WO2014092104A1 - Oxadiazole derivative and pharmaceutical use of same - Google Patents

Abstract

The invention provides compounds represented by formula (1) (in the formula, Het represents the formula (Het-1) or the like; A represents the formula (A-1) or the like; B represents (B-1) or the like; R^1A represents a hydrogen atom, alkyl group, or the like; R^2A, R⁵, R⁶, and R⁷ represent a hydrogen atom, halogen atom, alkyl group, or the like; R⁸ and R⁹ represent a hydrogen atom, alkyl group, or the like; and l is an integer of 0-4) or pharmaceutically acceptable salts thereof that are useful as agents for the treatment or prevention of various diseases or symptoms involving the serotonin 4 receptors (especially Alzheimer's disease and other such neuropsychiatric diseases).

Description

Oxadiazole derivatives and their pharmaceutical uses

The present invention includes a novel oxadiazole derivative having an agonistic action or a partial agonistic (partial agonist) action on serotonin 4 receptor (hereinafter sometimes referred to as 5-HT ₄ receptor) and the same It relates to a pharmaceutical composition.

From the study of the mechanism of action of metoclopramide [4-amino-5-chloro-N- (2-diethylaminoethyl) -2-methoxybenzamide], a gastrointestinal motility-promoting drug or gastrointestinal function-improving drug that is widely used clinically, serotonin A 5-HT ₄ receptor, a subtype of the receptor, has been found (see Non-Patent Document 1). 5-HT ₄ receptor agonists are known to have gastrointestinal motility promoting effects in the periphery, and mosapride, cisapride (discontinued after launch), tegaserod, etc. are already on the market. On the other hand, 5-HT ₄ receptor agonists in the center may show cognitive function improving action by acetylcholine release enhancing action and relative beta amyloid protein (Aβ) lowering action accompanying increase in soluble APPα by α secretase activation. Has been reported (see Non-Patent Document 2). PRX-03140 having a partial agonistic action on the 5-HT ₄ receptor has been reported to exhibit a cognitive function improving action and an Aβ lowering action in animal experiments using rats (see Non-Patent Document 1). Furthermore, it was reported that PRX-03140 showed an effect of improving cognitive function in a phase II clinical trial for AD patients (see Non-Patent Document 2). Based on the above, 5-HT ₄ receptor agonists are expected as therapeutic agents for novel mechanisms for Alzheimer's dementia (AD) and various dementias associated with neurodegenerative diseases.
With the arrival of a super-aging society in the immediate future, the number of patients with Alzheimer-type dementia (AD) is rapidly increasing, and the development of effective therapeutic agents for Alzheimer-type dementia is strongly desired.
It is known that 5-HT ₄ agonists having an amide group at the 3-position of the indazole ring are useful as gastrointestinal motility promoters, gastrointestinal function improvers and cognitive function improvers (Patent Document 1, Patents) Reference 2).
In addition, 5-HT ₄ agonists having an amide group at the 4-position of the benzimidazole ring are known to be useful as gastrointestinal motility promoting agents, gastrointestinal function improving agents and cognitive function improving agents (Patent Document 3). , See Patent Document 4).

However, a compound in which a 4-position carbon atom such as an indazole ring or a benzimidazole ring and an oxadiazole ring are bonded has not been reported.

US Patent Application Publication No. 2005197335 US Patent Application Publication No. 2006135764 US Patent Application Publication No. 2010249186 US Patent Application Publication No. 20102611752

37th SFN Meeting (2007) Abstract of presentations International Conference Alzheimer's Disease (ICAD) 2008 Abstract of presentations, No. HT-01-07

The problem to be solved by the present invention is to provide a serotonin 4 receptor agonist useful as a therapeutic agent for Alzheimer type dementia and the like.

As a result of intensive studies, the present inventors have found that the aromatic ring portion is a variety of heteroaromatic rings, and a compound having a 1,2,4-oxadiazole ring as a linker portion that connects the aromatic ring portion and the amine side chain. It was found that the group showed excellent agonist activity with respect to the 5-HT ₄ receptor and was useful as a therapeutic agent for Alzheimer type dementia and the like, and the present invention was completed. According to the present invention, an oxadiazole derivative represented by the following formula (1) (hereinafter sometimes referred to as “the compound of the present invention”) is provided.

［式中、
　Ｈｅｔは下記の式（Ｈｅｔ－１）、式（Ｈｅｔ－２）、式（Ｈｅｔ－３）、式（Ｈｅｔ－４）、式（Ｈｅｔ－５）、式（Ｈｅｔ－６）、式（Ｈｅｔ－７）、式（Ｈｅｔ－８）、式（Ｈｅｔ－９）、式（Ｈｅｔ－１０）、式（Ｈｅｔ－１１）、式（Ｈｅｔ－１２）、式（Ｈｅｔ－１３）、又は式（Ｈｅｔ－１４）：

（式中、
　Ｒ^１Ａは水素原子、置換されていてもよいＣ_１－６アルキル基、置換されていてもよいＣ_２－６アルケニル基、置換されていてもよいＣ_２－６のアルキニル基、置換されていてもよいＣ_３－８シクロアルキル基、置換されていてもよいＣ_５－８シクロアルケニル基、置換されていてもよいＣ_１－４ハロアルキル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されていてもよいＣ_１－６アルカノイル基、置換されていてもよいＣ_１－６アルコキシカルボニル基、カルバモイル基、スルファモイル基、又は置換されていてもよいＣ_１－６アルキルスルホニル基を意味し、
　ここにおいて、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_３－８シクロアルキル基、Ｃ_５－８シクロアルケニル基、Ｃ_１－４ハロアルキル基、Ｃ_１－６アルカノイル基、Ｃ_１－６アルコキシカルボニル基、およびＣ_１－６アルキルスルホニル基は、それぞれ独立して、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、アリール基、ヘテロアリール基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　アリール基、およびヘテロアリール基は、それぞれ独立して、置換可能な位置で、ハロゲン原子、ヒドロキシ基、Ｃ_１－６アルキル基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、Ｃ_１－６アルカノイル基、および置換されてもよいアミノ基からなる群から選択される１又は複数の置換基で置換されてもよく、
　Ｒ^２Ａは水素原子、ハロゲン原子、置換されていてもよいＣ_１－６アルキル基、置換されていてもよいＣ_２－６アルケニル基、置換されていてもよいＣ_２－６のアルキニル基、置換されていてもよいＣ_３－８シクロアルキル基、置換されていてもよいＣ_５－８シクロアルケニル基、置換されていてもよいＣ_１－６アルコキシ基、置換されていてもよいＣ_１－４ハロアルキル基、置換されていてもよいＣ_１－４ハロアルコキシ基、置換されていてもよいアリール基、又は置換されていてもよいヘテロアリール基を意味し、
　ここにおいて、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_３－８シクロアルキル基、Ｃ_５－８シクロアルケニル基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、およびＣ_１－４ハロアルコキシ基はそれぞれ独立して、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、アリール基、ヘテロアリール基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　アリール基、およびヘテロアリール基は、それぞれ独立して、置換可能な位置で、ハロゲン原子、ヒドロキシ基、Ｃ_１－６アルキル基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、Ｃ_１－６アルカノイル基、および置換されてもよいアミノ基からなる群から選択される１又は複数の置換基で置換されてもよく、および
　Ｒ^５、Ｒ^６およびＲ^７は、それぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ基、置換されていてもよいＣ_１－６アルキル基、置換されていてもよいＣ_２－６アルケニル基、置換されていてもよいＣ_２－６アルキニル基、置換されていてもよいＣ_３－８シクロアルキル基、置換されていてもよいＣ_５－８シクロアルケニル基、置換されていてもよいＣ_１－６アルコキシ基、置換されていてもよいＣ_１－４ハロアルキル基、置換されていてもよいＣ_１－４ハロアルコキシ基、シアノ基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されてもよいアリールオキシ基、または置換されてもよいアミノ基を意味し、
　ここにおいて、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_３－８シクロアルキル基、Ｃ_５－８シクロアルケニル基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、およびＣ_１－４ハロアルコキシ基は、それぞれ独立して、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、アリール基、ヘテロアリール基、アリールオキシ基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　アリール基、ヘテロアリール基およびアリールオキシ基は、それぞれ独立して、置換可能な位置で、ハロゲン原子、ヒドロキシ基、Ｃ_１－６アルキル基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、および置換されてもよいアミノ基からなる群から選択される１又は複数の置換基で置換されてもよい）
を意味し、
　Ａは下記の式（Ａ－１）、又は式（Ａ－２）：

（式中、
　ｌは０～４の整数を意味し、
　ｏおよびｐは、それぞれ独立して、０～２の整数を意味し、
　ｑは０～５の整数を意味し、および
　（Ａ－１）および（Ａ－２）は、置換可能な位置で、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、ヒドロキシ基、オキソ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよい）
を意味し、並びに
　Ｂは下記の式（Ｂ－１）、式（Ｂ－２）、式（Ｂ－３）、又は式（Ｂ－４）：

（式中、
　（Ｂ－２）、（Ｂ－３）および（Ｂ－４）は環内の可能な位置に不飽和結合があってもよく、
　ｍおよびｎは、それぞれ独立して、０～４の整数を意味し、ｍまたはｎが１～４の整数を意味する場合の－（ＣＨ_２）_ｍ－または－（ＣＨ_２）_ｎ－は、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、オキソ基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　ＸおよびＹは、それぞれ独立して、単結合、酸素原子又は窒素原子を意味し、
　Ｒ^８およびＲ^９はそれぞれ独立して以下の（１）および（２）に含まれる基からなる群から選択される基を意味し、
（１）水素原子、置換されていてもよいＣ_１－６アルキル基、置換されていてもよいＣ_２－６アルケニル基、置換されていてもよいＣ_２－６アルキニル基、置換されていてもよいＣ_３－８単環性、Ｃ_７－１０２環性もしくはＣ_７－１２３環性シクロアルキル基、置換されていてもよいＣ_５－８単環性もしくはＣ_７－１０２環性シクロアルケニル基、置換されてよいアリール基、および置換されてもよいヘテロアリール基を意味し、
　ここにおいて、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_３－８単環性、Ｃ_７－１０２環性もしくはＣ_７－１２３環性シクロアルキル基、Ｃ_５－８単環性もしくはＣ_７－１０２環性シクロアルケニル基、アリール基、およびヘテロアリール基は、それぞれ独立して、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、アリール基、ヘテロアリール基、アリールオキシ基、Ｃ_１－６アルカノイル基、フェナシル基、ハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよい；
（２）－（ＣＨ_２）_ｕ－Ｒ^１２
　ここにおいて、ｕは０～４の整数を意味し、ｕが１～４の整数を意味する場合の－（ＣＨ_２）_ｕ－はＣ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、オキソ基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　Ｒ^１２は下記の式（Ｒ^１２－１）、式（Ｒ^１２－２）、式（Ｒ^１２－３）、式（Ｒ^１２－４）、式（Ｒ^１２－５）、式（Ｒ^１２－６）、式（Ｒ^１２－７）、又は式（Ｒ^１２－８）：

（式中、
　Ｒ^１３は以下の（１）～（５）に含まれる基からなる群から選択される基を意味し、
（１）水素原子、およびホルミル基；
（２）置換されていてもよいＣ_１－６アルキル基、置換されていてもよいＣ_２－６アルケニル基、置換されていてもよいＣ_２－６アルキニル基、置換されていてもよいＣ_３－８シクロアルキル基、および置換されていてもよいＣ_５－８シクロアルケニル基、
　ここにおいて、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_３－８シクロアルキル基、およびＣ_５－８シクロアルケニル基は、それぞれ独立して、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、ハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよい；
（３）－ＣＯＲ^１６、－ＣＳＲ^１６、－ＳＯ_２Ｒ^１６、－ＣＯ－ＣＯＲ^１６、－ＣＯＯＲ^１６、および－ＣＯ－ＣＯＯＲ^１６（Ｒ^１６は置換されていてもよいＣ_１－６アルキル基、置換されていてもよいＣ_２－６アルケニル基、置換されていてもよいＣ_２－６アルキニル基、置換されていてもよいＣ_３－８シクロアルキル基、置換されていてもよいＣ_５－８シクロアルケニル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されていてもよい５～９員の単環性もしくは７～１０員の２環性の非芳香族性の不飽和へテロ環基（結合位置は該へテロ環上の炭素原子である）、又は置換されていてもよい４～９員の単環性もしくは７～１０員の２環性の飽和へテロ環基（結合位置は該へテロ環上の炭素原子である）を意味し、
　ここにおいて、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_３－８シクロアルキル基、Ｃ_５－８シクロアルケニル基、５～９員の単環性もしくは７～１０員の２環性の非芳香族性の不飽和へテロ環基、および４～９員の単環性もしくは７～１０員の２環性の飽和へテロ環基は、それぞれ独立して、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、アリール基、ヘテロアリール基、ハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　アリール基、およびヘテロアリール基は、それぞれ独立して、置換可能な位置で、ハロゲン原子、ヒドロキシ基、Ｃ_１－６アルキル基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、ニトロ基、Ｃ_１－６アルカノイル基、および置換されてもよいアミノ基からなる群から選択される１又は複数の置換基で置換されてもよい）；
（４）－ＣＯＮＲ^１７－ＯＲ^１８（Ｒ^１７およびＲ^１８はそれぞれ独立して、水素原子、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基又はＣ_２－６アルキニル基を意味する）；
（５）－ＣＯＮＲ^１９Ｒ^２０、－ＣＳＮＲ^１９Ｒ^２０および－ＳＯ_２ＮＲ^１９Ｒ^２０（Ｒ^１９およびＲ^２０は、それぞれ独立して、水素原子又は前記Ｒ^１６における任意の基を意味するか、或いはＲ^１９およびＲ^２０は、互いに結合して、隣接する窒素原子に加え、１～２個の窒素原子、１個の酸素原子および１個の硫黄原子からなる群から選択される０～２個のヘテロ原子を含む飽和もしくは不飽和の４～８員の単環性含窒素ヘテロ環基（該ヘテロ環基は、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、ハロゲン原子からなる群から選択される１又は複数の置換基で置換されていてもよい）を意味する）、
　Ｒ^１４およびＲ^１５は、それぞれ独立して、水素原子、置換されていてもよいＣ_１－６アルキル基、置換されていてもよいＣ_２－６アルケニル基、置換されていてもよいＣ_２－６アルキニル基、置換されていてもよいＣ_３－８シクロアルキル基、置換されていてもよいＣ_５－８シクロアルケニル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されていてもよい５～９員の単環性もしくは７～１０員の２環性の非芳香族性の不飽和へテロ環基（当該へテロ環基は環上の炭素原子が隣接する窒素原子と結合している）、置換されていてもよい４～９員の単環性もしくは７～１０員の２環性の飽和へテロ環基（当該へテロ環基は環上の炭素原子が隣接する窒素原子と結合している）、置換されていてもよいＣ_１－６アルカノイル基、置換されていてもよいＣ_１－６アルコキシカルボニル基、カルバモイル基、スルファモイル基、又は置換されていてもよいＣ_１－６アルキルスルホニル基を意味し、
　ここにおいて、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_３－８シクロアルキル基、Ｃ_５－８シクロアルケニル基、５～９員の単環性もしくは７～１０員の２環性の非芳香族性の不飽和へテロ環基、４～９員の単環性もしくは７～１０員の２環性の飽和へテロ環基、Ｃ_１－６アルカノイル基、Ｃ_１－６アルコキシカルボニル基、およびＣ_１－６アルキルスルホニル基は、それぞれ独立して、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、シアノ基、オキソ基、アリール基、ヘテロアリール基、アリールオキシ基およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　アリール基およびヘテロアリール基、それぞれ独立して、置換可能な位置で、ハロゲン原子、ヒドロキシ基、Ｃ_１－６アルキル基、Ｃ_１－６アルコキシ基、シアノ基、ニトロ基、Ｃ_１－６アルカノイル基、および置換されてもよいアミノ基からなる群から選択される１又は複数の置換基で置換されてもよく、
　或いはＲ^１４およびＲ^１５は、互いに結合して、隣接する窒素原子に加え、１～２個の窒素原子、１個の酸素原子および１個の硫黄原子からなら群から選択される０～２個のヘテロ原子を含む、飽和もしくは不飽和の４～９員の単環性もしくは７～１０員の２環性の含窒素ヘテロ環基（該ヘテロ環基は、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、アリール基、ヘテロアリール基、アリールオキシ基、シアノ基、オキソ基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されていてもよい）を形成してもよく、
　（Ｒ^１２－１）～（Ｒ^１２－４）は環内の可能な位置に不飽和結合があってもよく、
　Ｒ^８’およびＲ^９’は、それぞれ独立して、水素原子、置換されていてもよいＣ_１－６アルキル基、置換されていてもよいＣ_２－６アルケニル基、置換されていてもよいＣ_２－６アルキニル基、置換されていてもよいＣ_３－８シクロアルキル基、置換されていてもよいＣ_５－８シクロアルケニル基、置換されていてもよいアリール基、置換されていてもよいヘテロアリール基、置換されていてもよい５～９員の単環性もしくは７～１０員の２環性の非芳香族性の不飽和へテロ環基（当該へテロ環基は環上の炭素原子が隣接の窒素原子または酸素原子と結合している）、又は置換されていてもよい４～９員の単環性もしくは７～１０員の２環性の飽和へテロ環基（当該へテロ環基は環上の炭素原子が隣接の窒素原子または酸素原子と結合している）を意味し、
　ここにおいて、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_３－８シクロアルキル基、Ｃ_５－８シクロアルケニル基、５～９員の単環性もしくは７～１０員の２環性の非芳香族性の不飽和へテロ環基、および４～９員の単環性もしくは７～１０員の２環性の飽和へテロ環基は、それぞれ独立して、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、アリール基、ヘテロアリール基、アリールオキシ基、Ｃ_１－６アルカノイル基、フェナシル基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　アリール基、およびヘテロアリール基は、それぞれ独立して、置換可能な位置で、ハロゲン原子、ヒドロキシ基、Ｃ_１－６アルキル基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、ニトロ基、Ｃ_１－６アルカノイル基、および置換されてもよいアミノ基からなる群から選択される１又は複数の置換基で置換されてもよく、
　或いは、Ｒ^８’およびＲ^９’は、互いに結合して、隣接する窒素原子に加え、１～２個の窒素原子、１個の酸素原子および１個の硫黄原子からなる群から選択される０～２個のヘテロ原子を含む、飽和もしくは不飽和の４～９員の単環性もしくは７～１０員の２環性の含窒素ヘテロ環基を形成してもよく、
　ここにおいて、該含窒素へテロ環基は置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、アリール基、ヘテロアリール基、アリールオキシ基、シアノ基、オキソ基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　前記Ｒ^１０、Ｒ^１０’、Ｒ^１１およびＲ^１１’は、それぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ基、置換されていてもよいＣ_１－６アルキル基、置換されていてもよいＣ_２－６アルケニル基、置換されていてもよいＣ_２－６アルキニル基、置換されていてもよいＣ_１－６アルコキシ基、置換されてよいアリール基、置換されてもよいヘテロアリール基、置換されてもよいアリールオキシ基、シアノ基、又はオキソ基を意味し、
　ここにおいて、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_１－６アルコキシ基、アリール基、ヘテロアリール基およびアリールオキシ基は、それぞれ独立して、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、アリール基、ヘテロアリール基、アリールオキシ基、Ｃ_１－６アルカノイル基、フェナシル基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　或いはＲ^１０およびＲ^１１、並びにＲ^１０’およびＲ^１１’は、それぞれ独立して、互いに結合して、置換されていてもよい、１個の酸素原子を含んでもよい飽和もしくは不飽和の３～８員の環を形成し、Ｒ^１０およびＲ^１１、またはＲ^１０’およびＲ^１１’が結合している環と共に２環あるいはスピロ化合物を形成してもよく、
　ここにおいて、該飽和もしくは不飽和の３～８員の環は、置換可能な位置で、Ｃ_１－６アルキル基、ヒドロキシ基、Ｃ_１－６アルコキシ基、Ｃ_１－４ハロアルキル基、Ｃ_１－４ハロアルコキシ基、シアノ基、オキソ基、アリール基、ヘテロアリール基、アリールオキシ基、Ｃ_１－６アルカノイル基、フェナシル基、およびハロゲン原子からなる群から選択される１又は複数の置換基で置換されてもよく、
　前記ｒおよびｒ’は、それぞれ独立して、０～３の整数を意味し、
　前記ｓおよびｓ’は、それぞれ独立して、０～３の整数を意味し、
　前記ｔおよびｔ’は、それぞれ独立して、１又は２を意味し、および
　前記ｖは０～２の整数を意味する（但しｒおよびｓ、並びにｒ’およびｓ’は同時に０ではない））
を意味する）
を意味する]
で表される化合物又はその製薬学的に許容される塩。 [Claim 1]
Formula (1):

[Where:
Het is the following formula (Het-1), formula (Het-2), formula (Het-3), formula (Het-4), formula (Het-5), formula (Het-6), formula (Het− 7), Formula (Het-8), Formula (Het-9), Formula (Het-10), Formula (Het-11), Formula (Het-12), Formula (Het-13), or Formula (Het− 14):

(Where
R ^1A is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, An _optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 cycloalkenyl group, an _optionally substituted C _1-4 haloalkyl group, an optionally substituted aryl group, an optionally substituted An optionally substituted heteroaryl group, an optionally substituted C _1-6 alkanoyl group, an optionally substituted C _1-6 alkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, or an optionally substituted C _1-6 Means an alkylsulfonyl group,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a C _1-4 haloalkyl group, a C _{1- 6} alkanoyl group, C _1-6 alkoxycarbonyl group, and C _1-6 alkylsulfonyl group each independently represent a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group at a substitutable position, It may be substituted with one or more substituents selected from the group consisting of a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, an aryl group, a heteroaryl group, and a halogen atom. ,
The aryl group and heteroaryl group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1- May be substituted with one or more substituents selected from the group consisting of a _4- haloalkoxy group, a cyano group, a C _1-6 alkanoyl group, and an optionally substituted amino group,
R ^2A represents a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, a substituted An optionally substituted C _3-8 cycloalkyl group, an optionally substituted C _5-8 cycloalkenyl group, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _1-4 Means a haloalkyl group, an optionally substituted C _1-4 haloalkoxy group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
_{Here, C 1-6} alkyl _{groups, C 2-6} alkenyl _{groups, C 2-6} alkynyl _{group, C 3-8} cycloalkyl _{group, C 5-8} cycloalkenyl _{group, C 1-6} alkoxy _{groups, C 1- The 4} haloalkyl group and the C _1-4 haloalkoxy group each independently represent a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C ₁ at a substitutable position. _And may be substituted with one or more substituents selected from the group consisting of _-4 haloalkoxy groups, cyano groups, oxo groups, aryl groups, heteroaryl groups, and halogen atoms,
The aryl group and heteroaryl group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _{1- 4} haloalkoxy groups, cyano groups, C _1-6 alkanoyl groups, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted amino groups, and R ⁵ , R ⁶ and R ⁷ each independently represents a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or _optionally substituted. A C _2-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 cycloalkenyl group, an _optionally substituted C _1-6 alk Coxy group, C _1-4 haloalkyl group which may be substituted, C _1-4 haloalkoxy group which may be substituted, cyano group, aryl group which may be substituted, heteroaryl which may be substituted Group, an aryloxy group which may be substituted, or an amino group which may be substituted;
_{Here, C 1-6} alkyl _{groups, C 2-6} alkenyl _{groups, C 2-6} alkynyl _{group, C 3-8} cycloalkyl _{group, C 5-8} cycloalkenyl _{group, C 1-6} alkoxy _{groups, C 1- The 4} haloalkyl group and the C _1-4 haloalkoxy group each independently represent a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, C _1-4 may be substituted with one or more substituents selected from the group consisting of a haloalkoxy group, a cyano group, an oxo group, an aryl group, a heteroaryl group, an aryloxy group, and a halogen atom,
The aryl group, heteroaryl group and aryloxy group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group at a substitutable position, (It may be substituted with one or more substituents selected from the group consisting of a C _1-4 haloalkoxy group, a cyano group, and an optionally substituted amino group)
Means
A is the following formula (A-1) or formula (A-2):

(Where
l means an integer from 0 to 4;
o and p each independently represent an integer of 0 to 2,
q represents an integer of 0 to 5, and (A-1) and (A-2) are C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl at substitutable positions. Substituted with one or more substituents selected from the group consisting of a group, a hydroxy group, an oxo group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, and a halogen atom Also good)
And B is the following formula (B-1), formula (B-2), formula (B-3), or formula (B-4):

(Where
(B-2), (B-3) and (B-4) may have an unsaturated bond at a possible position in the ring,
m and n each independently represents an integer of 0 to 4, and — (CH ₂ ) _m — or — (CH ₂ ) _n — when m or n represents an integer of 1 to 4, A C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, an oxo group, and May be substituted with one or more substituents selected from the group consisting of halogen atoms,
X and Y each independently represent a single bond, an oxygen atom or a nitrogen atom,
R ⁸ and R ⁹ each independently represent a group selected from the group consisting of the groups included in the following (1) and (2):
(1) a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted Good C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic cycloalkyl group, optionally substituted C _5-8 monocyclic or C _7-10 bicyclic cyclo Means an alkenyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 monocyclic, a C _7-10 bicyclic or a C _7-12 tricyclic cycloalkyl group , C _5-8 monocyclic or C _7-10 bicyclic cycloalkenyl group, aryl group, and heteroaryl group are each independently a C _1-6 alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _1-6 alkanoyl group, phenacyl group, halogen May be substituted with one or more substituents selected from the group consisting of atoms;
(2)-(CH ₂ ) _u -R ¹²
Here, u represents an integer of 0 to 4, and when u represents an integer of 1 to 4, — (CH ₂ ) _u — represents a C _1-6 alkyl group, a C _2-6 alkenyl group, C _{2 May} be substituted with one or more substituents selected from the group consisting of a _-6 alkynyl group, a hydroxy group, a C _1-6 alkoxy group, an oxo group, and a halogen atom;
R ¹² is the following formula ^(R 12 -1), the formula ^(R 12 -2), the formula ^(R 12 -3), the formula ^(R 12 -4), the formula ^(R 12 -5), the formula ^{(R 12} - 6), formula (R ¹² -7), or formula (R ¹² -8):

(Where
R ¹³ means a group selected from the group consisting of the following groups (1) to (5):
(1) a hydrogen atom and a formyl group;
(2) an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _{3 A -8} cycloalkyl group, and an _optionally substituted C _5-8 cycloalkenyl group,
Here, the C _1-6 alkyl group, the C _2-6 alkenyl group, the C _2-6 alkynyl group, the C _3-8 cycloalkyl group, and the C _5-8 cycloalkenyl group are each independently substituted. In the position, selected from the group consisting of a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, and a halogen atom. May be substituted with one or more substituents;
(3) -COR ¹⁶ , -CSR ¹⁶ , -SO ₂ R ¹⁶ , -CO-COR ¹⁶ , -COOR ¹⁶ , and -CO-COOR ¹⁶ (wherein R ¹⁶ is an optionally substituted C _1-6 alkyl group, An optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 Cycloalkenyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted 5-9 membered monocyclic or 7-10 membered bicyclic non-aromatic An unsaturated heterocyclic group (the bonding position is a carbon atom on the heterocyclic ring), or an optionally substituted 4 to 9-membered monocyclic or 7 to 10-membered bicyclic saturated group Hetero ring group (bonding position on the hetero ring Means a is) carbon atom,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a _5-9 membered monocyclic or 7 The 10-membered bicyclic non-aromatic unsaturated heterocyclic group and the 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group are each independently C _1-6 alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl at substitutable positions A group, may be substituted with one or more substituents selected from the group consisting of halogen atoms,
The aryl group and heteroaryl group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _{1- 4} haloalkoxy group, cyano group, nitro group, C _1-6 alkanoyl group, and optionally substituted one or more substituents selected from the group consisting of optionally substituted amino groups;
(4) —CONR ¹⁷ —OR ¹⁸ (R ¹⁷ and R ¹⁸ each independently represents a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group);
(5) -CONR ¹⁹ R ²⁰ , -CSNR ¹⁹ R ²⁰ and -SO ₂ NR ¹⁹ R ²⁰ (R ¹⁹ and R ²⁰ each independently represent a hydrogen atom or an arbitrary group in R ¹⁶ , Alternatively, R ¹⁹ and R ²⁰ are bonded to each other, and in addition to the adjacent nitrogen atom, 0 to 2 selected from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom, and 1 sulfur atom Or a saturated or unsaturated 4- to 8-membered monocyclic nitrogen-containing heterocyclic group (wherein the heterocyclic group can be substituted at a C _1-6 alkyl group, a hydroxy group, C _1-6 An alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, or a halogen atom, which may be substituted with one or more substituents. ),
R ¹⁴ and ^{R 15} are each independently hydrogen atom, an optionally substituted _{C 1-6} alkyl group, an optionally substituted _{C 2-6} alkenyl group, an optionally substituted _{C 2- 6} Alkynyl group, C _3-8 cycloalkyl group which may be substituted, C _5-8 cycloalkenyl group which may be substituted, aryl group which may be substituted, heteroaryl group which may be substituted An optionally substituted 5- to 9-membered monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated heterocyclic group (which is adjacent to a carbon atom on the ring) 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group (which is a carbon atom on the ring), which may be substituted Atom is bound to an adjacent nitrogen atom), may be substituted A C _1-6 alkanoyl group, an optionally substituted C _1-6 alkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, or an optionally substituted C _1-6 alkylsulfonyl group,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a _5-9 membered monocyclic or 7 -10-membered bicyclic non-aromatic unsaturated heterocyclic group, 4- to 9-membered monocyclic or 7- to 10-membered bicyclic saturated heterocyclic group, C _1-6 alkanoyl group , C _1-6 alkoxycarbonyl group and C _1-6 alkylsulfonyl group are each independently a substitutable position at a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a cyano group, May be substituted with one or more substituents selected from the group consisting of an oxo group, an aryl group, a heteroaryl group, an aryloxy group and a halogen atom;
An aryl group and a heteroaryl group, each independently at a substitutable position, a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a cyano group, a nitro group, a C _1-6 alkanoyl group And may be substituted with one or more substituents selected from the group consisting of optionally substituted amino groups,
Alternatively, R ¹⁴ and R ¹⁵ are bonded to each other, and in addition to the adjacent nitrogen atom, 0 to 2 selected from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom A saturated or unsaturated 4- to 9-membered monocyclic or 7- to 10-membered bicyclic nitrogen-containing heterocyclic group containing a hetero atom (the heterocyclic group is a C _{1- 6} alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, aryl group, heteroaryl group, aryloxy group, cyano group, oxo group, and halogen atom Which may be substituted with one or more substituents selected from the group consisting of:
(R ¹² -1) to (R ¹² -4) may have an unsaturated bond at a possible position in the ring,
R ^{8 ′} and R ^{9 ′} each independently represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an _optionally substituted C _{A 2-6} alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 cycloalkenyl group, an _optionally substituted aryl group, an optionally substituted hetero An aryl group, optionally substituted 5-9 membered monocyclic or 7-10 membered bicyclic non-aromatic unsaturated heterocyclic group (the heterocyclic group is a carbon atom on the ring; Are bonded to an adjacent nitrogen atom or oxygen atom), or an optionally substituted 4 to 9-membered monocyclic or 7 to 10-membered bicyclic saturated heterocyclic group (the heterocyclic ring) A group consists of a carbon atom on the ring bonded to an adjacent nitrogen or oxygen atom. That) means,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a _5-9 membered monocyclic or 7 The 10-membered bicyclic non-aromatic unsaturated heterocyclic group and the 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group are each independently C _1-6 alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C, May be substituted with one or more substituents selected from the group consisting of _1-6 alkanoyl groups, phenacyl groups, and halogen atoms,
The aryl group and heteroaryl group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1- May be substituted with one or more substituents selected from the group consisting of a _4- haloalkoxy group, a cyano group, a nitro group, a C _1-6 alkanoyl group, and an optionally substituted amino group,
Alternatively, R ^{8 ′} and R ^{9 ′} are 0 each selected from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom, and 1 sulfur atom in addition to the adjacent nitrogen atoms. May form a saturated or unsaturated 4-9 membered monocyclic or 7-10 membered bicyclic nitrogen-containing heterocyclic group containing up to 2 heteroatoms;
Here, the nitrogen-containing heterocyclic group is a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, an aryl at a substitutable position. May be substituted with one or more substituents selected from the group consisting of a group, a heteroaryl group, an aryloxy group, a cyano group, an oxo group, and a halogen atom,
R ¹⁰ , R ^{10 ′} , R ¹¹ and R ^{11 ′} are each independently a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkyl group, or an _optionally substituted C. _2-6 alkenyl group, optionally substituted C _2-6 alkynyl group, optionally substituted C _1-6 alkoxy group, optionally substituted aryl group, optionally substituted heteroaryl group, substituted An aryloxy group, a cyano group, or an oxo group,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-6 alkoxy group, an aryl group, a heteroaryl group and an aryloxy group can be independently substituted. C _1-6 alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _1-6 May be substituted with one or more substituents selected from the group consisting of alkanoyl groups, phenacyl groups, and halogen atoms,
Alternatively, R ¹⁰ and R ¹¹ , and R ^{10 ′} and R ^{11 ′} are each independently bonded to each other, may be substituted, and may contain one oxygen atom. An 8-membered ring is formed, and a ring or a spiro compound may be formed together with a ring to which R ¹⁰ and R ¹¹ , or R ^{10 ′} and R ^{11 ′} are bonded,
Here, the saturated or unsaturated 3- to 8-membered ring is a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1- Substituted with one or more substituents selected from the group consisting of _4- haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _1-6 alkanoyl group, phenacyl group, and halogen atom May be,
R and r ′ each independently represents an integer of 0 to 3;
S and s ′ each independently represents an integer of 0 to 3,
And t and t ′ each independently represent 1 or 2, and v represents an integer of 0 to 2 (provided that r and s, and r ′ and s ′ are not 0 at the same time))
Means)
Means
Or a pharmaceutically acceptable salt thereof.

[Section 2]
Het is (Het-1) or (Het-2), R ^1A is a hydrogen atom, and R ^2A is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, a substituted Item 10. The compound according to Item 1 or Item 9 or a pharmaceutically acceptable salt thereof, which is an optionally substituted C _1-6 alkoxy group, or an optionally substituted C _1-4 haloalkyl group.

[Section 3]
Item 10. The compound according to Item 1 or Item 9, wherein Het is (Het-3), R ^1A is a hydrogen atom, and R ^2A is a hydrogen atom or an optionally substituted C _1-6 alkyl group, Its pharmaceutically acceptable salt.

[Claim 4]
R ⁶ and R ⁷ are hydrogen atom, and R ⁵ is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, substituted The compound according to any one of Items 1 to 3 and 9, which is an optionally substituted C _1-4 haloalkyl group or an optionally substituted C _1-4 haloalkoxy group, or a pharmaceutically acceptable salt thereof. Salt.

[Section 5]
Item 10. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 4 and 9, wherein A is (A-1) and 1 is 0 to 2.

[Claim 6]
Item 10. The compound according to any one of Items 1 to 5 and 9, wherein B is (B-2), s is 0 or 1, and r is 1 or 2, or a pharmaceutically acceptable salt thereof Salt.

[Claim 7]
Item 10. The compound according to any one of Items 1 to 5 and 9, wherein B is (B-4), Y is a single bond, s is 0 or 1, and r is 1 or 2. Its pharmaceutically acceptable salt.

[Section 8]
Terms 1 to 4 wherein A is (A-2), o is 0, p is 0, q is 1 or 3, and B is (B-1) or (B-4) And the compound according to any one of Items 9 and 9, or a pharmaceutically acceptable salt thereof.

[Claim 9]
Het is (Het-1), (Het-2) or (Het-3), R ^1A is a hydrogen atom, and R ^2A is a hydrogen atom, a halogen atom or an optionally substituted C _1-6 Item 6. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is an alkyl group, an optionally substituted C _1-6 alkoxy group, or an optionally substituted C _1-4 haloalkyl group.

[Section 10]
Item 10. A pharmaceutical composition comprising the compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

[Section 11]
Item 10. A serotonin 4 receptor agonist comprising the compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof.

[Claim 12]
Item 10. A therapeutic agent for Alzheimer-type dementia comprising the compound according to any one of Items 1 to 9 or a pharmaceutically acceptable salt thereof.

The present invention can provide a compound having an agonistic action or a partial agonistic (partial agonist) action on serotonin 4 receptor (hereinafter sometimes referred to as 5-HT ₄ receptor). A therapeutic or prophylactic agent for the disease or condition involved can be provided. Diseases or symptoms that have been suggested to involve serotonin 4 receptors include the following (i) to (v):
(I) neuropsychiatric diseases such as Alzheimer's dementia, Lewy body dementia, vascular dementia, depression, post-traumatic stress disorder (PTSD), memory impairment, anxiety, schizophrenia;
(Ii) Irritable bowel syndrome, flaccid constipation, habitual constipation, chronic constipation, constipation induced by drugs such as morphine and antipsychotics, constipation associated with Parkinson's disease, constipation associated with multiple sclerosis, constipation associated with diabetes Or diseases of the digestive system such as constipation or defecation disorder (as a pretreatment during endoscopy or barium intestinal X-ray examination);
(Iii) Functional dyspepsia, acute / chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastric neuropathy, postoperative paralytic ileus, senile ileus, non-erosive gastroesophageal reflux disease, NSAID ulcer, diabetic Gastrointestinal disorders such as gastric insufficiency, post-gastrectomy syndrome, or pseudo-intestinal obstruction;
(Iv) Gastrointestinal tract diseases, scleroderma, diabetes or loss of appetite in esophagus / biliary diseases, or nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, as described in (ii) and (iii) above Digestive symptoms such as heartburn or ambiguity;
(V) Urinary tract diseases accompanied by urination disorders such as urinary tract obstruction or enlarged prostate.
In addition, since the compound of the present invention exhibits excellent 5-HT ₄ receptor agonistic activity and brain transferability, the therapeutic agent for neuropsychiatric diseases such as Alzheimer's dementia described in (i) above, Useful as a preventive agent.

The present invention is described in further detail below.
In the present specification, the number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited, but is particularly limited as long as substitution is possible. There is no limit and one or more. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

The terms used in this specification are explained below.

_{Examples of the} “C _1-6 alkyl group” include linear or branched alkyl groups having 1 to 6 carbon atoms, and specifically include methyl group, ethyl group, propyl group, isopropyl group, butyl Group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group and hexyl group. A C _1-4 alkyl group is preferable, and specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.

_{Examples of the} “C _2-6 alkenyl group” include linear or branched alkenyl groups having 2 to 6 carbon atoms, and alkenyl groups containing 1 to 2 double bonds. Specifically, ethenyl group, 1-propenyl group, 1-methylvinyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2- Methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-methyl-1-butenyl group, 2-methyl-2-butenyl group, 2-methyl-3 -Butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-1-pentenyl group, 2-propyl-2-propenyl group, 1-ethyl -2-methyl-2-propenyl group, 1-methyl-3-methyl-3-butenyl group, 4-methyl-4-pentenyl group, 1,3-butadienyl group, 1,5-hexadienyl group, etc. That. Preferably, ethenyl group, 1-propenyl group, 1-methylvinyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methyl-2 -A propenyl group.

Examples of the “C _2-6 alkynyl group” include linear or branched alkynyl groups having 2 to 6 carbon atoms, and preferably include 1 to 2 triple bonds, more preferably 1 triple bond. An alkynyl group is mentioned. Specifically, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 2-butynyl group, 1-pentynyl group, 1-ethyl -2-propynyl group, 4-pentynyl group, 3-pentynyl group, 2-pentynyl group, 1-methyl-2-butynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, Examples include 5-hexynyl group. Preferably, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 2-butynyl group, 1-pentynyl group, 1-ethyl-2- Examples include propynyl group, 4-pentynyl group, 3-pentynyl group, 2-pentynyl group, and 1-methyl-2-butynyl group.

_{Examples of the} “C _3-8 cycloalkyl group” include 3- to 8-membered cycloalkyl groups, and specifically include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. Is mentioned. A cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group are preferable.

_{Examples of the} “C _5-8 cycloalkenyl group” include 5- to 8-membered cycloalkenyl groups, such as 1-cyclopentenyl group, 3-cyclopentenyl group, 4-cyclopentenyl group, 1-cyclohexenyl. Group, 3-cyclohexenyl group, 4-cyclohexenyl group, 1-cycloheptenyl group, 3-cycloheptenyl group, 4-cycloheptenyl group, 5-cycloheptenyl group, 1-cyclooctenyl group, 3-cyclooctenyl group, 4-cyclooctenyl group, 5 -Cyclooctenyl group and the like. Preferred are 1-cyclopentenyl group, 3-cyclopentenyl group, 4-cyclopentenyl group, 1-cyclohexenyl group, 3-cyclohexenyl group and 4-cyclohexenyl group.

Examples of the “C _1-4 haloalkyl group” include alkyl groups substituted with the same or different 1 to 5 halogen atoms having 1 to 4 carbon atoms, specifically, a fluoromethyl group, a difluoromethyl group, a trimethyl group. Examples include a fluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, and a 4-fluorobutyl group. Preferably a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group are mentioned.

Examples of the “aryl group” include 6- to 10-membered monocyclic or bicyclic aryl groups, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

The “heteroaryl group” is a 5- to 10-membered monocyclic group having 1 to 4 heteroatoms selected from 1 to 3 nitrogen atoms, 1 oxygen atom and 1 sulfur atom, or 2 And a cyclic heteroaryl group. Specific examples of monocyclic heteroaryl groups include pyrrolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl Groups and the like. Preferable examples include pyrrolyl group, imidazolyl group, triazolyl group, tetrazolyl group, furyl group, thienyl group, oxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridazinyl group.
Examples of the bicyclic heteroaryl group include indolyl group, benzofuryl group, benzothienyl group, quinolinyl group, and benzoisoxazolyl group. The bonding position of the heteroaryl group is not particularly limited as long as it is chemically stable, and may be bonded on any carbon atom or nitrogen atom. Preferably an indolyl group and a quinolinyl group are mentioned.

Examples of the “C _1-6 alkanoyl group” include linear or branched alkanoyl groups having 1 to 6 carbon atoms, and specific examples include acetyl group, propanoyl group, butanoyl group, 2-methylpropanoyl group. Examples include noyl group, pentanoyl group, 3-methylbutanoyl group, 2-methylbutanoyl group, hexanoyl group and the like. Preferably, an acetyl group, a propanoyl group, a butanoyl group, and a 2-methylpropanoyl group are used.

Examples of the “C _1-6 alkoxycarbonyl group” include a carbonyl group having a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxycarbonyl group, an ethoxycarbonyl group, Examples thereof include a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, and a hexyloxycarbonyl group. Preferred examples include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, and tert-butoxycarbonyl group.

_{Examples of the} “C _1-6 alkylsulfonyl group” include linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms, and specifically include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group. Isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, hexylsulfonyl group and the like. Preferred examples include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, and a tert-butylsulfonyl group.

_{Examples of the} “C _1-6 alkoxy group” include linear or branched alkoxy groups having 1 to 6 carbon atoms, and specifically include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Examples thereof include a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group. Preferable examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, and tert-butoxy group.

Examples of the “C _1-4 haloalkoxy group” include alkoxy groups substituted with the same or different 1 to 5 halogen atoms having 1 to 4 carbon atoms, specifically, a fluoromethoxy group, a difluoromethoxy group, Examples thereof include a trifluoromethoxy group, a pentafluoroethoxy group, a 2-fluoroethoxy group, and a 2,2-difluoroethoxy group. Preferred are a trifluoromethoxy group and a pentafluoroethoxy group.

“Halogen atom” includes fluorine atom, chlorine atom, bromine atom or iodine atom. Preferably a fluorine atom and a chlorine atom, More preferably, a fluorine atom is mentioned.

Examples of the “optionally substituted amino group” include amino, mono- or di-substituted amino, and 4- to 7-membered cyclic amino. Examples of the substituent of “mono- or di-substituted amino” include “C _1-6 alkyl”, “C _3-7 cycloalkyl”, “C _3-7 cycloalkyl C _1-4 alkyl” and the like. Is mentioned.
Specific examples of “mono-substituted amino” include, for example, “mono-C _1-6 alkylamino” (eg, methylamino, ethylamino, propylamino, 1-methylethylamino, butylamino, 2-methyl Propylamino, 1-methylpropylamino, 1,1-dimethylethylamino, etc.), “C _3-7 cycloalkylamino” (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, etc.) , “(C _3-7 cycloalkyl C _1-4 alkyl) amino” (for example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, cycloheptylmethylamino, etc.).
Specific examples of “di-substituted amino” include, for example, “di-C _1-6 alkylamino” (eg, dimethylamino, diethylamino, dipropylamino, di-1-methylethylamino, dibutylamino, dibutylamino) -2-methylpropylamino, di-1-methylpropylamino, di-1,1-dimethylethylamino, etc.), “N- (C _1-6 alkyl) -N- (C _3-7 cycloalkyl) amino” (For example, methylcyclopropylamino, methylcyclobutylamino, methylcyclopentylamino, methylcyclohexylamino, methylcycloheptylamino, etc.).
The “4- to 7-membered cyclic amino group” is, for example, a 4-membered to 7-membered single atom having 0 to 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a nitrogen atom. A cyclic cyclic amino group is mentioned. In the group, a nitrogen atom constituting the ring is a bond of “group”. Specific examples include azetidino, pyrrolidino, piperazino, piperidino, morpholino, thiomorpholino, azepano or oxoazepano. Preferred examples include amino, methylamino, ethylamino, cyclopropylamino, cyclobutylamino, dimethylamino, di-1-methylethylamino, methylcyclopropylamino, azetidino, pyrrolidino, piperazino, piperidino, morpholino, and more preferred Amino, methylamino, dimethylamino, azetidino, pyrrolidino, piperidino are mentioned.

Examples of the “aryloxy group” include aryloxy groups having 6 to 10 carbon atoms, and specific examples thereof include a phenoxy group and a naphthoxy group.

The “C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic cycloalkyl group” includes a 3- to 8-membered monocyclic cycloalkyl group and a 7- to 10-membered 2 group, respectively. Examples thereof include a cyclic cycloalkyl group and a 7-12 membered tricyclic cycloalkyl group. Specific examples of the monocyclic cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. A cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group are preferable.
Specific examples of the bicyclic cycloalkyl group include an octahydropentalenyl group, an octahydro-1H-indenyl group, a bicyclo [2.2.1] heptyl group, a bicyclo [2.2.2] octyl group, and a bicyclo [ 4.2.0] octyl group, decahydronaphthalenyl group and the like. Preferably, a bicyclo [2.2.1] heptyl group and a bicyclo [2.2.2] octyl group are used.
Specific examples of the tricyclic cycloalkyl group include an adamantyl group.

Examples of the “C _5-8 monocyclic or C _7-10 bicyclic cycloalkenyl group” include a 5- to 8-membered monocyclic cycloalkenyl group and a 7- to 10-membered bicyclic cycloalkenyl group, respectively. . Specific examples of the monocyclic cycloalkenyl group include 1-cyclopentenyl group, 3-cyclopentenyl group, 4-cyclopentenyl group, 1-cyclohexenyl group, 3-cyclohexenyl group, 4-cyclohexenyl group, 1-cyclopentenyl group, Examples include cycloheptenyl group, 3-cycloheptenyl group, 4-cycloheptenyl group, 5-cycloheptenyl group, 1-cyclooctenyl group, 3-cyclooctenyl group, 4-cyclooctenyl group, 5-cyclooctenyl group and the like. Preferred are 1-cyclopentenyl group, 3-cyclopentenyl group, 4-cyclopentenyl group, 1-cyclohexenyl group, 3-cyclohexenyl group and 4-cyclohexenyl group.
Specific examples of the bicyclic cycloalkenyl group include a bicyclo [2.2.1] hept-2-enyl group and a bicyclo [2.2.2] oct-2-enyl group.

“5 to 9-membered monocyclic or 7 to 10-membered bicyclic non-aromatic unsaturated heterocyclic group” includes 1 to 3 nitrogen atoms, 1 oxygen atom and 1 And 5- to 9-membered monocyclic or 7 to 10-membered bicyclic non-aromatic unsaturated heterocyclic group containing 1 to 4 heteroatoms selected from the following sulfur atoms. Monocyclic non-aromatic unsaturated heterocyclic groups include 5-membered containing 1 double bond or 6- or 7-membered non-aromatic containing 1 or 2 double bonds An unsaturated heterocyclic group is exemplified, and specific examples include a pyrrolinyl group and a 2,5-dihydrofuryl group.
The bicyclic non-aromatic unsaturated heterocyclic group is a 7 to 10-membered group obtained by substituting one or more double bonds of a bicyclic heteroaryl group with a single bond. Examples include non-aromatic unsaturated heterocyclic groups, and specific examples include 2,3-dihydrobenzofuryl group and 2,3-dihydrobenzothienyl group.
The bonding position of the non-aromatic unsaturated heterocyclic group is not particularly limited as long as it is chemically stable, and may be bonded on any carbon atom or nitrogen atom.

The “4 to 9-membered monocyclic or 7 to 10-membered bicyclic saturated heterocyclic group” is selected from 1 to 4 nitrogen atoms, 1 oxygen atom and 1 sulfur atom. 4 to 9-membered monocyclic or 7 to 10-membered bicyclic saturated heterocyclic group containing 1 to 4 heteroatoms. Specific examples of the monocyclic saturated heterocyclic group include azetidinyl group, pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, piperazinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, tetrahydropyranyl group, hexahydro Examples include azepinyl group, 1,4-hexahydrooxazepinyl group, 1,4-hexahydrodiazepinyl group and the like. Preferred are azetidinyl group, pyrrolidinyl group, tetrahydrofuryl group, piperazinyl group, piperidinyl group, morpholinyl group, and tetrahydropyranyl group. Examples of the bicyclic saturated heterocyclic group include 7 to 10-membered saturated heterocyclic groups, and specific examples include a quinuclidinyl group.
Any carbon atom on the saturated heterocyclic group may be substituted with an oxo group. Specific examples of the saturated heterocyclic group substituted with the oxo group include a 2-oxopyrrolidinyl group, 2 -Oxotetrahydrofuryl group and the like. The bonding position of the saturated heterocyclic group is not particularly limited as long as it is chemically stable, and may be bonded on any carbon atom or nitrogen atom.

“Saturated or unsaturated 4 to 4 containing 0 to 2 heteroatoms selected from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom in addition to the adjacent nitrogen atom As the “8-membered monocyclic nitrogen-containing heterocyclic group”, specifically, the saturated monocyclic nitrogen-containing heterocyclic group includes azetidinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, hexahydroaze Examples thereof include a pinyl group and a 1,4-hexahydrooxazepinyl group. Preferred are azetidinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, and morpholinyl group.
Specific examples of the unsaturated monocyclic nitrogen-containing heterocyclic group include a pyrrolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a 1,2,3,6-tetrahydropyridyl group, and a 2,5-dihydro-1H-pyrrolyl group. Groups and the like.

“Saturated or unsaturated 4 to 4 containing 0 to 2 heteroatoms selected from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom in addition to the adjacent nitrogen atom Specific examples of the “9-membered monocyclic or 7-10-membered bicyclic nitrogen-containing heterocyclic group” include azetidinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, hexahydroazepi Nyl group, 1,4-hexahydrooxazepinyl group, 1,4-hexahydrodiazepinyl group, indolinyl group, isoindolinyl group, 1,2,3,4-tetrahydroquinolinyl group, 1,2,3 , 4-tetrahydroisoquinolinyl group, 1,2,3,4-tetrahydroquinoxalinyl group, 3,4-dihydrobenzo-1,4-oxazinyl group, 3,4-dihydro Nzo-1,4-thiazinyl group, 3-azabicyclo [3.2.0] heptanyl group, octahydroisoindolyl group, octahydroindolyl group, decahydroquinolinyl group, decahydroisoquinolinyl group, Examples include decahydroquinoxalinyl group, octahydrobenzo-1,4-oxazinyl group, octahydrobenzo-1,4-thiazinyl group and the like. Preferably, azetidinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, morpholinyl group, hexahydroazepinyl group, 1,4-hexahydrooxazepinyl group, indolinyl group, isoindolinyl group, 1,2,3,4- Examples thereof include a tetrahydroquinolinyl group, 1,2,3,4-tetrahydroisoquinolinyl group, and 3,4-dihydrobenzo-1,4-oxazinyl group. More preferred are a pyrrolidinyl group, a piperazinyl group, a piperidinyl group, and a morpholinyl group.

Specific examples of the “saturated or unsaturated 3- to 8-membered ring optionally containing one oxygen atom” include cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring, An oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, an oxepane ring, a benzene ring and the like can be mentioned, and a cyclopropane ring, a cyclobutane ring, a cyclopentane ring and a cyclohexane ring are preferable.
Specific examples of the “two rings or spiro compound formed by the ring together with the ring to which R ¹⁰ and R ¹¹ or R ^{10 ′} and R ^{11 ′} are bonded” include indoline, isoindoline, 1,2, 3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 3-azabicyclo [3.2.0] heptane, 7-azabicyclo [2.2.1] heptane, 6-azabicyclo [3.1. 1] heptane, 2-azabicyclo [2.2.1] heptane, 3-azabicyclo [3.1.1] heptane, 8-azabicyclo [3.2.1] octane, 2-azabicyclo [2.2.2] Octane, 3-azabicyclo [3.2.1] octane, octahydroisoindone, octahydroindoline, decahydroquinoline, decahydroisoquinoline, octahi Roshikuropenta [b] pyrrole, octahydrocyclopenta [c] pyrrole, 2-oxa-7-azaspiro [3.5] nonane, 2-oxa-8-azaspiro [4.5] decane, and the like. Preferably indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 3-azabicyclo [3.2.0] heptane, 7-azabicyclo [2.2.1]. ] Heptane, 6-azabicyclo [3.1.1] heptane, 2-azabicyclo [2.2.1] heptane, 3-azabicyclo [3.1.1] heptane, 8-azabicyclo [3.2.1] octane 2-azabicyclo [2.2.2] octane and 3-azabicyclo [3.2.1] octane. More preferred examples include 7-azabicyclo [2.2.1] heptane, 8-azabicyclo [3.2.1] octane, and 3-azabicyclo [3.2.1] octane.

Each group in the present invention will be described.

Het is preferably formula (Het-1), formula (Het-2), formula (Het-3), formula (Het-4), formula (Het-5), formula (Het-6), formula (Het -7), or formula (Het-8), and more preferably, formula (Het-1), formula (Het-2), or formula (Het-3).

R ^1A is preferably a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group, or an _optionally substituted C _1-4 haloalkyl group. And more preferably a hydrogen atom or an optionally substituted C _1-6 alkyl group.

R ^2A is preferably a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an _optionally substituted C _3-8 cycloalkyl. Group, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _1-4 haloalkyl group, or an optionally substituted C _1-4 haloalkoxy group, and more preferably a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group, or substituted also include a C _1-6 alkoxy group, More preferable examples include a hydrogen atom and an optionally substituted C _1-6 alkyl group.

Preferred as R ^5, a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, an optionally substituted C _1-4 haloalkyl group , Or an optionally substituted C _1-4 haloalkoxy group, and more preferably a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C 1 _{A 1-6} alkoxy group, and more preferably a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkyl group.

R ⁶ is preferably a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group, more preferably a hydrogen atom, or A halogen atom is mentioned.

R ⁷ is preferably a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _1-6 alkoxy group, and more preferably a hydrogen atom, or A halogen atom is mentioned.

A is preferably the formula (A-2).

B is preferably formula (B-1), formula (B-2), or formula (B-4), more preferably formula (B-2) or formula (B-4). It is done.

L is preferably 0-2.

M is preferably 0-2.

N is preferably 0 to 2.

O is preferably 0 or 1.

Q is preferably 1 to 3.

Preferably, r and r ′ are each independently 0 to 2.

S and s ′ are preferably each independently 0 to 2.

T is preferably 1 independently of each other.

U is preferably 0 to 2, more preferably 0 or 1.

V is preferably 1 or 2.

X is preferably a single bond or an oxygen atom.

Y is preferably a single bond or a nitrogen atom.

R ⁸ and R ⁹ are preferably each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 monocyclic, or a C _7-10 bicyclic ring. Or a C _7-12 tricyclic cycloalkyl group, or — (CH ₂ ) _u —R ¹² .

R ¹² is preferably a formula (R ¹² -1), a formula (R ¹² -3), or a formula (R ¹² -5).

R ¹³ is preferably a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group, —COR ¹⁶ , —SO ₂ R ¹⁶ , —COOR ¹⁶ , Or —CONR ¹⁹ R ²⁰ , more preferably a C _1-6 alkyl group that may be substituted, a C _3-8 cycloalkyl group that may be substituted, —COR ¹⁶ , —SO ₂ R ¹⁶ Or —COOR ¹⁶ and more preferably —COR ¹⁶ , —SO ₂ R ¹⁶ , or —COOR ¹⁶ .

R ¹⁶ is preferably an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted aryl group, or an optionally substituted hetero An aryl group, and more preferably, an optionally substituted C _1-6 alkyl group or an optionally substituted C _3-8 cycloalkyl group.

R ¹⁴ and R ¹⁵ are preferably each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group, or _optionally substituted. An aryl group or an optionally substituted heteroaryl group is exemplified, and an optionally substituted C _1-6 alkyl group or an optionally substituted C _3-8 cycloalkyl group is exemplified. It is done.

Preferably, R ^{8 ′} and R ^{9 ′} are each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group, A C _5-8 cycloalkenyl group, an _optionally substituted aryl group, or an optionally substituted heteroaryl group, and more preferably, an optionally substituted C _1-6 alkyl group, Or an optionally substituted C _3-8 cycloalkyl group.

R ¹⁰ , R ^{10 ′} , R ¹¹ and R ^{11 ′} are preferably each independently a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkyl group, or an optionally substituted group. Preferred examples thereof include a C _1-6 alkoxy group, and more preferred examples include a hydrogen atom, an optionally substituted C _1-6 alkyl group, and an optionally substituted C _1-6 alkoxy group.

(A-1) and (A-2) are each independently selected from the group consisting of a C _1-6 alkyl group, a hydroxy group, and a C _1-6 alkoxy group at a substitutable position. May be substituted with one or more substituents.

R ⁸ and R ⁹ are each independently a C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 monocyclic, C _7-10 bicyclic or C Each of the groups represented by _7-12 tricyclic cycloalkyl group, or C _5-8 monocyclic or C _7-10 bicyclic cycloalkenyl group is preferably independently at a substitutable position. May be substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, and an aryl group.

When R ⁸ and R ⁹ each independently represents — (CH ₂ ) _u —R ¹² , and u represents an integer of 1 to 4, — (CH ₂ ) _u — is a substitutable position. Preferably, it may be substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group, a hydroxy group, and a C _1-6 alkoxy group.

When R ¹³ represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, or a C _5-8 cycloalkenyl group, Independently, at a substitutable position, preferably consists of a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, and a halogen atom It may be substituted with one or more substituents selected from the group.

R ¹⁶ is a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a 5- to 9-membered monocyclic group or 7 Each of which represents an -10-membered bicyclic non-aromatic unsaturated heterocyclic group, or a 4- to 9-membered monocyclic or 7- to 10-membered bicyclic saturated heterocyclic group Each group is independently a substitutable position, preferably a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, an oxo group. , An aryl group, a heteroaryl group, and one or more substituents selected from the group consisting of a halogen atom, and more preferably a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy Group, C _1-4 haloalkyl group And optionally substituted with one or more substituents selected from the group consisting of C _1-4 haloalkoxy groups.

When R ¹⁶ represents an aryl group or a heteroaryl group, each group is independently a substitutable position, preferably a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy It may be substituted with one or more substituents selected from the group consisting of a group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, and an optionally substituted amino group, and more preferably Is selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, and an optionally substituted amino group. or may be substituted with a substituent, more preferably a halogen atom, C _1-6 alkyl group, a C _1-6 alkoxy group and an amino group which may be substituted, It may be substituted with one or more substituents selected from that group.

0 to 2 selected from the group consisting of R ¹⁹ and R ²⁰ bonded to each other and in addition to the adjacent nitrogen atom, 1 to 2 nitrogen atoms, 1 oxygen atom, and 1 sulfur atom When a saturated or unsaturated 4- to 8-membered monocyclic nitrogen-containing heterocyclic group containing a hetero atom is represented, the group is preferably a substitutable position, preferably a C _1-6 alkyl group, a hydroxy group, C _It may be substituted with one or more substituents selected from the group consisting of _1-6 alkoxy groups, oxo groups, and halogen atoms.

R ¹⁴ and R ¹⁵ are each independently a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, 5 9 to 9-membered monocyclic or 7 to 10-membered bicyclic non-aromatic unsaturated heterocyclic group, 4 to 9-membered monocyclic or 7 to 10-membered bicyclic saturated hetero In the case of representing a cyclic group, a C _2-6 alkanoyl group, a C _1-6 alkoxycarbonyl group, or a C _1-6 alkylsulfonyl group, each group is independently a substitutable position, preferably C _1-6 alkyl group, hydroxy group, C _1-6 alkoxy group, oxo group, aryl group, heteroaryl group, and may be substituted with one or more substituents selected from the group consisting of halogen atoms, Preferably, C _1-6 It may be substituted with one or more substituents selected from the group consisting of an alkyl group, a hydroxy group, a C _1-6 alkoxy group, and a halogen atom.

R ¹⁴ and R ¹⁵ are bonded to each other and, in addition to the adjacent nitrogen atom, 0 to 2 heteroatoms selected from 1 to 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom; In the case of a saturated or unsaturated 4- to 9-membered monocyclic or 7 to 10-membered bicyclic nitrogen-containing heterocyclic group, the group is preferably a substitutable position, preferably C _1- Substituted with one or more substituents selected from the group consisting of ₆ alkyl groups, hydroxy groups, C _1-6 alkoxy groups, C _1-4 haloalkyl groups, C _1-4 haloalkoxy groups, oxo groups, and halogen atoms More preferably, it may be substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, an oxo group, and a halogen atom. Good.

R ^{8 ′} and R ^{9 ′} each independently represents a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, or a C _5-8 cycloalkenyl group. 5-9 membered monocyclic or 7-10 membered bicyclic non-aromatic unsaturated heterocyclic group, or 4-9 membered monocyclic or 7-10 membered bicyclic Each group in the case of representing a saturated heterocyclic group is independently a substitutable position, preferably a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 halo. It may be substituted with one or more substituents selected from the group consisting of an alkoxy group, an oxo group, an aryl group, a heteroaryl group, an aryloxy group, and a halogen atom, and more preferably a C _1-6 alkyl group , hydroxy _{group, C 1-6} alkoxy , Oxo group, and may be substituted with one or more substituents selected from the group consisting of halogen atoms.

0 to 2 selected from the group consisting of R ^{8 ′} and R ^{9 ′} bonded to each other and in addition to the adjacent nitrogen atom, 1 to 2 nitrogen atoms, 1 oxygen atom, and 1 sulfur atom When it represents a saturated or unsaturated 4 to 9-membered monocyclic or 7 to 10-membered bicyclic nitrogen-containing heterocyclic group containing 1 heteroatom, it is preferably substituted at a substitutable position. _It may be substituted with one or more substituents selected from the group consisting of _1-6 alkyl groups and oxo groups.

R ¹⁰ , R ^{10 ′} , R ¹¹ and R ^{11 ′} each independently represent a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, or a C _1-6 alkoxy group. Each group in the case is independently a substitutable position, preferably a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkoxy group, an oxo group, an aryl The alkyl group may be substituted with one or more substituents selected from the group consisting of a group, a heteroaryl group, an aryloxy group, and a halogen atom, and more preferably a C _1-6 alkyl group, a hydroxy group, a C _{1- It} may be substituted with one or more substituents selected from the group consisting of ₆ alkoxy groups and halogen atoms.

R ¹⁰ and R ¹¹ , and R ^{10 ′} and R ^{11 ′} are each independently bonded to each other and may contain a saturated or unsaturated 3 to 8 which may contain one oxygen atom Each group in the case of forming a member ring and representing a bicyclic ring or a spiro compound together with a ring to which R ¹⁰ and R ¹¹ , or R ^{10 ′} and R ^{11 ′} are bonded, can be independently substituted. In the position, it may be preferably substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, an oxo group, and a halogen atom.

Hereinafter, the compound represented by the formula (1) of the present invention will be further described.

The compound of the formula (1) is a concept including all tautomers, geometric isomers and stereoisomers depending on the type of substituent, and may be a mixture thereof.
That is, when one or more asymmetric carbon atoms are present in the compound of formula (1), diastereomers and optical isomers exist, but mixtures or isolated ones of these diastereomers and optical isomers exist. Are also included in the present invention.

The present invention also includes the fact that one or more atoms in the compound of formula (1) are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Isotope-labeled compounds, and pharmaceutically acceptable salts thereof, are also included in the present invention. Examples of isotopes contained in the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, bromine, and chlorine isotopes such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ^It includes isotopes such as ¹³ N, ¹⁵ N, ¹⁸ O, ¹⁷ O, ¹⁵ O, ¹⁸ F, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, and ³⁶ Cl. Also included in the present invention are compounds of the present invention that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts thereof.

Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ¹¹ C, ³ H and ¹⁸ F are incorporated, are particularly useful in drug and / or substrate tissue distribution assays, particularly serotonin receptors. It is useful as a diagnostic for identifying and localizing the 5-HT ₄ receptor subtype. Tritiated (ie, ³ H), carbon-11 (ie, ¹¹ C), and ¹⁸ F isotopes are particularly preferred because of their ease of production and detection. In this regard, such compounds are also useful for assessing the density of the receptors within each region of the central nervous system, as well as the receptor occupancy achieved with a given concentration of the compound. Such information will help establish doses or dose ranges for these compounds. Furthermore, these isotope-labeled compounds can also be used in this respect to characterize diseases that have not been diagnosed so far.

Furthermore, substitution with deuterium, a heavy isotope such as ² H, can provide certain therapeutic benefits due to increased metabolic stability. For example, it may be preferred in some circumstances because it results in an increased half-life in vivo or reduced dose requirements.

Examples of pharmaceutically acceptable salts include acid addition salts and base addition salts. For example, acid addition salts include hydrochloride, hydrobromide, sulfate, hydrogen sulfate, hydroiodide, nitrate, phosphate and other inorganic acid salts, citrate, oxalate, acetic acid Salt, formate, propionate, benzoate, trifluoroacetate, fumarate, maleate, malonate, succinate, tartrate, hydrogen tartrate, lactate, malate, pyruvate Salt, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate, paratoluenesulfonate, pamoate [1,1'-methylene-bis- (2-hydroxy-3-naphthoate)] And organic acid salts such as Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. . Moreover, basic amino acid salts or acidic amino acid salts such as arginine salt, aspartate, and glutamate can be exemplified. Preferred salts include hydrochloride, hydrobromide, sulfate, phosphate, citrate, fumarate, maleate, malonate, succinate, tartrate, lactate, malate , Pyruvate, methanesulfonate, and benzenesulfonate.

In addition, the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof may be a hydrate or a solvate such as an ethanol solvate, and these hydrates and / or solvates. Products are also encompassed by the compounds of the present invention.

で表される化合物の製造法について、例を挙げて説明するが、本発明はもとよりこれに限定されるものではない。
　式（１）で表される化合物は公知化合物から公知の合成方法を組み合わせることにより合成することができる。例えば、次の方法により合成できる。 The production method of the compound of the present invention In the following, the formula (1) in the present invention:

Although the manufacturing method of the compound represented by this will be described with examples, the present invention is not limited to this.
The compound represented by the formula (1) can be synthesized from known compounds by combining known synthesis methods. For example, it can be synthesized by the following method.

（式中、ｒ’、ｓ’、ｕ、Ａ、Ｂ、Ｈｅｔ、Ｒ^１０’、Ｒ^１１’およびＲ^１３は前掲と同じものを意味し、Ｌ^１は脱離基を意味する） (Manufacturing method 1)
In the case of the compound (1 ′) in which R ⁸ is (CH ₂ ) _u — (R ¹² −1), for example, the compound represented by the formula (1) can be produced by the following method.

(Wherein, r ′, s ′, u, A, B, Het, R ¹⁰ ′, R ¹¹ ′ and R ¹³ are the same as described above, and L ¹ is a leaving group)

That is, the compound represented by the formula (1 ′) is obtained by reacting the compound represented by the formula (1-1) with the reactivity represented by the formula (1-2) in the presence of a suitable additive such as a base. It can be produced by reacting with a derivative.
When —R ¹³ represents —COR ¹⁶ (wherein R ¹⁶ represents the same as described above), as the reactive derivative represented by formula (1-2), L ¹ represents a hydroxyl group. A carboxylic acid compound represented by the formula (1-3): R ¹⁶ —COOH (wherein R ¹⁶ means the same as described above), an alkyl ester (particularly a methyl ester) of the carboxylic acid compound, an active ester And acid anhydrides and carboxylic acid halides (particularly carboxylic acid chlorides).
When the carboxylic acid compound represented by the formula (1-3) is used, 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, N, N′-carbonyldisuccinic acid imide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide Can be reacted in the presence of a condensing agent such as propanephosphonic anhydride.
When 1,3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as the condensing agent, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-1, 2,3-benzotriazin-4 (3H) -one, N-hydroxy-5-norbornene-2,3-dicarboximide or the like may be added and reacted.
Specific examples of the active ester of the carboxylic acid compound represented by the formula (1-3) include p-nitrophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester 1-hydroxybenzotriazole ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester and the like.
As the acid anhydride of the carboxylic acid compound represented by the formula (1-3), a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include ethyl chlorocarbonate and isobutyl chlorocarbonate. Mixed acid anhydride with chlorocarbonic acid alkyl ester, mixed acid anhydride with chlorocarbonic acid aralkyl ester such as benzyl chlorocarbonate, mixed acid anhydride with chlorocarbonic acid aryl ester such as phenyl chlorocarbonate, isovaleric acid And mixed acid anhydrides with alkanoic acids such as pivalic acid.

In the formula (1 ′), when —R ¹³ represents —COOR ¹⁶ (wherein R ¹⁶ has the same meaning as described above), the reactive derivative represented by the formula (1-2) may be represented by the formula (1-4): R ¹⁶ O—CO—L ¹ (wherein L ¹ and R ¹⁶ are the same as those described above), and the like.
The compound in which L ¹ is a chlorine atom in formula (1-4) is commercially available, or can be produced by reacting R ¹⁶ OH with a phosgene equivalent such as phosgene, diphosgene, or triphosgene.

In the formula (1 ′), when —R ¹³ represents —SO ₂ —R ¹⁶ (wherein R ¹⁶ has the same meaning as described above), the reactive derivative represented by the formula (1-2) Is a compound represented by the formula (1-5): R ¹⁶ —SO ₂ —L ¹ (wherein L ¹ and R ¹⁶ are the same as those described above).

In the formula (1 ′), when —R ¹³ represents —CONR ¹⁹ R ²⁰ (wherein R ¹⁹ and R ²⁰ are the same as those described above), the reactivity represented by the formula (1-2) Examples of the derivatives include compounds represented by the formula (1-6): R ¹⁹ R ²⁰ N—CO-L ¹ (wherein L ¹ , R ¹⁹ and R ²⁰ are the same as those described above). Can do.

The reaction of the compound represented by the formula (1-1) and the reactive derivative represented by the formula (1-2) is performed in a solvent or in the absence of a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and cyclopentyl methyl ether. , Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, and water. Or, a mixture of two or more kinds may be used.

This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, triethylamine, and tricarbonate. Examples include organic bases such as butylamine, diisopropylethylamine, and N-methylmorpholine. An excess amount of the compound represented by formula (1-1) can also be used as a base.
While the reaction temperature varies depending on the kind of raw material compound used, it is generally about −30 ° C. to about 200 ° C., preferably about −10 ° C. to about 150 ° C.

Examples of the leaving group for L ¹ include halogen atoms such as chlorine, bromine and iodine, alkylsulfonyloxy groups such as methanesulfonyloxy group, and arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy. Halogen atoms, in particular chlorine and bromine, or methanesulfonyloxy and p-toluenesulfonyloxy are preferred.

In the case where Het represents the formula (Het-1) to (Het-6) and R ^1A represents a hydrogen atom, under the conditions described in Production Method 1, R ^1A is substituted with R ¹³ Although a product may be produced, a by-product can be led to a compound represented by (1 ′) by hydrolysis with a base.

The compound of formula (1-1) described in production method 1 is, for example, a compound (1) wherein B is (B-2), R ⁸ is (CH ₂ ) _u- (R ¹² -1), and u is 1. In the case of -1 ′), it can be produced by the method shown in the production method 2 below.
In the case where B is (B-2), R ⁸ is (CH ₂ ) _u- (R ¹² -1) and u is 0, the compound (1-1 '') Can be manufactured.

〔式中、ｒ、ｓ、ｒ’、ｓ’、Ａ、Ｈｅｔ、Ｒ^１０、Ｒ^１１、Ｒ^１０’およびＲ^１１’は前掲と同じものを意味し、Ｌ^２は加水分解もしくは加水素分解により脱離し得る保護基を意味し、Ｌ^３は－ＣＨ_２－Ｌ^４（Ｌ^４は脱離基を意味する）又はホルミル基を意味する〕 (Manufacturing method 2)

[Wherein, r, s, r ′, s ′, A, Het, R ¹⁰ , R ¹¹ , R ¹⁰ ′ and R ¹¹ ′ mean the same as described above, and L ² represents hydrolysis or hydrogenolysis] Means a protecting group capable of leaving, and L ³ means —CH ₂ -L ⁴ (L ⁴ means a leaving group) or a formyl group]

〔式中、ｒ、ｓ、ｒ’、ｓ’、Ａ、Ｈｅｔ、Ｒ^１０、Ｒ^１１、Ｒ^１０’およびＲ^１１’は前掲と同じものを意味し、Ｌ^２は加水分解もしくは加水素分解により脱離し得る保護基を意味し、Ｌ^５はオキソ基、又は脱離基を意味する〕 (Manufacturing method 3)

[Wherein, r, s, r ′, s ′, A, Het, R ¹⁰ , R ¹¹ , R ¹⁰ ′ and R ¹¹ ′ mean the same as described above, and L ² represents hydrolysis or hydrogenolysis] Means a protecting group capable of leaving, and L ⁵ means an oxo group or a leaving group]

Hereinafter, Step 1 to Step 4 in the production methods 2 and 3 will be described.
1) Alkylation step by substitution reaction (Step 1, Step 3)
In the compound of formula (2-2) which is a production intermediate of production method 2, when L ³ represents -CH ₂ -L ⁴ (L ⁴ represents a leaving group), and in the production intermediate of production method 3, When L ⁵ represents a leaving group in a compound of formula (3-1), Step 1 and Step 3 are alkylation steps by a substitution reaction, and are performed in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane. Halogenated hydrocarbons such as methylene chloride and chloroform, alcohols such as ethanol, isopropanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide. These solvents may be used alone or in combination of two or more.

This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, and N-methylmorpholine, but the compound represented by formula (2-1) is used as a base, An amount can also be used.

Examples of the leaving group for L ⁴ and L ⁵ include halogen atoms such as chlorine, bromine and iodine, alkylsulfonyloxy groups such as methanesulfonyloxy group, and arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy. Mention may be made of halogen atoms, in particular chlorine and bromine, or methanesulfonyloxy and p-toluenesulfonyloxy. When L ⁴ and L ⁵ are chlorine or bromine, the reaction proceeds smoothly when an alkali metal iodide such as sodium iodide or potassium iodide is added.
While the reaction temperature varies depending on the kind of raw material compound used, it is generally about 0 ° C. to about 200 ° C., preferably about 20 ° C. to about 150 ° C.

（式中、ｒ’、ｓ’、Ｒ^１０’、Ｒ^１１’及びＬ^２は前掲と同じものを意味し、Ｌ^４およびＬ^５は脱離基を意味する）
　例えば、式（２－２ａ）の化合物を四塩化炭素もしくは四臭化炭素及びトリフェニルホスフィンと反応させることにより、Ｌ^４が塩素原子もしくは臭素原子を表す化合物を製造できる。また、式（２－２ａ）の化合物を塩基の存在下に塩化ベンゼンスルホニル等の塩化スルホニル化合物と反応させることによりＬ^４がアリールスルホニルオキシ基やアルキルスルホニルオキシ基を表す化合物を製造できる。 Compounds of formula (2-2) and formula (3-1) are commercially available or can be prepared by known methods. That is, by converting a corresponding alcohol derivative of the formula (2-2a) or the formula (3-1a) into a leaving group by a conventional method, a formula (2-2) in which L ⁴ and L ⁵ mean a leaving group. Or a compound represented by the formula (3-1) can be produced.

(In the formula, r ′, s ′, R ¹⁰ ′, R ¹¹ ′ and L ² are the same as described above, and L ⁴ and L ⁵ are leaving groups.)
For example, a compound in which L ⁴ represents a chlorine atom or a bromine atom can be produced by reacting the compound of the formula (2-2a) with carbon tetrachloride or carbon tetrabromide and triphenylphosphine. In addition, a compound in which L ⁴ represents an arylsulfonyloxy group or an alkylsulfonyloxy group can be produced by reacting the compound of the formula (2-2a) with a sulfonyl chloride compound such as benzenesulfonyl chloride in the presence of a base.

2) Reductive alkylation step (step 1, step 3)
In the compound of formula (2-2) which is a production intermediate of production method 2, when L ³ represents a formyl group, and in the compound of formula (3-1) which is a production intermediate of production method 3, L ⁵ is oxo. In the case of representing a group, Step 1 and Step 3 are reductive alkylation steps. For example, the reaction can be performed under the following conditions. That is: 1. catalytic reduction catalyzed by platinum oxide or palladium on carbon in the presence of a catalytic amount of acid as required; Reduction with a borane complex such as pyridine-borane, triethylamine-borane, sodium borohydride, sodium triacetoxyhydroborate or sodium cyanoborohydride, in the presence of a catalytic or excess amount of acid as required, And so on. As the solvent to be used, the solvent used in the above 1) is used. As the acid used, p-toluenesulfonic acid, hydrogen chloride, titanium tetraisopropoxide and the like are used. The reaction temperature is generally about 0 ° C. to about 100 ° C., preferably about 20 ° C. to about 80 ° C.

（式中、ｒ’、ｓ’、Ｒ^１０’、Ｒ^１１’及びＬ^２は前掲と同じものを意味する）
　尚上記工程で用いられる式（２－２ｂ）で表される化合物は、市販されているか、或いは公知の方法により製造することができる。 The compounds of formula (2-2) and formula (3-1) used here are commercially available or can be prepared by known methods. That is, the corresponding alcohol derivatives of formula (2-2a) and formula (3-1a) are oxidized by a conventional method, and formula (2-2) in which L ³ represents a formyl group and formula in which L ⁵ represents an oxo group (3-1) can be manufactured. For example, the compounds of formula (2-2a) and formula (3-1a) can be oxidized with phosgene, dimethyl sulfoxide and triethylamine.
The compound of the formula (2-2) can also be produced by reducing the corresponding carboxylic acid or ester thereof by a conventional method. For example, it can be produced by reducing the compound of the formula (2-2b) with DIBAH (diisobutylaluminum hydride).

(Wherein r ′, s ′, R ¹⁰ ′, R ¹¹ ′ and L ² mean the same as above)
The compound represented by the formula (2-2b) used in the above step is commercially available or can be produced by a known method.

3) Deprotecting group step (step 2, step 4)
Steps 2 and 4 are deprotecting group reaction steps. In the production method 2 and the production method 3, among the protective groups used in L ² , examples of the protective group that can be eliminated by hydrolysis include ethoxycarbonyl group, tert-butoxycarbonyl group, acetyl group, benzoyl group, trifluoro Examples thereof include an acetyl group, a benzyloxycarbonyl group, a 3- or 4-chlorobenzyloxycarbonyl group, a triphenylmethyl group, a methanesulfonyl group, and a p-toluenesulfonyl group.
Deprotection by hydrolysis can be performed according to a conventional method, for example, by contacting with water in an appropriate solvent under acidic or basic conditions. As the solvent, for example, alcohols such as methanol, ethanol, and isopropanol, acetonitrile, dioxane, water, or a mixed solution thereof is used. Specific examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid. It is done. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate. The reaction temperature is usually about 0 ° C to 150 ° C.
Among the protecting groups used in L ² , examples of the protecting group that can be removed by hydrogenolysis include, for example, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, benzyl group, 4-methoxybenzyl. Groups and the like.
Deprotection by hydrogenolysis can be performed according to a conventional method, for example, by reacting in a suitable solvent in the presence of a catalyst such as palladium carbon or Raney nickel, in the presence of hydrogen or a hydrogen donor such as ammonium formate or cyclohexene. Done. Examples of the solvent include alcohols such as ethanol and methanol, water, acetic acid, dioxane, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide and the like. The reaction temperature is usually about 0 ° C. to about 80 ° C., and it is carried out at normal pressure or under pressure.

The compound of the formula (2-1) described in the production method 2 and the production method 3 can be produced by the methods shown in the following production methods 4 to 6.

（式中、ｌ、ｒ、ｓ、Ｈｅｔ、Ｒ^１０、Ｒ^１１及びＬ^２は前掲と同じものを意味し、Ｚは脱離基を意味し、Ｌ^７およびＬ^８は、それぞれ独立して、水酸基または脱離基を意味する）
で製造することができる。 (Manufacturing method 4)
For example, a compound of the formula (2-1 ′) in which A represents the formula (A-1) and B represents the formula (B-2) is prepared by the following production method:

(Wherein l, r, s, Het, R ¹⁰ , R ¹¹ and L ² are the same as described above, Z is a leaving group, and L ⁷ and L ⁸ are each independently, Meaning hydroxyl group or leaving group)
Can be manufactured.

Step 1 is a condensation step (step 1-1) and a subsequent dehydration step (step 1-2). Ammonia or an ammonia equivalent is used as a nitrogen source in the presence of a suitable additive such as a base (4- A carbamoyl compound of the formula (4-2) can be produced by reacting with the reactive derivative represented by 1), followed by a dehydration reaction to produce a nitrile compound of the formula (4-3). it can.
Condensation step (step 1-1)
Examples of the reactive derivative represented by the formula (4-1) include carboxylic acid compounds, alkyl esters (particularly methyl esters), active esters, acid anhydrides, and acid halides (equivalent to halides) of the carboxylic acid compounds. Including a leaving group).
Examples of ammonia equivalents include ammonium hydroxide, ammonium salts such as ammonium chloride, ammonium carbonate, ammonium hydrogen carbonate, and ammonium acetate, silylamines such as hexamethyldisilazide, urea, sulfamide, and the like. .
If the expression (4-1) is a carboxylic acid compound ^{(L 8} is a hydroxyl group), 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N, N'-carbonyldiimidazole Imidazole, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, N, N'-carbonyldisuccinic acid imide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl The reaction can be carried out in the presence of a condensing agent such as azide and propanephosphonic anhydride. When 1,3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as the condensing agent, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy- 1,2,3-benzotriazin-4 (3H) -one, N-hydroxy-5-norbornene-2,3-dicarboximide or the like may be added and reacted.
Specific examples when the formula (4-1) is an active ester include p-nitrophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzo Triazole ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester and the like can be mentioned.
When formula (4-1) is an acid anhydride, examples thereof include symmetric acid anhydrides and mixed acid anhydrides. Specific examples of mixed acid anhydrides include alkyl chlorocarbonates such as ethyl chlorocarbonate and isobutyl chlorocarbonate. Mixed acid anhydrides with esters, mixed acid anhydrides with chlorocarbonic aralkyl esters such as benzyl chlorocarbonate, mixed acid anhydrides with chlorocarbonic aryl esters such as phenyl chlorocarbonate, isovaleric acid, pivalic acid and so on And mixed acid anhydrides with alkanoic acids.

This reaction is performed in a solvent or in the absence of a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and cyclopentyl methyl ether. , Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. These solvents may be used alone or A mixture of two or more types is used.

This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but using an excess amount of the compound of formula (4-5) as a base You can also.

The reaction temperature varies depending on the type of starting compound used, but is usually about −30 ° C. to about 200 ° C., preferably about −10 ° C. to about 150 ° C.

When Formula (4-1) is an acid halide (including a leaving group equivalent to a halide), L ⁸ is, for example, a halogen atom such as chlorine, bromine, iodine, or the like, and is eliminated in the same manner as the halogen atom. Possible examples include alkylsulfonyloxy groups such as methanesulfonyloxy group, arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy, etc., but halogen atoms, particularly chlorine and bromine, or methanesulfonyloxy and trifluoromethanesulfonyl An oxy group is preferred.

This reaction is performed in a solvent or in the absence of a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and cyclopentyl methyl ether. , Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. These solvents may be used alone or A mixture of two or more types is used.

This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but using an excess amount of the compound of formula (4-5) as a base You can also.

The reaction temperature varies depending on the type of starting compound used, but is usually about 0 ° C. to about 200 ° C., preferably about 20 ° C. to about 150 ° C.

Dehydration process (process 1-2)
Step 1-2 is a step of obtaining a nitrile compound of the formula (4-3) by allowing a dehydrating agent to act on the carbamoyl group. This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, and pyridine. Solvents used are aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, methanol, Examples thereof include alcohols such as ethanol, isopropanol, and ethylene glycol, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, and sulfolane. These solvents are used alone or in combination of two or more. Examples of the dehydrating agent to be used include phosphorus oxychloride, thionyl chloride, oxalyl chloride, trifluoroacetic anhydride, cyanuric chloride, phosphorus pentoxide, phosphorus pentachloride, trifluoromethanesulfonic anhydride, and propanephosphonic anhydride.
The reaction temperature is generally about 0 ° C. to about 150 ° C., preferably 20 ° C. to about 80 ° C.

In addition, when the formula (4-1) means a carboxylic acid compound, US Patent Application Publication No. 20040167194, Tetrahedron Letters, 1982, vol. 23, # 14 ｐ p. Step 1 can also be performed in one pot by using the dehydrating agent in Step 1-2 as a condensing agent in Step 1-1 as in the method described in No. 1.

Step 2 is a reaction in which a hydroxylamine is allowed to act on a cyano group to obtain an amidoxime body. This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine. Solvents used are aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether, dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, ethanol, Examples include alcohols such as isopropanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, and water. These solvents may be used alone or in combination of two or more. Used. The reaction temperature is generally about 0 ° C. to about 150 ° C., preferably 20 ° C. to about 80 ° C.

Step 3 is a condensation step (Step 3-1) followed by a cyclization step (Step 3-2). The compound of Formula (4-5) is converted to Formula (4) in the presence of a suitable additive such as a base. The compound of formula (4-7) can be produced by reacting with the reactive derivative represented by −6), and the compound of formula (4-8) can be produced by subsequent cyclization reaction. it can.

Condensation step (Step 3-1)
Examples of the reactive derivative represented by (4-6) include carboxylic acid compounds, alkyl esters (particularly methyl esters), active esters, acid anhydrides, and acid halides (derivatives equivalent to halides) of the carboxylic acid compounds. Including a leaving group).
When (4-6) is a carboxylic acid compound (L ⁷ is a hydroxyl group), 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, N, N′-carbonyldisuccinimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide Can be reacted in the presence of a condensing agent such as propanephosphonic anhydride. When 1,3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as the condensing agent, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy- 1,2,3-benzotriazin-4 (3H) -one, N-hydroxy-5-norbornene-2,3-dicarboximide or the like may be added and reacted.
Specific examples when (4-6) is an active ester include p-nitrophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole Examples include esters, 8-hydroxyquinoline esters, 2-hydroxyphenyl esters and the like.
When (4-6) is an acid anhydride, examples thereof include symmetric acid anhydrides and mixed acid anhydrides. Specific examples of mixed acid anhydrides include chlorocarbonic acid alkyl esters such as ethyl chlorocarbonate and isobutyl chlorocarbonate. Mixed anhydrides with chlorocarbonic aralkyl esters such as benzyl chlorocarbonate, mixed anhydrides with chlorocarbonic aryl esters such as phenyl chlorocarbonate, isovaleric acid, pivalic acid and the like Examples thereof include mixed acid anhydrides with alkanoic acids.

This reaction is performed in a solvent or in the absence of a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and cyclopentyl methyl ether. , Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. These solvents may be used alone or A mixture of two or more types is used.

This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but using an excess amount of the compound of formula (4-5) as a base You can also.

The reaction temperature varies depending on the type of starting compound used, but is usually about −30 ° C. to about 200 ° C., preferably about −10 ° C. to about 150 ° C.

When (4-6) is an acid halide (including a leaving group equivalent to a halide), L ⁷ can be eliminated in the same manner as halogen atoms such as chlorine, bromine and iodine, and halogen atoms. Alkylsulfonyloxy groups such as methanesulfonyloxy group, and arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy, which are halogen atoms, particularly chlorine and bromine, or methanesulfonyloxy and trifluoromethanesulfonyloxy Groups are preferred.

This reaction is performed in a solvent or in the absence of a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and cyclopentyl methyl ether. , Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. These solvents may be used alone or A mixture of two or more types is used.

This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but using an excess amount of the compound of formula (4-5) as a base You can also.

The reaction temperature varies depending on the type of starting compound used, but is usually about 0 ° C. to about 200 ° C., preferably about 20 ° C. to about 150 ° C.

Cyclization step (step 3-2)
By reacting the compound of formula (4-7) in the presence or absence of a suitable additive such as a base in accordance with the literature (for example, Current Organic Chemistry, (2008), 12 (10), 850). A compound of formula (4-8) can be produced.

This reaction is performed in a solvent or in the absence of a solvent. The solvent to be used should be appropriately selected according to the type of the raw material compound and the like, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and cyclopentyl methyl ether. Halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, acetic acid and the like. Or a mixture of two or more.

Bases used include alkali carbonates such as sodium carbonate and potassium carbonate, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali acetates such as sodium acetate and potassium acetate, or triethylamine, tributylamine, diisopropylethylamine, Organic bases such as quaternary ammonium hydroxide salts such as N-methylmorpholine, tetrabutylammonium fluoride, and tetramethylammonium hydroxide are used. While the reaction temperature varies depending on the kind of raw material compound used, it is generally about 0 ° C. to about 200 ° C., preferably about 20 ° C. to about 110 ° C.

Step 4 is a step for performing a deprotection reaction. The compound of formula (2-1 ′) can be produced by deprotecting the compound of formula (4-8) in the same manner as in the case of L ^{2 described} above.

Step 5 is a nitrification step. A nitrile compound of formula (4-3) is reacted with a compound of formula (4-1 ′) and a cyanation reagent such as copper cyanide or sodium cyanide in an appropriate solvent. Can also be obtained. Furthermore, zinc cyanide may be subjected to a coupling reaction in the presence of a palladium catalyst typified by tetrakistriphenylphosphine palladium, a copper catalyst typified by copper iodide, or a hexacyanoferrate (II) potassium reagent. can get. Solvents used are aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, methanol, Examples include alcohols such as ethanol, isopropanol, and ethylene glycol; ketones such as acetone and methyl ethyl ketone; ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, and water. A mixture of the above is used. The reaction temperature is generally about 0 ° C. to about 150 ° C., preferably 20 ° C. to about 80 ° C. Examples of Z include halogen atoms such as fluorine, chlorine, bromine and iodine, and alkylsulfonyloxy groups such as methanesulfonyloxy group which can be eliminated similarly to halogen atoms, benzenesulfonyloxy, p-toluenesulfonyloxy and the like. An arylsulfonyloxy group is exemplified, but a halogen atom, particularly chlorine and bromine, or methanesulfonyloxy and trifluoromethanesulfonyloxy groups are preferable.

（式中、Ｒ^２Ａ、Ｒ^５、Ｒ^６、Ｒ^７、およびＬ^８は前掲と同じものを意味し、Ｒ^Ｅは水素原子、加水分解または加水素分解により脱保護可能なカルボキシル基の保護基を意味する。）
で製造することができる。 (Manufacturing method 5)
The compound of the formula (4-1) described in the production method 4 can be produced commercially or by a known method. For example, in the case where Het is the formula (Het-1) and R ^1A is the hydrogen atom (4-1 ″), the following production method:

(Wherein R ^2A , R ⁵ , R ⁶ , R ⁷ , and L ⁸ are the same as described above, and R ^E is a hydrogen atom, a protecting group for a carboxyl group that can be deprotected by hydrolysis or hydrogenolysis. Means.)
Can be manufactured.

Step 1 is a reaction in which deprotection is simultaneously performed when the imidazole ring is constructed and when R ^E is a protecting group of a carboxyl group that can be deprotected by hydrolysis or hydrogenolysis, and the o-phenylenediamine compound (5-1 ) And a carboxylic acid compound (5-2) by the reaction described in the literature (for example, J. Med. Chem. 2000, 43, 4084-4097) under acidic conditions, the formula (4-1 ″) ) Can be produced.

The solvent used in this reaction should be appropriately selected according to the type of raw material compound, etc., and the solvent used is, for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, cyclopentyl methyl ether. , Ethers such as dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, alcohols such as methanol, ethanol, isopropanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N , N-dimethylformamide, dimethyl sulfoxide and water, and these solvents may be used alone or in combination of two or more. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably 20 ° C. to about 80 ° C.

Examples of the acid to be used include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid, organic acids such as acetic acid and formic acid, polyphosphoric acid, and the like. As an excess, it can also be used, Preferably hydrochloric acid and polyphosphoric acid are mentioned. Moreover, these acids can also be used as a solvent.

R ^E is preferably a hydrogen atom or a protecting group that can be deprotected by hydrolysis, and more preferably a protecting group that can be deprotected under acidic conditions. Specifically, a lower alkyl group (particularly methyl, ethyl group, tert-butyl group, etc.) is preferable.

Step 2 is a reaction for constructing an indazole ring, and the o-phenylenediamine compound (5-1) and the aldehyde compound (5-3) are described in the literature (for example, J. Med. Chem. 2000, 43, 4084-4097). By the method described, the compound of formula (5-4) can be produced by reacting under acidic conditions in the presence of copper (II) acetate.

The solvent used in this reaction should be appropriately selected according to the type of raw material compound, etc., and the solvent used is, for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, cyclopentyl methyl ether. , Ethers such as dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, alcohols such as ethanol, isopropanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N -Dimethylformamide, dimethyl sulfoxide and water, and these solvents are used alone or in combination of two or more. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably 20 ° C. to about 80 ° C.

Examples of the acid to be used include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, organic acids such as acetic acid and formic acid, polyphosphoric acid, and preferably acetic acid. Moreover, these acids can also be used as a solvent.

Step 3 is a condensation step, and the o-phenylenediamine compound (5-1) and the carboxylic acid compound (5-5) are prepared according to the literature (for example, J. Med. Chem. 2000, 43, 4084-4097). A compound of formula (5-6) can be produced by condensation according to the method or the method described in Step 3-1 of Production Method 4.
The reactive derivatives represented by (5-5) include carboxylic acid compounds, alkyl esters (particularly methyl esters), active esters, acid anhydrides, and acid halides (derivatives equivalent to halides) of the carboxylic acid compounds. Including a leaving group).

Step 4 is a reaction for constructing an indazole ring. The compound of the formula (5-6) is reacted under acidic conditions by the method described in the literature (for example, J. Med. Chem. 2000, 43, 4084-4097). To produce a compound of formula (5-4).

The solvent used in this reaction should be appropriately selected according to the type of raw material compound, etc., and the solvent used is, for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, cyclopentyl methyl ether. , Ethers such as dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, alcohols such as ethanol, isopropanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, ethyl acetate, acetonitrile, N, N -Dimethylformamide, dimethyl sulfoxide and water, and these solvents are used alone or in combination of two or more. The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably 20 ° C. to about 80 ° C.

Examples of the acid to be used include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, organic acids such as acetic acid and formic acid, polyphosphoric acid, and preferably acetic acid. Moreover, these acids can also be used as a solvent.

Step 5 is a hydrolysis or hydrogenolysis step. Among the protecting groups used in R ^E in this step, examples of the protecting group that can be deprotected by hydrolysis include a methyl group, an ethyl group, a tert-butyl group, a phenyl group, and a benzyl group.
The elimination by hydrolysis can be performed according to a conventional method, for example, by contacting with water in an appropriate solvent under acidic or basic conditions. As the solvent, for example, alcohols such as methanol, ethanol, and isopropanol, acetonitrile, dioxane, water, or a mixed solution thereof is used. Specific examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid. It is done. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate. The reaction temperature is usually about 0 ° C to 150 ° C.
Among the protecting groups used in R ^E , examples of the protecting group that can be eliminated by hydrogenolysis include a benzyl group, a 3- or 4-chlorobenzyl group, and the like.
Deprotection by hydrogenolysis can be performed according to a conventional method, for example, by reacting in a suitable solvent in the presence of a catalyst such as palladium carbon or Raney nickel, in the presence of hydrogen or a hydrogen donor such as ammonium formate or cyclohexene. Done. Examples of the solvent include alcohols such as ethanol and methanol, water, acetic acid, dioxane, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide and the like. The reaction temperature is usually about 0 ° C. to about 80 ° C., and it is carried out at normal pressure or under pressure.

〔式中、ｒ、ｓ、Ａ、Ｈｅｔ、Ｒ^８、Ｒ^１０およびＲ^１１は、前掲と同じものを意味し、Ｌ^５はオキソ基（Ｒ^８の１級炭素原子上にＬ^５がある場合は、その炭素原子とともにホルミル基を形成する）又は脱離基を意味する〕 (Manufacturing method 6)
In addition, in the compound represented by the formula (1), for example, B is the formula (B-2), R ⁸ is a C _1-6 alkyl group which may be substituted, and C _3-6 may be substituted. An alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _3-8 monocyclic, a C _7-10 bicyclic or a C _7-12 tricyclic cycloalkyl group, and In the case of the compound (1 ″) which is an optionally substituted C _5-8 monocyclic or C _7-10 bicyclic cycloalkenyl group, it can also be produced by the following method.

[Wherein, r, s, A, Het, R ⁸ , R ¹⁰ and R ¹¹ are the same as those described above, and L ⁵ represents an oxo group (when L ⁵ is on the primary carbon atom of R ⁸ Means a formyl group together with the carbon atom) or a leaving group]

When L ⁵ is a leaving group, step 1 is an alkylation reaction, and the compound of formula (2-1) and the compound of formula (6-1) are converted to the alkylation reaction of 1) in production methods 2 and 3. The compound of the formula (1 ″) can be produced by reacting by the method.

When L ⁵ is an oxo group, step 1 is a reductive alkylation reaction, and the reductive alkylation of the compound of formula (2-1) and the compound of formula (6-1) in 2) in production methods 2 and 3 A compound of the formula (1 ″) can be produced by reacting in the same manner as in the reaction.

〔式中、ｒ、ｓ、ｒ’、ｓ’、ｕ、Ａ、Ｈｅｔ、Ｒ^１０、Ｒ^１１、Ｒ^１０’およびＲ^１１’は、前掲と同じものを意味し、Ｌ^５はオキソ基（式（７－１）の１級炭素原子上にＬ^５がある場合は、その炭素原子とともにホルミル基を形成する）又は脱離基を意味する〕 (Manufacturing method 7)
In addition, for example, when the compound represented by the formula (1) is a compound (1 ′ ″) in which B is the formula (B-2) and R ⁸ is the formula (R ¹² -3), the following method is used. Can also be manufactured.

[Wherein, r, s, r ′, s ′, u, A, Het, R ¹⁰ , R ¹¹ , R ¹⁰ ′ and R ¹¹ ′ mean the same as described above, and L ⁵ represents an oxo group (formula] (When there is L ⁵ on the primary carbon atom of (7-1), it forms a formyl group together with the carbon atom) or a leaving group]

When L ⁵ is a leaving group, step 1 is an alkylation reaction, and the compound of formula (2-1) and the compound of formula (7-1) are converted to the same alkylation reaction as 1) in production methods 2 and 3. The compound of the formula (1 ′ ″) can be produced by the reaction of

When L ⁵ is an oxo group, step 1 is a reductive alkylation reaction, and the reductive alkylation of the compound of formula (2-1) and the compound of formula (7-1) of 2) in production methods 2 and 3 A compound of the formula (1 ′ ″) can be produced by reacting in the same manner as in the reaction.

（式中、Ｈｅｔ、Ａ、Ｂ、およびＬ^７は前掲と同じものを意味する） (Manufacturing method 8)
Moreover, the compound represented by Formula (1) can be manufactured also with the following method.

(In the formula, Het, A, B, and L ⁷ are the same as described above.)

Step 1-1 is a condensation reaction, and Step 1-2 is a subsequent cyclization reaction. In accordance with the same method as in steps 3-1 and 3-2 in production method 4, the compound of formula (4-5) and the compound of formula (8-1) are subjected to a condensation reaction and subjected to a cyclization reaction, whereby ) Can be produced.

（式中、Ｈｅｔ、ｏ、ｐ、ｑ、Ｒ^８、Ｒ^９、Ｌ^２及びＬ^７は前掲と同じものを意味し、Ｌ^５及びＬ^１１はそれぞれ独立してオキソ基（１級炭素原子上にＬ^５もしくはＬ^１１がある場合は、その炭素原子とともにホルミル基を形成する）又は脱離基を意味する） (Manufacturing method 9)
The compound represented by the formula (1) is, for example, the following method when the compound formula (1 ″ ′ ″) in which A represents the formula (A-3) and B represents the formula (B-1) Can also be manufactured.

(In the formula, Het, o, p, q, R ⁸ , R ⁹ , L ² and L ⁷ are the same as described above, and L ⁵ and L ¹¹ are each independently an oxo group (on the primary carbon atom) In the case where L ⁵ or L ¹¹ is present, it forms a formyl group together with the carbon atom) or a leaving group)

Step 1 and Step 1 'are a condensation reaction followed by a cyclization reaction. By reacting the compound of formula (4-5) with the compound of formula (9-1) or formula (9-9) by the same method as in Steps 3-1 and 3-2 in Production Method 4, respectively, Compounds of (9-2) and formula (9-4) can be produced.

When L ¹¹ is a leaving group, Step 2 and Step 2 ′ are alkylation reactions, and the compound of Formula (9-2) and the compound of Formula (9-3) or Formula (9-8) are produced in Production Method 2. And the compound of formula (1 ′ ″ ″) and formula (1-2) can be produced by reacting in the same manner as the alkylation reaction of 1) in 3 and 3.

When L ¹¹ is an oxo group, step 2 and step 2 ′ are reductive alkylation reactions, and a method for producing a compound of formula (9-2) and a compound of formula (9-3) or formula (9-8) By reacting in the same manner as the reductive alkylation reaction of 2) in 2 and 3, the compounds of formula (1 ′ ″ ″) and formula (1-2) can be produced, respectively.

Step 3 is a deprotection reaction. A compound of formula (9-5) can be produced by subjecting the compound of formula (9-4) to a deprotection reaction in the same manner as the deprotection of L ^{2 described} above.

When L ⁵ is a leaving group, Step 4 and Step 5 are alkylation reactions. An alkylation reaction of 1) in the production methods 2 and 3 with the compound of the formula (9-5) and the compound of the formula (9-6), or the compound of the formula (1-2) and the compound of the formula (9-7); By reacting in the same manner, the compounds of formula (1-2) and formula (1 ′ ″ ″) can be produced, respectively.

When L ⁵ is an oxo group, step 4 and step 5 are reductive alkylation reactions, and the compound of formula (9-5) and the compound of formula (9-6) or the compound of formula (1-2) By reacting the compound of the formula (9-7) in the same manner as the reductive alkylation reaction of 2) in the production methods 2 and 3, respectively, the formula (1-2) and the formula (1 ′ ″ ″) are obtained. Can be produced.

（式中、Ｈｅｔ、Ｘ、ｍ、ｎ、ｏ、ｐ、ｑ、ｒ、ｓ、Ｒ^８、Ｒ^１０、及びＲ^１１は前掲と同じものを意味し、Ｌ^１１はオキソ基（１級炭素原子上にＬ^１１がある場合は、その炭素原子とともにホルミル基を形成する）又は脱離基を意味する） (Manufacturing method 10)
Further, the compound represented by the formula (1) is, for example, a production method when the compound formula (1 ″ ″ ″) is such that A represents the formula (A-2) and B represents the formula (B-4). In Step 2 of 9, the compound of the following formula (9-10) can be used instead of the compound of the formula (9-3).

(In the formula, Het, X, m, n, o, p, q, r, s, R ⁸ , R ¹⁰ , and R ¹¹ are the same as described above, and L ¹¹ represents an oxo group (primary carbon atom When L ¹¹ is present above, it forms a formyl group together with the carbon atom) or a leaving group)

（式中、Ｒ^５、Ｒ^６およびＲ^７は前掲と同じものを意味し、Ｚ^１は前掲のＺを意味するか、ニトリル基およびニトリル等価体「例えば、カルボキシル基、カルバモイル基、ハロゲン原子等の化学的変換によりニトリル基へと変換可能な官能基を意味する。」を意味し、Ｚ^２は脱離基を意味する。）
で製造することができる。 (Manufacturing method 11)
In addition, the compounds of formula (4-1 ′) and formula (4-3) described in production method 4 are commercially available and can be produced by known methods. For example, in the case where Het is the formula (Het-3) and R ^1A and R ^2A are hydrogen atoms (4-1 ′ ″), the following production method:

(Wherein R ⁵ , R ⁶ and R ⁷ are the same as those described above, and Z ¹ represents Z as described above, or a nitrile group and a nitrile equivalent “for example, a carboxyl group, a carbamoyl group, a halogen atom, etc. This means a functional group that can be converted to a nitrile group by chemical conversion of “.” And Z ² means a leaving group.)
Can be manufactured.

In step 1, benzaldehyde compound of formula (11-1) is synthesized with hydrazine in an appropriate solvent in the presence of various bases by the method described in the literature (for example, Journal of Organic Chemistry 2006, 71 (21), 8166-8172). This is a step of obtaining a compound of the formula (4-1 ′ ″) by reacting in the presence or reacting with hydrazine following addition of O-methylhydroxylamine.

Solvents used are aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, methanol, Examples include alcohols such as ethanol, isopropanol, and ethylene glycol; ketones such as acetone and methyl ethyl ketone; ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, and water. A mixture of the above is used.

The reaction temperature is usually about 0 ° C. to about 150 ° C., preferably 20 ° C. to about 80 ° C.

This reaction is performed in the presence of a base as necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. , Alkali bicarbonates such as potassium bicarbonate, or organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, and pyridine.

Examples of Z ² include halogen atoms such as fluorine, chlorine, bromine and iodine, and alkylsulfonyloxy groups such as methanesulfonyloxy group which can be eliminated similarly to the halogen atoms, benzenesulfonyloxy, p-toluenesulfonyloxy and the like. The arylsulfonyloxy group is preferably fluorine.

Step 2 is carried out in the presence of various acids or inorganic salts by the method described in the literature (for example, Tetrahedron Lett. 2002, 43, 2695-2697, Tetrahedron 2006, 62, 7772-7775, etc.). In this step, an azide compound is obtained by reacting a nitrite compound in an appropriate solvent, and then cyclized in the presence or absence of a crown ether to obtain a compound of the formula (4-1 ′ ″).

Solvents used are aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, cyclopentyl methyl ether and dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, methanol, Examples include alcohols such as ethanol, isopropanol, and ethylene glycol; ketones such as acetone and methyl ethyl ketone; ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, and water. A mixture of the above is used.

Among the acids or inorganic salts used in the azidation step, acids are preferred, and among them, mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, etc. are preferred, and hydrochloric acid is more preferred.

The nitrite compound used in the azidation step is preferably a nitrite ester or sodium nitrite.

In the azidation step, the reaction temperature is usually about −100 ° C. to about 150 ° C., preferably −78 ° C. to about 100 ° C.

Examples of the salt used in the cyclization step include sodium tetrafluoroborane, potassium acetate, sodium acetate, sodium bicarbonate, and potassium tert-butoxy, and preferably sodium tetrafluoroborane and potassium acetate.

In the cyclization step, the reaction temperature is usually 0 ° C. to about 100 ° C.

In the production method described above, if any functional group other than the reactive site reacts under the described reaction conditions or is inappropriate for carrying out the described method, the other reactive site is protected, After the reaction, the target compound can be obtained by deprotection. As the protecting group, for example, a usual protecting group as described in the above-mentioned Protective Groups in Organic Synthesis etc. can be used. More specifically, as the protecting group for amine, for example, , Ethoxycarbonyl, t-butoxycarbonyl, acetyl, benzyl and the like, and examples of the hydroxyl-protecting group include tri-lower alkylsilyl, acetyl, benzyl and the like.

The protecting group introduction reaction and elimination reaction can be carried out by methods commonly used in organic synthetic chemistry (see, for example, the above-mentioned Protective Groups in Organic Synthesis), or methods based thereon.
In addition, the intermediate and the target compound in each of the above production methods can be converted into another compound included in the present invention by appropriately converting the functional group. The functional group can be converted by a commonly used general method (for example, see Comprehensive Organic Transformations, RC Larock (1989), etc.). it can.

The starting materials and intermediates in the above production methods are known compounds or can be synthesized from known compounds by known methods.

The intermediates and target compounds in each of the above production methods can be isolated and purified by purification methods commonly used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. it can. Further, the intermediate can be used for the next reaction without any particular purification.

In addition, optical isomers such as enantiomers, plane asymmetric isomers, and axial asymmetric isomers are subjected to known separation steps such as a method using an optically active column and a fractional crystallization method in an appropriate step of each of the above production methods. Can be separated. An optically active substance can also be used as a starting material.

As a specific optical resolution method, when the compound of the present invention or an intermediate thereof has a basic functional group, it is used in an inert solvent (for example, alcohol solvents such as methanol, ethanol, 2-propanol, diethyl ether, etc. Ether solvents, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, acetonitrile and the like, and mixed solvents thereof), optically active acids (eg, mandelic acid, N-benzyloxyalanine, lactic acid, etc.) Monocarboxylic acids, tartaric acid, o-diisopropylidene tartaric acid, dicarboxylic acids such as malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) can also be formed into a salt.

When the compound of the present invention or an intermediate thereof has an acidic substituent such as a carboxyl group, an optically active amine (for example, organic amines such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine) and a salt Can also be formed. Examples of the temperature at which the salt is formed include a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the collected salt is collected by filtration, it can be cooled as necessary to improve the yield. The amount of the optically active acid or amine to be used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. Crystals in an inert solvent as required (for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, It can also be recrystallized with acetonitrile or a mixed solvent thereof to obtain a highly pure optically active salt. If necessary, the obtained salt can be treated with an acid or a base by a conventional method to obtain a free form.
The compound of the formula (1) can be obtained in the form of a free base or an acid addition salt depending on the type of the functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions. Can be converted to compounds. On the other hand, the compound of formula (1) can be converted into an acid addition salt by treating with various acids according to a conventional method.

When obtaining a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, it may be suspended and an acid or base is added to form a salt by a conventional method.
Moreover, although the compound of this invention and its pharmaceutically acceptable salt may exist in the form of an adduct with water or various solvents, these adducts are also included in the present invention. Furthermore, the present invention also includes all tautomers, any stereoisomers present, any optical isomers and crystal forms of all embodiments of the compounds of the present invention.

Since the compound of the present invention or a pharmaceutically acceptable salt thereof has a strong affinity for serotonin 4 receptor and agonist activity as described later, it has an agonistic action on serotonin 4 receptor, a partial It can be expected to be a useful pharmaceutical for a disease or symptom where an agonistic (partial agonist) action is desired and / or required.

Examples of diseases or symptoms in which an agonistic (agonist) action, a partial agonistic (partial agonist) action on a serotonin 4 receptor is desired and / or required include the following (i) to (v):
(I) neuropsychiatric diseases such as Alzheimer's dementia, Lewy body dementia, vascular dementia, depression, post-traumatic stress disorder (PTSD), memory impairment, anxiety, schizophrenia;
(Ii) Irritable bowel syndrome, flaccid constipation, habitual constipation, chronic constipation, constipation induced by drugs such as morphine and antipsychotics, constipation associated with Parkinson's disease, constipation associated with multiple sclerosis, constipation associated with diabetes Or diseases of the digestive system such as constipation or defecation disorder (as a pretreatment during endoscopy or barium intestinal X-ray examination);
(Iii) Functional dyspepsia, acute / chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastric neuropathy, postoperative paralytic ileus, senile ileus, non-diffuse gastroesophageal reflux disease, NSAID ulcer, diabetic Gastrointestinal disorders such as gastric insufficiency, post-gastrectomy syndrome, or pseudo-intestinal obstruction;
(Iv) Gastrointestinal tract diseases, scleroderma, diabetes or loss of appetite in esophagus / biliary diseases, or nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, as described in (ii) and (iii) above Digestive symptoms such as heartburn or ambiguity;
(V) Urinary tract diseases accompanied by urination disorders such as urinary tract obstruction or enlarged prostate.
In addition, since the compound of the present invention or a pharmaceutically acceptable salt thereof exhibits excellent 5-HT ₄ receptor agonist activity and brain transferability, the Alzheimer type dementia described in (i) above is particularly preferred. It is useful as a therapeutic agent for such neuropsychiatric diseases.

When the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a medicine, it is orally or parenterally (for example, intravenous, subcutaneous or instillation, intramuscular injection, subcutaneous injection, intranasal administration, eye drops Suppository, transdermal administration agent (ointment, cream, lotion, etc.)). Examples of forms for oral administration include tablets, capsules, pills, granules, powders, solutions, syrups, suspensions, etc. Examples of forms for parenteral administration include injection Aqueous or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like.
These preparations can be prepared using a conventionally known technique and can contain an acceptable normal carrier, excipient, binder, stabilizer, lubricant, disintegrant and the like. In addition, when used in an injection form, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added. Moreover, a flavoring agent can also be used suitably.

Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin and carboxymethyl starch; crystalline cellulose, low substitution Cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; organic excipients such as gum arabic; dextran; pullulan; and light anhydrous silicic acid, synthetic aluminum silicate Silicate derivatives such as magnesium aluminate metasilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfuric acid such as calcium sulfate ; Can be exemplified inorganic excipients such.

Examples of lubricants include stearic acid metal salts such as stearic acid, calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as bee gum and gay wax; boric acid: adipic acid; Sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; A starch derivative etc. can be mentioned.
Examples of the binder include polyvinyl pyrrolidone, macrogol and the same compound as the excipient.
Examples of the disintegrant include compounds similar to the above-mentioned excipients and chemically modified starch / celluloses such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.
Examples of the stabilizer include paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal Dehydroacetic acid; and sorbic acid.
Examples of the flavoring agent include commonly used sweeteners, acidulants, and fragrances.

For oral administration, tablets containing excipients may be used with granulating binders in addition to various disintegrants. Also, lubricants are often very useful for tableting. A similar type of solid composition may be used as a filler in gelatin capsules (preferred materials for this binding also include lactose or lactose, high molecular weight polyethylene glycols).
When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredients are combined with various sweetening, flavoring, coloring or dyeing agents and, if desired, emulsifiers and / or Suspending agents can also be combined with the diluent. Such diluents include water, ethanol, propylene glycol, glycerin, and mixtures thereof. In the case of animals, they are conveniently included in animal feed or drinking water at a concentration of 5-5000 ppm, preferably 25-5000 ppm.
For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use), a sterile injectable solution of the active ingredient is usually prepared. Sesame oil, peanut oil, or aqueous propylene glycol solution of the compound of the present invention can be used. These aqueous solutions may be adjusted to a suitable pH, buffered, or made isotonic with a liquid diluent, if necessary. This aqueous solution can also be used for intravenous injection. Oily solutions can also be used for intra-articular, intramuscular and subcutaneous injection. The manufacture of all these solutions under aseptic conditions is carried out by standard pharmaceutical techniques well known to those skilled in the art.

For intranasal administration or administration by inhalation, the compound of the invention or a pharmaceutically acceptable salt thereof may be in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or a pressurized container or As an aerosol spray from a nebulizer, it is supplied with the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that provides a metered volume. A pressurized container or nebulizer can hold a solution or suspension of the active compound.
Capsules and cartridges (eg manufactured from gelatin) for use in inhalers or insufflators can be formulated containing a powder formulation of the compound of the invention and a suitable powder base such as lactose or starch. .
The compound of the present invention or a pharmaceutically acceptable salt thereof is formulated using an anal composition such as a suppository or a retention enema containing a conventional suppository base such as cocoa butter or other glycerides. Can be

When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered, the amount to be used varies depending on symptoms, age, administration method, etc. For example, in the case of oral administration, It is desirable to administer 0.01 mg (preferably 1 mg) as the lower limit per day and 5000 mg (preferably 500 mg) as the upper limit in one or several divided doses depending on the symptoms. In the case of intravenous administration, for adults, 0.01 mg (preferably 0.1 mg) as the lower limit and 1000 mg (preferably 30 mg) as the upper limit per day, divided into one or several times, The effect is expected by administering according to the symptoms.

A compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of a disease described in the specification in which an agonistic (agonist) action or a partial agonistic (partial agonist) action is required for the serotonin 4 receptor; Alternatively, the pharmaceutical composition or preparation containing the compound of the present invention may be administered in combination with other drugs as necessary.

In particular, the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or preparation containing the compound of the present invention is used in combination with at least one of the therapeutic agents shown below, Further therapeutic effects are expected for various neuropsychiatric diseases described in i), particularly Alzheimer type dementia. That is,
Acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine, SNX-001, NP-61, etc.), cholinesterase inhibitors (huperzine A, etc.), NMDA receptor antagonists (memantine, dimebon, neramexane, etc.), 5-HT6 receptor antagonist Drugs (PF-5212365 (SAM-531), SB-742457, LU-AE58054, AVN-322, PF-05212377 (SAM-760), AVN101, etc.), α7nAChR agonist (TC-5619, EVP-6124, GTS- 21), α7nAChR positive allosteric modulators (PAMs) (AVL-3288, etc.), α4β2nACh receptor agonist (AZD-1446, CHANTIX (varenicline, etc.)), nAChR agonist (ABT-089, etc.), AMPA receptor agonist (CX-717, LY-451395, etc.), histamine H3 receptor antagonist (ABT-288, SAR-110894, PF-03654746, etc.), muscarinic M1 receptor agonist (MCD-386, GSK-1034702, etc.), PDE4 Inhibitors (etazolate, etc.), PDE9 inhibitors (PF-04447943, etc.), histone deacetylase inhibitors (EVP-0334, etc.), σ1 receptor agonists (Anavex-2-73, etc.), γ-secretase inhibitors (GSI) (BMS-708163, NIC5-15, ELND-006, MK-0752, etc.), γ-secretase modifier (GSM) (E-2212, CHF-5074, etc.), Aβ human monoclonal antibody (bapineuzumab, solanezumab, PF-4360365 (ponezumab), gantenerumab (R-1450), BAN-241, MABT-5102A, RG-7412, GSK-933776A, etc.), Aβ vaccine (ACC-001 (PF-05236806), AD-02, CAD- 106, V-950, UB-311, ACI-24, etc.), human immunoglobulin (GAMMAGARD, etc.), Aβ aggregation inhibitor (ELND-005 (AZD-103), PBT-2, NRM-8499, Exebryl-1) , Tau aggregation inhibitors (TRx-0014, LMTX, etc.), BACE inhibitors (ACI-91, posiphen, CTS-21166, HPP-854, LY-2886721, etc.), tyrosine kinase inhibitors (masitinib, etc.), GSK-3β Inhibitors / tau kinase inhibitors (NP-12, etc.), RAGE fusion proteins (TTP-4000, etc.), ApoA-I, HDL-C elevation (RVX-208, etc.), other agents with various neuroprotective actions (SK-PC) -B70M, T-817MA, davunetide, HF-0220, PF-4494700, PYM-50028, CERE-110, ASP-0777, TAK-065, AAD-2004, etc.) In combination with other drugs, further therapeutic effects are expected.

The present invention will be described more specifically with reference to the following reference examples and examples. However, the technical scope of the present invention is not limited to these examples. The compound was identified by proton nuclear magnetic resonance spectrum ( ¹ H-NMR), LC-MS and the like. Tetramethylsilane was used as an internal standard for the nuclear magnetic resonance spectrum.
In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

The following abbreviations may be used in Examples and Reference Examples.
THF: Tetrahydrofuran NaBH (OAc) ₃ : Sodium triacetoxyborohydride (Boc) ₂ O: Di-tert-butyl dicarbonate Pd (OH) ₂ : Palladium hydroxide DMF: N, N-dimethylformamide WSCI · HCl: 1 -(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride HOBt.H ₂ O: 1-hydroxybenzotriazole monohydrate NMP: 1-methyl-2-pyrrolidinone TFA: trifluoroacetic acid FA: formic acid CDCl ₃ : Deuterated chloroform CD ₃ OD: Deuterated methanol DMSO-d ₆ : Deuterated dimethyl sulfoxide Me: Methyl Et: Ethyl
ⁿ Pr: Normal propyl
ⁱ Pr: Isopropyl
^c Pr: Cyclopropyl
ⁿ Bu: normal butyl
ⁱ Bu: Isobutyl
^c Bu: cyclobutyl Ph: phenyl Ac: acetyl Ms: mesyl Ts: tosyl Boc: tert-butoxycarbonyl Bn: benzyl Pd-C: palladium-carbon NaBH ₃ (CN): sodium cyanoborohydride Cbz or Z: benzyloxy Carbonyl CH ₂ Cl ₂ : Methylene chloride Ns: Nosyl (2-nitrobenzenesulfonyl)
SEM: 2- (trimethylsilyl) ethoxymethyl NEt ₃ : triethylamine CDI: N, N′-carbonylimidazole TBAF: tetrabutylammonium fluoride MeO or OMe: methoxy BBr ₃ : boron tribromide LiHMDS: hexamethyldisilazane lithium BINAP: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl DMAP: N, N-dimethyl-4-aminopyridine T3P: propylphosphonic anhydride (cyclic trimer)
p. o. : Oral administration s: Single line d: Double line t: Triple line q: Quadruple line m: Multiple line br: Wide dd: Double double line td: Triple line double line J: Coupling constant ( coupling constant)
Hz: Hertz
N: Normal (for example, 2N HCl indicates 2N hydrochloric acid)
M: Molar concentration (mol / L) (Example: 2M methylamine indicates a 2 mol / L methylamine solution)
min: minute atm: atmospheric pressure

The purification conditions for preparative purification by reverse phase HPLC are as follows.
Condition FA: (TFA or FA as additive)
Equipment: Shimadzu & Gilson215
Column: Grace Vydac C18, 200x25 mm, 5μm
Flow rate: 30 ml / min
Column temperature: 40 ℃
Moving bed A1: distilled water (containing 0.075% TFA, v / v)
Moving bed A2: distilled water (containing 0.2% FA, v / v)
Moving bed B: Acetonitrile

Condition FB: (Basic or neutral condition)
Equipment: Shimadzu & Gilson215
Column: Durashell C18, 200x25 mm, 5μm
Flow rate: 30 ml / min
Column temperature: 30 ℃
Moving bed A1: Distilled water (containing 0.05% ammonia, v / v)
Moving bed A2: Distilled water moving bed B: Acetonitrile

Condition FC: (TFA)
Equipment: Shimadzu & Gilson281
Column: YMC ODS-AQ, 150x30 mm, 5μm
Flow rate: 28 ml / min
Column temperature: 40 ℃
Mobile layer A: distilled water (containing 0.075% TFA, v / v)
Moving bed B: Acetonitrile (containing 0.025% TFA, v / v)

Condition FD: (TFA)
Equipment: Gilson215
Column: YMC ODS-AQ, 150x30mm, 5μm
Flow rate: 28 ml / min
Column temperature: 40 ℃
Mobile layer A: distilled water (containing 0.075% TFA, v / v)
Moving bed B: Acetonitrile (containing 0.025% TFA, v / v)

Condition FE: (TFA)
Equipment: Gilson281
Column: Synergi max RP, 150x30 mm, 5 μm
Flow rate: 25 ml / min
Column temperature: 40 ℃
Mobile layer A: distilled water (containing 0.075% TFA, v / v)
Moving bed B: Acetonitrile (containing 0.025% TFA, v / v)

The LC / MS analysis conditions for compound identification are as follows.
High-performance liquid chromatograph / mass spectrometer; LCMS measurement conditions are as follows, and the observed mass spectrometry value [MS (m / z)] is indicated by [M + H] +. When the analytical compound is a salt compound, M means the mass number of the free base unless otherwise specified.
Measurement method A:
Detector: Agilent 1100 series for API series (Applied Biosystems)
HPLC: API150EX LC / MS system (Applied Biosystems)
Column: YMC CombiScreen ODS-A (S-5μm, 12nm, 4.6x50mm)
Solvent: Solution A: 0.05% TFA / H ₂ O, Solution B: 0.035% TFA / MeOH
Gradient Condition:
0.0-1.0 min A 75% (B 25%)
1.0-4.7 min Linear gradient from A 75% to 1% (B 25% to 99%)
4.7-5.7 min A 1% (B 99%)
5.7-6.1 min Linear gradient from A 1% to 75% (B 99% to 25%)
6.1-7.1 min A 75% (B 25%)
7.1-7.2 min Linear gradient from A 75% to 100% (B 25% to 0%)
Flow rate: 2.4 mL / min
UV: 220 nm

Measurement method B:
LC-MS: Waters ACQUITY ^TM UltraPerformance LC
Column: Waters ACQUITY UPLC BEH Phenyl 1.7μm, 2.1 × 50 mm
Solvent: Solution A: 0.05% formic acid / H ₂ O, Solution B: 0.05% formic acid / CH ₃ CN
Gradient Condition:
0.0 min; A / B = 90: 10
0.0-1.3 min; A / B = 90: 10-1: 99 (linear gradient)
1.3-1.5 minutes; A / B = 1: 99
1.5-2.0 min; A / B = 90: 10
Flow rate: 0.75 mL / min
UV: 220, 254 nm
Column temperature: 40 ° C

Measurement method C:
LCMS: Shimadzu LCMS-2010EV
Column: Shiseido CAPCELL PAK C18 MG II (4.6 mm x 50 mm)
Solvent: Liquid A: MeOH, Liquid B: 0.05% TFA / H ₂ O
Gradient Condition:
0.0-1.0 min; A / B = 30:70
1.0-7.0 min; A / B = 99: 1
7.1-12.0 min; A / B = 30:70
Flow rate: 2.8 mL / min
UV: 220 nm
Column temperature: 40 ° C

Measurement method D:
LCMS: Shimadzu LCMS-2010EV
Column: Ximate C18 3.0 m 2.1 mm × 30 mm
Solvent: Liquid A: 0.019% TFA / H ₂ O, Liquid B: 0.038% TFA / CH ₃ CN
Gradient Condition:
0.0min; A / B = 90:10
0.0-1.35 min; A / B = 20:80
1.35-2.25 min; A / B = 20:80
2.25-2.26 min; A / B = 90:10
2.26-3.00 min; A / B = 90:10
Flow rate: 0.8 mL / min
UV: 220 nm
Column temperature: 50 ° C

Measurement method E:
LCMS: Shimadzu LCMS-2020
Column: Phenomenex Kinetex 1.7 μm C18 (50 mm × 2.10 mm)
Solvent: Liquid A: MeOH, Liquid B: 0.05% TFA / H ₂ O
Gradient Condition:
0.0 min; A / B = 30: 70
0.0-1.90 min; A / B = 99: 1
1.91-3.00 min; A / B = 30: 70
Flow rate: 0.5 mL / min
UV: 220 nm
Column temperature: 40 ° C

NMR in this specification was measured using JEOL JNM-AL series LA300 and AL400.
Unless otherwise specified, commercially available materials were used for the raw material compounds, reaction reagents, and solvents.

　（１）２－アミノ－５－フルオロ安息香酸（４．０ｇ）をテトラヒドロフラン（４０ｍｌ）に溶かした後、０℃に冷却し無水トリフルオロ酢酸（１４．６ｍｌ）を滴下し、室温で終夜撹拌した。反応液を濃縮し、残渣に水を加え析出した結晶を濾取した。得られた結晶を減圧乾燥し、目的とする５－フルオロ－２－（２，２，２－トリフルオロアセトアミド）安息香酸（５．３８ｇ）を得た。
　（２）０℃に冷却した発煙硝酸（３０ｍｌ）に５－フルオロ－２－（２，２，２－トリフルオロアセトアミド）安息香酸（５．３８ｇ）を少しずつ加え、そのままの温度で４時間撹拌した。反応液を氷水に注ぎ、激しく撹拌した。生じた結晶を濾過し水で洗浄後、減圧乾燥させた。得られた結晶をエタノール（６０ｍｌ）に溶かし１０％水酸化ナトリウム水溶液（６０ｍｌ）を加え、８０℃下で４時間撹拌した。反応液を濃縮し、残渣に１Ｎ塩酸を加え希釈した。０℃下で撹拌し、生じた結晶を濾過後、得られた結晶を減圧乾燥させ、標記化合物（２．５ｇ）を得た。
LC-MS, m/z; 399 [2M-H]-. Reference example 001:
Production of 2-amino-5-fluoro-3-nitrobenzoic acid:

(1) 2-Amino-5-fluorobenzoic acid (4.0 g) was dissolved in tetrahydrofuran (40 ml), cooled to 0 ° C., trifluoroacetic anhydride (14.6 ml) was added dropwise, and the mixture was stirred overnight at room temperature. . The reaction mixture was concentrated, water was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain the desired 5-fluoro-2- (2,2,2-trifluoroacetamido) benzoic acid (5.38 g).
(2) 5-Fluoro-2- (2,2,2-trifluoroacetamido) benzoic acid (5.38 g) was added little by little to fuming nitric acid (30 ml) cooled to 0 ° C. and stirred at that temperature for 4 hours. did. The reaction mixture was poured into ice water and stirred vigorously. The resulting crystals were filtered, washed with water, and dried under reduced pressure. The obtained crystals were dissolved in ethanol (60 ml), 10% aqueous sodium hydroxide solution (60 ml) was added, and the mixture was stirred at 80 ° C. for 4 hr. The reaction mixture was concentrated, and the residue was diluted with 1N hydrochloric acid. The mixture was stirred at 0 ° C. and the resulting crystals were filtered. The obtained crystals were dried under reduced pressure to obtain the title compound (2.5 g).
LC-MS, m / z; 399 [2M-H]-.

　（１）抱水クロラール（３０ｇ）と硫酸ナトリウム（２５５ｇ）を水（２２５ｍｌ）に加えた懸濁液に、４－メトキシ－２－ニトロアニリン（１５ｇ）の濃塩酸溶液（２２．５ｍｌ）とヒドロキシルアミン塩酸塩（３１ｇ）の水溶液（２２５ｍｌ）を加え、２時間加熱還流した。反応混合物を室温に戻した後、析出した沈殿を濾取し、水（２０ｍｌ×５）で洗浄し、乾燥した。得られた粗生成物をシリカゲルカラムで精製し、（２Ｚ）－２－（ヒドロキシイミノ）－Ｎ－（４－メトキシ－２－ニトロフェニル）エタンアミド（１０ｇ）を得た。
¹H-NMR  (Methanol-d₄)  δ: 3.86 (3H, s), 7.28 (1H, dd, J = 9.2, 3.2 Hz), 7.49 (1H, s), 7.66 (1H, d, J = 2.8 Hz), 8.48 (1H, d, J = 9.6 Hz).
　（２）（２Ｚ）－２－（ヒドロキシイミノ）－Ｎ－（４－メトキシ－２－ニトロフェニル）エタンアミド（１０ｇ）を６０℃の濃硫酸（４０ｍｌ）にゆっくり加え、８０℃に昇温して１時間攪拌した。反応溶液を氷水に流し込み、生成した沈殿を濾取して水洗し（２０ｍｌ×５）、減圧乾燥した。得られた粗生成物をシリカゲルカラムで精製し、５－メトキシ－７－ニトロ－１Ｈ－インドール－２，３－ジオン（３．０ｇ）を得た。
¹H-NMR  (Methanol-d₄)  δ: 3.91 (3H, s), 7.40 (1H, d, J = 2.8 Hz), 7.59 (1H, d, J = 2.4 Hz).
　（３）５－メトキシ－７－ニトロ－１Ｈ－インドール－２，３－ジオン（２．０ｇ）を２Ｎ水酸化ナトリウム水溶液（３０ｍｌ）に加えた懸濁液に、氷冷下、３０％過酸化水素水（３ｍｌ）を滴下した。４時間室温で攪拌した後、反応混合物を２Ｎ塩酸水溶液で酸性にした。生成した沈殿を濾取して水洗し（１５ｍｌ×５）、減圧乾燥した。得られた粗生成物をシリカゲルカラムで精製し、２－アミノ－５－メトキシ－３－ニトロ安息香酸（１．５ｇ）を得た。
¹H-NMR  (Methanol-d₄) δ: 3.82 (3H, s), 7.89 (1H, d, J = 3.2 Hz), 7.95 (1H, d, J = 3.2 Hz). Reference example 002:
Preparation of 2-amino-5-methoxy-3-nitrobenzoic acid:

(1) A suspension of chloral hydrate (30 g) and sodium sulfate (255 g) in water (225 ml) was added to a concentrated hydrochloric acid solution (22.5 ml) of 4-methoxy-2-nitroaniline (15 g) and hydroxyl. An aqueous solution (225 ml) of amine hydrochloride (31 g) was added and heated to reflux for 2 hours. After returning the reaction mixture to room temperature, the deposited precipitate was collected by filtration, washed with water (20 ml × 5), and dried. The obtained crude product was purified with a silica gel column to obtain (2Z) -2- (hydroxyimino) -N- (4-methoxy-2-nitrophenyl) ethanamide (10 g).
¹ H-NMR (Methanol-d ₄ ) δ: 3.86 (3H, s), 7.28 (1H, dd, J = 9.2, 3.2 Hz), 7.49 (1H, s), 7.66 (1H, d, J = 2.8 Hz ), 8.48 (1H, d, J = 9.6 Hz).
(2) (2Z) -2- (Hydroxyimino) -N- (4-methoxy-2-nitrophenyl) ethanamide (10 g) was slowly added to concentrated sulfuric acid (40 ml) at 60 ° C., and the temperature was raised to 80 ° C. Stir for 1 hour. The reaction solution was poured into ice water, and the formed precipitate was collected by filtration, washed with water (20 ml × 5), and dried under reduced pressure. The obtained crude product was purified with a silica gel column to give 5-methoxy-7-nitro-1H-indole-2,3-dione (3.0 g).
¹ H-NMR (Methanol-d ₄ ) δ: 3.91 (3H, s), 7.40 (1H, d, J = 2.8 Hz), 7.59 (1H, d, J = 2.4 Hz).
(3) A suspension obtained by adding 5-methoxy-7-nitro-1H-indole-2,3-dione (2.0 g) to a 2N aqueous sodium hydroxide solution (30 ml) was cooled to 30% under ice cooling. Hydrogen water (3 ml) was added dropwise. After stirring for 4 hours at room temperature, the reaction mixture was acidified with 2N aqueous hydrochloric acid. The formed precipitate was collected by filtration, washed with water (15 ml × 5), and dried under reduced pressure. The obtained crude product was purified with a silica gel column to give 2-amino-5-methoxy-3-nitrobenzoic acid (1.5 g).
¹ H-NMR (Methanol-d ₄ ) δ: 3.82 (3H, s), 7.89 (1H, d, J = 3.2 Hz), 7.95 (1H, d, J = 3.2 Hz).

　（１）２－アミノ－５－メチル安息香酸（５ｇ）をテトラヒドロフラン（２６ｍｌ）に溶かし、０℃で撹拌下、トリフルオロ酢酸無水物（２６ｍｌ）を滴下し、室温で１５時間撹拌した。析出した固体をろ取し、水で洗浄後、乾燥することで、２－［ｂｉｓ（トリフルオロアセチル）アミノ］－５－メチル安息香酸の粗生成物（５ｇ）を白色固体として得た。
¹H-NMR (CDCl₃) δ: 2.54 (3H, s), 7.67 (1H, d, J = 8.4 Hz), 7.73 (1H, d, J = 8.4 Hz), 8.08 (1H, s).
　（２）上記粗生成物（５ｇ）に発煙硝酸（２２ｍｌ）を４℃下で加え、３時間撹拌した。反応溶液を氷水（１５ｇ）に注ぎ、析出した固体をろ取し、水（２０ｍｌ）で洗浄後、乾燥することで５－メチル－３－ニトロ－２－［（トリフルオロアセチル）アミノ］安息香酸（３．４ｇ）を黄色固体として得た。
¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 8.02 (1H, s), 8.17 (1H, s), 11.18 (1H, br s).
　（３）上記生成物（３．４ｇ）をエタノール（４０ｍｌ）に溶かし、２０％水酸化ナトリウム水溶液（４０ｍｌ）を加え８０℃にて５時間撹拌した。反応液を減圧濃縮し、得られた残渣に水（５０ｍｌ）を加え、５規定塩酸でｐＨ６とし、酢酸エチル（５０ｍｌ×２）で抽出した。有機層を水（３０ｍｌ）で洗浄後、乾燥し減圧濃縮することで、標記化合物（２ｇ）を橙色固体として得た。
¹H-NMR (DMSO-d₆) δ: 2.25 (3H, s), 8.07 (1H, s), 8.14 (1H, s), 8.35 (2H, br s). Reference example 003:
Preparation of 2-amino-5-methyl-3-nitrobenzoic acid:

(1) 2-Amino-5-methylbenzoic acid (5 g) was dissolved in tetrahydrofuran (26 ml), trifluoroacetic anhydride (26 ml) was added dropwise with stirring at 0 ° C., and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with water, and dried to give a crude product of 2- [bis (trifluoroacetyl) amino] -5-methylbenzoic acid (5 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H, s), 7.67 (1H, d, J = 8.4 Hz), 7.73 (1H, d, J = 8.4 Hz), 8.08 (1H, s).
(2) Fuming nitric acid (22 ml) was added to the crude product (5 g) at 4 ° C. and stirred for 3 hours. The reaction solution is poured into ice water (15 g), and the precipitated solid is collected by filtration, washed with water (20 ml), and dried to give 5-methyl-3-nitro-2-[(trifluoroacetyl) amino] benzoic acid. (3.4 g) was obtained as a yellow solid.
¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H, s), 8.02 (1H, s), 8.17 (1H, s), 11.18 (1H, br s).
(3) The product (3.4 g) was dissolved in ethanol (40 ml), 20% aqueous sodium hydroxide solution (40 ml) was added, and the mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water (50 ml) was added to the resulting residue, pH was adjusted to 6 with 5N hydrochloric acid, and the mixture was extracted with ethyl acetate (50 ml × 2). The organic layer was washed with water (30 ml), dried and concentrated under reduced pressure to give the title compound (2 g) as an orange solid.
¹ H-NMR (DMSO-d ₆ ) δ: 2.25 (3H, s), 8.07 (1H, s), 8.14 (1H, s), 8.35 (2H, br s).

　３－アミノ－４－メチル－２－ニトロ安息香酸（１０ｇ）をメタノール（１００ｍｌ）に溶解し、１０％パラジウム炭素（２．０ｇ）を加えて、室温で２０時間、水素雰囲気下で攪拌した。反応混合物をセライト濾過し、濾液を濃縮することで、２，３－ジアミノ－４－メチル安息香酸（８．１ｇ）を得た。
¹H-NMR  (Methanol-d₄) δ: 2.21 (3H, s), 6.48 (1H, d, J = 8.0 Hz), 7.32 (1H, d, J = 8.0 Hz). Reference example 004:
Production of 2,3-diamino-4-methylbenzoic acid:

3-Amino-4-methyl-2-nitrobenzoic acid (10 g) was dissolved in methanol (100 ml), 10% palladium on carbon (2.0 g) was added, and the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated to obtain 2,3-diamino-4-methylbenzoic acid (8.1 g).
¹ H-NMR (Methanol-d ₄ ) δ: 2.21 (3H, s), 6.48 (1H, d, J = 8.0 Hz), 7.32 (1H, d, J = 8.0 Hz).

Instead of 3-amino-4-methyl-2-nitrobenzoic acid in Reference Example 004, compounds corresponding to the following table (Reference Examples 005 to 006) were prepared in the same manner as in Reference Example 004 using the corresponding starting compounds. Manufactured.

　（１）Bioorganic & Medicinal Chemistry 11 (2003) 1769-1780に記載の方法を用いて、脱アセチル体を製造した。
LC-MS, m/z; 289 [M+H]+
　（２）参考例００４における３－アミノ－４－メチル－２－ニトロ安息香酸の代わりに、メチル ２－アミノ－５－ブロモ－６－メチル－３－ニトロベンゾエートを用いて、参考例００４と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 181 [M+H]+ Reference example 008:
Production of methyl 2,3-diamino-6-methylbenzoate:

(1) A deacetylated product was produced using the method described in Bioorganic & Medicinal Chemistry 11 (2003) 1769-1780.
LC-MS, m / z; 289 [M + H] +
(2) Similar to Reference Example 004 using methyl 2-amino-5-bromo-6-methyl-3-nitrobenzoate instead of 3-amino-4-methyl-2-nitrobenzoic acid in Reference Example 004 The title compound was prepared by the method of
LC-MS, m / z; 181 [M + H] +

　エチル ２－アミノ－６－フルオロ－３－ニトロベンゾエート（５．０ｇ）をメタノール（５０ｍｌ）に溶かし、０℃で撹拌下、１．９Ｍナトリウムメトキシド／メタノール溶液（５ｍｌ）を滴下し、室温で１時間撹拌した。反応液を０℃に冷却し、２規定塩酸を加えたのち、生成物をろ取し、水で洗浄することで表記化合物（５．４３ｇ）を得た。
LC-MS, m/z; 241 [M+H]+  Reference Example 009:
Preparation of ethyl 2-amino-6-methoxy-3-nitrobenzoate:

Ethyl 2-amino-6-fluoro-3-nitrobenzoate (5.0 g) was dissolved in methanol (50 ml), and 1.9 M sodium methoxide / methanol solution (5 ml) was added dropwise at 0 ° C. with stirring. Stir for 1 hour. The reaction mixture was cooled to 0 ° C., 2N hydrochloric acid was added, the product was collected by filtration, and washed with water to give the title compound (5.43 g).
LC-MS, m / z; 241 [M + H] +

　メチル ２－アミノ－５－クロロ－３－ニトロベンゾエート（５ｇ）をエタノール（１００ｍｌ）、水（５０ｍｌ）の混合溶媒に加えた懸濁液に、鉄（６．１ｇ）および塩化アンモニウム（２．４ｇ）を加え２時間加熱還流した。反応溶液をろ過後、ろ液を減圧濃縮し、残渣に水（１００ｍｌ）を加え、目的物を酢酸エチル（２００ｍｌ）で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮することで標記化合物の粗成生物（４．９ｇ）を茶色固体として得た。
¹H-NMR (CDCl₃) δ: 3.87 (3H, s), 6.81 (1H, d, J = 2.4 Hz), 7.43 (1H, d, J = 2.4 Hz). Reference example 010:
Production of methyl 2,3-diamino-5-chlorobenzoate:

To a suspension of methyl 2-amino-5-chloro-3-nitrobenzoate (5 g) in a mixed solvent of ethanol (100 ml) and water (50 ml) was added iron (6.1 g) and ammonium chloride (2.4 g). ) And heated to reflux for 2 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, water (100 ml) was added to the residue, and the target product was extracted with ethyl acetate (200 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound crude product (4.9 g) as a brown solid.
¹ H-NMR (CDCl ₃ ) δ: 3.87 (3H, s), 6.81 (1H, d, J = 2.4 Hz), 7.43 (1H, d, J = 2.4 Hz).

Instead of 3-amino-4-methyl-2-nitrobenzoic acid in Reference Example 004, the corresponding raw material compound was used and the compounds shown in the following table (Reference Examples 011 to 012) were prepared in the same manner as in Reference Example 004. Manufactured.

　ｐ－トルエンスルホン酸一水和物（２５．６ｇ）を減圧下で１時間、１２０℃で加熱し、乾燥した。そこにメチル ３－アミノ－４－クロロベンゾエート（１０ｇ）とプロピオノニトリル（２０ｍｌ）を加え、１６時間加熱還流した。反応混合物を放冷後、飽和炭酸水素ナトリウム水溶液（２５０ｍｌ）を加えて１０分間攪拌した。プロピオノニトリルを減圧留去した後、酢酸エチルで抽出した（５０ｍｌ×３）。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：石油エーテル／酢酸エチル）で精製し、標記化合物（８．５ｇ）を得た。
LC-MS, m/z; 241 [M+H]+ Reference Example 013:
Preparation of methyl 4-chloro-3- (propanimidoylamino) benzoate:

p-Toluenesulfonic acid monohydrate (25.6 g) was heated at 120 ° C. under reduced pressure for 1 hour and dried. Thereto were added methyl 3-amino-4-chlorobenzoate (10 g) and propiononitrile (20 ml), and the mixture was heated to reflux for 16 hours. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution (250 ml) was added, and the mixture was stirred for 10 min. Propiononitrile was distilled off under reduced pressure, followed by extraction with ethyl acetate (50 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: petroleum ether / ethyl acetate) to obtain the title compound (8.5 g).
LC-MS, m / z; 241 [M + H] +

The compounds shown in the following table (Reference Examples 014 to 015) were produced in the same manner as in Reference Example 013 using the corresponding starting compounds instead of methyl 3-amino-4-chlorobenzoate in Reference Example 013.

　メチル ４－メトキシ－３－プロピオンイミドアミドベンゾエートの粗生成物（１４．５ｇ）をメタノールに溶かし、０℃で撹拌下、５％次亜塩素酸ナトリウム溶液（１４ｍｌ）を加え、０℃にて１時間撹拌した。その後反応液に飽和炭酸水素ナトリウム水溶液（１５０ｍｌ）およびメタノール（１５０ｍｌ）を加え、７０℃にて２時間加熱した。反応終了後、メタノールを減圧留去し、目的物を酢酸エチル（１５０ｍｌ×３）で抽出した。有機層を飽和食塩水（１Ｌ）で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：石油エーテル／酢酸エチル＝１０：１～５：１）で精製することで、標記化合物（３．６ｇ）を白色固体として得た。
¹H-NMR (CDCl₃) δ: 1.45 (3H, t, J = 7.6 Hz), 2.97 (2H, q, J = 7.6 Hz), 3.95 (3H, s), 4.06 (3H, s), 6.68 (1H, d, J = 8.4 Hz), 7.82 (1H, d, J = 8.4 Hz). Reference Example 016:
Preparation of methyl 2-ethyl-7-methoxy-1H-benzimidazole-4-carboxylate:

A crude product of methyl 4-methoxy-3-propionimidoamidobenzoate (14.5 g) was dissolved in methanol, 5% sodium hypochlorite solution (14 ml) was added with stirring at 0 ° C., and 1 at 0 ° C. Stir for hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (150 ml) and methanol (150 ml) were added to the reaction solution, and the mixture was heated at 70 ° C. for 2 hours. After completion of the reaction, methanol was distilled off under reduced pressure, and the target product was extracted with ethyl acetate (150 ml × 3). The organic layer was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: petroleum ether / ethyl acetate = 10: 1 to 5: 1) to give the title compound (3.6 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.6 Hz), 2.97 (2H, q, J = 7.6 Hz), 3.95 (3H, s), 4.06 (3H, s), 6.68 ( 1H, d, J = 8.4 Hz), 7.82 (1H, d, J = 8.4 Hz).

　参考例０１６におけるメチル ４－メトキシ－３－プロピオンイミドアミドベンゾエートの代わりに、メチル ４－フルオロ－３－プロピオンイミドアミドベンゾエートを用いて、参考例０１６と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 223 [M+H]+ Reference Example 017:
Preparation of methyl 2-ethyl-7-fluoro-1H-benzimidazole-4-carboxylate:

The title compound was produced in the same manner as in Reference Example 016 using methyl 4-fluoro-3-propionimidoamidobenzoate instead of methyl 4-methoxy-3-propionimidoamidobenzoate in Reference Example 016.
LC-MS, m / z; 223 [M + H] +

　参考例０１６におけるメチル ４－メトキシ－３－プロピオンイミドアミドベンゾエートの代わりに、メチル ４－クロロ－３－プロピオンイミドアミドベンゾエートを用いて、参考例０１６と同様の方法、続く下記の参考例０１９と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 225 [M+H]+ Reference Example 018:
Preparation of 7-chloro-2-ethyl-1H-benzimidazole-4-carboxylic acid:

Using methyl 4-chloro-3-propionimidoamidobenzoate instead of methyl 4-methoxy-3-propionimidoamidobenzoate in Reference Example 016, the same method as Reference Example 016, followed by Reference Example 019 below The title compound was prepared by the method of
LC-MS, m / z; 225 [M + H] +

　メチル ２－エチル－７－フルオロ－１Ｈ－ベンズイミダゾール－４－カルボキシレートをエタノール（１０ｍｌ）、水（１０ｍｌ）の混合溶媒に溶かし、６規定水酸化ナトリウム水溶液（１５ｍｌ）を加え、３時間加熱還流した。反応溶液を減圧濃縮し、４規定塩酸を加えてｐＨ４とし、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：ジクロロメタン／メタノール＝２０：１～１０：１）で精製することで、標記化合物の粗生成物（７６０ｍｇ）を、茶色固体として得た。
LC-MS, m/z; 209 [M+H]+ Reference Example 019:
Preparation of 2-ethyl-7-fluoro-1H-benzimidazole-4-carboxylic acid:

Methyl 2-ethyl-7-fluoro-1H-benzimidazole-4-carboxylate is dissolved in a mixed solvent of ethanol (10 ml) and water (10 ml), 6N aqueous sodium hydroxide solution (15 ml) is added, and the mixture is heated to reflux for 3 hours. did. The reaction solution was concentrated under reduced pressure, 4N hydrochloric acid was added to pH 4, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: dichloromethane / methanol = 20: 1 to 10: 1) to give a crude product of the title compound (760 mg) as a brown solid.
LC-MS, m / z; 209 [M + H] +

　参考例０１９におけるメチル ２－エチル－７－フルオロ－１Ｈ－ベンズイミダゾール－４－カルボキシレートの代わりに、メチル ２－エチル－７－メトキシ－１Ｈ－ベンズイミダゾール－４－カルボキシレートを用いて、参考例０１９と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 221 [M+H]+ Reference Example 020:
Preparation of 2-ethyl-7-methoxy-1H-benzimidazole-4-carboxylic acid:

In place of methyl 2-ethyl-7-fluoro-1H-benzimidazole-4-carboxylate in Reference Example 019, methyl 2-ethyl-7-methoxy-1H-benzimidazole-4-carboxylate was used. The title compound was produced in the same manner as in 019.
LC-MS, m / z; 221 [M + H] +

　２，３－ジアミノ安息香酸（１．０ｇ）、プロピオン酸（１．４７ｍｌ）および４Ｎ塩酸（１０ｍｌ）の混合液を加熱還流下、終夜撹拌した。反応液を１０℃まで冷却後、１０Ｎ水酸化ナトリウム水溶液により中和し、生じた結晶を濾取した。得られた結晶をアセトニトリルに懸濁させ３０分撹拌後、濾取し、標記化合物（１．３７ｇ）を得た。
LC-MS, m/z; 191 [M+H]+ Reference Example 021:
Preparation of 2-ethyl-1H-benzimidazole-4-carboxylic acid:

A mixture of 2,3-diaminobenzoic acid (1.0 g), propionic acid (1.47 ml) and 4N hydrochloric acid (10 ml) was stirred overnight with heating under reflux. The reaction solution was cooled to 10 ° C., neutralized with 10N aqueous sodium hydroxide solution, and the resulting crystals were collected by filtration. The obtained crystals were suspended in acetonitrile, stirred for 30 minutes, and then collected by filtration to obtain the title compound (1.37 g).
LC-MS, m / z; 191 [M + H] +

Instead of 2,3-diaminobenzoic acid and propionic acid in Reference Example 021, the corresponding starting compound and carboxylic acid (R ^2A —COOH) were used in the same manner as in Reference Example 021. Examples 022 to 034) were prepared.

　エチル ２，３－ジアミノ－６－フルオロベンゾエート（１．０ｇ）、プロピオン酸（１．１３ｍｌ）および４Ｎ塩酸（１０ｍｌ）の混合液を加熱還流下撹拌した。５時間後さらにプロピオン酸（１．１３ｍｌ）を追加し、終夜加熱還流下撹拌した。反応液を１０℃まで冷却後、１０Ｎ水酸化ナトリウム水溶液により中和し、生じた結晶を濾取した。得られた結晶をアセトニトリルに懸濁させ３０分撹拌後、濾取し、目的とする標記化合物（８４７ｍｇ）を得た。
LC-MS, m/z; 209 [M+H]+ Reference Example 035:
Preparation of 2-ethyl-5-fluoro-1H-benzimidazole-4-carboxylic acid:

A mixture of ethyl 2,3-diamino-6-fluorobenzoate (1.0 g), propionic acid (1.13 ml) and 4N hydrochloric acid (10 ml) was stirred with heating under reflux. After 5 hours, more propionic acid (1.13 ml) was added, and the mixture was stirred overnight with heating under reflux. The reaction solution was cooled to 10 ° C., neutralized with 10N aqueous sodium hydroxide solution, and the resulting crystals were collected by filtration. The obtained crystals were suspended in acetonitrile, stirred for 30 minutes, and then collected by filtration to obtain the desired title compound (847 mg).
LC-MS, m / z; 209 [M + H] +

１）原料はＷＯ２００５／４２５３０に記載の方法により製造した。 In the same manner as in Reference Example 035, using the corresponding starting compound and carboxylic acid (R ^2A -COOH) instead of ethyl 2,3-diamino-6-fluorobenzoate and propionic acid in Reference Example 035, the following table was prepared. (Reference Examples 036 to 044) were produced.

1) The raw material was produced by the method described in WO2005 / 42530.

　２－エチル－１Ｈ－ベンズイミダゾール－４－カルボン酸（１．２ｇ）をスルホラン（６．０ｍｌ）に溶かし、塩化ホスホリル（１．２９ｍｌ）およびスルファミド（１．２１ｇ）を加え、１２０℃で２時間半撹拌した。反応液を０℃に冷却後、飽和炭酸水素ナトリウム水溶液（５０ｍｌ）を加えた。反応液に酢酸エチルを加え目的物を抽出し、有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をジオールシリカカラムクロマトグラフィー（ヘキサン／酢酸エチル）により精製し、標記化合物（４５４ｍｇ）を得た。
LC-MS, m/z; 172 [M+H]+ Reference Example 045:
Preparation of 2-ethyl-1H-benzimidazole-4-carbonitrile:

2-ethyl-1H-benzimidazole-4-carboxylic acid (1.2 g) was dissolved in sulfolane (6.0 ml), phosphoryl chloride (1.29 ml) and sulfamide (1.21 g) were added, and the mixture was stirred at 120 ° C. for 2 hours. Half stirred. The reaction mixture was cooled to 0 ° C., and saturated aqueous sodium hydrogen carbonate solution (50 ml) was added. Ethyl acetate was added to the reaction mixture to extract the desired product, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by diol silica column chromatography (hexane / ethyl acetate) to obtain the title compound (454 mg).
LC-MS, m / z; 172 [M + H] +

１）参考例０７１における副生成物 Instead of 2-ethyl-1H-benzimidazole-4-carboxylic acid in Reference Example 045, compounds corresponding to the following table (Reference Examples 046-072) were prepared in the same manner as in Reference Example 045 using the corresponding starting compounds. Manufactured.

1) By-product in Reference Example 071

　５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－カルボン酸（３００ｍｇ）を酢酸エチル（１５ｍｌ）に加えた懸濁液に、塩化アンモニウム（２４８ｍｇ）、トリエチルアミン（１．０７ｍｌ）および５０％プロピルホスホン酸無水物（環状トリマー）／酢酸エチル溶液（２．７ｍｌ）を加え、２４時間加熱還流した。反応液を室温に冷却し、水を加え、目的物を酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：クロロホルム／メタノール）で精製することで標記化合物（１６７ｍｇ）を白色固体として得た。
LC-MS, m/z; 176 [M+H]+ Reference Example 073:
Production of 5-fluoro-2-methyl-1H-benzimidazole-4-carbonitrile (another method of Reference Example 057):

To a suspension of 5-fluoro-2-methyl-1H-benzimidazole-4-carboxylic acid (300 mg) in ethyl acetate (15 ml) was added ammonium chloride (248 mg), triethylamine (1.07 ml) and 50% propyl. A phosphonic acid anhydride (cyclic trimer) / ethyl acetate solution (2.7 ml) was added, and the mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, water was added, and the target product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-FlashTM amino column, developing solvent: chloroform / methanol) to obtain the title compound (167 mg) as a white solid.
LC-MS, m / z; 176 [M + H] +

　（１）エチル ２，３－ジアミノ－６－フルオロベンゾエート（２０ｇ）をメタノール（１００ｍｌ）に溶解し、ｐ－トルエンスルホン酸（２．０ｇ）とテトラメトキシメタン（２０．８ｇ）を加え、室温で１８時間攪拌した。反応混合物を減圧濃縮し、残渣をシリカゲルカラム（展開溶媒：石油エーテル／酢酸エチル）で精製することで、エチル ５－フルオロ－２－メトキシ－１Ｈ－ベンズイミダゾール－４－カルボキシレート（１９ｇ）を得た。
LC-MS, m/z; ２３９ [M+H]+
　（２）エチル ５－フルオロ－２－メトキシ－１Ｈ－ベンズイミダゾール－４－カルボキシレート（１８ｇ）をメタノール（１００ｍｌ）に溶解し、２Ｎ水酸化カリウム水溶液（７６ｍｌ）を滴下して、室温下１８時間攪拌した。反応混合物を減圧濃縮して水（２０ｍｌ）を加え、４Ｎ塩酸水溶液でｐＨ５とした。生成した沈殿物を濾取し、減圧乾燥することで、５－フルオロ－２－メトキシ－１Ｈ－ベンズイミダゾール－４－カルボン酸（１２ｇ）を得た。
¹H-NMR (DMSO-d₆) δ: 4.06 (3H, s), 6.97 (1H, dd, J = 12.0, 8.8 Hz), 7.55 (1H, br s), 11.95 (1H, br s).
　（３）参考例０４５における２－エチル－１Ｈ－ベンズイミダゾール－４－カルボン酸の代わりに、５－フルオロ－２－メトキシ－１Ｈ－ベンズイミダゾール－４－カルボン酸を用いて、参考例０４５と同様の方法により、標記化合物を製造した。
LC-MS, m/z; １９６ [M+H]+ Reference Example 074:
Preparation of 2-chloro-5-fluoro-1H-benzimidazole-4-carbonitrile:

(1) Ethyl 2,3-diamino-6-fluorobenzoate (20 g) is dissolved in methanol (100 ml), p-toluenesulfonic acid (2.0 g) and tetramethoxymethane (20.8 g) are added, and at room temperature. Stir for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by a silica gel column (developing solvent: petroleum ether / ethyl acetate) to obtain ethyl 5-fluoro-2-methoxy-1H-benzimidazole-4-carboxylate (19 g). It was.
LC-MS, m / z; 239 [M + H] +
(2) Ethyl 5-fluoro-2-methoxy-1H-benzimidazole-4-carboxylate (18 g) was dissolved in methanol (100 ml), and 2N aqueous potassium hydroxide solution (76 ml) was added dropwise at room temperature for 18 hours. Stir. The reaction mixture was concentrated under reduced pressure, water (20 ml) was added, and the pH was adjusted to 5 with 4N aqueous hydrochloric acid. The produced precipitate was collected by filtration and dried under reduced pressure to obtain 5-fluoro-2-methoxy-1H-benzimidazole-4-carboxylic acid (12 g).
¹ H-NMR (DMSO-d ₆ ) δ: 4.06 (3H, s), 6.97 (1H, dd, J = 12.0, 8.8 Hz), 7.55 (1H, br s), 11.95 (1H, br s).
(3) Similar to Reference Example 045 except that 5-fluoro-2-methoxy-1H-benzimidazole-4-carboxylic acid was used in place of 2-ethyl-1H-benzimidazole-4-carboxylic acid in Reference Example 045 The title compound was prepared by the method of
LC-MS, m / z; 196 [M + H] +

　（１）２－クロロ－５－フルオロ－１Ｈ－ベンズイミダゾール－４－カルボニトリル（１．０ｇ）をＴＨＦ（５ｍｌ）に溶かし、水素化ナトリウム（３０６ｍｇ）を０℃にて加え、１時間撹拌した。反応液に２－（トリメチルシリル）エトキシメチルクロリド（１．２７ｇ）を０℃にて滴下し、室温で１８時間撹拌した。反応液を減圧濃縮し、残渣に水（５ｍｌ）を加え、塩化メチレン（２０ｍｌ×２）で目的物を抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（展開溶媒：石油エーテル／酢酸エチル＝２０：１～５：１）で精製することで２－クロロ－５－フルオロ－１－｛［２－（トリメチルシリル）エトキシ］メチル｝－１Ｈ－ベンズイミダゾール－４－カルボニトリル（１．０ｇ）を白色固体として得た。
¹H-NMR (DMSO-d₆) δ: -0.08 (3H, s), 0.85 (2H, t, J = 8.0 Hz), 3.58 (2H, t, J = 8.0 Hz), 5.72 (2H, s), 7.52-7.57 (1H, m), 8.13-8.18 (1H, m).
　（２）上記生成物（１．０ｇ）をメタノール（１０ｍｌ）に溶かし、２５℃で撹拌下、ナトリウムメトキシド（３３１ｍｇ）を加え、１８時間撹拌した。反応溶液を減圧濃縮し、残渣に水（１０ｍｌ）を加え、塩化メチレン（１０ｍｌ×３）で目的物を抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（展開溶媒：石油エーテル／酢酸エチル＝２０：１～３：１）で精製することで５－フルオロ－２－メトキシ－１－｛［２－（トリメチルシリル）エトキシ］メチル｝－１Ｈ－ベンズイミダゾール－４－カルボニトリル（０．９ｇ）を白色固体として得た。
¹H-NMR (DMSO-d₆) δ: -0.10 (3H, s), 0.82 (2H, t, J = 8.0 Hz), 3.53 (2H, t, J = 8.0 Hz), 4.20 (3H, s), 5.44 (2H, s), 7.21-7.27 (1H, m), 7.80-7.85 (1H, m).
　（３）５－フルオロ－２－メトキシ－１－｛［２－（トリメチルシリル）エトキシ］メチル｝－１Ｈ－ベンズイミダゾール－４－カルボニトリル（０．９ｇ）に１Ｍテトラブチルアンモニウムフルオリド／テトラヒドロフラン溶液（２８ｍｌ）を加え、８０℃にて４時間撹拌した。反応溶液を減圧濃縮し、残渣に水（１０ｍｌ）を加え、塩化メチレン（１０ｍｌ×３）で目的物を抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲルクロマトグラフィー（展開溶媒：石油エーテル／酢酸エチル＝２０：１～１：１）で精製することで標記化合物（２７０ｍｇ）を白色固体として得た。
¹H-NMR (DMSO-d₆) δ: 4.11 (3H, s), 7.10 (1H, m), 7.56 (1H, m). Reference Example 075:
Preparation of 5-fluoro-2-methoxy-1H-benzimidazole-4-carbonitrile:

(1) 2-Chloro-5-fluoro-1H-benzimidazole-4-carbonitrile (1.0 g) was dissolved in THF (5 ml), sodium hydride (306 mg) was added at 0 ° C., and the mixture was stirred for 1 hour. . 2- (Trimethylsilyl) ethoxymethyl chloride (1.27 g) was added dropwise to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, water (5 ml) was added to the residue, and the desired product was extracted with methylene chloride (20 ml × 2). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (developing solvent: petroleum ether / ethyl acetate = 20: 1 to 5: 1) to give 2-chloro-5 -Fluoro-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-benzimidazole-4-carbonitrile (1.0 g) was obtained as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ: -0.08 (3H, s), 0.85 (2H, t, J = 8.0 Hz), 3.58 (2H, t, J = 8.0 Hz), 5.72 (2H, s) , 7.52-7.57 (1H, m), 8.13-8.18 (1H, m).
(2) The product (1.0 g) was dissolved in methanol (10 ml), sodium methoxide (331 mg) was added with stirring at 25 ° C., and the mixture was stirred for 18 hours. The reaction solution was concentrated under reduced pressure, water (10 ml) was added to the residue, and the desired product was extracted with methylene chloride (10 ml × 3). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue is purified by silica gel chromatography (developing solvent: petroleum ether / ethyl acetate = 20: 1 to 3: 1) to give 5-fluoro-2. -Methoxy-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-benzimidazole-4-carbonitrile (0.9 g) was obtained as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ: -0.10 (3H, s), 0.82 (2H, t, J = 8.0 Hz), 3.53 (2H, t, J = 8.0 Hz), 4.20 (3H, s) , 5.44 (2H, s), 7.21-7.27 (1H, m), 7.80-7.85 (1H, m).
(3) 5-fluoro-2-methoxy-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-benzimidazole-4-carbonitrile (0.9 g) in 1M tetrabutylammonium fluoride / tetrahydrofuran solution ( 28 ml) was added and the mixture was stirred at 80 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, water (10 ml) was added to the residue, and the desired product was extracted with methylene chloride (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: petroleum ether / ethyl acetate = 20: 1 to 1: 1) to give the title compound (270 mg). Was obtained as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ: 4.11 (3H, s), 7.10 (1H, m), 7.56 (1H, m).

　４－ブロモ－１Ｈ－インダゾール（１００ｍｇ）をＮ－メチルピロリドン（２ｍｌ）に溶かし、シアン化亜鉛（６０％、１００ｍｇ）およびテトラキス（トリフェニルホスフィン）パラジウム（８８ｍｇ）を加え、８５℃で１７時間撹拌した。反応溶液に水を加え、酢酸エチルで目的物を抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：クロロホルム／メタノール）で精製することで標記化合物（１１９ｍｇ）を得た。
TLC Rf=0.25 (CHCl₃/MeOH=9:1) Reference Example 076:
Production of 1H-indazole-4-carbonitrile:

4-Bromo-1H-indazole (100 mg) was dissolved in N-methylpyrrolidone (2 ml), zinc cyanide (60%, 100 mg) and tetrakis (triphenylphosphine) palladium (88 mg) were added, and the mixture was stirred at 85 ° C. for 17 hours. did. Water was added to the reaction solution, and the target product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-FlashTM amino column, developing solvent: chloroform / methanol) to obtain the title compound (119 mg).
TLC Rf = 0.25 (CHCl ₃ / MeOH = 9: 1)

　参考例０７６における４－ブロモ－１Ｈ－インダゾールの代わりに、４－ブロモ－５－フルオロ－１Ｈ－インダゾール（ＷＯ２００８／１０７４５５ Ａ１に記載の方法により製造）を用いて、参考例０７６と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 160 [M-H]- Reference Example 077:
Preparation of 5-fluoro-1H-indazole-4-carbonitrile:

By using 4-bromo-5-fluoro-1H-indazole (produced by the method described in WO2008 / 107455 A1) instead of 4-bromo-1H-indazole in Reference Example 076, the same method as in Reference Example 076 The title compound was prepared.
LC-MS, m / z; 160 [MH]-

　１Ｈ－インダゾール－４－カルボニトリル（３７０ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）に溶かし、炭酸カリウム（１．０ｇ）およびヨウ化メチル（０．３２ｍｌ）を加え室温で１７時間撹拌した。反応溶液に水を加え、目的物を酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：クロロホルム／酢酸エチル）で精製することで１－メチル－１Ｈ－インダゾール－４－カルボニトリル（２５９ｍｇ）および２－メチル－２Ｈ－インダゾール－４－カルボニトリル（１２６ｍｇ）を得た。
１－メチル－１Ｈ－インダゾール－４－カルボニトリル
¹H-NMR (CDCl₃) δ: 4.14 (3H, s), 7.42-7.49 (1H, m), 7.53-7.57 (1H, m), 7.65-7.70 (1H, m), 8.17-8.19 (1H, m).
２－メチル－２Ｈ－インダゾール－４－カルボニトリル
¹H-NMR (CDCl₃) δ: 4.29 (3H, s), 7.29-7.36 (1H, m), 7.50-7.56 (1H, m), 7.92-7.97 (1H, m), 8.10-8.13 (1H, m). Reference examples 078-079:
Preparation of 1-methyl-1H-indazole-4-carbonitrile and 2-methyl-2H-indazole-4-carbonitrile:

1H-indazole-4-carbonitrile (370 mg) was dissolved in N, N-dimethylformamide (10 ml), potassium carbonate (1.0 g) and methyl iodide (0.32 ml) were added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, and the target product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-FlashTM, developing solvent: chloroform / ethyl acetate) to give 1-methyl-1H-indazole-4-carbonitrile (259 mg) and 2-methyl-2H -Indazole-4-carbonitrile (126 mg) was obtained.
1-methyl-1H-indazole-4-carbonitrile
¹ H-NMR (CDCl ₃ ) δ: 4.14 (3H, s), 7.42-7.49 (1H, m), 7.53-7.57 (1H, m), 7.65-7.70 (1H, m), 8.17-8.19 (1H, m).
2-Methyl-2H-indazole-4-carbonitrile
¹ H-NMR (CDCl ₃ ) δ: 4.29 (3H, s), 7.29-7.36 (1H, m), 7.50-7.56 (1H, m), 7.92-7.97 (1H, m), 8.10-8.13 (1H, m).

　２－エチル－１Ｈ－ベンズイミダゾール－４－カルボニトリル（４５０ｍｇ）をＴＨＦ／水（１０／１）混合液（１０ｍｌ）に溶かし、ヒドロキシルアミン塩酸塩（２３７ｍｇ）およびトリエチルアミン（７３２μｌ）を加え、加熱還流下終夜撹拌した。反応液を室温まで冷却し、酢酸エチルを加えて目的物を抽出し、有機層をさらに飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、標記化合物（４３０ｍｇ）を得た。
LC-MS, m/z; 205 [M+H]+ Reference Example 080:
Preparation of 2-ethyl-N′-hydroxy-1H-benzimidazole-4-carboximidamide:

2-Ethyl-1H-benzimidazole-4-carbonitrile (450 mg) is dissolved in a THF / water (10/1) mixture (10 ml), hydroxylamine hydrochloride (237 mg) and triethylamine (732 μl) are added, and the mixture is heated to reflux. Stirred overnight. The reaction mixture was cooled to room temperature, ethyl acetate was added to extract the desired product, and the organic layer was further washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (430 mg).
LC-MS, m / z; 205 [M + H] +

In the same manner as in Reference Example 080, instead of 2-ethyl-1H-benzimidazole-4-carbonitrile in Reference Example 080, the compounds in the following table (Reference Examples 081 to 109) were prepared in the same manner as in Reference Example 080. Manufactured.

Instead of 2-ethyl-1H-benzimidazole-4-carbonitrile in Reference Example 080, the corresponding raw material compound was used and the compounds shown in the following table (Reference Examples 110 to 112) were prepared in the same manner as in Reference Example 080. Manufactured.

　参考例０８０における２－エチル－１Ｈ－ベンズイミダゾール－４－カルボニトリルの代わりに、２－メチル－２Ｈ－インダゾール－４－カルボニトリルを用いて、参考例０８０と同様の方法により、標記化合物を製造した。
ＴＬＣ（アミノシリカゲル） Ｒｆ＝０．２０ （ＥｔＯＡｃ） Reference Example 113:
Preparation of N′-hydroxy-2-methyl-2H-indazole-4-carboximidamide:

The title compound was prepared in the same manner as in Reference Example 080 using 2-methyl-2H-indazole-4-carbonitrile instead of 2-ethyl-1H-benzimidazole-4-carbonitrile in Reference Example 080. did.
TLC (amino silica gel) Rf = 0.20 (EtOAc)

　Ｎ－Ｂｏｃ－ピペリジン－４－カルボン酸（０．５３ｇ）をテトラヒドロフラン（６．０ｍｌ）に溶かし、ＣＤＩ（０．３８ｇ）を加え、室温下１時間撹拌した。反応液に２－エチル－Ｎ’－ヒドロキシ－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミド（０．４３ｇ）のテトラヒドロフラン溶液（５．０ｍｌ）を加え、１時間加熱還流下撹拌した。反応液を室温まで冷却し、テトラブチルアンモニウムフルオリド（１Ｍ／ＴＨＦ溶液）（２．１１ｍｌ）を加え、５０℃下２時間撹拌した。反応液を室温まで冷却後、水を加えて希釈し、酢酸エチルにより目的物を抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－Ｆｌａｓｈ^ＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：ヘキサン：酢酸エチル）で精製することで標記化合物を０．９３ｇ得た。
LC-MS, m/z; 398 [M+H]+ Reference Example 114:
Preparation of tert-butyl 4- [3- (2-ethyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate:

N-Boc-piperidine-4-carboxylic acid (0.53 g) was dissolved in tetrahydrofuran (6.0 ml), CDI (0.38 g) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a tetrahydrofuran solution (5.0 ml) of 2-ethyl-N′-hydroxy-1H-benzimidazole-4-carboximidamide (0.43 g), and the mixture was stirred for 1 hour with heating under reflux. The reaction mixture was cooled to room temperature, tetrabutylammonium fluoride (1M / THF solution) (2.11 ml) was added, and the mixture was stirred at 50 ° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with water, and the target product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column; Hi-Flash ^™ amino column, developing solvent: hexane: ethyl acetate) to obtain 0.93 g of the title compound.
LC-MS, m / z; 398 [M + H] +

Instead of 2-ethyl-N′-hydroxy-1H-benzimidazole-4-carboximidoamide in Reference Example 114, the corresponding raw material compound was used and the compounds shown in the following table (Reference) were prepared in the same manner as in Reference Example 114. Examples 115-138) were prepared.

（式中、（Ｂ－２）は下記表に示す環状アミン構造を意味し、Ｂｏｃ基の結合位置は（Ｂ－２）の環状アミン上の窒素原子である）

Instead of 2-ethyl-N′-hydroxy-1H-benzimidazole-4-carboximidamide and 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid in Reference Example 114, the corresponding starting compound (benzimidazole derivative) ) And carboxylic acid (Boc- (B-2) -COOH) were prepared in the same manner as in Reference Example 114 to produce the compounds shown in the following table (Reference Examples 139 to 144).

(Wherein (B-2) means the cyclic amine structure shown in the following table, and the binding position of the Boc group is the nitrogen atom on the cyclic amine of (B-2))

　ｔｅｒｔ－ブチル ４－［３－（２－エチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレート（１．６ｇ）と炭酸カリウム（８２８ｍｇ）をＤＭＦ（１６ｍｌ）に加えた懸濁液に、ヨウ化メチル（０．６０ｍｌ）を加えて、室温で１６時間攪拌した。反応混合物に水を加え、酢酸エチルで目的物を抽出した。有機層を水洗して無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をアミノシリカゲルカラム（展開溶媒：石油エーテル／酢酸エチル）で精製することで、ｔｅｒｔ－ブチル ４－（３－（２－エチル－５－フルオロ－１－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル）ピペリジン－１－カルボキシレート（５００ｍｇ）とｔｅｒｔ－ブチル ４－（３－（２－エチル－６－フルオロ－１－メチル－１Ｈ－ベンズイミダゾール－７－イル）－１，２，４－オキサジアゾール－５－イル）ピペリジン－１－カルボキシレート（３７０ｍｇ）をそれぞれ得た。
TLC Rf (PE/EtOAc=1/1): 0.25, 0.45. Reference Example 145-146:
tert-Butyl 4- [3- (2-Ethyl-5-fluoro-1-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxy Rate <br/> and
tert-Butyl 4- [3- (2-Ethyl-6-fluoro-1-methyl-1H-benzimidazol-7-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxy Rate manufacturing:

tert-Butyl 4- [3- (2-ethyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate (1.6 g) and carbonic acid To a suspension obtained by adding potassium (828 mg) to DMF (16 ml), methyl iodide (0.60 ml) was added and stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the target product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with an amino silica gel column (developing solvent: petroleum ether / ethyl acetate) to give tert-butyl 4- (3- (2-ethyl-5-fluoro-1-methyl-1H-benzimidazole). 4-yl) -1,2,4-oxadiazol-5-yl) piperidine-1-carboxylate (500 mg) and tert-butyl 4- (3- (2-ethyl-6-fluoro-1-methyl-) 1H-benzimidazol-7-yl) -1,2,4-oxadiazol-5-yl) piperidine-1-carboxylate (370 mg) was obtained.
TLC Rf (PE / EtOAc = 1/1): 0.25, 0.45.

　５－フルオロ－Ｎ’－ヒドロキシ－２－メチル－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミド（１０４ｍｇ）、３－オキソシクロブタンカルボン酸（６３ｍｇ）、トリエチルアミン（０．２１ｍｌ）をＴＨＦに加えた懸濁液に、Ｔ３Ｐ（５０％酢酸エチル溶液、０．３５ｍｌ）を滴下した後、１時間加熱還流した。反応混合物に水を加え、クロロホルムで目的物を抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣をシリカゲルカラム（展開溶媒：クロロホルム／メタノール）で精製し、標記化合物（９８ｍｇ）を得た。
LC-MS, m/z; 287 [M+H]+ Reference example 147:
Preparation of 3- [3- (5-Fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclobutanone:

Suspension of 5-fluoro-N′-hydroxy-2-methyl-1H-benzimidazole-4-carboximidamide (104 mg), 3-oxocyclobutanecarboxylic acid (63 mg), triethylamine (0.21 ml) added to THF T3P (50% ethyl acetate solution, 0.35 ml) was added dropwise to the solution, and the mixture was heated to reflux for 1 hour. Water was added to the reaction mixture, and the target product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified with a silica gel column (developing solvent: chloroform / methanol) to obtain the title compound (98 mg).
LC-MS, m / z; 287 [M + H] +

　３－オキソシクロブタンカルボン酸（１４５ｍｇ）をテトラヒドロフラン（１０ｍｌ）に加えた懸濁液に、１，１’‐カルボニルジイミダゾール（２０６ｍｇ）を加え、室温で１時間撹拌した。反応溶液に５－フルオロ－Ｎ’－ヒドロキシ－２－イソプロピル－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミド（１４５ｍｇ）を加え、５０℃で終夜撹拌した。反応終了後、反応溶液を減圧濃縮し、得られた残渣を酢酸エチルに溶かし、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮することで５－フルオロ－２－イソプロピル－Ｎ’－（３－オキソシクロブタンカルボニルオキシ）－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミドの粗生成物を得た。５－フルオロ－２－イソプロピル－Ｎ’－（３－オキソシクロブタンカルボニルオキシ）－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミドの粗生成物（５６４ｍｇ）を酢酸（５ｍｌ）に溶かし、９０℃で２時間撹拌した。反応溶液を室温に冷却し、炭酸水素ナトリウム水溶液を加え、酢酸エチルで目的物を抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：ヘキサン／酢酸エチル）で精製することで標記化合物（１４７ｍｇ）を得た。
LC-MS, m/z; 315 [M+H]+ Reference example 148:
Preparation of 3- {3- [5-fluoro-2- (propan-2-yl) -1H-benzimidazol-4-yl] -1,2,4-oxadiazol-5-yl} cyclobutanone:

To a suspension of 3-oxocyclobutanecarboxylic acid (145 mg) in tetrahydrofuran (10 ml) was added 1,1′-carbonyldiimidazole (206 mg), and the mixture was stirred at room temperature for 1 hour. 5-Fluoro-N′-hydroxy-2-isopropyl-1H-benzimidazole-4-carboximidamide (145 mg) was added to the reaction solution, and the mixture was stirred at 50 ° C. overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude product of 5-fluoro-2-isopropyl-N ′-(3-oxocyclobutanecarbonyloxy) -1H-benzimidazole-4-carboximidoamide. Obtained. 5-Fluoro-2-isopropyl-N ′-(3-oxocyclobutanecarbonyloxy) -1H-benzimidazole-4-carboximidamide crude product (564 mg) was dissolved in acetic acid (5 ml) and dissolved at 90 ° C. for 2 hours. Stir. The reaction solution was cooled to room temperature, aqueous sodium hydrogen carbonate solution was added, and the desired product was extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (column; Hi-FlashTM, developing solvent: hexane / ethyl acetate) to give the title compound (147 mg). It was.
LC-MS, m / z; 315 [M + H] +

　参考例１４８における５－フルオロ－Ｎ’－ヒドロキシ－２－（プロパン－２－イル）－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミドおよび３－オキソシクロブタンカルボン酸の代わりに、２－エチル－５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミドおよび４－オキソシクロヘキサンカルボン酸を用いて、参考例１４８と同様の方法により、標記化合物を製造した。
¹H-NMR (CDCl₃) δ: 1.51 (3H, t, J = 7.6 Hz), 2.28-2.40 (2H, m), 2.53-2.70 (6H, m), 3.04 (2H, q, J = 7.6 Hz), 3.58-3.67 (1H, m), 7.15 (1H, dd, J = 11.6, 8.8 Hz), 7.80 (1H, dd, J = 8.8, 4.2 Hz), 10.37 (1H, br s). Reference Example 149:
Preparation of 4- [3- (2-Ethyl-5-fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclohexanone:

Instead of 5-fluoro-N′-hydroxy-2- (propan-2-yl) -1H-benzimidazole-4-carboximidamide and 3-oxocyclobutanecarboxylic acid in Reference Example 148, 2-ethyl-5- The title compound was produced in the same manner as in Reference Example 148 using fluoro-N′-hydroxy-1H-benzimidazole-4-carboximidamide and 4-oxocyclohexanecarboxylic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, t, J = 7.6 Hz), 2.28-2.40 (2H, m), 2.53-2.70 (6H, m), 3.04 (2H, q, J = 7.6 Hz ), 3.58-3.67 (1H, m), 7.15 (1H, dd, J = 11.6, 8.8 Hz), 7.80 (1H, dd, J = 8.8, 4.2 Hz), 10.37 (1H, br s).

Similar to Reference Example 148 using the corresponding starting material compound instead of 5-fluoro-N′-hydroxy-2- (propan-2-yl) -1H-benzimidazole-4-carboximidamide in Reference Example 148 The compounds shown in the following table (Reference Examples 150 to 153) were produced by the method described above.

　窒素雰囲気下、７－ブロモ－１Ｈ－インダゾール（５００ｍｇ）、シアン化亜鉛（６００ｍｇ）及びビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム（６５ｍｇ）のＮ－メチル－２－ピロリドン（１０ｍｌ）溶液をマイクロウェーブ照射下１５０℃で３０分間攪拌した。反応液を減圧濃縮し、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＝１００／０～０／１００）で精製して標記化合物（１９６ｍｇ）を得た。
LC-MS, m/z; 144 [M+H]+ Reference Example 154:
Production of 1H-indazole-7-carbonitrile:

In a nitrogen atmosphere, a solution of 7-bromo-1H-indazole (500 mg), zinc cyanide (600 mg) and bis (tri-tert-butylphosphine) palladium (65 mg) in N-methyl-2-pyrrolidone (10 ml) was microwaved. The mixture was stirred at 150 ° C. for 30 minutes under irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100 / 0-0 / 100) to give the title compound (196 mg).
LC-MS, m / z; 144 [M + H] +

　７－ブロモ－１Ｈ－インダゾール（１．５３ｇ）のジメチルホルムアミド（２０ｍｌ）溶液に６０％水素化ナトリウム（４７３ｍｇ）を徐々に加え、室温で３０分間攪拌した。ヨウ化イソプロピル（１．５５ｇ）を加えさらに２時間攪拌した。反応液を氷水（５０ｍｌ）に注ぎ、水層から酢酸エチル（１０ｍｌ×３）により目的物を抽出した。有機層を無水硫酸マグネシウムで乾燥、濾過、減圧濃縮した。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＝１００／０～８０／２０）で精製して７－ブロモ－１－（プロパン－２－イル）－１Ｈ－インダゾール（１．２ｇ）及び７－ブロモ－２－（プロパン－２－イル）－２Ｈ－インダゾール（６７０ｍｇ）を得た。
７－ブロモ－１－（プロパン－２－イル）－１Ｈ－インダゾール: LC-MS, m/z; 240 [M+H]+
７－ブロモ－２－（プロパン－２－イル）－２Ｈ－インダゾール: LC-MS, m/z; 240 [M+H]+ Reference examples 155-156:
Preparation of 7-bromo-1- (propan-2-yl) -1H-indazole and 7-bromo-2- (propan-2-yl) -2H-indazole:

To a solution of 7-bromo-1H-indazole (1.53 g) in dimethylformamide (20 ml), 60% sodium hydride (473 mg) was gradually added and stirred at room temperature for 30 minutes. Isopropyl iodide (1.55 g) was added and the mixture was further stirred for 2 hours. The reaction solution was poured into ice water (50 ml), and the target product was extracted from the aqueous layer with ethyl acetate (10 ml × 3). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100/0 to 80/20) to give 7-bromo-1- (propan-2-yl) -1H-indazole (1.2 g) and 7-bromo. -2- (Propan-2-yl) -2H-indazole (670 mg) was obtained.
7-Bromo-1- (propan-2-yl) -1H-indazole: LC-MS, m / z; 240 [M + H] +
7-Bromo-2- (propan-2-yl) -2H-indazole: LC-MS, m / z; 240 [M + H] +

　参考例１５４における７－ブロモ－１Ｈ－インダゾールの代わりに、７－ブロモ－１－（プロパン－２－イル）－１Ｈ－インダゾールを用いて、参考例１５４と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 186 [M+H]+ Reference Example 157:
Preparation of 1- (propan-2-yl) -1H-indazole-7-carbonitrile:

The title compound was prepared in the same manner as in Reference Example 154 using 7-bromo-1- (propan-2-yl) -1H-indazole instead of 7-bromo-1H-indazole in Reference Example 154. .
LC-MS, m / z; 186 [M + H] +

　参考例１５４における７－ブロモ－１Ｈ－インダゾールの代わりに、７－ブロモ－２－（プロパン－２－イル）－２Ｈ－インダゾールを用いて、参考例１５４と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 186 [M+H]+ Reference Example 158:
Preparation of 2- (propan-2-yl) -2H-indazole-7-carbonitrile:

The title compound was prepared in the same manner as in Reference Example 154 using 7-bromo-2- (propan-2-yl) -2H-indazole instead of 7-bromo-1H-indazole in Reference Example 154. .
LC-MS, m / z; 186 [M + H] +

　（１）２－ブロモ－６－フルオロベンズアルデヒド（１．５ｇ）と炭酸セシウム（７．２ｇ）をＮ，Ｎ－ジメチルホルムアミド（３０ｍｌ）に加えた懸濁液に、ベンジルメルカプタン（１．３ｍｌ）を加え室温で終夜撹拌した。その後、５０℃にて３時間加熱撹拌し、さらに７０℃にて１．５時間加熱撹拌した。反応終了後、室温にて水を加え、析出した淡黄色固体をろ取し、ヘキサン／酢酸エチル１：１混合溶媒にて洗浄後、乾燥することで、２－（ベンジルスルファニル）－６－ブロモベンズアルデヒド（１．４７ｇ）を得た。
¹H-NMR (CDCl₃) δ: 4.16 (2H, s), 7.23-7.44 (9H, m), 10.49 (1H, s).
　（２）２－（ベンジルスルファニル）－６－ブロモベンズアルデヒド（４５０ｍｇ）をアセトニトリル（３ｍｌ）と水（３ｍｌ）の混合溶媒に溶かし、硫酸ナトリウム（２１ｍｇ）およびヒドロキシルアミン－Ｏ－スルホン酸（２５５ｍｇ）を加え室温で２時間撹拌した。反応溶液に炭酸水素ナトリウム（８００ｍｇ）およびジクロロメタン（３ｍｌ）を加え、さらに２時間半撹拌した。反応液に水を加え、酢酸エチルで目的物を抽出し、有機層を無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－Ｆｌａｓｈ^ＴＭ、展開溶媒：ヘキサン／酢酸エチル）で精製することで、標記化合物（３４３ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 7.38 (1H, dd, J = 8.0, 7.6Hz), 7.58 (1H, d, J = 7.6 Hz), 7.90 (1H, d, J = 8.0 Hz), 9.00 (1H, s). Reference Example 159:
Preparation of 4-bromo-1,2-benzisothiazole:

(1) To a suspension of 2-bromo-6-fluorobenzaldehyde (1.5 g) and cesium carbonate (7.2 g) added to N, N-dimethylformamide (30 ml), benzyl mercaptan (1.3 ml) is added. The mixture was further stirred at room temperature overnight. Thereafter, the mixture was heated and stirred at 50 ° C. for 3 hours, and further stirred at 70 ° C. for 1.5 hours. After completion of the reaction, water was added at room temperature, and the precipitated pale yellow solid was collected by filtration, washed with a mixed solvent of hexane / ethyl acetate 1: 1, and dried to give 2- (benzylsulfanyl) -6-bromo. Benzaldehyde (1.47 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 4.16 (2H, s), 7.23-7.44 (9H, m), 10.49 (1H, s).
(2) 2- (Benzylsulfanyl) -6-bromobenzaldehyde (450 mg) was dissolved in a mixed solvent of acetonitrile (3 ml) and water (3 ml), and sodium sulfate (21 mg) and hydroxylamine-O-sulfonic acid (255 mg) were added. The mixture was further stirred at room temperature for 2 hours. Sodium hydrogen carbonate (800 mg) and dichloromethane (3 ml) were added to the reaction solution, and the mixture was further stirred for 2.5 hours. Water was added to the reaction solution, the target product was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (column; Hi-Flash ^™ , developing solvent: hexane / ethyl acetate) to obtain the title compound (343 mg).
¹ H-NMR (CDCl ₃ ) δ: 7.38 (1H, dd, J = 8.0, 7.6 Hz), 7.58 (1H, d, J = 7.6 Hz), 7.90 (1H, d, J = 8.0 Hz), 9.00 ( 1H, s).

　参考例１５４におけると７－ブロモ－１Ｈ－インダゾールの代わりに、４－ブロモ－１，２－ベンゾイソチアゾールを用いて、参考例１５４と同様の方法により、標記化合物を製造した。
¹H-NMR (CDCl₃) δ: 7.63 (1H, dd, J = 8.3, 7.2 Hz), 7.82 (1H, dd, J = 7.2, 0.9 Hz), 8.22 (1H, dd, J = 8.3, 0.9 Hz), 9.16 (1H, d, J = 0.9 Hz). Reference example 160:
Preparation of 1,2-benzisothiazole-4-carbonitrile:

The title compound was prepared in the same manner as in Reference Example 154 using 4-bromo-1,2-benzisothiazole instead of 7-bromo-1H-indazole in Reference Example 154.
¹ H-NMR (CDCl ₃ ) δ: 7.63 (1H, dd, J = 8.3, 7.2 Hz), 7.82 (1H, dd, J = 7.2, 0.9 Hz), 8.22 (1H, dd, J = 8.3, 0.9 Hz) ), 9.16 (1H, d, J = 0.9 Hz).

　（１）２－（プロパン－２－イル）－１，３－ベンゾオキサゾール－４－カルボン酸（２．００ｇ）、ピリジン（０．４８ｍｌ）を１，４－ジオキサン（４０ｍｌ）に溶解し、二炭酸ジ－ｔｅｒｔ－ブチル（２．７７ｇ）を加え、室温で数時間攪拌した。次いで重炭酸アンモニウム（０．９２ｇ）を加え、更に室温で終夜攪拌した。反応混合液を減圧濃縮して水を加え、酢酸エチルで目的物を抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮することで２－（プロパン－２－イル）－１，３－ベンゾオキサゾール－４－カルボキサミド（２．１３ｇ）を得た。
　（２）２－（プロパン－２－イル）－１，３－ベンゾオキサゾール－４－カルボキサミド（２．１３ｇ）、トリエチルアミン（２．９ｍｌ）をジクロロメタン（２０ｍｌ）に溶解し、トリフルオロ酢酸無水物（１．５ｍｌ）を０℃にて滴下し、室温で終夜攪拌した。反応混合液を減圧濃縮し、残渣に水を加え、ジクロロメタンで目的物を抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：ヘキサン：酢酸エチル）により精製し、標記化合物を製造した。
LC-MS, m/z; ３７３  [２M+H]+ Reference Example 161:
Preparation of 2- (propan-2-yl) -1,3-benzoxazole-4-carbonitrile:

(1) 2- (propan-2-yl) -1,3-benzoxazole-4-carboxylic acid (2.00 g) and pyridine (0.48 ml) are dissolved in 1,4-dioxane (40 ml). Di-tert-butyl carbonate (2.77 g) was added, and the mixture was stirred at room temperature for several hours. Then ammonium bicarbonate (0.92 g) was added and further stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the desired product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2- (propan-2-yl) -1,3-benzoxazole-4-carboxamide (2.13 g). Obtained.
(2) 2- (propan-2-yl) -1,3-benzoxazole-4-carboxamide (2.13 g) and triethylamine (2.9 ml) were dissolved in dichloromethane (20 ml), and trifluoroacetic anhydride ( 1.5 ml) was added dropwise at 0 ° C., and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the desired product was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-Flash ™, developing solvent: hexane: ethyl acetate) to produce the title compound.
LC-MS, m / z; 373 [2M + H] +

（式中、（Ｈｅｔ）は下記表中の構造を意味する）

Instead of 2-ethyl-1H-benzimidazole-4-carbonitrile in Reference Example 080, the corresponding starting compound was used and the compounds shown in the following table (Reference Examples 162-165) were prepared in the same manner as in Reference Example 080. Manufactured.

(Wherein (Het) means the structure in the table below)

　Ｎ’－ヒドロキシ－２－（プロパン－２－イル）－１，３－ベンゾオキサゾール－４－カルボキシイミドアミド（５８９ｍｇ）をＤＭＦ（６．０ｍｌ）に溶解し、水素化ナトリウム（６０％ｉｎシリコンオイル，１３５ｍｇ）を加えて０℃で３０分間攪拌した。次いで１－ｔｅｒｔ－ブチル ４－エチル ピペリジン－１，４－ジカルボキシレート（９００ｍｇ）を加え、室温で終夜攪拌した。反応混合液に水を加え、目的物を酢酸エチルで抽出した。有機層は飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した後に減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：ヘキサン：酢酸エチル）により精製し、標記化合物（２８ｍｇ）を得た。
LC-MS, m/z; ４１３  [M+H]+ Reference Example 167:
tert-Butyl 4- {3- [2- (propan-2-yl) -1,3-benzoxazol-4-yl] -1,2,4-oxadiazol-5-yl} piperidine-1-carboxy Rate manufacturing:

N'-hydroxy-2- (propan-2-yl) -1,3-benzoxazole-4-carboximidamide (589 mg) was dissolved in DMF (6.0 ml) and sodium hydride (60% in silicone oil) , 135 mg), and the mixture was stirred at 0 ° C. for 30 minutes. Next, 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (900 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the target product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-Flash ™, developing solvent: hexane: ethyl acetate) to obtain the title compound (28 mg).
LC-MS, m / z; 413 [M + H] +

　ｔｅｒｔ－ブチル ４－［３－（２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレート（４４２ｍｇ）をジクロロメタン（２３ｍｌ）に溶かし、トリフルオロ酢酸（３．５ｍｌ）を加え室温で３時間撹拌した。反応液を減圧濃縮することにより、標記化合物を定量的に得た。
LC-MS, m/z; ２８４ [M+H]+ Example 001
Preparation of 2-methyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate):

tert-Butyl 4- [3- (2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate (442 mg) in dichloromethane (23 ml ), Trifluoroacetic acid (3.5 ml) was added, and the mixture was stirred at room temperature for 3 hours. The title compound was obtained quantitatively by concentrating the reaction solution under reduced pressure.
LC-MS, m / z; 284 [M + H] +

　ｔｅｒｔ－ブチル ４－［３－（２－エチル－７－フルオロ－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレート（３００ｍｇ）を酢酸エチル（１０ｍｌ）に溶かし、４規定塩酸／酢酸エチル溶液（１０ｍｌ）を加え室温で４時間攪拌した。反応液を減圧留去することにより標記化合物（２８０ｍｇ）を白色固体として得た。
LC-MS, m/z; 316 [M+H]+ Example 002:
Preparation of 2-ethyl-7-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole dihydrochloride:

tert-Butyl 4- [3- (2-Ethyl-7-fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate (300 mg) Was dissolved in ethyl acetate (10 ml), 4N hydrochloric acid / ethyl acetate solution (10 ml) was added, and the mixture was stirred at room temperature for 4 hr. The reaction solution was distilled off under reduced pressure to obtain the title compound (280 mg) as a white solid.
LC-MS, m / z; 316 [M + H] +

（式中、ＨＸは塩酸もしくはトリフルオロ酢酸を意味する。）

Tert-Butyl 4- [3- (2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate in Example 001 or Example Of tert-butyl 4- [3- (2-ethyl-7-fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate at 002 Instead, the compounds shown in the following table (Examples 003 to 026) were produced in the same manner as in Example 001 or Example 002 using the corresponding starting compounds.

(In the formula, HX means hydrochloric acid or trifluoroacetic acid.)

　実施例００２におけるｔｅｒｔ－ブチル ４－［３－（２－エチル－７－フルオロ－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートの代わりに、ｔｅｒｔ－ブチル ４－［３－（２－エチル－６－フルオロ－１－メチル－１Ｈ－ベンズイミダゾール－７－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートを用いて、実施例００２と同様の方法により、標記化合物を製造した。
¹H-NMR (CDCl₃) δ: 1.46 (3H, t, J = 7.4 Hz), 1.68-1.95 (2H, m), 2.19-2.22 (2H, m), 2.80-2.92 (4H, m), 3.20-3.26 (3H, m), 3.47 (3H, s), 7.18 (1H, dd, J = 10.0, 9.2 Hz), 7.80 (1H, dd, J = 8.8, 4.8 Hz).  (free base) Example 027:
Preparation of 2-ethyl-6-fluoro-1-methyl-7- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole dihydrochloride:

Tert-Butyl 4- [3- (2-ethyl-7-fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxyl in Example 002 Instead of tert-butyl 4- [3- (2-ethyl-6-fluoro-1-methyl-1H-benzimidazol-7-yl) -1,2,4-oxadiazol-5-yl] The title compound was produced in the same manner as in Example 002 using piperidine-1-carboxylate.
¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, t, J = 7.4 Hz), 1.68-1.95 (2H, m), 2.19-2.22 (2H, m), 2.80-2.92 (4H, m), 3.20 -3.26 (3H, m), 3.47 (3H, s), 7.18 (1H, dd, J = 10.0, 9.2 Hz), 7.80 (1H, dd, J = 8.8, 4.8 Hz). (Free base)

（式中、（Ｂ－２）は下記表に示す環状アミン構造を意味し、ＨＸは塩酸もしくはトリフルオロ酢酸を意味する。Ｂｏｃ基の結合位置は （Ｂ－２）の環状アミン上の窒素原子である）

Tert-Butyl 4- [3- (2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate in Example 001 or Example Of tert-butyl 4- [3- (2-ethyl-7-fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate at 002 Instead, the compounds shown in the following table (Examples 028 to 033) were produced in the same manner as in Example 001 or Example 002 using the corresponding starting compounds.

(Wherein (B-2) means the cyclic amine structure shown in the following table, and HX means hydrochloric acid or trifluoroacetic acid. The binding position of the Boc group is the nitrogen atom on the cyclic amine of (B-2). Is)

　２－エチル－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－ベンズイミダゾール ビス（トリフルオロ酢酸塩）（１５０ｍｇ）をジクロロメタン（３．０ｍｌ）に溶かし、ｎ－ブチルアルデヒド（４１μｌ）、水素化トリアセトキシホウ素ナトリウム（１９４ｍｇ）を加えて室温で３時間撹拌した。反応液を０℃に冷却し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにより目的物を抽出した。得られた有機層を水で洗浄後、無水硫酸ナトリウムにより乾燥、ろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－Ｆｌａｓｈ^ＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：ヘキサン：酢酸エチル）で精製することで標記化合物（７３ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J = 7.3 Hz), 1.28-1.43 (2H, m), 1.45-1.59 (5H, m), 2.00-2.24 (6H, m), 2.34-2.44 (2H, m), 2.94-3.14 (5H, m), 7.34 (1H, t, J = 7.8 Hz), 7.86 (1H, d, J = 8.1 Hz), 7.98 (1H, d, J = 7.5 Hz), 10.13 (1H, s).
LC-MS, m/z; 354[M+H]+ Example 034:
Preparation of 4- [5- (1-butylpiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -2-ethyl-1H-benzimidazole:

2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate) (150 mg) was added to dichloromethane (3 0.0 ml), n-butyraldehyde (41 μl) and sodium triacetoxyborohydride (194 mg) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the desired product was extracted with chloroform. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-Flash ^TM amino column, developing solvent: hexane: ethyl acetate) to obtain the title compound (73 mg).
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3 Hz), 1.28-1.43 (2H, m), 1.45-1.59 (5H, m), 2.00-2.24 (6H, m), 2.34 -2.44 (2H, m), 2.94-3.14 (5H, m), 7.34 (1H, t, J = 7.8 Hz), 7.86 (1H, d, J = 8.1 Hz), 7.98 (1H, d, J = 7.5 Hz), 10.13 (1H, s).
LC-MS, m / z; 354 [M + H] +

（式中、ＨＸは塩酸もしくはトリフルオロ酢酸を意味する。）

Instead of 2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate salt) in Example 034 The compounds shown in the following table (Examples 035 to 045) were produced in the same manner as in Example 034 using the corresponding starting compounds.

(In the formula, HX means hydrochloric acid or trifluoroacetic acid.)

（式中、ＨＸは塩酸もしくはトリフルオロ酢酸を意味する。）

2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate) and butyraldehyde in Example 034 The compounds shown in the following table (Examples 046 to 052) were produced in the same manner as in Example 034 using the corresponding starting compounds and tetrahydropyran-4-carbaldehyde instead of.

(In the formula, HX means hydrochloric acid or trifluoroacetic acid.)

（式中、Ｒ^２Ａ、Ｒ^５、Ｒ^８は下記表に示す構造式を意味し、ＨＸは塩酸もしくはトリフルオロ酢酸を意味する。）

１）反応に酢酸を添加 2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate) and butyraldehyde in Example 034 The compounds shown in the following table (Examples 053 to 056) were produced in the same manner as in Example 034 using the corresponding starting compounds and aldehydes or ketones instead of.

(In the formula, R ^2A , R ⁵ and R ⁸ mean the structural formulas shown in the following table, and HX means hydrochloric acid or trifluoroacetic acid.)

1) Add acetic acid to the reaction

（式中、Ｒ^８は下記表に示す構造式を意味する。）

1)反応にチタンテトライソプロポキシドを添加 2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate) and butyraldehyde in Example 034 The compounds shown in the following table (Examples 057 to 058) were produced in the same manner as in Example 034 using the corresponding starting compounds and aldehydes instead of.

(In the formula, R ⁸ means a structural formula shown in the following table.)

1) Add titanium tetraisopropoxide to the reaction

（式中、Ｒ^８は下記表に示す構造式を意味する。）

1)反応にチタンテトライソプロポキシドを添加 2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate) and butyraldehyde in Example 034 The compounds shown in the following table (Examples 059 to 060) were produced in the same manner as in Example 034 using the corresponding starting compounds and aldehydes instead of.

(In the formula, R ⁸ means a structural formula shown in the following table.)

1) Add titanium tetraisopropoxide to the reaction

（式中、Ｒ^８は下記表に示す構造式を意味する。）

1)反応にチタンテトライソプロポキシドを添加 2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate) and butyraldehyde in Example 034 The compounds shown in the following table (Examples 061 to 062) were produced in the same manner as in Example 034 using the corresponding starting compounds and aldehydes instead of.

(In the formula, R ⁸ means a structural formula shown in the following table.)

1) Add titanium tetraisopropoxide to the reaction

（式中、Ｒ^８は下記表に示す構造式を意味する。）

1)反応にチタンテトライソプロポキシドを添加 2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate) and butyraldehyde in Example 034 The compounds shown in the following table (Examples 063 to 064) were produced in the same manner as in Example 034 using the corresponding starting compounds and aldehydes instead of

(In the formula, R ⁸ means a structural formula shown in the following table.)

1) Add titanium tetraisopropoxide to the reaction

　（１）２－エチル－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－ベンズイミダゾール ビス（トリフルオロ酢酸塩）（４００ｍｇ）をテトラヒドロフラン（５．０ｍｌ）に懸濁させ、１－Ｂｏｃ－４－ピペリドン（１６７ｍｇ）、チタンテトライソプロポキシド（０．６８ｍｌ）を加え室温で１時間撹拌した後、水素化トリアセトキシホウ素ナトリウム（３２３ｍｇ）を加え室温で３時間撹拌した。反応液を冷却し、飽和炭酸水素ナトリウム水溶液を加え、生じた不溶物を濾去した。濾液からを目的物を酢酸エチルで抽出し、有機層を水で洗浄後、無水硫酸ナトリウムで乾燥、濾過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－Ｆｌａｓｈ^ＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：ヘキサン：酢酸エチル）で精製することでｔｅｒｔ－ブチル ４－（３－（２－エチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル）－１，４’－ビピペリジン－１’－カルボキシレート（３９１ｍｇ）を得た。
　（２）ｔｅｒｔ－ブチル ４－（３－（２－エチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル）－１，４’－ビピペリジン－１’－カルボキシレート（３９１ｍｇ）をジクロロメタン（１０ｍｌ）に溶かし、トリフルオロ酢酸（５．０ｍｌ）を加え、室温で２時間撹拌した。反応溶液を濃縮し、ジエチルエーテルを加えて結晶化させた。生じた結晶を濾取、ジエチルエーテルで洗浄後乾燥することで５－（１，４’－ビピペリジン－４－イル）－３－（２－エチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール ３トリフルオロ酢酸塩（４８７ｍｇ）を得た。
　（３）５－（１，４’－ビピペリジン－４－イル）－３－（２－エチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール ３トリフルオロ酢酸塩（１６０ｍｇ）をジクロロメタン（５．０ｍｌ）と飽和炭酸水素ナトリウム水溶液（５．０ｍｌ）の混合溶液に溶かし、クロロ炭酸メチル（３１μｌ）を加え、室温で１時間撹拌した。１０Ｎ水酸化ナトリウム水溶液を加え強塩基性とし、メタノール（５．０ｍｌ）を加え、室温で３時間撹拌した。酢酸エチルを加え目的物を抽出し、有機層をさらに飽和食塩水で洗浄後、硫酸ナトリウムで乾燥、濾過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－Ｆｌａｓｈ^ＴＭ アミノ Ｃｏｌｕｍｎ）で精製することで標記化合物（４７ｍｇ）を得た。
LC-MS, m/z; 439 [M+H]+ Example 065:
Preparation of methyl 4- [3- (2-ethyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidine-1′-carboxylate :

(1) 2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetate) (400 mg) Suspended in tetrahydrofuran (5.0 ml), 1-Boc-4-piperidone (167 mg) and titanium tetraisopropoxide (0.68 ml) were added and stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (323 mg) was added. ) And stirred at room temperature for 3 hours. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate solution was added, and the resulting insoluble material was removed by filtration. The desired product was extracted from the filtrate with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-Flash ^™ amino column, developing solvent: hexane: ethyl acetate) to give tert-butyl 4- (3- (2-ethyl-1H-benzimidazole- 4-yl) -1,2,4-oxadiazol-5-yl) -1,4′-bipiperidine-1′-carboxylate (391 mg) was obtained.
(2) tert-butyl 4- (3- (2-ethyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl) -1,4′-bipiperidine-1 ′ -Carboxylate (391 mg) was dissolved in dichloromethane (10 ml), trifluoroacetic acid (5.0 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and crystallized by adding diethyl ether. The resulting crystals were collected by filtration, washed with diethyl ether and dried to give 5- (1,4′-bipiperidin-4-yl) -3- (2-ethyl-1H-benzimidazol-4-yl) -1, 2,4-oxadiazole 3 trifluoroacetate (487 mg) was obtained.
(3) 5- (1,4′-bipiperidin-4-yl) -3- (2-ethyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazole 3 trifluoroacetate ( 160 mg) was dissolved in a mixed solution of dichloromethane (5.0 ml) and saturated aqueous sodium hydrogen carbonate solution (5.0 ml), methyl chlorocarbonate (31 μl) was added, and the mixture was stirred at room temperature for 1 hour. 10N Aqueous sodium hydroxide solution was added to make it strongly basic, methanol (5.0 ml) was added, and the mixture was stirred at room temperature for 3 hr. Ethyl acetate was added to extract the desired product, and the organic layer was further washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-Flash ^™ amino column) to obtain the title compound (47 mg).
LC-MS, m / z; 439 [M + H] +

2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetic acid) in step (1) of Example 065 Salt) and the compounds shown in the following table (Examples 066 to 068) in the same manner as in Example 065, using the corresponding starting compound and methyl chlorocarbonate or acetic anhydride instead of methyl chlorocarbonate in step (3). Manufactured.

（式中、ＨＸは塩酸もしくはトリフルオロ酢酸を意味する。）

2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetic acid) in step (1) of Example 065 Salt) and N-Boc-4-piperidone instead of the corresponding starting compounds and 1-acetylpiperidin-4-one, the compounds of the following table ( Examples 069-083) were prepared.

(In the formula, HX means hydrochloric acid or trifluoroacetic acid.)

　実施例０６５の工程（１）における２－エチル－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－ベンズイミダゾール ビス（トリフルオロ酢酸塩）とＮ－Ｂｏｃ－４－ピペリドンの代わりに、２－エチル－６－フルオロ－１－メチル－７－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－ベンズイミダゾール ２塩酸塩および１－アセチルピペリジン－４－オンを用いて、実施例０６５の工程（１）と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 455 [M+H]+ Example 084:
1- {4- [3- (2-Ethyl-6-fluoro-1-methyl-1H-benzimidazol-7-yl) -1,2,4-oxadiazol-5-yl] -1,4 ′ -Production of bipiperidin-1'-yl} ethanone:

2-ethyl-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole bis (trifluoroacetic acid) in step (1) of Example 065 Salt) and N-Boc-4-piperidone instead of 2-ethyl-6-fluoro-1-methyl-7- [5- (piperidin-4-yl) -1,2,4-oxadiazole-3 The title compound was prepared in the same manner as in Step (1) of Example 065 using -yl] -1H-benzimidazole dihydrochloride and 1-acetylpiperidin-4-one.
LC-MS, m / z; 455 [M + H] +

　１’－アセチル－１，４’－ビピペリジン－４－カルボン酸（９９ｍｇ）、トリエチルアミン（０．１３ｍｌ）をＴＨＦ（１．９ｍｌ）に加えた懸濁液に、氷冷下でクロロ炭酸イソプロピル（４８ｍｇ）を滴下し、４０℃で１時間攪拌した。次いで２－エチル－５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミド（６７ｍｇ）を加え、４０℃で３時間半攪拌した。その後、フッ化テトラ－ｎ－ブチルアンモニウム（１Ｍ ＴＨＦ溶液、０．９ｍｌ）を加え、６０℃で更に終夜攪拌した。反応混合物を減圧濃縮した後、得られた残渣（１４９ｍｇ）をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：クロロホルム：メタノール）により精製し、標記化合物（１２１ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.41-1.58 (5H, m), 1.89 (2H, t, J = 14.1 Hz), 1.98-2.13 (5H, m), 2.18-2.26 (2H, m), 2.42 (2H, q, J = 10.6 Hz), 2.52-2.63 (2H, m), 2.96-3.16 (6H, m), 3.89 (1H, d, J = 13.9 Hz), 4.68 (1H, d, J = 13.2 Hz), 7.08-7.15 (1H, m), 7.76 (1H, dd, J = 8.5, 4.1 Hz), 10.48 (1H, br s).
LC-MS, m/z; 441 [M+H]+ Example 085:
1- {4- [3- (2-Ethyl-5-fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidine-1 Production of '-Il} ethanone:

To a suspension of 1′-acetyl-1,4′-bipiperidine-4-carboxylic acid (99 mg) and triethylamine (0.13 ml) in THF (1.9 ml) was added isopropyl chlorocarbonate (48 mg) under ice cooling. ) Was added dropwise and stirred at 40 ° C. for 1 hour. Subsequently, 2-ethyl-5-fluoro-N′-hydroxy-1H-benzimidazole-4-carboximidamide (67 mg) was added, and the mixture was stirred at 40 ° C. for 3.5 hours. Thereafter, tetra-n-butylammonium fluoride (1M THF solution, 0.9 ml) was added, and the mixture was further stirred at 60 ° C. overnight. After the reaction mixture was concentrated under reduced pressure, the obtained residue (149 mg) was purified by silica gel column chromatography (column; Hi-Flash ™, developing solvent: chloroform: methanol) to obtain the title compound (121 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.41-1.58 (5H, m), 1.89 (2H, t, J = 14.1 Hz), 1.98-2.13 (5H, m), 2.18-2.26 (2H, m), 2.42 (2H, q, J = 10.6 Hz), 2.52-2.63 (2H, m), 2.96-3.16 (6H, m), 3.89 (1H, d, J = 13.9 Hz), 4.68 (1H, d, J = 13.2 Hz), 7.08-7.15 (1H, m), 7.76 (1H, dd, J = 8.5, 4.1 Hz), 10.48 (1H, br s).
LC-MS, m / z; 441 [M + H] +

１）１Ｍテトラブチルアンモニウムフルオリド／ＴＨＦ溶液の代わりに水酸化テトラメチルアンモニウム水溶液を用い、参考例０８５と同様にして環化反応を行った。 The corresponding raw material compound was used instead of 2-ethyl-5-fluoro-N′-hydroxy-1H-benzimidazole-4-carboximidoamide of Example 085, and the following table was prepared in the same manner as in Example 085. (Examples 086 to 088) were prepared.

1) A cyclization reaction was carried out in the same manner as in Reference Example 085, using an aqueous tetramethylammonium hydroxide solution instead of the 1M tetrabutylammonium fluoride / THF solution.

　３－［３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］シクロブタノン（１９５ｍｇ）を１，２－ジクロロエタンに溶かし、ピペリジン（０．０８１ｍｌ）、チタンテトライソプロポキシド（０．５ｍｌ）を加え、室温で１時間攪拌した。次いで、水素化トリアセトキシホウ素ナトリウム（２０１ｍｇ）、酢酸（０．０７８ｍｌ）を加え室温で終夜攪拌した。反応混合物に２規程水酸化ナトリウム水溶液を加え、セライトろ過を行い、塩化メチレンで目的物を抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：ヘキサン／酢酸エチル）により精製し、再度シリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：クロロホルム／メタノール）により精製することで、標記化合物（３７．５ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.43-1.57 (2H, m), 1.58-1.70 (4H, m), 2.27-2.41 (4H, m), 2.42-2.57 (2H, m), 2.60-2.78 (5H, m), 2.79-2.91 (1H, m), 3.48-3.62 (1H, m), 7.11 (1H, dd, J = 11.6, 8.6 Hz), 7.73 (1H, dd, J = 8.6, 4.2 Hz), 10.69 (1H, br s)
LC-MS, m/z; 356 [M+H]+ Example 089:
Preparation of 5-fluoro-2-methyl-4- {5- [cis-3- (piperidin-1-yl) cyclobutyl] -1,2,4-oxadiazol-3-yl} -1H-benzimidazole:

3- [3- (5-Fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclobutanone (195 mg) was dissolved in 1,2-dichloroethane. Piperidine (0.081 ml) and titanium tetraisopropoxide (0.5 ml) were added, and the mixture was stirred at room temperature for 1 hour. Next, sodium triacetoxyborohydride (201 mg) and acetic acid (0.078 ml) were added and stirred overnight at room temperature. 2N aqueous sodium hydroxide solution was added to the reaction mixture, the mixture was filtered through Celite, and the target product was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-FlashTM amino column, developing solvent: hexane / ethyl acetate), and again purified by silica gel column chromatography (column; Hi-FlashTM, developing solvent: chloroform / methanol). The title compound (37.5 mg) was obtained by purification.
¹ H-NMR (CDCl ₃ ) δ: 1.43-1.57 (2H, m), 1.58-1.70 (4H, m), 2.27-2.41 (4H, m), 2.42-2.57 (2H, m), 2.60-2.78 ( 5H, m), 2.79-2.91 (1H, m), 3.48-3.62 (1H, m), 7.11 (1H, dd, J = 11.6, 8.6 Hz), 7.73 (1H, dd, J = 8.6, 4.2 Hz) , 10.69 (1H, br s)
LC-MS, m / z; 356 [M + H] +

（式中、Ｒ^２Ａ、（Ｂ－４）は下記表中の構造を意味する）

Instead of 3- [3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclobutanone in Example 089 and piperidine The compounds shown in the following table (Examples 090 to 098) were produced in the same manner as in Example 089 using the starting material compound and cyclic secondary amine compound.

(Wherein R ^2A and (B-4) represent the structures in the following table)

（式中、（Ｂ－４）は下記表中の構造を意味する）

Instead of 3- [3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclobutanone of Example 089, 4- [ Using 3- (2-ethyl-5-fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclohexanone in the same manner as in Example 089, the following The compounds in the table (Examples 099-100) were prepared.

(Wherein (B-4) means the structure in the following table)

　（１）２－エチル－５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミド（１００ｍｇ）をＴＨＦ（２．０ｍｌ）に加えた懸濁液に、氷冷下でクロロアセチルクロリド（５６ｍｇ）を滴下し、室温で１５分間攪拌した。次いで、フッ化テトラ－ｎ－ブチルアンモニウム（１Ｍ ＴＨＦ溶液、１．４ｍｌ）を加え、室温で２時間、５０℃で２時間攪拌した。反応混合物を減圧濃縮した後、得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：クロロホルム／メタノール）により精製し、５－（クロロメチル）－３－（２－エチル－５－フルオロ－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール（３４ｍｇ）を得た。
LC-MS, m/z; 281 [M+H]+
　（２）５－（クロロメチル）－３－（２－エチル－５－フルオロ－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール（３４ｍｇ）、ピペリジン（２０ｍｇ）、ヨウ化ナトリウム（４ｍｇ）、炭酸カリウム（４９ｍｇ）をアセトニトリル（１．７ｍｌ）に加えた懸濁液を、５０℃で１時間攪拌した。反応混合物をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：クロロホルム／メタノール）により精製した後、更に分取サイズ排除クロマトグラフィー（移動相：クロロホルム）により精製することで、標記化合物（１８ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.43-1.53 (5H, m), 1.62-1.72 (4H, m), 2.57-2.66 (4H, m), 3.01 (2H, q, J = 7.6 Hz), 3.98 (2H, s), 7.13 (1H, dd, J = 11.5, 8.8 Hz), 7.78 (1H, dd, J = 8.7, 4.3 Hz), 10.73 (1H, br s).
LC-MS, m/z; 330 [M+H]+ Example 101:
Preparation of 2-ethyl-5-fluoro-4- [5- (piperidin-1-ylmethyl) -1,2,4-oxadiazol-3-yl] -1H-benzimidazole:

(1) To a suspension obtained by adding 2-ethyl-5-fluoro-N′-hydroxy-1H-benzimidazole-4-carboximidamide (100 mg) to THF (2.0 ml), chloroacetyl was added under ice cooling. Chloride (56 mg) was added dropwise and stirred at room temperature for 15 minutes. Subsequently, tetra-n-butylammonium fluoride (1M THF solution, 1.4 ml) was added, and the mixture was stirred at room temperature for 2 hours and at 50 ° C. for 2 hours. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (column; Hi-FlashTM, developing solvent: chloroform / methanol), and 5- (chloromethyl) -3- (2-ethyl-5 -Fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazole (34 mg) was obtained.
LC-MS, m / z; 281 [M + H] +
(2) 5- (chloromethyl) -3- (2-ethyl-5-fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazole (34 mg), piperidine (20 mg), iodine A suspension obtained by adding sodium chloride (4 mg) and potassium carbonate (49 mg) to acetonitrile (1.7 ml) was stirred at 50 ° C. for 1 hour. The reaction mixture was purified by silica gel column chromatography (column; Hi-FlashTM amino column, developing solvent: chloroform / methanol), and further purified by preparative size exclusion chromatography (mobile phase: chloroform) to give the title compound ( 18 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.43-1.53 (5H, m), 1.62-1.72 (4H, m), 2.57-2.66 (4H, m), 3.01 (2H, q, J = 7.6 Hz), 3.98 (2H, s), 7.13 (1H, dd, J = 11.5, 8.8 Hz), 7.78 (1H, dd, J = 8.7, 4.3 Hz), 10.73 (1H, br s).
LC-MS, m / z; 330 [M + H] +

　（１）５－フルオロ－Ｎ’－ヒドロキシ－２－メチル－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミド（１００ｍｇ）を１，４－ジオキサン（２．０ｍｌ）に加えた懸濁液に、氷冷下で３－クロロプロパノイルクロリド（１２２ｍｇ）を滴下し、５０℃で２時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムとメタノール混合溶媒（１０：１）で目的物を抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮することでＮ’－（３－クロロプロパノイルオキシ）－５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミドの粗生成物（１４０ｍｇ）を得た。
LC-MS, m/z; 299 [M+H]+
　（２）Ｎ’－（３－クロロプロパノイルオキシ）－５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミドの粗生成物（１４０ｍｇ）を酢酸（４．０ｍｌ）に加えた懸濁を、９０℃で４時間攪拌した。反応混合物を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：クロロホルム／メタノール）により精製することで、５－（２－クロロエチル）－３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾールの粗生成物（６６ｍｇ）を得た。
　（３）５－（２－クロロエチル）－３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾールの粗生成物（６６ｍｇ）、ピペリジン（４０ｍｇ）、ヨウ化ナトリウム（７ｍｇ）、炭酸カリウム（９８ｍｇ）をアセトニトリル（３．３ｍｌ）に加えた懸濁液を、６０℃で３時間攪拌した。反応混合物をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：クロロホルム／メタノール）により精製した後、更に分取サイズ排除クロマトグラフィー（移動相：クロロホルム）により精製することで、標記化合物（２７ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.42-1.50 (2H, m), 1.58-1.66 (4H, m), 2.49-2.57 (4H, m), 2.69 (3H, s), 2.95 (2H, t, J = 7.4 Hz), 3.26 (2H, t, J = 7.4 Hz), 7.12 (1H, dd, J = 11.5, 8.8 Hz), 7.73 (1H, dd, J = 8.7, 4.3 Hz), 10.53 (1H, br s).
LC-MS, m/z; 330 [M+H]+ Example 102:
Preparation of 5-fluoro-2-methyl-4- {5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazol-3-yl} -1H-benzimidazole:

(1) To a suspension obtained by adding 5-fluoro-N′-hydroxy-2-methyl-1H-benzimidazole-4-carboximidamide (100 mg) to 1,4-dioxane (2.0 ml), ice-cooled 3-Chloropropanoyl chloride (122 mg) was added dropwise thereto, and the mixture was stirred at 50 ° C. for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the desired product was extracted with a mixed solvent of chloroform and methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of N ′-(3-chloropropanoyloxy) -5-fluoro-2-methyl-1H-benzimidazole-4-carboximidamide ( 140 mg) was obtained.
LC-MS, m / z; 299 [M + H] +
(2) Crude product (140 mg) of N ′-(3-chloropropanoyloxy) -5-fluoro-2-methyl-1H-benzimidazole-4-carboximidamide was added to acetic acid (4.0 ml). The suspension was stirred at 90 ° C. for 4 hours. The reaction mixture is concentrated, and the obtained residue is purified by silica gel column chromatography (column; Hi-FlashTM, developing solvent: chloroform / methanol) to give 5- (2-chloroethyl) -3- (5-fluoro- A crude product (66 mg) of 2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazole was obtained.
(3) 5- (2-chloroethyl) -3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazole crude product (66 mg), piperidine (40 mg), sodium iodide (7 mg), potassium carbonate (98 mg) added to acetonitrile (3.3 ml) was stirred at 60 ° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography (column; Hi-FlashTM, developing solvent: chloroform / methanol), and further purified by preparative size exclusion chromatography (mobile phase: chloroform) to give the title compound (27 mg) Got.
¹ H-NMR (CDCl ₃ ) δ: 1.42-1.50 (2H, m), 1.58-1.66 (4H, m), 2.49-2.57 (4H, m), 2.69 (3H, s), 2.95 (2H, t, J = 7.4 Hz), 3.26 (2H, t, J = 7.4 Hz), 7.12 (1H, dd, J = 11.5, 8.8 Hz), 7.73 (1H, dd, J = 8.7, 4.3 Hz), 10.53 (1H, br s).
LC-MS, m / z; 330 [M + H] +

　（１）２－エチル－５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミド（３００ｍｇ）を１，４－ジオキサン（１０ｍｌ）に溶かし、氷冷下で３－クロロプロパノイルクロリド（２０６ｍｇ）を滴下し、８０℃で１時間攪拌した。反応溶液を室温に冷却し、三フッ化ホウ素エーテル錯体（４７％、０．６ｍｌ）を加え、再度８０℃に加熱し、終夜攪拌した。その後、反応溶液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにより精製することで５－（２－クロロエチル）－３－（２－エチル－５－フルオロ－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾールと副生成物（脱塩酸体）との混合物（１７０ｍｇ）を黄色固体として得た。
　（２）実施例１０２の工程（３）における５－（２－クロロエチル）－３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾールの代わりに、５－（２－クロロエチル）－３－（２－エチル－５－フルオロ－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾールを用いて、実施例１０２の工程（３）と同様の方法により、標記化合物を製造した。
¹H-NMR (CDCl₃) δ: 1.40-1.52 (5H, m), 1.55-1.65 (4H, m), 2.42-2.58 (4H, m), 2.93 (2H, t, J = 7.6 Hz), 3.01 (2H, q, J = 7.6 Hz), 3.24 (2H, t, J = 7.6 Hz), 7.12 (1H, dd, J = 11.4, 8.8 Hz), 7.76 (1H, dd, J = 8.8, 4.4 Hz), 10.51 (1H, br s).
LC-MS, m/z; 344 [M+H]+ Example 103:
Preparation of 2-ethyl-5-fluoro-4- {5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazol-3-yl} -1H-benzimidazole:

(1) 2-Ethyl-5-fluoro-N′-hydroxy-1H-benzimidazole-4-carboximidamide (300 mg) is dissolved in 1,4-dioxane (10 ml), and 3-chloropropanoyl is cooled with ice. Chloride (206 mg) was added dropwise and stirred at 80 ° C. for 1 hour. The reaction solution was cooled to room temperature, boron trifluoride ether complex (47%, 0.6 ml) was added, heated again to 80 ° C., and stirred overnight. Thereafter, the reaction solution is concentrated, and the obtained residue is purified by silica gel column chromatography to give 5- (2-chloroethyl) -3- (2-ethyl-5-fluoro-1H-benzimidazol-4-yl). A mixture (170 mg) of -1,2,4-oxadiazole and a by-product (dehydrochlorinated product) was obtained as a yellow solid.
(2) 5- (2-Chloroethyl) -3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazole in Step (3) of Example 102 In place of 5- (2-chloroethyl) -3- (2-ethyl-5-fluoro-1H-benzimidazol-4-yl) -1,2,4-oxadiazole, The title compound was produced in the same manner as in step (3).
¹ H-NMR (CDCl ₃ ) δ: 1.40-1.52 (5H, m), 1.55-1.65 (4H, m), 2.42-2.58 (4H, m), 2.93 (2H, t, J = 7.6 Hz), 3.01 (2H, q, J = 7.6 Hz), 3.24 (2H, t, J = 7.6 Hz), 7.12 (1H, dd, J = 11.4, 8.8 Hz), 7.76 (1H, dd, J = 8.8, 4.4 Hz) , 10.51 (1H, br s).
LC-MS, m / z; 344 [M + H] +

　４－（ピペリジン－１－イル）酪酸（１２８ｍｇ）をＴＨＦ（２ｍｌ）に溶解し、ＣＤＩ（１１１ｍｇ）を加えて、室温で１時間攪拌した。次いで２－エチル－５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－ベンズイミダゾール－４－カルボキシイミドアミド（１１１ｍｇ）を加え、更に５０℃で１８時間攪拌した。反応混合物を減圧濃縮し、残渣を逆相ＨＰＬＣにて分取精製することで、標記化合物（５．１ｍｇ）を得た。
LC-MS, m/z; 358 [M+H]+ Example 104:
Preparation of 2-ethyl-5-fluoro-4- {5- [3- (piperidin-1-yl) propyl] -1,2,4-oxadiazol-3-yl} -1H-benzimidazole:

4- (Piperidin-1-yl) butyric acid (128 mg) was dissolved in THF (2 ml), CDI (111 mg) was added, and the mixture was stirred at room temperature for 1 hr. Subsequently, 2-ethyl-5-fluoro-N′-hydroxy-1H-benzimidazole-4-carboximidamide (111 mg) was added, and the mixture was further stirred at 50 ° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by reverse phase HPLC to obtain the title compound (5.1 mg).
LC-MS, m / z; 358 [M + H] +

　実施例１０２の３－クロロプロパノイル クロライドの代わりに、５－クロロペンタノイル クロライドを用いて、実施例１０２と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 372 [M+H]+ Example 105:
Preparation of 2-ethyl-5-fluoro-4- {5- [4- (piperidin-1-yl) butyl] -1,2,4-oxadiazol-3-yl} -1H-benzimidazole:

The title compound was prepared in a similar manner to that described in Example 102 using 5-chloropentanoyl chloride in place of 3-chloropropanoyl chloride of Example 102.
LC-MS, m / z; 372 [M + H] +

　１’－アセチル－１，４’－ビピペリジン－４－カルボン酸（９１ｍｇ）、トリエチルアミン（０．０６９ｍｌ）をＴＨＦ（１ｍｌ）に加えた懸濁液に、クロロ炭酸イソプロピル（０．０４１ｍｌ）を滴下し、４０℃で１時間攪拌した。次いでＮ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミド（４２ｍｇ）を加え、４０℃で３時間攪拌した。その後、フッ化テトラ－ｎ－ブチルアンモニウム（１Ｍ ＴＨＦ溶液、１ｍｌ）を加え、７０℃で更に３時間攪拌した。反応混合物に水を加え、目的物を酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：クロロホルム／メタノール）により精製し、再度シリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：酢酸エチル／メタノール）により精製することで、標記化合物（４６ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.41-1.64 (2H, m), 1.80-1.94 (2H, m), 1.97-2.26 (7H, m), 2.35-2.49 (2H, m), 2.50-2.64 (2H, m), 2.94-3.12 (4H, m), 3.83-3.93 (1H, m), 4.63-4.73 (1H, m), 7.50 (1H, dd, J = 8.5, 7.2 Hz), 7.66 (1H, d, J = 8.5 Hz), 8.00 (1H, d, J = 7.2 Hz), 8.73 (1H, s), 10.40 (1H, br s)
LC-MS, m/z; 395 [M+H]+ Example 106:
Production of 1- {4- [3- (1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidin-1′-yl} ethanone:

To a suspension of 1′-acetyl-1,4′-bipiperidine-4-carboxylic acid (91 mg) and triethylamine (0.069 ml) in THF (1 ml), isopropyl chlorocarbonate (0.041 ml) was added dropwise. , And stirred at 40 ° C. for 1 hour. Next, N′-hydroxy-1H-indazole-4-carboximidamide (42 mg) was added and stirred at 40 ° C. for 3 hours. Thereafter, tetra-n-butylammonium fluoride (1M THF solution, 1 ml) was added, and the mixture was further stirred at 70 ° C. for 3 hours. Water was added to the reaction mixture, and the target product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-FlashTM amino column, developing solvent: chloroform / methanol), and again silica gel column chromatography (column; Hi-FlashTM amino column, developing solvent: ethyl acetate / methanol). ) To give the title compound (46 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.41-1.64 (2H, m), 1.80-1.94 (2H, m), 1.97-2.26 (7H, m), 2.35-2.49 (2H, m), 2.50-2.64 ( 2H, m), 2.94-3.12 (4H, m), 3.83-3.93 (1H, m), 4.63-4.73 (1H, m), 7.50 (1H, dd, J = 8.5, 7.2 Hz), 7.66 (1H, d, J = 8.5 Hz), 8.00 (1H, d, J = 7.2 Hz), 8.73 (1H, s), 10.40 (1H, br s)
LC-MS, m / z; 395 [M + H] +

（式中、（Ｈｅｔ）は下記表中の構造を意味する）

The compounds shown in the following table (Examples 107 to 109) were prepared in the same manner as in Example 106 using the corresponding starting compounds instead of N′-hydroxy-1H-indazole-4-carboximidamide in Example 106. Manufactured.

(Wherein (Het) means the structure in the table below)

　１－｛４－［３－（１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］－１，４’－ビピペリジン－１’－イル｝エタノン（３０ｍｇ）を酢酸（０．５ｍｌ）に溶かし、無水酢酸（１ｍｌ）を加え室温で５時間半攪拌した。反応混合物に水を加え、目的物を酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥、ろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：クロロホルム／メタノール）により精製し、標記化合物（１０．５ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.38-1.62 (2H, m), 1.83-2.33 (9H, m), 2.42-2.73 (4H, m), 2.79-2.89 (3H, m), 2.97-3.18 (4H, m), 3.83-3.95 (1H, m), 4.63-4.75 (1H, m), 7.66 (1H, dd, J = 8.4, 7.5 Hz), 8.13 (1H, d, J = 7.5 Hz), 8.61 (1H, d, J = 8.4 Hz), 8.82 (1H, s)
LC-MS, m/z; 437 [M+H]+ Example 110:
1- {4- [5- (1′-acetyl-1,4′-bipiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazol-1-yl} ethanone Manufacturing of:

1- {4- [3- (1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidin-1′-yl} ethanone (30 mg) The residue was dissolved in acetic acid (0.5 ml), acetic anhydride (1 ml) was added, and the mixture was stirred at room temperature for 5 and a half hours. Water was added to the reaction mixture, and the target product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-Flash ™, developing solvent: chloroform / methanol) to obtain the title compound (10.5 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.38-1.62 (2H, m), 1.83-2.33 (9H, m), 2.42-2.73 (4H, m), 2.79-2.89 (3H, m), 2.97-3.18 ( 4H, m), 3.83-3.95 (1H, m), 4.63-4.75 (1H, m), 7.66 (1H, dd, J = 8.4, 7.5 Hz), 8.13 (1H, d, J = 7.5 Hz), 8.61 (1H, d, J = 8.4 Hz), 8.82 (1H, s)
LC-MS, m / z; 437 [M + H] +

　１－｛４－［３－（１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］－１，４’－ビピペリジン－１’－イル｝エタノン（２２ｍｇ）をジクロロメタン（１ｍｌ）に溶かし、トリエチルアミン（０．０２３ｍｌ）、メタンスルホニルクロリド（０．００８７ｍｌ）を加え室温で３時間半攪拌した。反応混合物を減圧濃縮した後、得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－ＦｌａｓｈＴＭ、展開溶媒：クロロホルム／メタノール）により精製し、標記化合物（１７．５ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.36-1.56 (2H, m), 1.78-2.30 (9H, m), 2.35-2.73 (4H, m), 2.92-3.15 (4H, m), 3.45 (3H, s), 3.78-3.90 (1H, m), 4.56-4.71 (1H, m), 7.45 (1H, dd, J = 9.0, 6.9 Hz), 7.83 (1H, d, J = 9.0 Hz), 7.97 (1H, d, J = 6.9 Hz), 9.12 (1H, s)
LC-MS, m/z; 473 [M+H]+ Example 111:
1- (4- {3- [1- (methylsulfonyl) -1H-indazol-4-yl] -1,2,4-oxadiazol-5-yl} -1,4′-bipiperidine-1′- Il) Manufacture of ethanone:

1- {4- [3- (1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidin-1′-yl} ethanone (22 mg) It was dissolved in dichloromethane (1 ml), triethylamine (0.023 ml) and methanesulfonyl chloride (0.0087 ml) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (column; Hi-FlashTM, developing solvent: chloroform / methanol) to obtain the title compound (17.5 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.36-1.56 (2H, m), 1.78-2.30 (9H, m), 2.35-2.73 (4H, m), 2.92-3.15 (4H, m), 3.45 (3H, s), 3.78-3.90 (1H, m), 4.56-4.71 (1H, m), 7.45 (1H, dd, J = 9.0, 6.9 Hz), 7.83 (1H, d, J = 9.0 Hz), 7.97 (1H , d, J = 6.9 Hz), 9.12 (1H, s)
LC-MS, m / z; 473 [M + H] +

（式中、（Ｈｅｔ）は下記表中の構造を意味する）

１）得られた組成生物を１Ｎ塩酸／ジエチルエーテル溶液で処理することにより、塩酸塩を得た。 The compounds shown in the following tables (Examples 112 to 115) were prepared in the same manner as in Example 106 using the corresponding starting compounds instead of N′-hydroxy-1H-indazole-4-carboximidamide in Example 106. Manufactured.

(Wherein (Het) means the structure in the table below)

1) The obtained composition was treated with 1N hydrochloric acid / diethyl ether solution to obtain hydrochloride.

　（１）実施例００１におけるｔｅｒｔ－ブチル ４－［３－（２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートの代わりに、ｔｅｒｔ－ブチル ４－｛３－［２－（プロパン－２－イル）－１，３－ベンゾオキサゾール－４－イル］－１，２，４－オキサジアゾール－５－イル｝ピペリジン－１－カルボキシレートを用いて、実施例００１と同様の方法により、４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－２－（プロパン－２－イル）－１，３－ベンゾオキサゾール トリフルオロ酢酸塩を製造した。
　（２）４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－２－（プロパン－２－イル）－１，３－ベンゾオキサゾール トリフルオロ酢酸塩（３０ｍｇ）をアセトニトリル（１ｍｌ）に加えた懸濁液に、ｎ－ブチルブロマイド（１２ｍｇ）、炭酸カリウム（７８ｍｇ）、ヨウ化ナトリウム（２１ｍｇ）を加え、９０℃にて撹拌した。反応液を室温に放冷後、反応液に水を加え、クロロホルムで目的物を抽出後、有機層を水、飽和食塩水にて洗浄し、無水硫酸ナトリウムで乾燥、ろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（カラム；Ｈｉ－Ｆｌａｓｈ^ＴＭ アミノ Ｃｏｌｕｍｎ、展開溶媒：ヘキサン／酢酸エチル）で精製し、標記化合物（６．８ｍｇ）を得た。
LC-MS, m/z; ３６９ [M+H]+ Example 116:
Preparation of 4- [5- (1-butylpiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -2- (propan-2-yl) -1,3-benzoxazole:

(1) tert-Butyl 4- [3- (2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate in Example 001 Instead of tert-butyl 4- {3- [2- (propan-2-yl) -1,3-benzooxazol-4-yl] -1,2,4-oxadiazol-5-yl} piperidine 4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -2- (propane) by the same method as in Example 001 using -1-carboxylate -2-yl) -1,3-benzoxazole trifluoroacetate was prepared.
(2) 4- [5- (Piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -2- (propan-2-yl) -1,3-benzoxazole trifluoroacetic acid N-Butyl bromide (12 mg), potassium carbonate (78 mg) and sodium iodide (21 mg) were added to a suspension obtained by adding salt (30 mg) to acetonitrile (1 ml), and the mixture was stirred at 90 ° C. The reaction solution is allowed to cool to room temperature, water is added to the reaction solution, and the desired product is extracted with chloroform. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate is reduced in pressure. Concentrated. The obtained residue was purified by silica gel column chromatography (column; Hi-Flash ^TM amino column, developing solvent: hexane / ethyl acetate) to obtain the title compound (6.8 mg).
LC-MS, m / z; 369 [M + H] +

（式中、（Ｂ－４）は下記表中の構造を意味する）

The compounds shown in the following table (Examples 117 to 123) were prepared in the same manner as in Step (3) of Example 102 using the corresponding cyclic secondary amine compound instead of piperidine in Step (3) of Example 102. Manufactured.

(Wherein (B-4) means the structure in the following table)

（式中、（Ｂ－４）は下記表中の構造を意味する）

The compounds shown in the following tables (Examples 124 to 129) were produced in the same manner as in Example 089 using the corresponding cyclic secondary amine compound instead of piperidine in Example 089.

(Wherein (B-4) means the structure in the following table)

　（１）亜鉛（１４６ｍｇ）と１，２－ジブロモエタン（０．１７ｍＬ）をテトラヒドロフラン（３．５ｍＬ）中において窒素雰囲気下６５℃で５分間撹拌した。室温に冷却した後、トリメチルシリルクロリド（０．２４ｍＬ）を加え、室温で３０分間撹拌した。次いで、ｔｅｒｔ－ブチル ３－ヨードアゼチジン－１－カルボキシレート（４．８ｇ）のテトラヒドロフラン溶液（８．６ｍＬ）をゆっくり加え、室温で４５分間撹拌した。得られた反応混合物に２－ブロモ－４－フルオロピリジン（３．０ｇ）、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム（８７０ｍｇ）およびヨウ化銅（３３０ｍｇ）を加え、窒素雰囲気下６０℃にて６時間撹拌した。反応混合物を室温に冷却した後、濾過して濾液を減圧濃縮した。得られた残渣を分取ＨＰＬＣで精製することにより、ｔｅｒｔ－ブチル ３－（４－フルオロピリジン－２－イル）アゼチジン－１－カルボキシレート（５００ｍｇ）を得た。
　（２）ｔｅｒｔ－ブチル ３－（４－フルオロピリジン－２－イル）アゼチジン－１－カルボキシレート（５００ｍｇ）をトリフルオロ酢酸（２ｍＬ）／ジクロロメタン（８ｍＬ）混合溶媒中で室温にて２時間撹拌した。得られた反応混合物を減圧下濃縮することにより、標記化合物（３．０ｇ）を得た。  Reference Example 168:
Preparation of 2- (azetidin-3-yl) -4-fluoropyridine 2 trifluoroacetate:

(1) Zinc (146 mg) and 1,2-dibromoethane (0.17 mL) were stirred in tetrahydrofuran (3.5 mL) at 65 ° C. for 5 minutes under a nitrogen atmosphere. After cooling to room temperature, trimethylsilyl chloride (0.24 mL) was added and stirred at room temperature for 30 minutes. Next, a tetrahydrofuran solution (8.6 mL) of tert-butyl 3-iodoazetidine-1-carboxylate (4.8 g) was slowly added and stirred at room temperature for 45 minutes. To the obtained reaction mixture, 2-bromo-4-fluoropyridine (3.0 g), bis (tri-tert-butylphosphine) palladium (870 mg) and copper iodide (330 mg) were added, and a nitrogen atmosphere at 60 ° C. Stir for 6 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to give tert-butyl 3- (4-fluoropyridin-2-yl) azetidine-1-carboxylate (500 mg).
(2) tert-butyl 3- (4-fluoropyridin-2-yl) azetidine-1-carboxylate (500 mg) was stirred in a mixed solvent of trifluoroacetic acid (2 mL) / dichloromethane (8 mL) at room temperature for 2 hours. . The resulting reaction mixture was concentrated under reduced pressure to obtain the title compound (3.0 g).

（式中、Ｒ^１０は下記表中の構造を意味する）

The compounds shown in the following tables (Reference Examples 169 to 170) were obtained in the same manner as in Reference Example 168 using the corresponding heteroaryl bromide instead of 2-bromo-4-fluoropyridine in Reference Example 168.

(In the formula, R ¹⁰ means the structure in the following table)

　（１）７－フルオロ－１Ｈ－インダゾール－４－カルボニトリル（１．０ｇ）、塩酸ヒドロキシルアミン（８６０ｍｇ）および炭酸水素ナトリウム（１．０ｇ）をエタノール（２８ｍＬ）／水（４ｍＬ）混合溶媒中で１２時間加熱還流した。反応混合物を減圧濃縮して残渣に水を加え、酢酸エチルで抽出した。有機層を減圧濃縮することにより、７－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミド（８００ｍｇ）を得た。
¹H-NMR (DMSO-d₆) δ: 5.88 (2H, s), 7.19 (1H, m), 7.36 (1H, m), 8.39 (1H, d, J = 3.2 Hz), 9.83 (1H, s), 13.69 (1H, br s).
　（２）１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－カルボン酸（９．５ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（４０ｍＬ）に１，１’－カルボニルジイミダゾール（６．７ｇ）を加え、室温で１時間撹拌した。次いで７－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミド（８００ｍｇ）を加え、１２０℃で１０時間撹拌した。反応混合物を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（石油エーテル／酢酸エチル）で精製することにより、標記化合物（９００ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 1.91-1.96 (2H, m), 2.10-2.22 (2H, m), 3.03 (2H, m), 3.22 (1H, m), 4.06-4.26 (2H, m), 7.19 (1H, dd, J = 10.4, 8.0 Hz), 7.96 (1H, dd, J = 8.0, 4.0 Hz), 8.76 (1H, d, J = 3.2 Hz). Reference Example 171:
Preparation of tert-butyl 4- [3- (7-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate:

(1) 7-Fluoro-1H-indazole-4-carbonitrile (1.0 g), hydroxylamine hydrochloride (860 mg) and sodium hydrogen carbonate (1.0 g) in a mixed solvent of ethanol (28 mL) / water (4 mL) Heated to reflux for 12 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 7-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide (800 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 5.88 (2H, s), 7.19 (1H, m), 7.36 (1H, m), 8.39 (1H, d, J = 3.2 Hz), 9.83 (1H, s ), 13.69 (1H, br s).
(2) 1,1′-carbonyldiimidazole (6.7 g) was added to an N, N-dimethylformamide solution (40 mL) of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (9.5 g), Stir at room temperature for 1 hour. Subsequently, 7-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide (800 mg) was added and stirred at 120 ° C. for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (900 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.91-1.96 (2H, m), 2.10-2.22 (2H, m), 3.03 (2H, m), 3.22 (1H, m), 4.06 -4.26 (2H, m), 7.19 (1H, dd, J = 10.4, 8.0 Hz), 7.96 (1H, dd, J = 8.0, 4.0 Hz), 8.76 (1H, d, J = 3.2 Hz).

　参考例１７１の工程（１）における７－フルオロ－１Ｈ－インダゾール－４－カルボニトリルの代わりに、６－フルオロ－１Ｈ－インダゾール－４－カルボニトリルを用いて、参考例１７１の工程（１）、（２）と同様の方法により、標記化合物（５００ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 1.89-2.03 (2H, m), 2.12-2.24 (2H, m), 3.06 (2H, t, J = 11.6 Hz), 3.26 (1H, m), 4.06-4.29 (2H, m), 7.34 (1H, d, J = 8.4 Hz), 7.80 (1H, dd, J = 9.6, 2.0 Hz), 8.72 (1H, s). Reference Example 172:
Preparation of tert-butyl 4- [3- (6-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate:

In place of 7-fluoro-1H-indazole-4-carbonitrile in step (1) of Reference Example 171, 6-fluoro-1H-indazole-4-carbonitrile was used to replace Step (1) of Reference Example 171; In the same manner as in (2), the title compound (500 mg) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 1.89-2.03 (2H, m), 2.12-2.24 (2H, m), 3.06 (2H, t, J = 11.6 Hz), 3.26 (1H , m), 4.06-4.29 (2H, m), 7.34 (1H, d, J = 8.4 Hz), 7.80 (1H, dd, J = 9.6, 2.0 Hz), 8.72 (1H, s).

　参考例１７１の工程（１）における７－フルオロ－１Ｈ－インダゾール－４－カルボニトリルの代わりに、５－フルオロ－１Ｈ－インダゾール－４－カルボニトリルを用いて、参考例１６９の工程（１）、（２）と同様の方法により、標記化合物（６．７ｇ）を得た。
LC-MS, m/z; 388 [M+H]+ Reference Example 173:
Preparation of tert-butyl 4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate:

In place of 7-fluoro-1H-indazole-4-carbonitrile in the step (1) of Reference Example 171, 5-fluoro-1H-indazole-4-carbonitrile was used to replace the step (1) of Reference Example 169, In the same manner as in (2), the title compound (6.7 g) was obtained.
LC-MS, m / z; 388 [M + H] +

　５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミド（２００ｍｇ）のジクロロメタン溶液（５ｍＬ）に３－クロロプロピオン酸クロリド（１４０ｍｇ）とトリエチルアミン（０．２２ｍＬ）を加え、室温で１時間撹拌した。次いで反応溶液を減圧濃縮し、酢酸（２ｍＬ）を加え、９０℃で終夜撹拌した。得られた反応溶液を飽和炭酸水素ナトリウム水溶液で中和し、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥し減圧濃縮することで、標記化合物の粗生成物を得た。 Reference Example 174:
Preparation of 4- [5- (2-chloroethyl) -1,2,4-oxadiazol-3-yl] -5-fluoro-1H-indazole:

3-Chloropropionic acid chloride (140 mg) and triethylamine (0.22 mL) were added to a dichloromethane solution (5 mL) of 5-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide (200 mg), and 1 at room temperature. Stir for hours. The reaction solution was then concentrated under reduced pressure, acetic acid (2 mL) was added, and the mixture was stirred at 90 ° C. overnight. The resulting reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound.

　参考例１７４における３－クロロプロピオン酸クロリドの代わりに、５－クロロ吉草酸クロリドを用いて、参考例１７４と同様の方法により、標記化合物の粗生成物を得た。 Reference Example 175:
Preparation of 4- [5- (4-chlorobutyl) -1,2,4-oxadiazol-3-yl] -5-fluoro-1H-indazole:

A crude product of the title compound was obtained in the same manner as in Reference Example 174 using 5-chlorovaleric acid chloride in place of 3-chloropropionic acid chloride in Reference Example 174.

　５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミド（３００ｍｇ）のテトラヒドロフラン溶液（５ｍＬ）に１，１’－カルボニルジイミダゾール（３７０ｍｇ）を加え、室温で１時間撹拌した。次いで３－オキソアゼチジン－１－カルボン酸（２７０ｍｇ）を加え、室温で終夜撹拌した。反応混合物を減圧濃縮し、残渣を酢酸（５ｍＬ）に溶解し、９０℃で２時間撹拌した。得られた反応混合物を減圧濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥して減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（石油エーテル／酢酸エチル）で精製することにより、標記化合物（２５０ｍｇ）を得た。
¹H-NMR (MeOD) δ: 3.67-3.74 (4H, m), 4.16 (1H, m), 7.41 (1H, m), 7.78 (1H, m), 8.60 (1H, s). Reference Example 176:
Production of 3- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclobutanone:

1,1′-carbonyldiimidazole (370 mg) was added to a tetrahydrofuran solution (5 mL) of 5-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide (300 mg), and the mixture was stirred at room temperature for 1 hour. Subsequently, 3-oxoazetidine-1-carboxylic acid (270 mg) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetic acid (5 mL) and stirred at 90 ° C. for 2 hours. The obtained reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (250 mg).
¹ H-NMR (MeOD) δ: 3.67-3.74 (4H, m), 4.16 (1H, m), 7.41 (1H, m), 7.78 (1H, m), 8.60 (1H, s).

　参考例１７１の工程（２）における１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－カルボン酸と７－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミドの代わりに、１－（ｔｅｒｔ－ブトキシカルボニル）ピロリジン－３－カルボン酸と５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミドを用いて、参考例１７１の工程（２）と同様の方法により、標記化合物の粗精製物（３．１ｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.38-2.54 (2H, m), 3.48-4.02 (5H, m), 7.32 (1H, t, J = 10.0 Hz), 7.64 (1H, dd, J = 9.2, 4.0 Hz), 8.70 (1H, s). Reference Example 177:
Preparation of tert-butyl 3- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] pyrrolidine-1-carboxylate:

Instead of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid and 7-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide in step (2) of Reference Example 171, 1- (tert -Butoxycarbonyl) pyrrolidine-3-carboxylic acid and 5-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide were used in the same manner as in Step (2) of Reference Example 171 to Crude product (3.1 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.38-2.54 (2H, m), 3.48-4.02 (5H, m), 7.32 (1H, t, J = 10.0 Hz), 7.64 (1H , dd, J = 9.2, 4.0 Hz), 8.70 (1H, s).

　参考例１７１の工程（２）における１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－カルボン酸と７－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミドの代わりに、１－（ｔｅｒｔ－ブトキシカルボニル）アゼチジン－３－カルボン酸と５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミドを用いて、参考例１７１の工程（２）と同様の方法により、標記化合物（１３ｇ）を得た。
¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 4.19 (1H, m), 4.37-4.50 (4H, m), 7.34 (1H, t, J = 10.4 Hz), 7.66 (1H, dd, J = 9.2, 4.0 Hz), 8.73 (1H, s). Reference Example 178:
Preparation of tert-butyl 3- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] azetidine-1-carboxylate:

Instead of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid and 7-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide in step (2) of Reference Example 171, 1- (tert The title compound (-butoxycarbonyl) azetidine-3-carboxylic acid and 5-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide were prepared in the same manner as in Step (2) of Reference Example 171. 13 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 4.19 (1H, m), 4.37-4.50 (4H, m), 7.34 (1H, t, J = 10.4 Hz), 7.66 (1H, dd , J = 9.2, 4.0 Hz), 8.73 (1H, s).

　ベンジル ピペリジン－４－カルボキシレート 塩酸塩（４．２ｇ）および１，６－ジオキサスピロ［２．５］オクタン（４．２ｇ）をエタノール（１５０ｍｌ）に溶かし、ジイソプロピルエチルアミン（４．３ｇ）を加え、室温で一晩撹拌したのち、２時間加熱還流した。反応溶液を減圧濃縮し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した後に減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製することにより、表記化合物（３．５ｇ）を得た。
LC-MS, m/z; 334 [M+H]+ Reference Example 179:
Preparation of benzyl 1-[(4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidine-4-carboxylate:

Benzyl piperidine-4-carboxylate hydrochloride (4.2 g) and 1,6-dioxaspiro [2.5] octane (4.2 g) are dissolved in ethanol (150 ml), diisopropylethylamine (4.3 g) is added, and room temperature is added. The mixture was stirred overnight at rt and heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (3.5 g).
LC-MS, m / z; 334 [M + H] +

　ベンジル １－［（４－ヒドロキシテトラヒドロ－２Ｈ－ピラン－４－イル）メチル］ピペリジン－４－カルボキシレート（３．５ｇ）およびパラジウム炭素（３．０ｇ）をメタノール（５０ｍｌ）に懸濁し、水素雰囲気下、室温で２時間撹拌した。反応混合物をセライトろ過したのち、減圧濃縮することで、表記化合物（３．１ｇ）を得た。
LC-MS, m/z; 244 [M+H]+ Reference example 180:
Preparation of 1-[(4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidine-4-carboxylic acid:

Benzyl 1-[(4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidine-4-carboxylate (3.5 g) and palladium on carbon (3.0 g) are suspended in methanol (50 ml) and hydrogen atmosphere The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (3.1 g).
LC-MS, m / z; 244 [M + H] +

　１－［（４－ヒドロキシテトラヒドロ－２Ｈ－ピラン－４－イル）メチル］ピペリジン－４－カルボン酸（１７０ｍｇ）をＴＨＦ（５ｍｌ）に溶かし、クロロ炭酸イソプロピル（８６ｍｇ）およびトリエチルアミン（１４２ｍｇ）を滴下し、４０℃にて１時間撹拌した。次いで、５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミド（７５ｍｇ）を加え、４０℃にてさらに１時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮することで、表記化合物を粗生成物として得た。
LC-MS, m/z; 420 [M+H]+ Reference Example 181:
Of 5-fluoro-N ′-[({1-[(4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidin-4-yl} carbonyl) oxy] -1H-indazole-4-carboximidamide Manufacturing:

1-[(4-Hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidine-4-carboxylic acid (170 mg) is dissolved in THF (5 ml), and isopropyl chlorocarbonate (86 mg) and triethylamine (142 mg) are added dropwise. And stirred at 40 ° C. for 1 hour. Subsequently, 5-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide (75 mg) was added, and the mixture was further stirred at 40 ° 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 dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a crude product.
LC-MS, m / z; 420 [M + H] +

（式中、（Ｂ－４）は下記表中の構造を意味する）

The compounds shown in the following table (Examples 130 to 172) were obtained in the same manner as in Step (3) of Example 102 using the corresponding amine compound instead of piperidine in Step (3) of Example 102. .

(Wherein (B-4) means the structure in the following table)

（式中、（Ｂ－４）は下記表中の構造を意味する）

The compounds shown in the following table (Examples 173 to 178) were obtained in the same manner as in Example 089, using the corresponding amine compound instead of the piperidine in Example 089.

(Wherein (B-4) means the structure in the following table)

　シス－３－［３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］－Ｎ－（プロパン－２－イル）シクロブタンアミン（５０ｍｇ）と３７％ホルムアルデヒド水溶液（１ｍＬ）をギ酸（２ｍＬ）中で室温にて終夜撹拌した。反応混合物を減圧濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を減圧濃縮し、残渣を分取ＨＰＬＣで精製することにより、標記化合物（２４ｍｇ）を得た。
LC-MS, m/z; 344 [M+H]+ Example 179:
Cis-3- [3- (5-Fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] -N-methyl-N- (propane- Preparation of 2-yl) cyclobutanamine:

Cis-3- [3- (5-Fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] -N- (propan-2-yl) Cyclobutanamine (50 mg) and 37% aqueous formaldehyde solution (1 mL) were stirred in formic acid (2 mL) at room temperature overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (24 mg).
LC-MS, m / z; 344 [M + H] +

In the same manner as in Example 179, cis-3- [3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl]- Instead of N-methyl-N- (propan-2-yl) cyclobutanamine, N- {cis-3- [3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1, 2,4-oxadiazol-5-yl] cyclobutyl} tetrahydro-2H-pyran-4-amine, or 1- [4-({cis-3- [3- (5-fluoro-2-methyl-1H- By using benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclobutyl} amino) piperidin-1-yl] ethanone, the compounds in the following table (Examples 180 and 181) were obtained. That Obtained.

　実施例０６５の工程（３）における５－（１，４’－ビピペリジン－４－イル）－３－（２－エチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール ３トリフルオロ酢酸塩とクロロ炭酸メチルの代わりに、１－｛２－［３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］エチル｝ピペリジン－４－アミン ３トリフルオロ酢酸塩と無水酢酸を用いて、実施例０６５の工程（３）と同様の方法により、標記化合物（１７ｍｇ）を得た。
LC-MS, m/z; 387 [M+H]+ Example 182:
N- (1- {2- [3- (5-Fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] ethyl} piperidine-4- I) Production of acetamide:

5- (1,4′-bipiperidin-4-yl) -3- (2-ethyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazole in step (3) of Example 065 1- {2- [3- (5-Fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazole-in place of 3 trifluoroacetate and methyl chlorocarbonate 5-yl] ethyl} piperidin-4-amine 3trifluoroacetate and acetic anhydride were used to obtain the title compound (17 mg) in the same manner as in Step (3) of Example 065.
LC-MS, m / z; 387 [M + H] +

　実施例０６５の工程（３）における５－（１，４’－ビピペリジン－４－イル）－３－（２－エチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール ３トリフルオロ酢酸塩の代わりに、１－｛２－［３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］エチル｝ピペリジン－４－アミン ３トリフルオロ酢酸塩を用いて、実施例０６５の工程（３）と同様の方法により、標記化合物（２１ｍｇ）を得た。
LC-MS, m/z; 403 [M+H]+ Example 183:
Methyl (1- {2- [3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] ethyl} piperidin-4-yl ) Production of carbamate:

5- (1,4′-bipiperidin-4-yl) -3- (2-ethyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazole in step (3) of Example 065 1- {2- [3- (5-Fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] instead of 3 trifluoroacetate Ethyl} piperidin-4-amine 3trifluoroacetate was used to give the title compound (21 mg) in the same manner as in Step (3) of Example 065.
LC-MS, m / z; 403 [M + H] +

　７－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾール 塩酸塩（１２０ｍｇ）、テトラヒドロ－４Ｈ－ピラン－４－オン（７４ｍｇ）およびトリエチルアミン（５２μＬ）をジクロロメタン（６．０ｍＬ）中で４０℃にて２時間撹拌した。次いで水素化トリアセトキシホウ素ナトリウム（１１０ｍｇ）と酢酸（触媒量）を加え、４０℃でさらに終夜撹拌した。反応混合物を減圧濃縮し、残渣をジクロロメタン（２０ｍＬ）中で３０分間撹拌した。不溶物を濾別して、濾液を減圧濃縮することにより、標記化合物（１００ｍｇ）を得た。
LC-MS, m/z; 372 [M+H]+ Example 184:
Preparation of 7-fluoro-4- {5- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole :

7-Fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole hydrochloride (120 mg), tetrahydro-4H-pyran-4-one (74 mg) and triethylamine (52 μL) were stirred in dichloromethane (6.0 mL) at 40 ° C. for 2 hours. Next, sodium triacetoxyborohydride (110 mg) and acetic acid (catalytic amount) were added, and the mixture was further stirred at 40 ° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was stirred in dichloromethane (20 mL) for 30 minutes. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (100 mg).
LC-MS, m / z; 372 [M + H] +

　実施例１８４における７－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾール 塩酸塩の代わりに、６－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾール 塩酸塩を用いて、実施例１８４と同様の方法で標記化合物（２１ｍｇ）を得た。
LC-MS, m/z; 372 [M+H]+ Example 185:
Preparation of 6-fluoro-4- {5- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole :

Instead of 7-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole in Example 184, 6-fluoro-4 -[5- (Piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole The title compound (21 mg) was prepared in the same manner as in Example 184 using hydrochloride. Obtained.
LC-MS, m / z; 372 [M + H] +

　実施例１０２の工程（３）における５－（２－クロロエチル）－３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾールの代わりに、４－［５－（２－クロロエチル）－１，２，４－オキサジアゾール－３－イル］－５－フルオロ－１Ｈ－インダゾールを用いて、実施例１０２の工程（３）と同様の方法により、標記化合物（３．８ｍｇ）を得た。
LC-MS, m/z; 316 [M+H]+ Example 186:
Preparation of 5-fluoro-4- {5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazol-3-yl} -1H-indazole:

Instead of 5- (2-chloroethyl) -3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazole in step (3) of Example 102 , 4- [5- (2-chloroethyl) -1,2,4-oxadiazol-3-yl] -5-fluoro-1H-indazole, a method similar to step (3) of Example 102 Gave the title compound (3.8 mg).
LC-MS, m / z; 316 [M + H] +

　４－ピペリジン－１－イルブタン酸（３９３ｍｇ）のテトラヒドロフラン溶液（５．０ｍＬ）に１，１’－カルボニルジイミダゾール（３７３ｍｇ）を加え、室温で１時間撹拌した。次いで、５－フルオロ－Ｎ’－ヒドロキシ－１Ｈ－インダゾール－４－カルボキシイミドアミド（３００ｍｇ）を加え、室温で終夜撹拌した。反応混合物を減圧濃縮し、残渣に酢酸（５．０ｍＬ）を加え９０℃で２時間撹拌した。得られた反応混合物を減圧濃縮後、飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、残渣を分取ＨＰＬＣで精製することにより、標記化合物（４２ｍｇ）を得た。
LC-MS, m/z; 330 [M+H]+ Example 187:
Preparation of 5-fluoro-4- {5- [3- (piperidin-1-yl) propyl] -1,2,4-oxadiazol-3-yl} -1H-indazole:

1,1′-carbonyldiimidazole (373 mg) was added to a tetrahydrofuran solution (5.0 mL) of 4-piperidin-1-ylbutanoic acid (393 mg), and the mixture was stirred at room temperature for 1 hour. Subsequently, 5-fluoro-N′-hydroxy-1H-indazole-4-carboximidamide (300 mg) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, acetic acid (5.0 mL) was added to the residue, and the mixture was stirred at 90 ° C. for 2 hr. The obtained reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (42 mg).
LC-MS, m / z; 330 [M + H] +

　実施例１０２の工程（３）における５－（２－クロロエチル）－３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾールの代わりに、４－［５－（４－クロロブチル）－１，２，４－オキサジアゾール－３－イル］－５－フルオロ－１Ｈ－インダゾールを用いて、実施例１０２の工程（３）と同様の方法により、標記化合物（１９ｍｇ）を得た。
LC-MS, m/z; 344 [M+H]+ Example 188:
Preparation of 5-fluoro-4- {5- [4- (piperidin-1-yl) butyl] -1,2,4-oxadiazol-3-yl} -1H-indazole:

Instead of 5- (2-chloroethyl) -3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazole in step (3) of Example 102 , 4- [5- (4-Chlorobutyl) -1,2,4-oxadiazol-3-yl] -5-fluoro-1H-indazole, a method similar to step (3) of Example 102 Gave the title compound (19 mg).
LC-MS, m / z; 344 [M + H] +

　実施例０８９の３－［３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］シクロブタノンの代わりに、３－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］シクロブタノンを用いて、実施例０８９と同様の方法により、標記化合物をそれぞれ得た。
シス体：４６ｍｇ、LC-MS, m/z; 342 [M+H]+
トランス体：１８ｍｇ、LC-MS, m/z; 342 [M+H]+ Examples 189-190:
5-Fluoro-4- {5- [cis-3- (piperidin-1-yl) cyclobutyl] -1,2,4-oxadiazol-3-yl} -1H-indazole
and
Preparation of 5-fluoro-4- {5- [trans-3- (piperidin-1-yl) cyclobutyl] -1,2,4-oxadiazol-3-yl} -1H-indazole:

Instead of 3- [3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclobutanone in Example 089 The title compound was obtained in the same manner as in Example 089 using 3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] cyclobutanone. .
Cis form: 46 mg, LC-MS, m / z; 342 [M + H] +
Trans isomer: 18 mg, LC-MS, m / z; 342 [M + H] +

　実施例１８４における７－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾール 塩酸塩の代わりに、５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾールを用いて、実施例１８４と同様の方法により、標記化合物（７９ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 8.68-8.64 (1H, m), 7.64-7.56 (1H, m), 7.33-7.26 (1H, m), 4.07-3.99 (2H, m), 3.43-3.33 (2H, m), 3.15-2.99 (3H, m), 2.58-2.48 (1H, m), 2.44-2.34 (2H, m), 2.27-2.17 (2H, m), 2.13-2.00 (2H, m), 1.81-1.73 (2H, m), 1.69-1.56 (2H, m).
LC-MS, m/z; 372 [M+H]+ Example 191
Preparation of 5-fluoro-4- {5- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole :

Instead of 7-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole hydrochloride in Example 184, 5-fluoro-4 The title compound (79 mg) was obtained in the same manner as in Example 184, using-[5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole. It was.
¹ H-NMR (CDCl ₃ ) δ: 8.68-8.64 (1H, m), 7.64-7.56 (1H, m), 7.33-7.26 (1H, m), 4.07-3.99 (2H, m), 3.43-3.33 ( 2H, m), 3.15-2.99 (3H, m), 2.58-2.48 (1H, m), 2.44-2.34 (2H, m), 2.27-2.17 (2H, m), 2.13-2.00 (2H, m), 1.81-1.73 (2H, m), 1.69-1.56 (2H, m).
LC-MS, m / z; 372 [M + H] +

（式中、Ｒ^８は下記表中の構造を意味する）

7-Fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole hydrochloride and tetrahydro-4H-pyran-4 in Example 184 Instead of -one using 5-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole and the corresponding aldehyde or ketone The compounds shown in the following table (Examples 192 to 196) were obtained in the same manner as in Example 184.

(Wherein R ⁸ means the structure in the following table)

　５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾール（５０ｍｇ）、１－ブロモ－３－フルオロプロパン（２９ｍｇ）、炭酸カリウム（１４０ｍｇ）およびヨウ化ナトリウム（０．２等量）をアセトニトリル（５．０ｍＬ）に懸濁し、６０℃で終夜撹拌した。反応混合物を減圧濃縮し、残渣を分取ＨＰＬＣで精製することにより、標記化合物（１１ｍｇ）を得た。
LC-MS, m/z; 348 [M+H]+ Example 197:
Preparation of 5-fluoro-4- {5- [1- (3-fluoropropyl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole:

5-Fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole (50 mg), 1-bromo-3-fluoropropane (29 mg) , Potassium carbonate (140 mg) and sodium iodide (0.2 equivalent) were suspended in acetonitrile (5.0 mL) and stirred at 60 ° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (11 mg).
LC-MS, m / z; 348 [M + H] +

（式中、Ｒ^８は下記表中の構造を意味する）

The compounds shown in the following tables (Examples 198 to 203) were obtained in the same manner as in Example 197 using the corresponding alkyl halide instead of 1-bromo-3-fluoropropane in Example 197.

(Wherein R ⁸ means the structure in the following table)

　５－フルオロ－Ｎ’－［（｛１－［（４－ヒドロキシテトラヒドロ－２Ｈ－ピラン－４－イル）メチル］ピペリジン－４－イル｝カルボニル）オキシ］－１Ｈ－インダゾール－４－カルボキシイミドアミドの粗生成物をＴＨＦ（１０ｍｌ）に溶かし、２５％水酸化テトラメチルアンモニウム水溶液（０．１ｍｌ）を加え、５０℃で１時間撹拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製することにより、表記化合物（１１０ｍｇ）を得た。
LC-MS, m/z; 402 [M+H]+ Example 204:
4-({4- [3- (5-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} methyl) tetrahydro-2H-pyran Production of -4-ol:

Of 5-fluoro-N ′-[({1-[(4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidin-4-yl} carbonyl) oxy] -1H-indazole-4-carboximidamide The crude product was dissolved in THF (10 ml), 25% aqueous tetramethylammonium hydroxide solution (0.1 ml) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (110 mg).
LC-MS, m / z; 402 [M + H] +

　５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾール（５０ｍｇ）およびプロピレンオキシド（１００ｍｇ）をエタノール（３．０ｍＬ）中で１６時間加熱還流した。反応混合物を減圧濃縮し、残渣を分取ＨＰＬＣで精製することにより、標記化合物（１２ｍｇ）を得た。
LC-MS, m/z; 346 [M+H]+ Example 205:
Production of 1- {4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} propan-2-ol:

5-Fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole (50 mg) and propylene oxide (100 mg) were added to ethanol (3.0 mL). ) For 16 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (12 mg).
LC-MS, m / z; 346 [M + H] +

　実施例２０５におけるプロピレンオキシドの代わりに６－オキサビシクロ［３．１．０］ヘキサンを用いて、実施例２０５と同様の方法により、標記化合物（１１ｍｇ）を得た。
LC-MS, m/z; 372 [M+H]+ Example 206:
Preparation of trans-2- {4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} cyclopentanol:

The title compound (11 mg) was obtained in the same manner as in Example 205, using 6-oxabicyclo [3.1.0] hexane in place of propylene oxide in Example 205.
LC-MS, m / z; 372 [M + H] +

　５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾール（５０ｍｇ）、（メチルスルホニル）エテン（２０ｍｇ）およびトリエチルアミン（３２μＬ）をテトラヒドロフラン中において６０℃で１６時間撹拌した。反応混合物を減圧濃縮し、残渣を分取ＨＰＬＣで精製することにより、標記化合物（１２ｍｇ）を得た。
LC-MS, m/z; 394 [M+H]+ Example 207:
Preparation of 5-fluoro-4- (5- {1- [2- (methylsulfonyl) ethyl] piperidin-4-yl} -1,2,4-oxadiazol-3-yl) -1H-indazole:

5-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole (50 mg), (methylsulfonyl) ethene (20 mg) and triethylamine ( 32 μL) was stirred in tetrahydrofuran at 60 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (12 mg).
LC-MS, m / z; 394 [M + H] +

　５－フルオロ－４－｛５－［１－（テトラヒドロ－２Ｈ－チオピラン－４－イル）ピペリジン－４－イル］－１，２，４－オキサジアゾール－３－イル｝－１Ｈ－インダゾール（４５０ｍｇ）のメタノール溶液（５．０ｍＬ）にメタクロロ過安息香酸（２００ｍｇ）を加え、室温で２時間撹拌した。反応混合物を減圧濃縮し、残渣を分取ＨＰＬＣで精製することにより、標記化合物をそれぞれ得た。
スルホキシド体：４．７ｍｇ、LC-MS, m/z; 404 [M+H]+
スルホン体：２３ｍｇ、LC-MS, m/z; 420 [M+H]+ Examples 208-209:
5-Fluoro-4- {5- [1- (1-oxidetetrahydro-2H-thiopyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1H- Indazole <br/> and
4- {5- [1- (1,1-dioxidetetrahydro-2H-thiopyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -5-fluoro Production of -1H-indazole:

5-Fluoro-4- {5- [1- (tetrahydro-2H-thiopyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole (450 mg ) To a methanol solution (5.0 mL) was added metachloroperbenzoic acid (200 mg) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound.
Sulfoxide form: 4.7 mg, LC-MS, m / z; 404 [M + H] +
Sulfone form: 23 mg, LC-MS, m / z; 420 [M + H] +

　４－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］－１，４’－ビピペリジン ２トリフルオロ酢酸塩（７５ｍｇ）のテトラヒドロフラン溶液（３．０ｍＬ）に、２．５Ｎ 炭酸カリウム水溶液（３．０ｍＬ）とメタンスルホニルクロリド（０．１０ｍＬ）を加え、室温で１時間撹拌した。２層に分離した反応溶液のうち、有機層を分離して減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、標記化合物（４５ｍｇ）を得た。
LC-MS, m/z; 449 [M+H]+ Example 210:
Preparation of 4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1 ′-(methylsulfonyl) -1,4′-bipiperidine :

4- [3- (5-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidine 2trifluoroacetate (75 mg) in tetrahydrofuran To the solution (3.0 mL) were added 2.5N aqueous potassium carbonate solution (3.0 mL) and methanesulfonyl chloride (0.10 mL), and the mixture was stirred at room temperature for 1 hour. Of the reaction solution separated into two layers, the organic layer was separated and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (ethyl acetate) to obtain the title compound (45 mg).
LC-MS, m / z; 449 [M + H] +

　実施例２１０において、メタンスルホニルクロリドの代わりにクロロ炭酸メチルを用いて、実施例２１０と同様の方法により、標記化合物（４２ｍｇ）を得た。
¹H-NMR (CDCl₃) δ: 8.71 (1H, d, J = 0.9 Hz), 7.62 (1H, ddd, J = 9.2, 3.7, 0.9 Hz), 7.30 (1H, dd, J = 10.5, 9.2 Hz), 4.37-3.99 (2H, m), 3.69 (3H, s), 3.15-2.95 (3H, m), 2.85-2.69 (2H, m), 2.56-2.37 (3H, m), 2.26-2.16 (2H, m), 2.13-2.00 (2H, m), 1.87-1.76 (2H, m), 1.55-1.40 (2H, m).
LC-MS, m/z; 429 [M+H]+ Example 211:
Preparation of methyl 4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidine-1′-carboxylate:

The title compound (42 mg) was obtained in the same manner as in Example 210 except that methyl chlorocarbonate was used instead of methanesulfonyl chloride in Example 210.
¹ H-NMR (CDCl ₃ ) δ: 8.71 (1H, d, J = 0.9 Hz), 7.62 (1H, ddd, J = 9.2, 3.7, 0.9 Hz), 7.30 (1H, dd, J = 10.5, 9.2 Hz ), 4.37-3.99 (2H, m), 3.69 (3H, s), 3.15-2.95 (3H, m), 2.85-2.69 (2H, m), 2.56-2.37 (3H, m), 2.26-2.16 (2H , m), 2.13-2.00 (2H, m), 1.87-1.76 (2H, m), 1.55-1.40 (2H, m).
LC-MS, m / z; 429 [M + H] +

　実施例２１０において、メタンスルホニルクロリドの代わりにジメチルカルバモイルクロリドを用いて、実施例２１０と同様の方法により、標記化合物（３６ｍｇ）を得た。
LC-MS, m/z; 442 [M+H]+ Example 212:
4- [3- (5-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -N, N-dimethyl-1,4′-bipiperidine-1′- Carboxamide production:

The title compound (36 mg) was obtained in the same manner as in Example 210 except that dimethylcarbamoyl chloride was used in place of methanesulfonyl chloride in Example 210.
LC-MS, m / z; 442 [M + H] +

　４－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］－１，４’－ビピペリジン ２トリフルオロ酢酸塩（１００ｍｇ）の１，４－ジオキサン溶液（５．０ｍＬ）に３７％ホルムアルデヒド水溶液（０．３ｍＬ）を加え、室温で４時間撹拌した。次いでシアノ水素化ホウ素ナトリウム（１７ｍｇ）を加え、更に室温で１０時間撹拌した。反応混合物を減圧濃縮し、残渣を分取ＨＰＬＣと薄層クロマトグラフィー（ジクロロメタン／メタノール）で精製することにより、標記化合物（２０ｍｇ）を得た。
LC-MS, m/z; 385 [M+H]+ Example 213:
Production of 4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1′-methyl-1,4′-bipiperidine:

4- [3- (5-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidine 2trifluoroacetate (100 mg) A 37% aqueous formaldehyde solution (0.3 mL) was added to the 1,4-dioxane solution (5.0 mL), and the mixture was stirred at room temperature for 4 hours. Next, sodium cyanoborohydride (17 mg) was added, and the mixture was further stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC and thin layer chromatography (dichloromethane / methanol) to obtain the title compound (20 mg).
LC-MS, m / z; 385 [M + H] +

4- [3- (5-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidine bistrifluoroacetate and methane in Example 210 In the same manner as in Example 210 using the corresponding amine compound and acylating agent (acetic anhydride, methanesulfonyl chloride, methyl chlorocarbonate, or dimethylcarbamoyl chloride) instead of sulfonyl chloride, the compounds shown in the following table (Examples) 214-235).

　実施例１９１における５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾールの代わりに、５－フルオロ－４－｛５－［１－（ピペリジン－４－イル）ピロリジン－３－イル］－１，２，４－オキサジアゾール－３－イル｝－１Ｈ－インダゾールを用いて、実施例１９１と同様の方法により、標記化合物（１５ｍｇ）を得た。
LC-MS, m/z; 358 [M+H]+ Example 236:
Preparation of 5-fluoro-4- {5- [1- (tetrahydro-2H-pyran-4-yl) pyrrolidin-3-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole :

Instead of 5-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole in Example 191, 5-fluoro-4- { Using 5- [1- (piperidin-4-yl) pyrrolidin-3-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole in the same manner as in Example 191, The title compound (15 mg) was obtained.
LC-MS, m / z; 358 [M + H] +

　実施例１９１における５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾールの代わりに、４－［５－（アゼチジン－３－イル）－１，２，４－オキサジアゾール－３－イル］－５－フルオロ－１Ｈ－インダゾールを用いて、実施例１９１と同様の方法により、標記化合物（５３ｍｇ）を得た。
LC-MS, m/z; 344 [M+H]+ Example 237:
Production of 5-fluoro-4- {5- [1- (tetrahydro-2H-pyran-4-yl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole :

Instead of 5-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole in Example 191, 4- [5- (azetidine The title compound (53 mg) was obtained in the same manner as in Example 191 using -3-yl) -1,2,4-oxadiazol-3-yl] -5-fluoro-1H-indazole.
LC-MS, m / z; 344 [M + H] +

　実施例１０２の工程（３）におけるピペリジンの代わりに、ｔｅｒｔ－ブチル ピペリジン－４－イルカルバメートを用いて、実施例１０２の工程（３）と同様の方法により、標記化合物（１２０ｍｇ）を得た。
LC-MS, m/z; 445 [M+H]+ Example 238:
tert-Butyl (1- {2- [3- (5-Fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] ethyl} piperidine-4 -Il) Production of carbamate:

The title compound (120 mg) was obtained in the same manner as in Step (3) of Example 102 using tert-butyl piperidin-4-ylcarbamate instead of piperidine in Step (3) of Example 102.
LC-MS, m / z; 445 [M + H] +

　実施例００１におけるｔｅｒｔ－ブチル ４－［３－（２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートの代わりに、ｔｅｒｔ－ブチル （１－｛２－［３－（５－フルオロ－２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］エチル｝ピペリジン－４－イル）カルバメートを用いて、実施例００１と同様の方法により、標記化合物（９９ｍｇ）を得た。
LC-MS, m/z; 345 [M+H]+ Example 239:
1- {2- [3- (5-Fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] ethyl} piperidin-4-amine 3tri Production of fluoroacetates:

Instead of tert-butyl 4- [3- (2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate in Example 001 Tert-butyl (1- {2- [3- (5-fluoro-2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] ethyl} piperidine- The title compound (99 mg) was obtained in the same manner as in Example 001 using 4-yl) carbamate.
LC-MS, m / z; 345 [M + H] +

　ｔｅｒｔ－ブチル ４－［３－（７－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレート（３００ｍｇ）を酢酸エチル（３ｍＬ）に溶解し、４Ｎ 塩酸／酢酸エチル溶液（２ｍＬ）を加えて室温で６時間撹拌した。反応混合物を減圧下で濃縮することにより、標記化合物（２１０ｍｇ）を得た。
¹H-NMR (MeOH-d₄) δ: 2.13-2.28 (2H, m), 2.45-2.54 (2H, m), 3.08 (1H, m), 3.24-3.35 (2H, m), 3.52-3.64 (3H, m), 7.30 (1H, dd, J = 10.4, 8.0 Hz), 7.98 (1H, dd, J = 8.0, 4.0 Hz), 8.65 (1H, d, J = 3.6 Hz). Example 240:
Preparation of 7-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole hydrochloride:

tert-Butyl 4- [3- (7-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate (300 mg) was added to ethyl acetate (3 mL 4N hydrochloric acid / ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (210 mg).
¹ H-NMR (MeOH-d ₄ ) δ: 2.13-2.28 (2H, m), 2.45-2.54 (2H, m), 3.08 (1H, m), 3.24-3.35 (2H, m), 3.52-3.64 ( 3H, m), 7.30 (1H, dd, J = 10.4, 8.0 Hz), 7.98 (1H, dd, J = 8.0, 4.0 Hz), 8.65 (1H, d, J = 3.6 Hz).

　実施例２４０におけるｔｅｒｔ－ブチル ４－［３－（７－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートの代わりに、ｔｅｒｔ－ブチル ４－［３－（６－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートを用いて、実施例２４０と同様の方法により、標記化合物（３５０ｍｇ）を得た。
LC-MS, m/z; 288 [M+H]+ Example 241
Preparation of 6-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole hydrochloride:

Instead of tert-butyl 4- [3- (7-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate in example 240 tert-Butyl 4- [3- (6-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate was used with Example 240 In the same manner, the title compound (350 mg) was obtained.
LC-MS, m / z; 288 [M + H] +

　実施例２４０におけるｔｅｒｔ－ブチル ４－［３－（７－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートの代わりに、ｔｅｒｔ－ブチル ４－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートを用いて、実施例２４０と同様の方法により、標記化合物（４．４ｇ）を得た。
LC-MS, m/z; 288 [M+H]+ Example 242:
Preparation of 5-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole:

Instead of tert-butyl 4- [3- (7-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate in example 240 tert-Butyl 4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate was used with Example 240 In the same manner, the title compound (4.4 g) was obtained.
LC-MS, m / z; 288 [M + H] +

　５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾール（５００ｍｇ）の１，４－ジオキサン溶液（１０ｍＬ）にテトラヒドロ－４Ｈ－チオピラン－４－オン（２２０ｍｇ）、酢酸（触媒量）およびシアノ水素化ホウ素ナトリウム（１１０ｍｇ）を加え、室温で１６時間撹拌した。反応混合物を減圧濃縮し、残渣に酢酸エチルを加え、水で洗浄した。有機層を無水硫酸ナトリウムで乾燥、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製することにより、標記化合物（４５０ｍｇ）を得た。
¹H-NMR (DMSO-d₆) δ: 1.59-3.20 (18H, m), 7.44 (1H, dd, J = 10.8, 8.8 Hz), 7.84 (1H, dd, J = 8.8, 3.6 Hz), 8.48 (1H, s). Example 243:
Preparation of 5-fluoro-4- {5- [1- (tetrahydro-2H-thiopyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole :

To a solution of 5-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole (500 mg) in 1,4-dioxane (10 mL) was added tetrahydro -4H-thiopyran-4-one (220 mg), acetic acid (catalytic amount) and sodium cyanoborohydride (110 mg) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (450 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 1.59-3.20 (18H, m), 7.44 (1H, dd, J = 10.8, 8.8 Hz), 7.84 (1H, dd, J = 8.8, 3.6 Hz), 8.48 (1H, s).

　実施例１０６における１’－アセチル－１，４’－ビピペリジン－４－カルボン酸の代わりに１’－（ｔｅｒｔ－ブトキシカルボニル）－１，４’－ビピペリジン－４－カルボン酸を用い、実施例１０６と同様の方法により、標記化合物（２６０ｍｇ）を得た。
LC-MS, m/z; 471 [M+H]+ Example 244:
of tert-butyl 4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidine-1′-carboxylate Manufacturing:

In place of 1′-acetyl-1,4′-bipiperidine-4-carboxylic acid in Example 106, 1 ′-(tert-butoxycarbonyl) -1,4′-bipiperidine-4-carboxylic acid was used. The title compound (260 mg) was obtained by a method similar to that described above.
LC-MS, m / z; 471 [M + H] +

　実施例００１におけるｔｅｒｔ－ブチル ４－［３－（２－メチル－１Ｈ－ベンズイミダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートの代わりに、ｔｅｒｔ－ブチル ４－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］－１，４’－ビピペリジン－１’－カルボキシレートを用いて、実施例００１と同様の方法により、標記化合物（３８０ｍｇ）を得た。
LC-MS, m/z; 371 [M+H]+ Example 245:
Preparation of 4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidine 2 trifluoroacetate:

Instead of tert-butyl 4- [3- (2-methyl-1H-benzimidazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate in Example 001 , Tert-butyl 4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] -1,4′-bipiperidine-1′-carboxylate Was used to give the title compound (380 mg) in the same manner as in Example 001.
LC-MS, m / z; 371 [M + H] +

　５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾール（１．０ｇ）、ｔｅｒｔ－ブチル （２－オキソエチル）カルバメート（１．１ｇ）および酢酸（０．５０ｍＬ）の１，４－ジオキサン溶液（１５ｍＬ）にシアノ水素化ホウ素ナトリウム（２００ｍｇ）を加え、室温で１６時間撹拌した。反応混合物を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（石油エーテル／酢酸エチル）で精製することにより、標記化合物（７００ｍｇ）を得た。
LC-MS, m/z; 431 [M+H]+ Example 246:
of tert-butyl (2- {4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} ethyl) carbamate Manufacturing:

5-Fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole (1.0 g), tert-butyl (2-oxoethyl) carbamate Sodium cyanoborohydride (200 mg) was added to a 1,4-dioxane solution (15 mL) of (1.1 g) and acetic acid (0.50 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (700 mg).
LC-MS, m / z; 431 [M + H] +

　ｔｅｒｔ－ブチル （２－｛４－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－イル｝エチル）カルバメート（５５０ｍｇ）のジクロロメタン溶液（２０ｍＬ）にトリフルオロ酢酸（２．０ｍＬ）を加え、室温で１６時間撹拌した。反応混合物にアンモニア水を加え、生成した沈殿物を濾取して乾燥することにより、標記化合物（４００ｍｇ）を得た。
LC-MS, m/z; 331 [M+H]+ Example 247:
Preparation of 2- {4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} ethanamine:

tert-butyl (2- {4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} ethyl) carbamate ( 550 mg) in dichloromethane (20 mL) was added trifluoroacetic acid (2.0 mL) and stirred at room temperature for 16 hours. Ammonia water was added to the reaction mixture, and the resulting precipitate was collected by filtration and dried to obtain the title compound (400 mg).
LC-MS, m / z; 331 [M + H] +

The compounds shown in the following table (Examples 248 to 252) were obtained in the same manner as in Examples 246 and 247 using the corresponding aldehyde compound instead of tert-butyl (2-oxoethyl) carbamate in Example 246. .

　実施例２４０におけるｔｅｒｔ－ブチル ４－［３－（７－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－カルボキシレートの代わりに、ｔｅｒｔ－ブチル ３－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピロリジン－１－カルボキシレートを用いて、実施例２４０と同様の方法により、標記化合物（５００ｍｇ）を得た。
¹H-NMR (MeOH-d₄) δ: 2.21-2.46 (2H, m), 3.01-3.20 (2H, m), 3.24-3.45 (2H, m), 3.78 (1H, m), 7.38 (1H, dd, J = 10.8, 9.2 Hz), 7.75 (1H, dd, J = 8.8, 3.2 Hz), 8.57 (1H, s). Example 253:
Preparation of 5-fluoro-4- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole:

Instead of tert-butyl 4- [3- (7-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate in example 240 tert-Butyl 3- [3- (5-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] pyrrolidine-1-carboxylate was used with Example 240 In the same manner, the title compound (500 mg) was obtained.
¹ H-NMR (MeOH-d ₄ ) δ: 2.21-2.46 (2H, m), 3.01-3.20 (2H, m), 3.24-3.45 (2H, m), 3.78 (1H, m), 7.38 (1H, dd, J = 10.8, 9.2 Hz), 7.75 (1H, dd, J = 8.8, 3.2 Hz), 8.57 (1H, s).

　ｔｅｒｔ－ブチル ３－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］アゼチジン－１－カルボキシレート（６．０ｇ）のジクロロメタン溶液（５０ｍＬ）に氷冷下でトリフルオロ酢酸（１０ｍＬ）を加え、室温で１６時間撹拌した。反応混合物を水酸化ナトリウム水溶液で中和し、ジクロロメタンを減圧下で留去した。生成した沈殿物を濾取し、飽和炭酸水素ナトリウム水溶液と水で洗浄した後、乾燥することにより、標記化合物（３．８ｇ）を得た。
¹H-NMR (MeOH-d₄) δ: 4.52-4.67 (5H, m), 7.41 (1H, dd, J = 10.8, 9.2 Hz), 7.80 (1H, dd, J = 8.8, 3.6 Hz), 8.65 (1H, s). Example 254:
Preparation of 4- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -5-fluoro-1H-indazole:

tert-Butyl 3- [3- (5-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] azetidine-1-carboxylate (6.0 g) in dichloromethane (50 mL) was added with trifluoroacetic acid (10 mL) under ice-cooling and stirred at room temperature for 16 hours. The reaction mixture was neutralized with aqueous sodium hydroxide solution, and dichloromethane was distilled off under reduced pressure. The formed precipitate was collected by filtration, washed with a saturated aqueous sodium hydrogen carbonate solution and water, and dried to obtain the title compound (3.8 g).
¹ H-NMR (MeOH-d ₄ ) δ: 4.52-4.67 (5H, m), 7.41 (1H, dd, J = 10.8, 9.2 Hz), 7.80 (1H, dd, J = 8.8, 3.6 Hz), 8.65 (1H, s).

　実施例２４６における５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾールとｔｅｒｔ－ブチル （２－オキソエチル）カルバメートの代わりに、５－フルオロ－４－［５－（ピロリジン－３－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾールとｔｅｒｔ－ブチル ４－オキソピペリジン－１－カルボキシレートを用いて、実施例２４６と同様の方法により、標記化合物を得た。
LC-MS, m/z; 457 [M+H]+ Example 255:
tert-Butyl 4- {3- [3- (5-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] pyrrolidin-1-yl} piperidine-1-carboxy Rate manufacturing:

Of 5-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole and tert-butyl (2-oxoethyl) carbamate in Example 246 Instead, 5-fluoro-4- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole and tert-butyl 4-oxopiperidine-1-carboxyl The title compound was obtained in the same manner as in Example 246 using the rate.
LC-MS, m / z; 457 [M + H] +

　実施例２４７におけるｔｅｒｔ－ブチル （２－｛４－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－イル｝エチル）カルバメートの代わりに、ｔｅｒｔ－ブチル ４－｛３－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピロリジン－１－イル｝ピペリジン－１－カルボキシレートを用いて、実施例２４７と同様の方法により、標記化合物を得た。
LC-MS, m/z; 357 [M+H]+ Example 256:
Preparation of 5-fluoro-4- {5- [1- (piperidin-4-yl) pyrrolidin-3-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole:

Tert-Butyl (2- {4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} in Example 247 Ethyl) carbamate instead of tert-butyl 4- {3- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] pyrrolidin-1- The title compound was obtained in the same manner as in Example 247 using yl} piperidine-1-carboxylate.
LC-MS, m / z; 357 [M + H] +

　実施例２４６における５－フルオロ－４－［５－（ピペリジン－４－イル）－１，２，４－オキサジアゾール－３－イル］－１Ｈ－インダゾールとｔｅｒｔ－ブチル （２－オキソエチル）カルバメートの代わりに、４－［５－（アゼチジン－３－イル）－１，２，４－オキサジアゾール－３－イル］－５－フルオロ－１Ｈ－インダゾールとｔｅｒｔ－ブチル ４－オキソピペリジン－１－カルボキシレートを用いて、実施例２４６と同様の方法により、標記化合物を得た。
LC-MS, m/z; 443 [M+H]+　 Example 257:
tert-Butyl 4- {3- [3- (5-Fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] azetidin-1-yl} piperidine-1-carboxy Rate manufacturing:

Of 5-fluoro-4- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1H-indazole and tert-butyl (2-oxoethyl) carbamate in Example 246 Instead, 4- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -5-fluoro-1H-indazole and tert-butyl 4-oxopiperidine-1-carboxyl The title compound was obtained in the same manner as in Example 246 using the rate.
LC-MS, m / z; 443 [M + H] +

　実施例２４７におけるｔｅｒｔ－ブチル （２－｛４－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］ピペリジン－１－イル｝エチル）カルバメートの代わりに、ｔｅｒｔ－ブチル ４－｛３－［３－（５－フルオロ－１Ｈ－インダゾール－４－イル）－１，２，４－オキサジアゾール－５－イル］アゼチジン－１－イル｝ピペリジン－１－カルボキシレートを用いて、実施例２４７と同様の方法により、標記化合物を得た。
LC-MS, m/z; 343 [M+H] Example 258:
Preparation of 5-fluoro-4- {5- [1- (piperidin-4-yl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -1H-indazole:

Tert-Butyl (2- {4- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} in Example 247 Ethyl) carbamate instead of tert-butyl 4- {3- [3- (5-fluoro-1H-indazol-4-yl) -1,2,4-oxadiazol-5-yl] azetidine-1- The title compound was obtained in the same manner as in Example 247 using yl} piperidine-1-carboxylate.
LC-MS, m / z; 343 [M + H]

Pharmacological tests The following are pharmacological test methods and results for representative compounds of the present invention, but the present invention is not limited to these test examples.

Test Example 1: Serotonin 4 (5-HT ₄ ) Receptor Binding Test The 5-HT ₄ receptor binding test and the preparation of the receptor membrane preparation were performed according to the method of Grossman et al. [British J. Pharmacol., (1993) 109, 618]].
After decapitation of the Slc-Hartley guinea pig (body weight 300 to 400 g), the brain was immediately removed, the striatum was separated, and stored frozen at −80 ° C. until use. A 15-fold volume of Hepes buffer (50 mM, pH 7.4, 4 ° C.) is added to the obtained tissue, homogenized with a Teflon (registered trademark) homogenizer, and centrifuged at 48,000 × g (4 ° C.) for 15 minutes. did. A hepes buffer solution was added to the resulting sediment at a ratio of 1 ml to a wet weight of 30 mg of tissue to prepare a receptor membrane preparation.
The assay tube contains 0.1 nM [ ³ H] -GR113808 {chemical name: [1- [2- (methylsulfonylamino) ethyl] -4-piperidinyl] methyl 1-methylindole-3-carboxylate} 1 ml of a Hepes buffer solution (50 mM, pH 7.4, 4 ° C.) containing a receptor membrane preparation and a test compound or 30 μM serotonin was incubated at 37 ° C. for 30 minutes. The reaction was stopped by rapid filtration using a Brandel cell harvester on Whatman GF / B filters soaked in 0.1% polyethyleneimine for 1 hour, and using 4 ml of ice-cooled 50 mM Tris-HCl (pH 7.7). This was done by washing 3 times. Radioactivity was measured with a liquid scintillation counter after adding a liquid scintillator (eco scintillation) to the filtered filter.
The 50% inhibitory concentration (IC ₅₀ ) was determined from the inhibition rate of the test compound against the specific binding obtained by subtracting nonspecific binding from the total binding amount of [ ³ H] -GR113808.
The results of the serotonin 4 (5-HT ₄ ) receptor binding test are shown in the table below.
(Tests were conducted using the compounds prepared in the corresponding Example numbers above. IC ₅₀ indicates the average value for each group.)
Guinea pig 5-HT ₄ receptor binding test

Test Example 2: Serotonin 4 (5-HT ₄ ) Receptor Binding Test CHO-K1 cells stably expressing human 5-HT _4b receptor were added to Hepes buffer (50 mM, pH 7.4, 4 ° C.). Was added and homogenized to prepare cell lysate.
To a 96-well microplate, 0.25 nM [ ³ H] -GR113808 {chemical name: [1- [2- (methylsulfonylamino) ethyl] -4-piperidinyl] methyl 1-methylindole-3-carboxylate- }, 200 μl of Hepes buffer solution (50 mM, pH 7.4, 4 ° C.) containing cell lysate and test compound or 30 μM serotonin was added and incubated at room temperature for 60 minutes. The reaction was stopped three times with 200 μl of ice-cooled 50 mM Tris-HCl (pH 7.7) by rapid filtration using a vacuum manifold on a multi-screen glass filter soaked in 0.03% polyethyleneimine for 30 minutes. This was done by washing. Radioactivity was measured with a liquid scintillation counter after adding a liquid scintillator (eco scintillation) to the filtered filter.
The 50% inhibitory concentration (IC ₅₀ ) was determined from the inhibition rate of the test compound against the specific binding obtained by subtracting nonspecific binding from the total binding amount of [ ³ H] -GR113808.
The results of the serotonin 4 (5-HT ₄ ) receptor binding test are shown in the table below.
(Tests were conducted using the compounds prepared in the corresponding Example numbers above. IC ₅₀ indicates the average value for each group.)
Human 5-HT ₄ receptor binding test

Test Example 3 Serotonin 4 (5-HT ₄ ) Receptor Agonist Activity Measurement Test The cAMP measurement test was performed using CISBIO HTRF (registered trademark) cAMP Hirange kit according to the attached manual.
Human 5-HT _4b receptor-expressing CHO cells were cultured in medium 1 (DMEM / 1% NEAA, 1% penicillin / streptomycin (P / S), 0.2 mg / mL GENETICIN (G418), 10% FBS) at 37 ° C. They were cultured in · 5% CO ₂ conditions. After replacing with medium 2 (DMEM / 10000 cut FBS, G-418, P / S, NEAA), cells were collected by trypsin treatment with EDTA after 1-2 hours. The collected cells were suspended in Assay Buffer 1 (100 mM Hanks / HEPES buffer (pH 7.4)), mixed with the test compound on a 384 well plate, and incubated at 31 ° C. for 15 minutes. cAMP-cryptate solution and cAMP-d2 solution were added and incubated at room temperature for 1 hour. Time-resolved fluorescence (excitation wavelength: 330 nm, fluorescence wavelength: 620/665 nm) was measured with En Vision.
From the obtained data, the intrinsic activity (IA;%) of the compound and the concentration EC ₅₀ (nM) showing the effect of 50% of the intrinsic activity were calculated. Intrinsic activity (IA) was calculated with the maximum activity of 5-HT (measured from 10 ⁻¹¹ to 10 ⁻⁷ M) as 100%.
The results of the serotonin 4 (5-HT ₄ ) receptor agonist activity measurement test are shown in the following table.
(Tests were carried out using the compounds prepared in the corresponding example numbers above. EC ₅₀ indicates the mean value for each group.)

Test Example 4: Serotonin 4 (5-HT ₄ ) Receptor Agonist Activity Measurement Test The cAMP measurement test was performed using a CISBIO HTRF (registered trademark) cAMP Hirange kit according to the attached manual.
Human 5-HT _4b receptor-expressing CHO cells were cultured in medium 1 (DMEM / 1% NEAA, 1% penicillin / streptomycin (P / S), 0.2 mg / mL GENETICIN (G418), 10% FBS) at 37 ° C. They were cultured in · 5% CO ₂ conditions. The cells were collected by trypsin treatment with EDTA, seeded in 96-well plates, and cultured overnight. Replace with medium 2 (DMEM / 10000 cut FBS, G-418, P / S, NEAA) 1-2 hours later, replace with test compound solution diluted with Assay Buffer 1 (100 mM Hanks / HEPES buffer (pH 7.4)) And incubated at 37 ° C. for 30 minutes. After removing the reaction solution, Lysis buffer was added to lyse the cells, cAMP-cryptate solution and cAMP-d2 solution were added and incubated at room temperature for 1 hour. Time-resolved fluorescence (excitation wavelength: 330 nm, fluorescence wavelength: 620/665 nm) was measured with En Vision.
From the obtained data, the intrinsic activity (IA;%) of the compound and the concentration EC ₅₀ (nM) showing the effect of 50% of the intrinsic activity were calculated. Intrinsic activity (IA) was calculated with the maximum activity of 5-HT (measured from 10 ⁻¹¹ to 10 ⁻⁷ M) as 100%.
The results of the serotonin 4 (5-HT ₄ ) receptor agonist activity measurement test are shown in the following table.
(Tests were performed using the compounds prepared in the corresponding Example numbers above. EC ₅₀ and IA indicate the mean value for each group.)

Specific indications include the following diseases (i) to (v):
(I) neuropsychiatric diseases such as Alzheimer's dementia, Lewy body dementia, vascular dementia, depression, post-traumatic stress disorder (PTSD), memory impairment, anxiety, schizophrenia;
(Ii) Irritable bowel syndrome, flaccid constipation, habitual constipation, chronic constipation, constipation induced by drugs such as morphine and antipsychotics, constipation associated with Parkinson's disease, constipation associated with multiple sclerosis, constipation associated with diabetes Or diseases of the digestive system such as constipation or defecation disorder (as a pretreatment during endoscopy or barium intestinal X-ray examination);
(Iii) Functional dyspepsia, acute / chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastric neuropathy, postoperative paralytic ileus, senile ileus, non-erosive gastroesophageal reflux disease, NSAID ulcer, diabetic Gastrointestinal disorders such as gastric insufficiency, post-gastrectomy syndrome, or pseudo-intestinal obstruction;
(Iv) Gastrointestinal tract diseases, scleroderma, diabetes or loss of appetite in esophagus / biliary diseases, or nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, as described in (ii) and (iii) above Digestive symptoms such as heartburn or ambiguity;
(V) Urinary tract diseases accompanied by urination disorders such as urinary tract obstruction or enlarged prostate.
As described above, the compound of the present invention can be used for the treatment and prevention of various diseases described above, in particular, neuropsychiatric diseases and various digestive dysfunctions associated with the treatment of various diseases described above. That is, since the compound of the present invention exhibits excellent 5-HT ₄ receptor agonist activity and brain transferability, it is particularly useful as a therapeutic agent for neuropsychiatric diseases such as Alzheimer type dementia described in (i) above. Useful.

Further, when used in combination with the compound of the present invention and at least one of the therapeutic agents shown below, further therapeutic effects on various neuropsychiatric diseases described in (i), particularly Alzheimer's dementia are expected. . That is,
Acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine, SNX-001, NP-61, etc.), cholinesterase inhibitors (huperzine A, etc.), NMDA receptor antagonists (memantine, dimebon, neramexane, etc.), 5-HT6 receptor antagonist Drugs (PF-5212365 (SAM-531), SB-742457, LU-AE58054, AVN-322, PF-05212377 (SAM-760), AVN101, etc.), α7nAChR agonist (TC-5619, EVP-6124, GTS- 21), α7nAChR positive allosteric modulators (PAMs) (AVL-3288, etc.), α4β2nACh receptor agonist (AZD-1446, CHANTIX (varenicline, etc.)), nAChR agonist (ABT-089, etc.), AMPA receptor agonist (CX-717, LY-451395, etc.), histamine H3 receptor antagonist (ABT-288, SAR-110894, PF-03654746, etc.), muscarinic M1 receptor agonist (MCD-386, GSK-1034702, etc.), PDE4 Inhibitors (etazolate, etc.), PDE9 inhibitors (PF-04447943, etc.), histone deacetylase inhibitors (EVP-0334, etc.), σ1 receptor agonists (Anavex-2-73, etc.), γ-secretase inhibitors (GSI) (BMS-708163, NIC5-15, ELND-006, MK-0752, etc.), γ-secretase modifier (GSM) (E-2212, CHF-5074, etc.), Aβ human monoclonal antibody (bapineuzumab, solanezumab, PF-4360365 (ponezumab), gantenerumab (R-1450), BAN-241, MABT-5102A, RG-7412, GSK-933776A, etc.), Aβ vaccine (ACC-001 (PF-05236806), AD-02, CAD- 106, V-950, UB-311, ACI-24, etc.), human immunoglobulin (GAMMAGARD, etc.), Aβ aggregation inhibitor (ELND-005 (AZD-103), PBT-2, NRM-8499, Exebryl-1) , Tau aggregation inhibitors (TRx-0014, LMTX, etc.), BACE inhibitors (ACI-91, posiphen, CTS-21166, HPP-854, LY-2886721, etc.), tyrosine kinase inhibitors (masitinib, etc.), GSK-3β Inhibitors / tau kinase inhibitors (NP-12, etc.), RAGE fusion proteins (TTP-4000, etc.), ApoA-I, HDL-C elevation (RVX-208, etc.), other agents with various neuroprotective actions (SK-PC) -B70M, T-817MA, davunetide, HF-0220, PF-4494700, PYM-50028, CERE-110, ASP-0777, TAK-065, AAD-2004, etc.) Concomitant use with other drugs.

The compound of the present invention is useful as a therapeutic or prophylactic agent for diseases or conditions involving serotonin 4 receptor. Diseases or symptoms that have been suggested to involve serotonin 4 receptors include the following (i) to (v):
(I) neuropsychiatric diseases such as Alzheimer's dementia, Lewy body dementia, vascular dementia, depression, post-traumatic stress disorder (PTSD), memory impairment, anxiety, schizophrenia;
(Ii) Irritable bowel syndrome, flaccid constipation, habitual constipation, chronic constipation, constipation induced by drugs such as morphine and antipsychotics, constipation associated with Parkinson's disease, constipation associated with multiple sclerosis, constipation associated with diabetes Or diseases of the digestive system such as constipation or defecation disorder (as a pretreatment during endoscopy or barium intestinal X-ray examination);
(Iii) Functional dyspepsia, acute / chronic gastritis, reflux esophagitis, gastric ulcer, duodenal ulcer, gastric neuropathy, postoperative paralytic ileus, senile ileus, non-erosive gastroesophageal reflux disease, NSAID ulcer, diabetic Gastrointestinal disorders such as gastric insufficiency, post-gastrectomy syndrome, or pseudo-intestinal obstruction;
(Iv) Gastrointestinal tract diseases, scleroderma, diabetes or loss of appetite in esophagus / biliary diseases, or nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, as described in (ii) and (iii) above Digestive symptoms such as heartburn or ambiguity;
(V) Urinary tract diseases accompanied by urination disorders such as urinary tract obstruction or enlarged prostate.
In addition, since the compound of the present invention exhibits excellent 5-HT ₄ receptor agonistic activity and brain transferability, the therapeutic agent for neuropsychiatric diseases such as Alzheimer's dementia described in (i) above, Useful as a preventive agent.

Claims (8)

Formula (1):

[Where:
Het is the following formula (Het-1), formula (Het-2), formula (Het-3), formula (Het-4), formula (Het-5), formula (Het-6), formula (Het− 7), Formula (Het-8), Formula (Het-9), Formula (Het-10), Formula (Het-11), Formula (Het-12), Formula (Het-13), or Formula (Het− 14):

(Where
R ^1A is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, An _optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 cycloalkenyl group, an _optionally substituted C _1-4 haloalkyl group, an optionally substituted aryl group, an optionally substituted An optionally substituted heteroaryl group, an optionally substituted C _1-6 alkanoyl group, an optionally substituted C _1-6 alkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, or an optionally substituted C _1-6 Means an alkylsulfonyl group,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a C _1-4 haloalkyl group, a C _{1- 6} alkanoyl group, C _1-6 alkoxycarbonyl group, and C _1-6 alkylsulfonyl group each independently represent a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group at a substitutable position, It may be substituted with one or more substituents selected from the group consisting of a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, an aryl group, a heteroaryl group, and a halogen atom. ,
The aryl group and heteroaryl group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1- May be substituted with one or more substituents selected from the group consisting of a _4- haloalkoxy group, a cyano group, a C _1-6 alkanoyl group, and an optionally substituted amino group,
R ^2A represents a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, a substituted An optionally substituted C _3-8 cycloalkyl group, an optionally substituted C _5-8 cycloalkenyl group, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _1-4 Means a haloalkyl group, an optionally substituted C _1-4 haloalkoxy group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;
_{Here, C 1-6} alkyl _{groups, C 2-6} alkenyl _{groups, C 2-6} alkynyl _{group, C 3-8} cycloalkyl _{group, C 5-8} cycloalkenyl _{group, C 1-6} alkoxy _{groups, C 1- The 4} haloalkyl group and the C _1-4 haloalkoxy group each independently represent a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C ₁ at a substitutable position. _And may be substituted with one or more substituents selected from the group consisting of _-4 haloalkoxy groups, cyano groups, oxo groups, aryl groups, heteroaryl groups, and halogen atoms,
The aryl group and heteroaryl group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _{1- 4} haloalkoxy groups, cyano groups, C _1-6 alkanoyl groups, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted amino groups, and R ⁵ , R ⁶ and R ⁷ each independently represents a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or _optionally substituted. A C _2-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 cycloalkenyl group, an _optionally substituted C _1-6 alk Coxy group, C _1-4 haloalkyl group which may be substituted, C _1-4 haloalkoxy group which may be substituted, cyano group, aryl group which may be substituted, heteroaryl which may be substituted Group, an aryloxy group which may be substituted, or an amino group which may be substituted;
_{Here, C 1-6} alkyl _{groups, C 2-6} alkenyl _{groups, C 2-6} alkynyl _{group, C 3-8} cycloalkyl _{group, C 5-8} cycloalkenyl _{group, C 1-6} alkoxy _{groups, C 1- The 4} haloalkyl group and the C _1-4 haloalkoxy group each independently represent a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, C _1-4 may be substituted with one or more substituents selected from the group consisting of a haloalkoxy group, a cyano group, an oxo group, an aryl group, a heteroaryl group, an aryloxy group, and a halogen atom,
The aryl group, heteroaryl group and aryloxy group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group at a substitutable position, (It may be substituted with one or more substituents selected from the group consisting of a C _1-4 haloalkoxy group, a cyano group, and an optionally substituted amino group)
Means
A is the following formula (A-1) or formula (A-2):

(Where
l means an integer from 0 to 4;
o and p each independently represent an integer of 0 to 2,
q represents an integer of 0 to 5, and (A-1) and (A-2) are C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl at substitutable positions. Substituted with one or more substituents selected from the group consisting of a group, a hydroxy group, an oxo group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, and a halogen atom Also good)
And B is the following formula (B-1), formula (B-2), formula (B-3), or formula (B-4):

(Where
(B-2), (B-3) and (B-4) may have an unsaturated bond at a possible position in the ring,
m and n each independently represents an integer of 0 to 4, and — (CH ₂ ) _m — or — (CH ₂ ) _n — when m or n represents an integer of 1 to 4, A C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, an oxo group, and May be substituted with one or more substituents selected from the group consisting of halogen atoms,
X and Y each independently represent a single bond, an oxygen atom or a nitrogen atom,
R ⁸ and R ⁹ each independently represent a group selected from the group consisting of the groups included in the following (1) and (2):
(1) a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted Good C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic cycloalkyl group, optionally substituted C _5-8 monocyclic or C _7-10 bicyclic cyclo Means an alkenyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group;
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 monocyclic, a C _7-10 bicyclic or a C _7-12 tricyclic cycloalkyl group , C _5-8 monocyclic or C _7-10 bicyclic cycloalkenyl group, aryl group, and heteroaryl group are each independently a C _1-6 alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _1-6 alkanoyl group, phenacyl group, halogen May be substituted with one or more substituents selected from the group consisting of atoms;
(2)-(CH ₂ ) _u -R ¹²
Here, u represents an integer of 0 to 4, and when u represents an integer of 1 to 4, — (CH ₂ ) _u — represents a C _1-6 alkyl group, a C _2-6 alkenyl group, C _{2 May} be substituted with one or more substituents selected from the group consisting of a _-6 alkynyl group, a hydroxy group, a C _1-6 alkoxy group, an oxo group, and a halogen atom;
R ¹² is the following formula ^(R 12 -1), the formula ^(R 12 -2), the formula ^(R 12 -3), the formula ^(R 12 -4), the formula ^(R 12 -5), the formula ^{(R 12} - 6), formula (R ¹² -7), or formula (R ¹² -8):

(Where
R ¹³ means a group selected from the group consisting of the following groups (1) to (5):
(1) a hydrogen atom and a formyl group;
(2) an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _{3 A -8} cycloalkyl group, and an _optionally substituted C _5-8 cycloalkenyl group,
Here, the C _1-6 alkyl group, the C _2-6 alkenyl group, the C _2-6 alkynyl group, the C _3-8 cycloalkyl group, and the C _5-8 cycloalkenyl group are each independently substituted. In the position, selected from the group consisting of a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, and a halogen atom. May be substituted with one or more substituents;
(3) -COR ¹⁶ , -CSR ¹⁶ , -SO ₂ R ¹⁶ , -CO-COR ¹⁶ , -COOR ¹⁶ , and -CO-COOR ¹⁶ (wherein R ¹⁶ is an optionally substituted C _1-6 alkyl group, An optionally substituted C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 Cycloalkenyl group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted 5-9 membered monocyclic or 7-10 membered bicyclic non-aromatic An unsaturated heterocyclic group (the bonding position is a carbon atom on the heterocyclic ring), or an optionally substituted 4 to 9-membered monocyclic or 7 to 10-membered bicyclic saturated group Hetero ring group (bonding position on the hetero ring Means a is) carbon atom,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a _5-9 membered monocyclic or 7 The 10-membered bicyclic non-aromatic unsaturated heterocyclic group and the 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group are each independently C _1-6 alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl at substitutable positions A group, may be substituted with one or more substituents selected from the group consisting of halogen atoms,
The aryl group and heteroaryl group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _{1- 4} haloalkoxy group, cyano group, nitro group, C _1-6 alkanoyl group, and optionally substituted one or more substituents selected from the group consisting of optionally substituted amino groups;
(4) —CONR ¹⁷ —OR ¹⁸ (R ¹⁷ and R ¹⁸ each independently represents a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group);
(5) -CONR ¹⁹ R ²⁰ , -CSNR ¹⁹ R ²⁰ and -SO ₂ NR ¹⁹ R ²⁰ (R ¹⁹ and R ²⁰ each independently represent a hydrogen atom or an arbitrary group in R ¹⁶ , Alternatively, R ¹⁹ and R ²⁰ are bonded to each other, and in addition to the adjacent nitrogen atom, 0 to 2 selected from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom, and 1 sulfur atom Or a saturated or unsaturated 4- to 8-membered monocyclic nitrogen-containing heterocyclic group (wherein the heterocyclic group can be substituted at a C _1-6 alkyl group, a hydroxy group, C _1-6 An alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, or a halogen atom, which may be substituted with one or more substituents. ),
R ¹⁴ and ^{R 15} are each independently hydrogen atom, an optionally substituted _{C 1-6} alkyl group, an optionally substituted _{C 2-6} alkenyl group, an optionally substituted _{C 2- 6} Alkynyl group, C _3-8 cycloalkyl group which may be substituted, C _5-8 cycloalkenyl group which may be substituted, aryl group which may be substituted, heteroaryl group which may be substituted An optionally substituted 5- to 9-membered monocyclic or 7- to 10-membered bicyclic non-aromatic unsaturated heterocyclic group (which is adjacent to a carbon atom on the ring) 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group (which is a carbon atom on the ring), which may be substituted Atom is bound to an adjacent nitrogen atom), may be substituted A C _1-6 alkanoyl group, an optionally substituted C _1-6 alkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, or an optionally substituted C _1-6 alkylsulfonyl group,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a _5-9 membered monocyclic or 7 -10-membered bicyclic non-aromatic unsaturated heterocyclic group, 4- to 9-membered monocyclic or 7- to 10-membered bicyclic saturated heterocyclic group, C _1-6 alkanoyl group , C _1-6 alkoxycarbonyl group and C _1-6 alkylsulfonyl group are each independently a substitutable position at a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a cyano group, May be substituted with one or more substituents selected from the group consisting of an oxo group, an aryl group, a heteroaryl group, an aryloxy group and a halogen atom;
An aryl group and a heteroaryl group, each independently at a substitutable position, a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a cyano group, a nitro group, a C _1-6 alkanoyl group And may be substituted with one or more substituents selected from the group consisting of optionally substituted amino groups,
Alternatively, R ¹⁴ and R ¹⁵ are bonded to each other, and in addition to the adjacent nitrogen atom, 0 to 2 selected from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom and 1 sulfur atom A saturated or unsaturated 4- to 9-membered monocyclic or 7- to 10-membered bicyclic nitrogen-containing heterocyclic group containing a hetero atom (the heterocyclic group is a C _{1- 6} alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, aryl group, heteroaryl group, aryloxy group, cyano group, oxo group, and halogen atom Which may be substituted with one or more substituents selected from the group consisting of:
(R ¹² -1) to (R ¹² -4) may have an unsaturated bond at a possible position in the ring,
R ^{8 ′} and R ^{9 ′} each independently represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or an _optionally substituted C _{A 2-6} alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 cycloalkenyl group, an _optionally substituted aryl group, an optionally substituted hetero An aryl group, optionally substituted 5-9 membered monocyclic or 7-10 membered bicyclic non-aromatic unsaturated heterocyclic group (the heterocyclic group is a carbon atom on the ring; Are bonded to an adjacent nitrogen atom or oxygen atom), or an optionally substituted 4 to 9-membered monocyclic or 7 to 10-membered bicyclic saturated heterocyclic group (the heterocyclic ring) A group consists of a carbon atom on the ring bonded to an adjacent nitrogen or oxygen atom. That) means,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a _5-9 membered monocyclic or 7 The 10-membered bicyclic non-aromatic unsaturated heterocyclic group and the 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group are each independently C _1-6 alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C, May be substituted with one or more substituents selected from the group consisting of _1-6 alkanoyl groups, phenacyl groups, and halogen atoms,
The aryl group and heteroaryl group each independently represent a halogen atom, a hydroxy group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1- May be substituted with one or more substituents selected from the group consisting of a _4- haloalkoxy group, a cyano group, a nitro group, a C _1-6 alkanoyl group, and an optionally substituted amino group,
Alternatively, R ^{8 ′} and R ^{9 ′} are 0 each selected from the group consisting of 1 to 2 nitrogen atoms, 1 oxygen atom, and 1 sulfur atom in addition to the adjacent nitrogen atoms. May form a saturated or unsaturated 4-9 membered monocyclic or 7-10 membered bicyclic nitrogen-containing heterocyclic group containing up to 2 heteroatoms;
Here, the nitrogen-containing heterocyclic group is a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, an aryl at a substitutable position. May be substituted with one or more substituents selected from the group consisting of a group, a heteroaryl group, an aryloxy group, a cyano group, an oxo group, and a halogen atom,
R ¹⁰ , R ^{10 ′} , R ¹¹ and R ^{11 ′} are each independently a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkyl group, or an _optionally substituted C. _2-6 alkenyl group, optionally substituted C _2-6 alkynyl group, optionally substituted C _1-6 alkoxy group, optionally substituted aryl group, optionally substituted heteroaryl group, substituted An aryloxy group, a cyano group, or an oxo group,
Here, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-6 alkoxy group, an aryl group, a heteroaryl group and an aryloxy group can be independently substituted. C _1-6 alkyl group, hydroxy group, C _1-6 alkoxy group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _1-6 May be substituted with one or more substituents selected from the group consisting of alkanoyl groups, phenacyl groups, and halogen atoms,
Alternatively, R ¹⁰ and R ¹¹ , and R ^{10 ′} and R ^{11 ′} are each independently bonded to each other, may be substituted, and may contain one oxygen atom. An 8-membered ring is formed, and a ring or a spiro compound may be formed together with a ring to which R ¹⁰ and R ¹¹ , or R ^{10 ′} and R ^{11 ′} are bonded,
Here, the saturated or unsaturated 3- to 8-membered ring is a C _1-6 alkyl group, a hydroxy group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1- Substituted with one or more substituents selected from the group consisting of _4- haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _1-6 alkanoyl group, phenacyl group, and halogen atom May be,
R and r ′ each independently represents an integer of 0 to 3;
S and s ′ each independently represents an integer of 0 to 3,
And t and t ′ each independently represent 1 or 2, and v represents an integer of 0 to 2 (provided that r and s, and r ′ and s ′ are not 0 at the same time))
Means)
Means
Or a pharmaceutically acceptable salt thereof. Het is (Het-1) or (Het-2), R ^1A is a hydrogen atom, and R ^2A is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, a substituted 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is an optionally substituted C _1-6 alkoxy group or an optionally substituted C _1-4 haloalkyl group. The compound according to claim 1, wherein Het is (Het-3), R ^1A is a hydrogen atom, and R ^2A is a hydrogen atom or an optionally substituted C _1-6 alkyl group. A chemically acceptable salt. R ⁶ and R ⁷ are hydrogen atom, and R ⁵ is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, substituted The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which may be an optionally substituted C _1-4 haloalkyl group or an optionally substituted C _1-4 haloalkoxy group. salt. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein A is (A-1) and 1 is 0 to 2. 6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein B is (B-2), s is 0 or 1, and r is 1 or 2. . 6. The compound according to claim 1, wherein B is (B-4), Y is a single bond, s is 0 or 1, and r is 1 or 2. A chemically acceptable salt. A is (A-2), o is 0, p is 0, q is 1 or 3, and B is (B-1) or (B-4). 5. The compound according to any one of 4 or a pharmaceutically acceptable salt thereof.