz), 5.93 (1H, d, J = 10.4 Hz), 6.23 (1H, s), 6.58 (1H, s), 6.77 (1H, s).
ジメチルアミノ体
¹H-NMR (400 MHz, CDCl₃) δ 1.39 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.29-2.35 (2H, m), 2.83 (6H, s), 3.68-3.73 (2H, m), 4.02-4.08 (2H, m), 4.40 (2H, q, J = 7.3 Hz), 5.70 (2H, s), 5.79 (1H, d, J = 10.4 Hz), 5.93 (1H, d, J = 10.4 Hz), 6.44 (1H, s), 6.57 (1H, s), 6.92 (1H, s).

1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (methylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Ethyl carboxylate 1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole 1-[[6-Amino-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-ethyl carboxylate under argon atmosphere To an acetone solution (0.6 mL) of ethyl methyl-1H-pyrazole-3-carboxylate (42 mg), iodomethane (0.03 mL) and potassium carbonate (146 mg) were added at room temperature, and at room temperature for 2 hours. It was 拌. 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 evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to give the title compound as a colorless liquid (methylamino compound (16 mg), dimethylamino compound (19 mg)).
Methylamino form
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 2.29-2.35 (2H, m), 2.76 (3H, s), 3.66-3.74 (2H, m), 4.02-4.08 (2H, m), 4.40 (2H, q, J = 7.3 Hz), 5.67 (2H, s), 5.79 (1H, d, J = 10.4 Hz), 5.93 (1H, d, J = 10.4 Hz), 6.23 (1H, s), 6.58 (1H, s), 6.77 (1H, s).
Dimethylamino form
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.39 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.29-2.35 (2H, m), 2.83 (6H, s), 3.68-3.73 (2H, m), 4.02-4.08 (2H, m), 4.40 (2H, q, J = 7.3 Hz), 5.70 (2H, s), 5.79 (1H, d, J = 10.4 Hz), 5.93 (1H, d, J = 10.4 Hz), 6.44 (1H, s), 6.57 (1H, s), 6.92 (1H, s).

<Example 15-2>

1-[[6-Chloro-2-[[(furan-2-yl) methyl] (methyl) amino] benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carvone Ethyl 1-[[6-chloro-2-[[(furan-2-yl) methyl] amino] benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid To a solution of ethyl (40.8 mg) in acetone (2.0 mL), potassium carbonate (64.0 mg) and methyl iodide (0.017 mL) were added. The reaction solution was reacted at 80 ° C. for 40 minutes using a microwave (CEM, 150 W). The reaction solution was purified by silica gel column chromatography (NH, hexane: ethyl acetate = 10: 1 to 3: 1) to give the title compound as a colorless solid (27.9 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 3.17 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 4.75 (2H, s), 5.69 (2H, s), 6.32-6.36 (2H, m), 6.61 (1H, s), 6.81 (1H, d, J = 1.8 Hz), 7.39 (1H, d, J = 1.8 Hz), 7.48 (1H, d, J = 1.8 Hz).

<Example 16-1>

1-[[6-Chloro-2- (propan-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[[6-chloro 2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (20.0 mg) of ethyl acetate (1. To the 0 mL) solution, platinum oxide (5.0 mg) was added. After replacing the reaction vessel with hydrogen, the mixture was vigorously stirred at room temperature for 3 hours. Insolubles were removed with Celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 1: 1) to give the title compound as a colorless oil (15.1 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.3 Hz), 1.48 (6H, d, J = 7.3 Hz), 2.26 (3H, s), 3.36-3.46 (1H, m ), 4.41 (2H, q, J = 7.3 Hz), 5.86 (2H, s), 6.64 (1H, s), 6.93 (1H, d, J = 2.4 Hz), 7.74 (1H, d, J = 2.4 Hz ).

<Example 16-2>

1-[(6-Chloro-2-cyclohexylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[[6-chloro-2- (1- To a solution of cyclohexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (30.0 mg) in ethyl acetate (1.0 mL), Platinum oxide (15.0 mg) was added. After replacing the reaction vessel with hydrogen, the mixture was vigorously stirred at room temperature for 30 hours. Insolubles were removed with Celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 1: 1) to give the title compound as a colorless oil (13.8 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.26-1.52 (6H, m), 1.63 (2H, dq, J = 12.7, 3.6 Hz), 1.73-1.83 (1H, m), 1.90 (2H, dt, J = 12.7, 3.6 Hz), 2.16-2.24 (2H, m), 2.25 (3H, s), 3.10 (1H, tt, J = 11.5, 3.6 Hz), 4.42 (2H, q, J = 7.1 Hz), 5.86 (2H, s), 6.64 (1H, s), 6.90 (1H, d, J = 1.8 Hz), 7.74 (1H, d, J = 1.8 Hz).

<Example 17-1>

1-[(6-Chloro-2-cyclopropylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[(6-chloro-2-iodobenzo [ d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (100 mg) in tetrahydrofuran (1.0 mL) in a separately prepared cyclopropyl zinc (II) bromide { Likezinc (1.13 mL, 0.764 mol / L tetrahydrofuran solution) was added to a solution of bromocyclopropane (52.5 mg) in tetrahydrofuran (1.0 mL), and the mixture was stirred at room temperature for 2 hours. }, Tetrakis (triphenylphosphine) palladium (0) (8.0 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-3: 1) to give the title compound as a colorless solid (25.0 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.18-1.31 (4H, m), 1.40 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.35-2.41 (1H, m), 4.41 (2H, q, J = 7.3 Hz), 5.80 (2H, s), 6.63 (1H, s), 6.88 (1H, d, J = 1.8 Hz), 7.67 (1H, d, J = 1.8 Hz).

<Example 18-1>

6-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] oxy] pyridine-2-carboxylate methyl under argon atmosphere To a solution of 2- (3,6-dihydropyridin-1 (2H) -yl) -4-hydroxybenzo [d] thiazole (26.6 mg) in N, N-dimethylformamide (1.0 mL), Methyl fluoropyridine-2-carboxylate (15.5 mg) and potassium carbonate (27.6 mg) were added, and the mixture was stirred at 100 ° C. for 2 hr. After cooling to room temperature, water, ethyl acetate, and hexane (ethyl acetate / hexane = 1/1) were added and the layers were separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH, hexane: ethyl acetate = 20: 1 to 1: 1) to obtain the title compound as a colorless solid (15.1 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.19-2.26 (2H, m), 3.60 (2H, t, J = 5.8 Hz), 3.92 (2H, t, J = 2.7 Hz), 3.94 (3H, s ), 5.66-5.73 (1H, m), 5.84-5.91 (1H, m), 6.99 (1H, d, J = 7.3 Hz), 7.18 (1H, d, J = 1.8 Hz), 7.44 (1H, d, J = 1.8 Hz), 7.78 (1H, t, J = 7.3 Hz), 7.86 (1H, d, J = 7.3 Hz).

The following Examples 18-2 to 18-4 were obtained in the same manner as in Example 18-1, using the corresponding halogen compound. Their structures and spectral data are shown in Table 106.

<Example 19-1>

3-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] benzoate in an argon atmosphere under 6-chloro-2- (3,6-Dihydropyridin-1 (2H) -yl) benzo [d] thiazole-4-boronic acid (47.0 mg), methyl 3- (bromomethyl) benzoate (44.0 mg), potassium phosphate (85. 0 mg), dichlorobis (triphenylphosphine) palladium (II) (12.0 mg), N, N-dimethylformamide (1 mL), and water (0.2 mL) were stirred at 80 ° C. for 1 hour. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a yellow powder (41.4 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.28-2.37 (2H, m), 3.76 (2H, t, J = 5.5 Hz), 3.90 (3H, s), 4.07-4.13 (2H, m), 4.29 (2H, s), 5.76-5.83 (1H, m), 5.90-5.98 (1H, m), 7.01 (1H, d, J = 2.4 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.42 ( 1H, d, J = 2.4 Hz), 7.52 (1H, d, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 8.08 (1H, s).

  Next, with respect to the compounds of the present invention, the results supporting the usefulness are shown by test 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 and using the forward primer shown in SEQ ID NO: 1 and the reverse primer shown in SEQ ID NO: 2, KOD-Plus-Ver2.0 (Toyobo) The first PCR was carried out using this method. 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 cultivation, 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) (Concentration 0.1 mM) and fetal bovine serum (MoregateBiotech, final concentration: 10%) in D-MEM liquid medium (containing high glucose and L-glutamine, Invitrogen Corporation) under 5% CO ₂ gas conditions The cells were cultured in an incubator at 37 ° C. 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 a D-MEM liquid medium (containing high glucose and L-glutamine, Invitrogen Corporation) supplemented with a final concentration of 10%. 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) Rat EP ₁ Expression Vector Introduction Lipofectamine 2000 (Invitrogen Corporation) was used for introduction of the rat EP ₁ expression vector. The rat EP ₁ expression vector was diluted with 200ng / 25μL / to be well OPTI-MEM (R) I Reduced-Serum Medium (Invitrogen, Inc.). At the same time, Lipofectamine 2000 (Invitrogen Corp.) was diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corp.) to 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 cells into which the complex of rat EP ₁ expression vector / Lipofectamine 2000 was dispensed were cultured at 37 ° C. for 24 hours in an incubator under 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) Examination of inhibitory action on increase in intracellular calcium concentration Using rat EP ₁ receptor-expressing cells, the inhibitory effect of each test compound on the increase in intracellular calcium concentration induced by prostaglandin E ₂ was as shown below. investigated.
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 (Dojin Chemical Laboratories)) to a final concentration of 0.0004%, and then assay buffer was added, and 4 μmol / L Fluo 4-L An AM solution was prepared. 100 μL of this solution was added to each well and incubated at 37 ° C. for 90 minutes in an incubator. Thereafter, all of the cell supernatant was aspirated, 100 μL of assay buffer containing 2.5 mM probenecid was added to each well, incubated for 15 minutes in an incubator, and then the intracellular calcium concentration was measured.
The intracellular calcium concentration was measured as a fluorescence signal using FlexStation (registered trademark) (manufactured by Molecular Devices). 50 μL of each test compound (final concentration: 0.1 nM to 10 μM) diluted with the assay buffer 20 seconds after the start of reading the fluorescence signal 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 taken as 0%, and 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 the compound (I) of the present invention 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) Creation of experimental animals
Anesthesia was induced in Wistar male rats by subcutaneous administration (sc) of a 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. A midline incision was made in the dorsal skin, the muscles on both sides of the chest were incised along the spine, the muscle layer was opened with a retractor, and the thorax spine was exposed. 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 ligate 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 chip was placed under the trachea, and the trachea was lifted up slightly to secure the airway.

(2) Experimental method Rats were placed in a dorsal position on a small animal heating pad, and a rectal temperature probe was inserted from 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 the 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, give 17-PTP 9 times (5 minutes, 35 minutes, 65 minutes, 95 minutes, 125 minutes, 155 minutes, 185 minutes, 215 minutes, 245 minutes after test compound administration) Changes in bladder contraction pressure were observed. The number of 17-PTP ia 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 was used as the amount of change (ΔmmHg) in the bladder pressure due to 17-PTP . 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 the compound (I) of the present invention 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 a reverse primer (a reverse primer used to amplify the DNA of SEQ ID NO: 5)
3 'primer).
<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 (21)

A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof

[Wherein the ring containing Y ¹ and Y ² represents the following a) to d):

A nitrogen-containing 5-membered heterocycle selected from the group consisting of:

A is the following e) to i):

A group selected from the group consisting of:
R ^a is a hydrogen atom, a halogen atom or a C _1-6 alkyl group;
W ¹ is —CH═ or a nitrogen atom;
W ² is an oxygen atom or a sulfur atom;
One of W ³ and W ⁴ is a nitrogen atom, and the other is —CH═ or a nitrogen atom;
Y ³ is C _1-6 alkylene, —O—, —S— or —NR ^b —;
R ^b is a hydrogen atom, a C _1-6 alkyl group or a (C _1-6 alkoxy) carbonyl group;
R ¹ represents the following j) to o):
j) -C (= O) -OZ ¹
k) —C (═O) —NHSO ₂ Z ²
l) -C (= O) -NHOH
m) -C (= O) -NHCN
n) a group selected from the group consisting of —NH—C (═O) —Z ³ , and o) an acidic 5-membered heterocyclic 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 independently the following p) to t):
p) a C _1-6 alkyl group,
q) a halo C _1-6 alkyl group,
r) a C _3-6 cycloalkyl group,
s) unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of halogen atoms, C _1-6 alkyl groups, halo C _1-6 alkyl groups and C _1-6 alkoxy groups An aryl group, and t) a group selected from the group consisting of heterocyclic groups;

R ² represents the following aa) to ll):
aa) a C _1-6 alkyl group or a C _1-6 alkoxy C _1-6 alkyl group,
bb) a C _3-6 cycloalkyl group that is unsubstituted or substituted on the ring by one C _1-6 alkyl group,
cc) a C _2-6 alkenyl group,
dd) a C _5-8 cycloalkenyl group,
ee) a phenyl group whose ring is substituted with 1 to 5 groups independently selected from the group consisting of unsubstituted or halogen atoms, C _1-6 alkoxy groups and C _7-10 aralkyloxy groups;
ff) a heterocyclic group,
gg) Independent of a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkoxy C _1-6 alkyl group, a C _4-6 heterocycloalkyl group and a C _4-10 heteroaralkyl group An amino group substituted with one or two groups selected by
hh) a 4-7 membered cyclic amino wherein the ring is substituted with 1 to 3 groups independently selected from the group consisting of unsubstituted, C _1-6 alkyl groups, and C _1-6 alkylenedioxy groups Group,
ii) a C _1-6 alkoxy group,
jj) C _7-10 aralkyl group,
kk) C _1-6 alkylsulfanyl group, and ll) 6-membered aliphatic cyclic amino group is a radical selected from the group consisting of C _1-6 alkyl group substituted;

R ³ represents the following A) to N):
A) a hydrogen atom,
B) a halogen atom,
C) a cyano group,
D) Nitro group,
E) a C _3-6 cycloalkyl group or a C _5-8 cycloalkenyl group,
F) a C _2-8 alkenyl group,
G) a C _1-7 alkanoyl group,
H) an amino group which is unsubstituted or substituted by one or two C _1-6 alkyl groups,
I) a C _1-6 alkyl group,
J) C _1-6 alkoxy group,
K) a halo C _1-6 alkoxy group,
L) a phenyl group which is unsubstituted or substituted with 1 to 5 halogen atoms, a C _1-6 alkyl group or a C _1-6 alkoxy group,
M) a 5-membered aromatic heterocyclic group, and N) a carboxyl group,
A group selected from the group consisting of:
R ⁴ and R ⁵ each independently represent a hydrogen atom or a halogen atom (provided that a bond marked with (*) is bonded to Y ^3, and a bond marked with (**) is R ¹ and Represents binding.) ].
In the general formula (I), A represents the following e), f), h) and i):

[R ^a , W ¹ , W ² , W ³ , W ⁴ are as defined above (provided that a bond marked with (*) is linked to Y ^3, and a bond marked with (**) is linked to R ¹ Represents binding.) ].
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 1, which is a group selected from the group consisting of:
In the general formula (I), A represents the following e1), f1), h) and i1):

[R ^a has the same meaning as described above (provided that a bond marked with (*) is linked to Y ³ and a bond marked with (**) is linked to R ¹ ). ].
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 2, which is a group selected from the group consisting of:
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 3, wherein R ^a in the general formula (I) is a hydrogen atom or a C _1-6 alkyl group.
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein Y ³ in the general formula (I) is a methylene, oxygen atom or sulfur atom.
In the above formula (I), ^{Z 1} is a hydrogen atom or a _{C 1-6} alkyl group, ^{Z 2} is a _{C 1-6} alkyl group, claim 5 benzene-fused nitrogen-containing 5-membered heterocyclic described A compound or a pharmacologically acceptable salt thereof.
In the general formula (I), R ³ is the following A) to C), F), G), I) to K) and M):
A) a hydrogen atom,
B) a halogen atom,
C) a cyano group,
F) a C _2-8 alkenyl group,
G) a C _1-7 alkanoyl group,
I) a C _1-6 alkyl group,
J) C _1-6 alkoxy group,
K) a halo C _1-6 alkoxy group, and M) a 5-membered aromatic heterocyclic group,
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 6, which is a group selected from the group consisting of:
In the general formula (I), R ² represents the following aa1), bb) to dd), ee1), ff1), gg1) and hh1):
aa1) a C _1-6 alkyl group,
bb) a C _3-6 cycloalkyl group that is unsubstituted or substituted on the ring by one C _1-6 alkyl group,
cc) a C _2-6 alkenyl group,
dd) a C _5-8 cycloalkenyl group,
ee1) a phenyl group which is unsubstituted or whose ring is substituted with 1 to 5 halogen atoms,
ff1) a 6-membered aromatic heterocyclic group,
gg1) an amino group substituted with one or two groups independently selected from a C _1-6 alkyl group and a C _2-6 alkenyl group, and hh1) unsubstituted or independent from a C _1-6 alkyl group A 4- to 7-membered cyclic amino group in which the ring is substituted with 1 to 3 groups selected as
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 7, which is a group selected from the group consisting of:
In the general formula (I), A is the following e1) or f1):

[R ^a has the same meaning as described above (provided that a bond marked with (*) is linked to Y ³ and a bond marked with (**) is linked to R ¹ ). ].
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 8, which is a group selected from the group consisting of:
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein Y ³ in the general formula (I) is methylene.
In formula (I), is ^{R 3,} a hydrogen atom, a halogen _{atom, C 2-8} alkenyl _{group, C 1-6} alkoxy group, a halo _{C 1-6} alkoxy group, according to claim 10, wherein the benzene ring-condensed A nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof.
In the general formula (I), R ² represents the following cc), dd), gg2) and hh2):
cc) a C _2-6 alkenyl group,
dd) a C _5-8 cycloalkenyl group,
gg2) an amino group substituted with two independently selected C _1-6 alkyl groups, and hh2) a 4-7 membered cyclic amino group,
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 11, which is a group selected from the group consisting of:
In the general formula (I), the ring containing Y ¹ and Y ² is the following a), b) and d):

[R ² is as defined above]
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 12, which is a nitrogen-containing 5-membered heterocyclic ring selected from the group consisting of:
In the general formula (I), the ring containing Y ¹ and Y ² is a):

[R ² is as defined above]
The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 13, which is a nitrogen-containing 5-membered heterocyclic ring selected from the group consisting of:
The general formula (I) is
1-[[6-Bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1 -[[6-Chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (3 6-Dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (5-methyl) -3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- ( 1-propen-2-yl) Nzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-vinylbenzo [D] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 6-chloro-4-[[5-methyl-3- (1H-tetrazol-5-yl) -1H- Pyrazol-1-yl] methyl] -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole 1-[(5-chloro-2- (1-methylcyclopropyl) benzo [d ] Thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[(6-chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl- 1H-pyrazo 1-[(5-chloro-2- (3-chlorophenyl) benzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[ 2- (3,6-Dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[2 -(3,6-dihydropyridin-1 (2H) -yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1- [[2- (3,6-Dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro -2- (pipe Lysine-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (morpholin-4-yl) benzo [ d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] Methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole- 1-[[6-Chloro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1- [3-carboxylate [6-Chloro 2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2 -(4-Methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro 2- (Pyridin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6-chloro-2- (2-methyl-) 1-propen-1-yl Benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[[6- (dimethylamino) -2- (3,6-dihydropyridine-1 (2H)- Yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl] ) Benzo [d] thiazol-4-yl] oxy] furan-2-carboxylic acid 5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4 -Yl] thio] furan-2-carboxylic acid 1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazol-4-yl] methyl] -5 Methyl-1H-pyrazo The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to claim 1, which is ru-3-carboxylic acid. A pharmaceutical composition comprising as an active ingredient the benzene ring-fused nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15. An EP ₁ receptor antagonist comprising, as an active ingredient, the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15. A therapeutic or prophylactic agent for lower urinary tract symptoms comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15 as an active ingredient. It comprises administering to a patient a pharmaceutical composition comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 15 as an active ingredient. Treatment or prevention of lower urinary tract symptoms. The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable product thereof according to any one of claims 1 to 15, for producing a pharmaceutical composition for preventing or treating lower urinary tract symptoms. Salt used. The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15, for use in the prevention or treatment of lower urinary tract symptoms.